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Does diabetes affect paraneoplastic thrombocytosis in colorectal cancer?

  • Gyorgy Herczeg ORCID logo , Aniko Somogyi ORCID logo , Magdolna Herold ORCID logo , Agnes Fodor ORCID logo , Klara Rosta ORCID logo , Magdolna Dank ORCID logo , Zsolt Lang ORCID logo and Zoltan Herold ORCID logo EMAIL logo
Published/Copyright: January 13, 2022
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Open Medicine
From the journal Open Medicine Volume 17 Issue 1

Abstract

Background

A large variety of factors can affect colorectal cancer (CRC) survival, including type 2 diabetes mellitus (T2DM) and paraneoplastic thrombocytosis. Although several common factors play a role in their development and platelets are damaged in both diseases, the combined relationship of the three conditions was never investigated previously.

Methods

A prospective, real-life observational cohort study was conducted with the inclusion of 108 CRC patients and 166 voluntary non-CRC subjects. Plasma interleukin-6 and thrombopoietin levels were measured.

Results

Study participants were divided into cohorts based on the presence of T2DM. Platelet count (p < 0.0500) and interleukin-6 (p < 0.0100) level were significantly higher in the CRC groups. Thrombopoietin level was higher in the T2DM, CRC, and CRC + T2DM groups (p < 0.0500). Analysis of parameter changes over time and survival models revealed that neither platelet count, interleukin-6, nor thrombopoietin levels were affected by T2DM. Death of patients was associated with higher baseline platelet count (p = 0.0042) and interleukin-6 level (p < 0.0001).

Conclusion

Although the independent, disease-worsening effect of paraneoplastic thrombocytosis and T2DM is known, the coexistence of the two did not further impair the survival of CRC patients, suggesting that T2DM has no significant effect over paraneoplastic thrombocytosis.

Keywords: colorectal neoplasms; diabetes mellitus; type 2; interleukin-6; thrombocytosis; thrombopoietin

1 Introduction

Thrombocytosis – platelet counts above the upper value of normal range (usually ≥400 × 109/L) – is described as a poor prognostic sign in colorectal cancer (CRC). Both preoperative and postoperative thrombocytoses are associated with worse patient survival [1,2]. Thrombocytosis may develop for several reasons, such as the bleeding of the tumor or a metabolic change caused by the tumor itself called paraneoplastic thrombocytosis [1,3]. The proposed paracrine-signaling pathway of paraneoplastic thrombocytosis [3,4] includes the overproduction of various cytokines (e.g., interleukin-6) by the tumor, which causes increased hepatic thrombopoietin production that modulates the production of platelets within the bone marrow, ultimately resulting in an increased platelet count.

Diabetes mellitus is one of the most prevalent diseases in our time; based on the latest estimations available in the ninth edition of IDF Diabetes Atlas [5], the incidence of the disease varies between 4 and 10.4%, with over 460 million diabetes patients around the world [5]. Approximately 90% of diabetes patients are suffering from type 2 diabetes mellitus (T2DM), which develops in later ages [6], similar to that of CRC [7]. Over the age of 60 years, T2DM may occur in every fourth or fifth person [5,8], and compared to the healthy population, an increased occurrence of malignancies is confirmed in T2DM [9,10,11]. CRC occurs approximately 1.5× more often in patients with T2DM [12,13]; furthermore, the coexistence of T2DM is associated with an increased risk for a shorter survival in CRC [14,15]. Similar to CRC, T2DM can be also described by various platelet abnormalities and an increased thrombopoietin production is also known [16,17,18].

Although several potential mechanisms link cancers and T2DM together [19], and platelets are affected in both diseases [1,2,3,4,16,17,18], the relationship among T2DM, (paraneoplastic) thrombocytosis, and CRC is poorly investigated. An earlier retrospective study [20] from our group has found that a personalized thrombocytosis measure calculated from preoperative and precancer platelet counts can better predict the patient survival, and it has been associated with various clinicopathological parameters, including T2DM. Although our earlier study has revealed some possible connections between the three conditions, the exact biological effect of T2DM on CRC-related paraneoplastic thrombocytosis could not have been investigated via that retrospective manner. Therefore, a prospective, real-life observational cohort study was conducted where paraneoplastic thrombocytosis was investigated within diabetic and nondiabetic CRC cohorts through the changes in platelet counts, plasma interleukin-6, and thrombopoietin levels.

2 Methods

2.1 Patients and study design

A prospective, real-life observational cohort study was carried out. A total of 108 patients diagnosed with CRC and 166 voluntary non-CRC subjects were enrolled for the study between 2017 and 2019. CRC patients attended at both the Department of Internal Medicine and Hematology, Semmelweis University, Budapest and the Department of General Surgery, Szent Imre University Teaching Hospital, Budapest. Written informed consent was collected from all study participants before performing any study-specific procedures. Exclusion criteria included age <18 years, any previous malignancies, known inflammatory bowel- and/or chronic kidney- and/or systemic autoimmune- and/or inadequately controlled thyroid- and/or hematologic- and/or any mental diseases, the usage of erythropoiesis-stimulating agents and/or recent blood transfusion, and patients with an Eastern Cooperative Oncology Group (ECOG) performance status >2.

Voluntary non-CRC subjects consisted of healthy young controls, older controls, and T2DM patients. Rationale of the inclusion of healthy young subjects was that some of the measured parameters have no reference values and that the older volunteers included both completely healthy individuals and nonmetabolic disease patients (e.g., hypertension). T2DM patients attended at the Metabolic Outpatient Clinic of the Department of Internal Medicine and Hematology, Semmelweis University, Budapest. In addition to the exclusion criteria described by CRC patients above, voluntary nondiseased subjects were excluded in the presence of prediabetes or any other metabolic disorders.

2.2 Clinical and laboratory data measurements

Anamnestic data including comorbidities and recent medications, body weight, and height were collected, and fasting blood samples were drawn according to the following protocol: (1) at the diagnosis of CRC, before any oncological treatments or the surgical resection of the primary tumor, (2) at least 6 weeks, (3) 6 months, and (4) 12 months after the tumor removal surgery. At the time of postoperative measurements, oncological treatments were stopped/paused only as part of the patients’ standard of oncological care, and sampling was performed only at least 6 weeks after the last treatment due to the known platelet influencing effects of several cytotoxic regimens [21,22]. If it was not feasible to stop/pause the oncological treatment, in the best interest of the patient, the visit was omitted. Complete blood count, aspartate- and alanine transaminase, gamma-glutamyl transferase, plasma glucose, and creatinine were measured at the Central Laboratory of Semmelweis University and at the Central Laboratory of Szent Imre University Teaching Hospital. Estimated glomerular filtration rate was calculated using the Chronic Kidney Disease-Epidemiology Collaboration equations [23]. Plasma interleukin-6 and thrombopoietin levels were measured using the ELECSYS® Interleukin-6 electrochemiluminescence immunoassay (ECLIA) (Roche Diagnostics GmbH, Mannheim, Germany) and the Human Thrombopoietin Quantikine® enzyme-linked immunosorbent assay (ELISA) (catalog number: DTP00B, R&D Systems, Minneapolis, MN, USA) kits, respectively. Plasma thrombopoietin level was measured from platelet-poor plasma, as per manufacturer description.

Side of CRC was described as right sided if the tumor was originating from cecum, ascending colon, and proximal two-third of the transverse colon and left sided if originating from the distal one-third of the transverse colon, descending colon, sigmoid colon, and rectum [24]. Staging was given by histopathological examination of surgical specimens and imaging studies; the American Joint Committee on Cancer grouping was used [25]. The usage of biological agents was recorded as a dummy variable and chemotherapy was grouped as adjuvant if no metastasis and first-line, second-line, etc., if metastasis was present. The overall survival of patients was defined as the length of time from the date of CRC diagnosis until death. Follow-up of cancer patients was terminated on January 31, 2021, patients alive at this time point were right censored.

2.3 Statistical analysis

Statistical analysis was performed with R version 4.0.5 [26]. Wilcoxon–Mann–Whitney U test, Fisher’s exact test, Kruskal–Wallis test with p-value corrected pairwise Wilcoxon–Mann–Whitney U tests as post-hoc, and Spearman rank correlation were used. To detect the changes of various parameters in time, linear mixed effect models were used (R-package nlme [27]). Survival of patients was analyzed for both preoperative and longitudinal data with Cox regression models and Bayesian univariate and multivariate joint survival models (R-package rstanarm [28]), respectively. p < 0.05 was considered as statistically significant, and p-values were corrected with the Holm method [29] for the problem of multiple comparisons. Compared to the “conventional” frequentist methods, Bayesian methods give only a probability distribution for the investigated parameter but no p-values. Interpretation of joint model results was as follows. If the Bayesian equivalent to the frequentist confidence interval (CI), the 95% credible interval contained the hazard ratio (HR) of 1, the model was considered as clinically not relevant. However, if the 95% credible interval was less than or more than HR = 1, the effect of the parameter was considered as a good or bad sign of patient survival, respectively. Results were expressed as mean ± standard deviation and as the number of observations (percentage) for continuous and count data, respectively. Naïve Kaplan–Meier and longitudinal survival curves were drawn with the R-package survminer (Kassambara, Kosinski, and Biecek, version 0.4.9, 2021) and the built-in methods of rstanarm, respectively.

  1. Informed consent: Informed consent has been obtained from all individuals included in this study.

  2. Ethical approval: The study was approved by the Regional and Institutional Committee of Science and Research Ethics, Semmelweis University (SE TUKEB 21-12/1994, approval date of latest modification: February 10, 2017), by the Institutional Review Board of Szent Imre University Teaching Hospital (SZIK IKEB 5/2017), and by the Committee of Science and Research Ethics, Hungarian Medical Research Council (ETT TUKEB 8951-3/2015/EKU).

3 Results

A total of 274 study participants were included: 108 CRC patients and 166 voluntary, non-CRC subjects. CRC patients were divided into two cohorts based on the presence of T2DM. Patients without diabetes (n = 82) were assigned to the “CRC” group, whereas patients with a history of T2DM (n = 26) were assigned to the “CRC + T2DM” group. Duration of diabetes was 6.88 ± 6.10 years, from which T2DM was diagnosed in four cases around the time of CRC diagnosis.

In most parameters, the two tumor groups did not differ from each other, whereas plasma glucose was significantly higher (p = 0.0018), and tendentiously higher white blood cell-, neutrophil-, eosinophil-, and monocyte counts were observed in the CRC + T2DM group. Platelet aggregation inhibition therapy was more common in CRC + T2DM patients; no difference was found in radiotherapy (neoadjuvant only), whereas no-line or late-line chemotherapy was more common in those CRC patients with T2DM than those of without (p = 0.0560; Table 1).

Table 1

Metabolic, clinical, and other parameters of CRC patients

Parameter CRC CRC + T2DM p-value
(n = 82) (n = 26)
Age (years) 67.42 ± 9.33 70.83 ± 7.24 0.3919
Sex (male:female) 51:31 (62.2:37.8%) 20:6 (76.9:23.1%) 0.3778
Body mass index (kg/m2) 27.26 ± 3.87 27.43 ± 4.64 0.7778
Systolic blood pressure (mmHg) 144.49 ± 18.48 141.12 ± 19.55 0.7654
Diastolic blood pressure (mmHg) 78.99 ± 10.19 78.20 ± 9.10 0.7527
Heart rate (1/min) 77.88 ± 13.76 80.76 ± 16.36 0.7654
White blood cell count (109/L) 8.14 ± 2.91 11.11 ± 7.46 0.3919*
 Neutrophil count (109/L) 5.60 ± 2.57 7.87 ± 5.59 0.3919*
 Eosinophil count (109/L) 0.18 ± 0.16 0.59 ± 1.73 0.3919*
 Basophil count (109/L) 0.06 ± 0.05 0.06 ± 0.04 0.7654
 Monocyte count (109/L) 0.61 ± 0.46 0.78 ± 0.51 0.3919*
 Lymphocyte count (109/L) 1.74 ± 1.11 1.81 ± 0.92 0.7654
Red blood cell count (1012/L) 4.50 ± 0.58 4.42 ± 0.52 0.7527
Hemoglobin (g/dL) 12.42 ± 2.14 12.14 ± 2.11 0.7654
Hematocrit (L/L) 0.38 ± 0.06 0.38 ± 0.06 0.7778
Mean corpuscular volume (fL) 84.84 ± 8.22 84.31 ± 8.54 0.9471
Mean corpuscular hemoglobin (pg) 27.30 ± 3.41 27.32 ± 3.81 0.9853
Mean corpuscular hemoglobin concentration (g/L) 322.35 ± 15.29 324.20 ± 24.53 0.7527
Red blood cell distribution width (%) 14.63 ± 3.74 15.53 ± 3.47 0.4409
Platelet count (109/L) 308.38 ± 124.66 339.85 ± 118.86 0.7527
Aspartate transaminase (U/L) 25.86 ± 21.03 26.37 ± 16.12 0.9853
Alanine transaminase (U/L) 21.75 ± 12.52 23.10 ± 13.35 0.7654
Gamma-glutamyl transferase (U/L) 68.33 ± 117.56 97.24 ± 167.79 0.7527
Plasma glucose (mmol/L) 5.45 ± 0.86 6.62 ± 1.71 0.0018
Creatinine (µmol/L) 76.99 ± 19.19 82.33 ± 22.41 0.7527
Estimated glomerular filtration rate mL min ⋅ 1.73 m 2 82.17 ± 16.81 78.23 ± 18.30 0.7527
AJCC staging [25]
 Stage I 19 (23.2%) 9 (34.6%) 0.4021
 Stage II 23 (28.0%) 4 (15.4%)
 Stage III 20 (24.4%) 4 (15.4%)
 Stage IV 20 (24.4%) 9 (34.6%)
Side of CRC
 Left-sided 60 (73.2%) 15 (57.7%) 0.2987
 Right-sided 22 (26.8%) 11 (42.3%)
Chemotherapy
 None 37 (45.1%) 16 (61.5%) 0.0560**
 Adjuvant 21 (25.6%) 2 (7.7%)
 First-line 12 (14.6%) 0 (0.0%)
 Second-line 7 (8.5%) 7 (26.9%)
 Third or later-line 5 (6.1%) 1 (3.8%)
Radiotherapy 14 (17.1%) 3 (11.5%) 0.7568
Usage of biological therapy 15 (18.3%) 7 (26.9%) 0.4611
Known comorbidities
 Hypertension 48 (58.5%) 20 (76.9%) 0.2851
 Major cardiovascular event(s) before CRC 16 (19.5%) 6 (23.1%) 0.7809
Platelet aggregation inhibition 14 (17.1%) 9 (34.6%) 0.2851*

T2DM: type 2 diabetes mellitus. *Without p-value correction, the differences are marginal (white blood cells: p = 0.0843; neutrophils: p = 0.0919; eosinophils: p = 0.0648; monocytes: p = 0.0918; platelet aggregation inhibition therapy: p = 0.0959). **Without p-value correction, the differences in the distribution of chemotherapy regimens is statistically significant (p = 0.0070).

Voluntary non-CRC subjects were divided into three cohorts: 51, 50, and 65 subjects were assigned to the “Young controls,” “Control,” and “T2DM” groups, respectively. Duration of diabetes was 14.91 ± 9.50 within the T2DM group. Anamnestic, clinical, and laboratory parameters of control groups are shown in Table 2. Comparison between the volunteer groups revealed that, as expected, Young controls had the lowest body mass index (p < 0.0001 vs T2DM and Controls), systolic blood pressure (p = 0.0250 vs Controls, p = 0.0410 vs T2DM), mean corpuscular volume (p = 0.0002 vs Controls, p = 0.0041 vs T2DM), red blood cell distribution width (p = 0.0023 vs Controls, p < 0.0001 vs T2DM), fasting plasma glucose (p < 0.0001 vs Controls and T2DM), and the highest heart rate (p = 0.0002 vs Controls, p = 0.0242 vs T2DM) and estimated glomerular filtration rate (p < 0.0001 vs Controls and T2DM). T2DM patients had the highest body mass index (p = 0.0098 vs Controls, p < 0.0001 vs Young controls), white blood cell count (p = 0.0430 vs Controls, p = 0.0008 vs Young controls), gamma-glutamyl transferase (p = 0.0633 vs Controls, p = 0.0003 vs Young controls) and fasting plasma glucose (p < 0.0001 vs Controls and Young controls). Significant differences of comparisons among all five groups have been indicated in Table 2.

Table 2

Metabolic, clinical, and other parameters of voluntary control subjects

Parameter Young controls Control T2DM
(n = 51) (n = 50) (n = 65)
Age (years) 26.13 ± 4.501 60.31 ± 11.004 64.68 ± 8.307
Sex (male:female) 24: 27 22: 287 35: 30
(47.1:52.9%) (44.0:56.0%) (53.8:46.2%)
Body mass index (kg/m2) 23.25 ± 3.951 27.99 ± 5.426 30.73 ± 5.121
Systolic blood pressure (mmHg) 129.82 ± 15.60 138.27 ± 17.34 136.58 ± 16.64
Diastolic blood pressure (mmHg) 77.27 ± 9.10 80.98 ± 11.85 76.06 ± 10.83
Heart rate (1/min) 77.59 ± 11.08 67.76 ± 7.951 73.23 ± `9.18
White blood cell count (109/L) 6.48 ± 1.592 7.04 ± 2.007 7.97 ± 2.23
 Neutrophil count (109/L) 3.66 ± 1.372 4.35 ± 1.684 4.93 ± 1.827
 Eosinophil count (109/L) 0.19 ± 0.17 0.18 ± 0.13 0.21 ± 0.13
 Basophil count (109/L) 0.06 ± 0.08 0.06 ± 0.03 0.06 ± 0.05
 Monocyte count (109/L) 0.44 ± 0.152 0.44 ± 0.112 0.52 ± 0.14
 Lymphocyte count (109/L) 2.09 ± 0.663 2.15 ± 0.773 2.25 ± 0.803
Red blood cell count (1012/L) 4.97 ± 0.534 4.92 ± 0.534 4.81 ± 0.384
Hemoglobin (g/dL) 14.60 ± 1.354 14.69 ± 1.384 14.07 ± 1.044
Hematocrit (L/L) 0.43 ± 0.044 0.44 ± 0.044 0.42 ± 0.034
Mean corpuscular volume (fL) 86.27 ± 3.005 89.32 ± 4.183 88.04 ± 3.44
Mean corpuscular hemoglobin (pg) 29.49 ± 1.393 30.02 ± 1.614 29.32 ± 1.473
Mean corpuscular hemoglobin concentration (g/L) 339.16 ± 9.732 337.18 ± 8.404 332.95 ± 8.933
Red blood cell distribution width (%) 12.59 ± 0.791 13.15 ± 0.927 13.23 ± 0.837
Platelet count (109/L) 267.86 ± 50.18 272.18 ± 72.66 263.92 ± 67.23
Aspartate transaminase (U/L) 27.47 ± 13.96 24.64 ± 6.49 25.34 ± 9.82
Alanine transaminase (U/L) 25.08 ± 14.77 24.88 ± 11.323 27.91 ± 14.86
Gamma-glutamyl transferase (U/L) 25.06 ± 12.566 32.70 ± 31.24 40.64 ± 29.40
Plasma glucose (mmol/L) 4.58 ± 0.451 4.99 ± 0.571 8.17 ± 2.631
Creatinine (µmol/L) 73.69 ± 12.72 70.20 ± 12.72 75.11 ± 19.05
Estimated glomerular filtration rate mL min ⋅ 1.73 m 2 109.33 ± 14.971 89.66 ± 12.42 83.98 ± 16.05
Known comorbidities
 Hypertension 0 (0.0%)1 16 (32.0%)1 56 (86.2%)3
 Major cardiovascular event(s) prior visit date 0 (0.0%)2 5 (10.0%) 13 (20.0%)
Platelet aggregation inhibition 0 (0.0%)2 6 (12.0%)6 50 (76.9%)4

T2DM: type 2 diabetes mellitus, 1 p < 0.05 vs all other four groups, 2 p < 0.05 vs all diseased groups, 3 p < 0.01 vs the CRC without T2DM group, 4 p < 0.01 vs both tumor groups, 5 p < 0.05 vs Control and T2DM groups, 6 p < 0.05 vs T2DM, and 7 p < 0.01 vs the CRC with T2DM group.

The duration of diabetes was shorter within the CRC + T2DM group compared to those of the T2DM group. A higher proportion of oral antidiabetic drug usage and diet-only therapy was observable within the CRC + T2DM group, whereas the need for insulin therapy was greater in those within the T2DM group (p = 0.0006). Furthermore, lower glycated hemoglobin (HbA1C) level and fewer diabetic complications were found in the CRC + T2DM patients (Table 3). The occurrence of hypertension (p = 0.7790) and the proportion of previous major cardiovascular event(s) before the first visit (p = 0.7004) did not differ between the two diabetic groups. Comparison of diabetes-related parameters is summarized in Table 3.

Table 3

Diabetes-related parameters of T2DM and CRC + T2DM patients

Parameter T2DM CRC + T2DM p-value
(n = 65) (n = 26)
Duration of T2DM (years) 14.91 ± 9.50 6.88 ± 6.10 0.0015
HbA1C (%) 7.40 ± 1.26 6.30 ± 1.04 0.0012
Treatment used for T2DM
 Only diet 3 (4.6%) 7 (26.9%) 0.0006
 Oral hypoglycemic  medications 32 (49.2%) 18 (69.2%)
 Combination therapy (oral + basal insulin) 14 (21.5%) 1 (3.8%)
 Intensive insulin therapy 16 (24.6%) 0 (0.0%)
Diabetic complications1
 Retinopathy 16 (24.6%) 2 (7.7%) 0.4203
 Nephropathy 6 (9.2%) 0 (0.0%) 0.5319
 Neuropathy 14 (21.5%) 5 (19.2%) 1.0000
 Angiopathy 9 (13.8%) 1 (3.8%) 0.5420
 Albuminuria 9 (13.8%) 0 (0.0%) 0.33302
Number of diabetic comorbidities
 None 35 (53.8%) 20 (76.9%) 0.4203
 One 15 (23.1%) 4 (15.4%)
 More than one 15 (23.1%) 2 (7.7%)
Hyperlipidemia 44 (67.7%) 10 (38.5%) 0.12103

HbA1C: glycated hemoglobin, 1All developed prior CRC, 2Without p-value correction p = 0.0555, and 3Without p-value correction p = 0.0173.

3.1 Baseline measurement of paraneoplastic thrombocytosis-related parameters

Plasma level of paraneoplastic thrombocytosis parameters of patients was compared to those of all control groups at the time of CRC diagnosis. Highest platelet counts were observed within the two tumor groups: platelet count of CRC patients was significantly higher than those of within the T2DM group (p = 0.0369), whereas the platelet count of the CRC + T2DM group was significantly higher than all of the control groups (p = 0.0369 vs Young Control and Control, p = 0.0278 vs T2DM; Figure 1a). Lowest plasma interleukin-6 levels were observed within Young controls (p < 0.0010 vs all other cohorts). Subjects of the Control and T2DM groups had similar interleukin-6 levels; and interleukin-6 was significantly higher in both tumor groups, compared to all of those observed in control groups (p < 0.0001 CRC vs Control and T2DM, p = 0.0011 CRC + T2DM vs Control, and p = 0.0069 CRC + T2DM vs T2DM; Figure 1b). Thrombopoietin level was basically the same in the Young control and Control groups, and a separate cluster was formed by the remaining three groups. The highest thrombopoietin levels were observed in the CRC + T2DM group (Figure 1c). No further difference could have been justified in any of the study groups if they were further subdivided by the usage of platelet aggregation inhibition therapy, antidiabetic drugs, or in the presence of any diabetic complications.

Figure 1 Comparison of paraneoplastic thrombocytosis-related parameters within the five study groups. (a) The platelet count was significantly higher in CRC patients with T2DM, compared to those in all control groups, and it also differed between the CRC and T2DM groups. (b) The plasma interleukin-6 level was significantly higher in all tumor patients1, whereas (c) the plasma thrombopoietin level was significantly lower within the T2DM and CRC, and significantly higher in the CRC + T2DM groups, compared to those of control subjects. Note: p-value correction was used for all between-groups comparisons. 1Due to better visibility, six and one outlier(s) over 40 pg/mL were not shown in the CRC and CRC + T2DM groups; maximum values were 220.20 and 77.19 pg/mL, respectively.
Figure 1

Comparison of paraneoplastic thrombocytosis-related parameters within the five study groups. (a) The platelet count was significantly higher in CRC patients with T2DM, compared to those in all control groups, and it also differed between the CRC and T2DM groups. (b) The plasma interleukin-6 level was significantly higher in all tumor patients1, whereas (c) the plasma thrombopoietin level was significantly lower within the T2DM and CRC, and significantly higher in the CRC + T2DM groups, compared to those of control subjects. Note: p-value correction was used for all between-groups comparisons. 1Due to better visibility, six and one outlier(s) over 40 pg/mL were not shown in the CRC and CRC + T2DM groups; maximum values were 220.20 and 77.19 pg/mL, respectively.

Highest platelet counts were found if interleukin-6 was high as well (CRC: Spearman ρ: +0.34, p = 0.0017; CRC + T2DM: p = 0.0786; CRC groups combined: Spearman ρ: +0.32, p = 0.0009). Correlation between platelet count and thrombopoietin levels was only significant in the CRC group (Spearman ρ: –0.24, p = 0.0332), whereas no (p = 0.8486) and marginal association (p = 0.0643) was found in the CRC + T2DM and in the two tumor groups combined, respectively. No correlation was found between interleukin-6 and thrombopoietin levels (CRC: p = 0.4279, CRC + T2DM: p = 0.9921, tumor groups combined: p = 0.5383). No correlation was found between the thrombocytosis-related parameters and the duration of T2DM or the preoperative level of HbA1C.

3.2 Changes in the parameters of paraneoplastic thrombocytosis with the course of CRC

For the 108 CRC subjects, a total of 215 measurements were available. 108, 48, 37, and 22 preoperative, postoperative, 6-month, and 12-month measurements were available, respectively. Significant decrease in later measurements occurred due to the death of patients, disease progression resulting in higher ECOG performance status and patient’s unavailability to attend at later visits, the need to initiate chemotherapy earlier than the postoperative visit window, or continuous chemotherapy without drug holiday after the second study visit. Due to the decreasing number of follow-ups, a more robust statistical method not sensitive to the loss of follow-up had to be chosen; therefore, it was investigated via age-corrected and stage-corrected linear mixed effect interaction models as to how T2DM and worse clinical outcome (death) affect the changes of platelet count, interleukin-6, and thrombopoietin levels with the course of the disease. Average survival time: 16.96 ± 11.43 months, all within the first 3 years after CRC diagnosis. Diabetes had no significant effect on any of the changes (platelet count: p = 0.1190; interleukin-6: p = 0.5571; thrombopoietin: p = 0.3062, Figure 2a, c, and e). Platelet counts of all patients decreased, but among those patients who died during the time of the study, the average baseline platelet count was significantly higher (273.70 vs 353.00 × 109/L; p = 0.0042) and a faster decrease could have been seen within the first 12 months after the tumor removal surgery compared to those of who survived (Figure 2b). Similarly, increased baseline interleukin-6 levels (5.76 vs 27.42 pg/mL; p < 0.0001) and marginally faster decreasing levels (p = 0.0613) were observed in deceased patients over time, whereas in those who survived the plasma interleukin-6 level was constant during our observation (p = 0.1273, Figure 2d). The initial thrombopoietin level did not differ between surviving and deceased patients (p = 0.5747), and its change was not affected by the worse clinical outcome (p = 0.5940, Figure 2f). Usage of radiotherapy and chemotherapy did not affect any of the response variables, if included within any of the models.

Figure 2 Change in the parameters of paraneoplastic thrombocytosis with the course of the disease. No difference was found in any of the parameters (a, c, e) when stratified with the presence of T2DM. (b) Platelet count and (d) plasma interleukin-6 were significantly higher at the time of CRC diagnosis in those patients who died during the observation period. Within the first year after tumor removal surgery, a significantly faster platelet count decrease was found in those patients who died (b), whereas the significant difference in plasma interleukin-6 levels remained throughout the whole study between survivors and those patients who died (d). No statistical difference was found in plasma thrombopoietin levels of survivors and nonsurvivors (p = 0.5940, f).
Figure 2

Change in the parameters of paraneoplastic thrombocytosis with the course of the disease. No difference was found in any of the parameters (a, c, e) when stratified with the presence of T2DM. (b) Platelet count and (d) plasma interleukin-6 were significantly higher at the time of CRC diagnosis in those patients who died during the observation period. Within the first year after tumor removal surgery, a significantly faster platelet count decrease was found in those patients who died (b), whereas the significant difference in plasma interleukin-6 levels remained throughout the whole study between survivors and those patients who died (d). No statistical difference was found in plasma thrombopoietin levels of survivors and nonsurvivors (p = 0.5940, f).

3.3 Survival analysis of paraneoplastic thrombocytosis-related parameters and T2DM

Thirty of the 108 patients (27.8%) died during the study, from which 20 and 10 belonged to the CRC and CRC + T2DM group, respectively. Patients were followed up no later than January 31, 2021. The survival analysis was performed on both the preoperative (single-time) and longitudinal data. Despite the higher occurrence of death (24 vs 40%) within the diabetic tumor group and the difference that appears to be significant on the naïve Kaplan–Meier figure (Figure 3), the univariate Cox model of preoperative data suggested that T2DM had no effect on patient survival (p = 0.1450). A higher preoperative platelet count (HR: 1.0026, 95% CI: 1.0010–1.0050, p = 0.0052) could be considered as a poor prognostic sign. Interleukin-6 and thrombopoietin levels had no significant univariate effect; however, if combined with T2DM in a multivariate model, higher interleukin-6 levels had marginal effect (HR: 1.0007, 95% CI: 0.9995–1.0140, p = 0.0692) on patient survival. Similar to the univariate model, higher platelet counts had the same significant effect in the multivariate model as well (HR: 1.0028, 95% CI: 1.0009–1.0050, p = 0.0043). T2DM did not have any effect in either multivariate model. A subgroup analysis within the CRC + T2DM group only revealed that neither the duration of diabetes (p = 0.5590), the use of any antidiabetics (p = 0.2620), the presence of any diabetic complications (p = 0.2860), nor the preoperative level of HbA1C (p = 0.5370) affected patient survival.

Figure 3 Naïve Kaplan–Meier curves of CRC patients with and without T2DM. It should be noted that although the two curves do not appear to be similar, neither Cox regression (p = 0.1450), nor log-rank test (p = 0.0908) could justify a statistical difference.
Figure 3

Naïve Kaplan–Meier curves of CRC patients with and without T2DM. It should be noted that although the two curves do not appear to be similar, neither Cox regression (p = 0.1450), nor log-rank test (p = 0.0908) could justify a statistical difference.

To analyze the effect of paraneoplastic thrombocytosis-related parameter changes in time, Bayesian joint models were used. First, three univariate joint models (a single parameter is analyzed within the longitudinal submodel) were constructed: the survival effect of the changes of platelet count, interleukin-6, or thrombopoietin over time was included in the longitudinal submodel, and T2DM was included in the survival submodel. An additional multivariate joint model was also constructed, where all three paraneoplastic thrombocytosis parameters were included within the longitudinal submodel, and no change was applied to the survival submodel. Interpretation of the clinical significance of parameters on patient survival was assessed as described in Section 2.

Based on the result of the univariate joint models, after the surgical removal of the primary tumor, higher platelet count and plasma interleukin-6 level is a sign of poorer survival (Figure 4). Thrombopoietin and diabetes did not affect the survival of patients in any of the univariate models. Multivariate joint model results suggested that interleukin-6 had the strongest effect on patient survival, whereas the platelet count was marginal; thrombopoietin and diabetes had no clinically relevant effect, similar to those observed in univariate models (Figures 4 and 5).

Figure 4 Longitudinal and survival predictions of the Bayesian joint models. No difference was found between CRC patients with or without T2DM. Increasing platelet count and plasma interleukin-6 level were associated with a higher risk of shorter survival times (left), whereas no change or a slow decline in these parameters is a good prognostic sign (right). Thrombopoietin levels had no clinically relevant effect neither in univariate nor in multivariate survival models.
Figure 4

Longitudinal and survival predictions of the Bayesian joint models. No difference was found between CRC patients with or without T2DM. Increasing platelet count and plasma interleukin-6 level were associated with a higher risk of shorter survival times (left), whereas no change or a slow decline in these parameters is a good prognostic sign (right). Thrombopoietin levels had no clinically relevant effect neither in univariate nor in multivariate survival models.

Figure 5 Results of the Bayesian joint survival models. Platelet count and/or plasma interleukin-6 level increasing over time is a poor prognostic factor, whereas diabetes and plasma thrombopoietin changes did not affect patient survival (Note: credible interval is the Bayesian equivalent of the frequentists’ CI.).
Figure 5

Results of the Bayesian joint survival models. Platelet count and/or plasma interleukin-6 level increasing over time is a poor prognostic factor, whereas diabetes and plasma thrombopoietin changes did not affect patient survival (Note: credible interval is the Bayesian equivalent of the frequentists’ CI.).

4 Discussion

In CRC, the occurrence of thrombocytosis, either prior or after the primary tumor removal surgery, is associated with shorter survival of patients [1,2,30,31,32,33]. The background of thrombocytosis may vary due to several factors, including the bleeding (reactive thrombocytosis) or metabolic changes (paraneoplastic thrombocytosis) of the tumor. In the latter, the tumor produces cytokines, such as interleukin-6, in higher quantities, and those higher cytokine concentrations stimulate hepatic thrombopoietin production, which ultimately results in the overproduction of platelets [4,34]. A platelet count of >400 × 109/L or >450 × 109/L is the most common definition of thrombocytosis [1,3,35], but several earlier studies reported other cut-off values [1], indicating that the definition of thrombocytosis may not be perfect. In an earlier study [20], we have reported that a personalized, relative platelet measure can predict disease outcome significantly better than “traditional” thrombocytosis, which further strengthened that the definition of thrombocytosis needs to be revised. The biochemical detection of paraneoplastic thrombocytosis in CRC is a novel research area [36]. In the current study, we observed higher interleukin-6 and thrombopoietin levels of CRC patients, compared to those of control subjects, supporting the presence of paraneoplastic thrombocytosis, which was further strengthened by the result of correlation and survival analysis, in line with earlier findings [1,2,31,32,33,36,37,38].

There is a strong relationship between CRC and various cytokines, including interleukin-6, which can play significant roles both in the development and progression of the disease [39,40,41]. Specifically, interleukin-6 is known to for its significant role in tumor proliferation, migration, induction of microsatellite instability, and angiogenesis [42,43]. It has been reported that interleukin-6 is produced by cancer-associated mesenchymal stem cells [44]. When combined with glycoprotein 130 (gp130, synonyms: IL6ST or CD130) interleukin-6 can regulate disease progression through the Shp2-Ras-ERK, JAK1/2-STAT3, and PI3K-Akt-mTOR pathways, and its higher serum levels were associated with larger tumor size, presence of metastases, and worse overall- and disease-free survival [40,41,45,46]. Due to its strong connection with CRC, interleukin-6 has been proposed as a good prognostic marker of CRC [47,48,49]. In the current study, we could also confirm the prognostic role of interleukin-6 over patient survival. The result that preoperative interleukin-6 did not affected survival was possibly due to the heterogeneity of study population, which was somewhat confirmed by the results obtained from the multivariate Cox models, as the predictive effect of interleukin-6 on survival increased. As a novel result, we found that constantly higher interleukin-6 level could have been observed in those patients, who died within the first 3 years after CRC diagnosis.

Research on CRC and thrombopoietin is limited. Earlier studies have identified that cancer cells can induce circulating thrombopoietin production [50]; furthermore, higher thrombopoietin level is associated with gastrointestinal cancers, and a possible relationship between more advanced clinical stages and thrombopoietin has been also suggested [51,52]. Similar to the observations above, we found that the thrombopoietin level of CRC patients is higher than those of healthy subjects; however, the effect of thrombopoietin levels over survival was negligible, and no change with the course of the disease could have been identified in either of our longitudinal models.

T2DM, similarly to (paraneoplastic) thrombocytosis, has a known negative effect on CRC [15,53]. Several potential mechanisms link the two diseases together [19], including the increased plasma glucose levels (hyperglycemia), the presence of insulin resistance and hyperinsulinemia, increased insulin-like growth factor-1 levels, increased oxidative stress, higher cytokine concentrations, and increased platelet activation [9,10,13,19,53]. CRC is known to have an increased incidence in T2DM patients compared to those of within the healthy population [9,10]; a 1.3-fold increased risk of CRC has been reported [54,55]. T2DM has been described to have a negative effect on overall-, cancer-specific-, disease-free-, and recurrence-free survival of CRC patients [56,57]. In contrast to earlier findings, we found that T2DM did not affect patient survival in the current study statistically, but it has to be noted, that the percentage of patients who died was higher in the CRC + T2DM group (24 vs 40%), and similarly, the survival curves on Figure 3 also suggested a tendency toward significant difference. The effect of T2DM on patient survival was further investigated through the presence of diabetic complications, the preoperative HbA1C level, and the duration of T2DM. Despite the fact that the duration of diabetes was basically twice as long in patients of the T2DM group, a greater number of diabetic complications were present, and a more significant proportion of patients required (intensive) insulin therapy, no significant effect could be justified for any of the above-mentioned parameters. It has to be mentioned though that the sample size of CRC + T2DM patients was low, but we could not even prove tendentious differences similar to that of observed in Figure 3.

The relationship between CRC-related paraneoplastic thrombocytosis and T2DM through biochemical measurements has not been investigated previously. It has to be mentioned though, that various platelet abnormalities and increased interleukin-6 and thrombopoietin production are known in T2DM [16,17,18,58,59,60]. Due to the above-mentioned effects and the high risk of cardiovascular events, the usage of platelet aggregation inhibition therapy is very common in T2DM [61,62]. Based on the available literature, our prestudy hypothesis was that CRC patients who also suffer from T2DM would probably have higher interleukin-6 and thrombopoietin levels than those who are not affected by T2DM. In contrast to our hypothesis, no differences could have been justified in any of the parameters related to paraneoplastic thrombocytosis between the CRC and CRC + T2DM groups. Furthermore, platelet aggregation inhibition also did not have any effect on the parameters of paraneoplastic thrombocytosis even though that the therapy was more common within the CRC + T2DM group. Similarly, the diabetes-related parameters also did not affect the paraneoplastic thrombocytosis-related parameters. The fact that plasma thrombopoietin level of non-CRC T2DM patients was more similar to those of CRC patients than those of control subjects was most likely related to the already known fact that thrombopoietin levels are higher in T2DM [58], but no previous data are available on how similar these values of CRC and T2DM patients should be. The presented data suggest that T2DM does not increase the effect of CRC-related paraneoplastic thrombocytosis, in most probability, and the disease-worsening effect of T2DM, which has been described in earlier publications [11], must be carried out through other factors. To identify those factors, further investigations are needed.

4.1 Limitations

Limitations of the current study were the small sample size and the heterogeneity of CRC population – the latter may be also compensated with a larger sample size. The proportion of T2DM patients within the tumor cohort corresponded to the healthy Hungarian population (approximately every fourth person, over 60 years of age [8]). Due to patients’ decision, a large number of potential subjects did not agree to be included in the study. Despite the low number of cases, it is important to emphasize that the presence of paraneoplastic thrombocytosis could have been already detected at such a low number of cases, showing its significance in CRC. The low number of T2DM in those of CRC patients allowed us only to pinpoint tendentious differences in several parameters.

5 Conclusion

To summarize the results of the current study, our data suggested that although some metabolic changes do occur to platelet counts and to the interleukin-6 and/or thrombopoietin synthesis in T2DM and in paraneoplastic thrombocytosis-affected CRC patients, no combined effect have been observed. Based on the current study, there is no significant relationship between the two conditions with high probability and the known disease-worsening effect of diabetes on CRC survival is presumably independent of paraneoplastic thrombocytosis.

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Acknowledgments

None.

  1. Funding information: Research was supported by the National Research, Development and Innovation Office (grant number K-116128) and by the research grant of Hungarian Diabetes Association. Z.H. was supported by the UNKP-20-4-I New National Excellence Program of the Ministry for Innovation and Technology from the source of the National Research, Development and Innovation Fund.

  2. Author contributions: ZH, MH, and AS built the study design; MH, GH, AF, and ZH were involved in the collection of samples; ZH and ZL analyzed the data; GH, ZH, MH, MD, and ZL interpreted data; ZH and GH prepared the draft of the manuscript; all authors were involved in editing and reviewing; and AS received funding and supervised the study. All authors have read and agreed to the published version of the manuscript.

  3. Conflict of interest: The authors declare no conflicts of interest. The funding bodies have no role in the design of the study; collection, analysis, and interpretation of data; or in writing the manuscript.

  4. Data availability statement: The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Received: 2021-04-29
Revised: 2021-11-05
Accepted: 2021-11-15
Published Online: 2022-01-13

© 2022 Gyorgy Herczeg et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution 4.0 International License.

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  29. miR-29c-5p knockdown reduces inflammation and blood–brain barrier disruption by upregulating LRP6
  30. Cardiac contractility modulation ameliorates myocardial metabolic remodeling in a rabbit model of chronic heart failure through activation of AMPK and PPAR-α pathway
  31. Quercitrin protects human bronchial epithelial cells from oxidative damage
  32. Smurf2 suppresses the metastasis of hepatocellular carcinoma via ubiquitin degradation of Smad2
  33. circRNA_0001679/miR-338-3p/DUSP16 axis aggravates acute lung injury
  34. Sonoclot’s usefulness in prediction of cardiopulmonary arrest prognosis: A proof of concept study
  35. Four drug metabolism-related subgroups of pancreatic adenocarcinoma in prognosis, immune infiltration, and gene mutation
  36. Decreased expression of miR-195 mediated by hypermethylation promotes osteosarcoma
  37. LMO3 promotes proliferation and metastasis of papillary thyroid carcinoma cells by regulating LIMK1-mediated cofilin and the β-catenin pathway
  38. Cx43 upregulation in HUVECs under stretch via TGF-β1 and cytoskeletal network
  39. Evaluation of menstrual irregularities after COVID-19 vaccination: Results of the MECOVAC survey
  40. Histopathologic findings on removed stomach after sleeve gastrectomy. Do they influence the outcome?
  41. Analysis of the expression and prognostic value of MT1-MMP, β1-integrin and YAP1 in glioma
  42. Optimal diagnosis of the skin cancer using a hybrid deep neural network and grasshopper optimization algorithm
  43. miR-223-3p alleviates TGF-β-induced epithelial-mesenchymal transition and extracellular matrix deposition by targeting SP3 in endometrial epithelial cells
  44. Clinical value of SIRT1 as a prognostic biomarker in esophageal squamous cell carcinoma, a systematic meta-analysis
  45. circ_0020123 promotes cell proliferation and migration in lung adenocarcinoma via PDZD8
  46. miR-22-5p regulates the self-renewal of spermatogonial stem cells by targeting EZH2
  47. hsa-miR-340-5p inhibits epithelial–mesenchymal transition in endometriosis by targeting MAP3K2 and inactivating MAPK/ERK signaling
  48. circ_0085296 inhibits the biological functions of trophoblast cells to promote the progression of preeclampsia via the miR-942-5p/THBS2 network
  49. TCD hemodynamics findings in the subacute phase of anterior circulation stroke patients treated with mechanical thrombectomy
  50. Development of a risk-stratification scoring system for predicting risk of breast cancer based on non-alcoholic fatty liver disease, non-alcoholic fatty pancreas disease, and uric acid
  51. Tollip promotes hepatocellular carcinoma progression via PI3K/AKT pathway
  52. circ_0062491 alleviates periodontitis via the miR-142-5p/IGF1 axis
  53. Human amniotic fluid as a source of stem cells
  54. lncRNA NONRATT013819.2 promotes transforming growth factor-β1-induced myofibroblastic transition of hepatic stellate cells by miR24-3p/lox
  55. NORAD modulates miR-30c-5p-LDHA to protect lung endothelial cells damage
  56. Idiopathic pulmonary fibrosis telemedicine management during COVID-19 outbreak
  57. Risk factors for adverse drug reactions associated with clopidogrel therapy
  58. Serum zinc associated with immunity and inflammatory markers in Covid-19
  59. The relationship between night shift work and breast cancer incidence: A systematic review and meta-analysis of observational studies
  60. LncRNA expression in idiopathic achalasia: New insight and preliminary exploration into pathogenesis
  61. Notoginsenoside R1 alleviates spinal cord injury through the miR-301a/KLF7 axis to activate Wnt/β-catenin pathway
  62. Moscatilin suppresses the inflammation from macrophages and T cells
  63. Zoledronate promotes ECM degradation and apoptosis via Wnt/β-catenin
  64. Epithelial-mesenchymal transition-related genes in coronary artery disease
  65. The effect evaluation of traditional vaginal surgery and transvaginal mesh surgery for severe pelvic organ prolapse: 5 years follow-up
  66. Repeated partial splenic artery embolization for hypersplenism improves platelet count
  67. Low expression of miR-27b in serum exosomes of non-small cell lung cancer facilitates its progression by affecting EGFR
  68. Exosomal hsa_circ_0000519 modulates the NSCLC cell growth and metastasis via miR-1258/RHOV axis
  69. miR-455-5p enhances 5-fluorouracil sensitivity in colorectal cancer cells by targeting PIK3R1 and DEPDC1
  70. The effect of tranexamic acid on the reduction of intraoperative and postoperative blood loss and thromboembolic risk in patients with hip fracture
  71. Isocitrate dehydrogenase 1 mutation in cholangiocarcinoma impairs tumor progression by sensitizing cells to ferroptosis
  72. Artemisinin protects against cerebral ischemia and reperfusion injury via inhibiting the NF-κB pathway
  73. A 16-gene signature associated with homologous recombination deficiency for prognosis prediction in patients with triple-negative breast cancer
  74. Lidocaine ameliorates chronic constriction injury-induced neuropathic pain through regulating M1/M2 microglia polarization
  75. MicroRNA 322-5p reduced neuronal inflammation via the TLR4/TRAF6/NF-κB axis in a rat epilepsy model
  76. miR-1273h-5p suppresses CXCL12 expression and inhibits gastric cancer cell invasion and metastasis
  77. Clinical characteristics of pneumonia patients of long course of illness infected with SARS-CoV-2
  78. circRNF20 aggravates the malignancy of retinoblastoma depending on the regulation of miR-132-3p/PAX6 axis
  79. Linezolid for resistant Gram-positive bacterial infections in children under 12 years: A meta-analysis
  80. Rack1 regulates pro-inflammatory cytokines by NF-κB in diabetic nephropathy
  81. Comprehensive analysis of molecular mechanism and a novel prognostic signature based on small nuclear RNA biomarkers in gastric cancer patients
  82. Smog and risk of maternal and fetal birth outcomes: A retrospective study in Baoding, China
  83. Let-7i-3p inhibits the cell cycle, proliferation, invasion, and migration of colorectal cancer cells via downregulating CCND1
  84. β2-Adrenergic receptor expression in subchondral bone of patients with varus knee osteoarthritis
  85. Possible impact of COVID-19 pandemic and lockdown on suicide behavior among patients in Southeast Serbia
  86. In vitro antimicrobial activity of ozonated oil in liposome eyedrop against multidrug-resistant bacteria
  87. Potential biomarkers for inflammatory response in acute lung injury
  88. A low serum uric acid concentration predicts a poor prognosis in adult patients with candidemia
  89. Antitumor activity of recombinant oncolytic vaccinia virus with human IL2
  90. ALKBH5 inhibits TNF-α-induced apoptosis of HUVECs through Bcl-2 pathway
  91. Risk prediction of cardiovascular disease using machine learning classifiers
  92. Value of ultrasonography parameters in diagnosing polycystic ovary syndrome
  93. Bioinformatics analysis reveals three key genes and four survival genes associated with youth-onset NSCLC
  94. Identification of autophagy-related biomarkers in patients with pulmonary arterial hypertension based on bioinformatics analysis
  95. Protective effects of glaucocalyxin A on the airway of asthmatic mice
  96. Overexpression of miR-100-5p inhibits papillary thyroid cancer progression via targeting FZD8
  97. Bioinformatics-based analysis of SUMOylation-related genes in hepatocellular carcinoma reveals a role of upregulated SAE1 in promoting cell proliferation
  98. Effectiveness and clinical benefits of new anti-diabetic drugs: A real life experience
  99. Identification of osteoporosis based on gene biomarkers using support vector machine
  100. Tanshinone IIA reverses oxaliplatin resistance in colorectal cancer through microRNA-30b-5p/AVEN axis
  101. miR-212-5p inhibits nasopharyngeal carcinoma progression by targeting METTL3
  102. Association of ST-T changes with all-cause mortality among patients with peripheral T-cell lymphomas
  103. LINC00665/miRNAs axis-mediated collagen type XI alpha 1 correlates with immune infiltration and malignant phenotypes in lung adenocarcinoma
  104. The perinatal factors that influence the excretion of fecal calprotectin in premature-born children
  105. Effect of femoral head necrosis cystic area on femoral head collapse and stress distribution in femoral head: A clinical and finite element study
  106. Does the use of 3D-printed cones give a chance to postpone the use of megaprostheses in patients with large bone defects in the knee joint?
  107. lncRNA HAGLR modulates myocardial ischemia–reperfusion injury in mice through regulating miR-133a-3p/MAPK1 axis
  108. Protective effect of ghrelin on intestinal I/R injury in rats
  109. In vivo knee kinematics of an innovative prosthesis design
  110. Relationship between the height of fibular head and the incidence and severity of knee osteoarthritis
  111. lncRNA WT1-AS attenuates hypoxia/ischemia-induced neuronal injury during cerebral ischemic stroke via miR-186-5p/XIAP axis
  112. Correlation of cardiac troponin T and APACHE III score with all-cause in-hospital mortality in critically ill patients with acute pulmonary embolism
  113. LncRNA LINC01857 reduces metastasis and angiogenesis in breast cancer cells via regulating miR-2052/CENPQ axis
  114. Endothelial cell-specific molecule 1 (ESM1) promoted by transcription factor SPI1 acts as an oncogene to modulate the malignant phenotype of endometrial cancer
  115. SELENBP1 inhibits progression of colorectal cancer by suppressing epithelial–mesenchymal transition
  116. Visfatin is negatively associated with coronary artery lesions in subjects with impaired fasting glucose
  117. Treatment and outcomes of mechanical complications of acute myocardial infarction during the Covid-19 era: A comparison with the pre-Covid-19 period. A systematic review and meta-analysis
  118. Neonatal stroke surveillance study protocol in the United Kingdom and Republic of Ireland
  119. Oncogenic role of TWF2 in human tumors: A pan-cancer analysis
  120. Mean corpuscular hemoglobin predicts the length of hospital stay independent of severity classification in patients with acute pancreatitis
  121. Association of gallstone and polymorphisms of UGT1A1*27 and UGT1A1*28 in patients with hepatitis B virus-related liver failure
  122. TGF-β1 upregulates Sar1a expression and induces procollagen-I secretion in hypertrophic scarring fibroblasts
  123. Antisense lncRNA PCNA-AS1 promotes esophageal squamous cell carcinoma progression through the miR-2467-3p/PCNA axis
  124. NK-cell dysfunction of acute myeloid leukemia in relation to the renin–angiotensin system and neurotransmitter genes
  125. The effect of dilution with glucose and prolonged injection time on dexamethasone-induced perineal irritation – A randomized controlled trial
  126. miR-146-5p restrains calcification of vascular smooth muscle cells by suppressing TRAF6
  127. Role of lncRNA MIAT/miR-361-3p/CCAR2 in prostate cancer cells
  128. lncRNA NORAD promotes lung cancer progression by competitively binding to miR-28-3p with E2F2
  129. Noninvasive diagnosis of AIH/PBC overlap syndrome based on prediction models
  130. lncRNA FAM230B is highly expressed in colorectal cancer and suppresses the maturation of miR-1182 to increase cell proliferation
  131. circ-LIMK1 regulates cisplatin resistance in lung adenocarcinoma by targeting miR-512-5p/HMGA1 axis
  132. LncRNA SNHG3 promoted cell proliferation, migration, and metastasis of esophageal squamous cell carcinoma via regulating miR-151a-3p/PFN2 axis
  133. Risk perception and affective state on work exhaustion in obstetrics during the COVID-19 pandemic
  134. lncRNA-AC130710/miR-129-5p/mGluR1 axis promote migration and invasion by activating PKCα-MAPK signal pathway in melanoma
  135. SNRPB promotes cell cycle progression in thyroid carcinoma via inhibiting p53
  136. Xylooligosaccharides and aerobic training regulate metabolism and behavior in rats with streptozotocin-induced type 1 diabetes
  137. Serpin family A member 1 is an oncogene in glioma and its translation is enhanced by NAD(P)H quinone dehydrogenase 1 through RNA-binding activity
  138. Silencing of CPSF7 inhibits the proliferation, migration, and invasion of lung adenocarcinoma cells by blocking the AKT/mTOR signaling pathway
  139. Ultrasound-guided lumbar plexus block versus transversus abdominis plane block for analgesia in children with hip dislocation: A double-blind, randomized trial
  140. Relationship of plasma MBP and 8-oxo-dG with brain damage in preterm
  141. Identification of a novel necroptosis-associated miRNA signature for predicting the prognosis in head and neck squamous cell carcinoma
  142. Delayed femoral vein ligation reduces operative time and blood loss during hip disarticulation in patients with extremity tumors
  143. The expression of ASAP3 and NOTCH3 and the clinicopathological characteristics of adult glioma patients
  144. Longitudinal analysis of factors related to Helicobacter pylori infection in Chinese adults
  145. HOXA10 enhances cell proliferation and suppresses apoptosis in esophageal cancer via activating p38/ERK signaling pathway
  146. Meta-analysis of early-life antibiotic use and allergic rhinitis
  147. Marital status and its correlation with age, race, and gender in prognosis of tonsil squamous cell carcinomas
  148. HPV16 E6E7 up-regulates KIF2A expression by activating JNK/c-Jun signal, is beneficial to migration and invasion of cervical cancer cells
  149. Amino acid profiles in the tissue and serum of patients with liver cancer
  150. Pain in critically ill COVID-19 patients: An Italian retrospective study
  151. Immunohistochemical distribution of Bcl-2 and p53 apoptotic markers in acetamiprid-induced nephrotoxicity
  152. Estradiol pretreatment in GnRH antagonist protocol for IVF/ICSI treatment
  153. Long non-coding RNAs LINC00689 inhibits the apoptosis of human nucleus pulposus cells via miR-3127-5p/ATG7 axis-mediated autophagy
  154. The relationship between oxygen therapy, drug therapy, and COVID-19 mortality
  155. Monitoring hypertensive disorders in pregnancy to prevent preeclampsia in pregnant women of advanced maternal age: Trial mimicking with retrospective data
  156. SETD1A promotes the proliferation and glycolysis of nasopharyngeal carcinoma cells by activating the PI3K/Akt pathway
  157. The role of Shunaoxin pills in the treatment of chronic cerebral hypoperfusion and its main pharmacodynamic components
  158. TET3 governs malignant behaviors and unfavorable prognosis of esophageal squamous cell carcinoma by activating the PI3K/AKT/GSK3β/β-catenin pathway
  159. Associations between morphokinetic parameters of temporary-arrest embryos and the clinical prognosis in FET cycles
  160. Long noncoding RNA WT1-AS regulates trophoblast proliferation, migration, and invasion via the microRNA-186-5p/CADM2 axis
  161. The incidence of bronchiectasis in chronic obstructive pulmonary disease
  162. Integrated bioinformatics analysis shows integrin alpha 3 is a prognostic biomarker for pancreatic cancer
  163. Inhibition of miR-21 improves pulmonary vascular responses in bronchopulmonary dysplasia by targeting the DDAH1/ADMA/NO pathway
  164. Comparison of hospitalized patients with severe pneumonia caused by COVID-19 and influenza A (H7N9 and H1N1): A retrospective study from a designated hospital
  165. lncRNA ZFAS1 promotes intervertebral disc degeneration by upregulating AAK1
  166. Pathological characteristics of liver injury induced by N,N-dimethylformamide: From humans to animal models
  167. lncRNA ELFN1-AS1 enhances the progression of colon cancer by targeting miR-4270 to upregulate AURKB
  168. DARS-AS1 modulates cell proliferation and migration of gastric cancer cells by regulating miR-330-3p/NAT10 axis
  169. Dezocine inhibits cell proliferation, migration, and invasion by targeting CRABP2 in ovarian cancer
  170. MGST1 alleviates the oxidative stress of trophoblast cells induced by hypoxia/reoxygenation and promotes cell proliferation, migration, and invasion by activating the PI3K/AKT/mTOR pathway
  171. Bifidobacterium lactis Probio-M8 ameliorated the symptoms of type 2 diabetes mellitus mice by changing ileum FXR-CYP7A1
  172. circRNA DENND1B inhibits tumorigenicity of clear cell renal cell carcinoma via miR-122-5p/TIMP2 axis
  173. EphA3 targeted by miR-3666 contributes to melanoma malignancy via activating ERK1/2 and p38 MAPK pathways
  174. Pacemakers and methylprednisolone pulse therapy in immune-related myocarditis concomitant with complete heart block
  175. miRNA-130a-3p targets sphingosine-1-phosphate receptor 1 to activate the microglial and astrocytes and to promote neural injury under the high glucose condition
  176. Review Articles
  177. Current management of cancer pain in Italy: Expert opinion paper
  178. Hearing loss and brain disorders: A review of multiple pathologies
  179. The rationale for using low-molecular weight heparin in the therapy of symptomatic COVID-19 patients
  180. Amyotrophic lateral sclerosis and delayed onset muscle soreness in light of the impaired blink and stretch reflexes – watch out for Piezo2
  181. Interleukin-35 in autoimmune dermatoses: Current concepts
  182. Recent discoveries in microbiota dysbiosis, cholangiocytic factors, and models for studying the pathogenesis of primary sclerosing cholangitis
  183. Advantages of ketamine in pediatric anesthesia
  184. Congenital adrenal hyperplasia. Role of dentist in early diagnosis
  185. Migraine management: Non-pharmacological points for patients and health care professionals
  186. Atherogenic index of plasma and coronary artery disease: A systematic review
  187. Physiological and modulatory role of thioredoxins in the cellular function
  188. Case Reports
  189. Intrauterine Bakri balloon tamponade plus cervical cerclage for the prevention and treatment of postpartum haemorrhage in late pregnancy complicated with acute aortic dissection: Case series
  190. A case of successful pembrolizumab monotherapy in a patient with advanced lung adenocarcinoma: Use of multiple biomarkers in combination for clinical practice
  191. Unusual neurological manifestations of bilateral medial medullary infarction: A case report
  192. Atypical symptoms of malignant hyperthermia: A rare causative mutation in the RYR1 gene
  193. A case report of dermatomyositis with the missed diagnosis of non-small cell lung cancer and concurrence of pulmonary tuberculosis
  194. A rare case of endometrial polyp complicated with uterine inversion: A case report and clinical management
  195. Spontaneous rupturing of splenic artery aneurysm: Another reason for fatal syncope and shock (Case report and literature review)
  196. Fungal infection mimicking COVID-19 infection – A case report
  197. Concurrent aspergillosis and cystic pulmonary metastases in a patient with tongue squamous cell carcinoma
  198. Paraganglioma-induced inverted takotsubo-like cardiomyopathy leading to cardiogenic shock successfully treated with extracorporeal membrane oxygenation
  199. Lineage switch from lymphoma to myeloid neoplasms: First case series from a single institution
  200. Trismus during tracheal extubation as a complication of general anaesthesia – A case report
  201. Simultaneous treatment of a pubovesical fistula and lymph node metastasis secondary to multimodal treatment for prostate cancer: Case report and review of the literature
  202. Two case reports of skin vasculitis following the COVID-19 immunization
  203. Ureteroiliac fistula after oncological surgery: Case report and review of the literature
  204. Synchronous triple primary malignant tumours in the bladder, prostate, and lung harbouring TP53 and MEK1 mutations accompanied with severe cardiovascular diseases: A case report
  205. Huge mucinous cystic neoplasms with adhesion to the left colon: A case report and literature review
  206. Commentary
  207. Commentary on “Clinicopathological features of programmed cell death-ligand 1 expression in patients with oral squamous cell carcinoma”
  208. Rapid Communication
  209. COVID-19 fear, post-traumatic stress, growth, and the role of resilience
  210. Erratum
  211. Erratum to “Tollip promotes hepatocellular carcinoma progression via PI3K/AKT pathway”
  212. Erratum to “Effect of femoral head necrosis cystic area on femoral head collapse and stress distribution in femoral head: A clinical and finite element study”
  213. Erratum to “lncRNA NORAD promotes lung cancer progression by competitively binding to miR-28-3p with E2F2”
  214. Retraction
  215. Expression and role of ABIN1 in sepsis: In vitro and in vivo studies
  216. Retraction to “miR-519d downregulates LEP expression to inhibit preeclampsia development”
  217. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part II
  218. Usefulness of close surveillance for rectal cancer patients after neoadjuvant chemoradiotherapy
https://doi.org/10.1515/med-2021-0407
Keywords for this article
colorectal neoplasms; diabetes mellitus; type 2; interleukin-6; thrombocytosis; thrombopoietin
Creative Commons
BY 4.0

Articles in the same Issue

  1. Research Articles
  2. AMBRA1 attenuates the proliferation of uveal melanoma cells
  3. A ceRNA network mediated by LINC00475 in papillary thyroid carcinoma
  4. Differences in complications between hepatitis B-related cirrhosis and alcohol-related cirrhosis
  5. Effect of gestational diabetes mellitus on lipid profile: A systematic review and meta-analysis
  6. Long noncoding RNA NR2F1-AS1 stimulates the tumorigenic behavior of non-small cell lung cancer cells by sponging miR-363-3p to increase SOX4
  7. Promising novel biomarkers and candidate small-molecule drugs for lung adenocarcinoma: Evidence from bioinformatics analysis of high-throughput data
  8. Plasmapheresis: Is it a potential alternative treatment for chronic urticaria?
  9. The biomarkers of key miRNAs and gene targets associated with extranodal NK/T-cell lymphoma
  10. Gene signature to predict prognostic survival of hepatocellular carcinoma
  11. Effects of miRNA-199a-5p on cell proliferation and apoptosis of uterine leiomyoma by targeting MED12
  12. Does diabetes affect paraneoplastic thrombocytosis in colorectal cancer?
  13. Is there any effect on imprinted genes H19, PEG3, and SNRPN during AOA?
  14. Leptin and PCSK9 concentrations are associated with vascular endothelial cytokines in patients with stable coronary heart disease
  15. Pericentric inversion of chromosome 6 and male fertility problems
  16. Staple line reinforcement with nebulized cyanoacrylate glue in laparoscopic sleeve gastrectomy: A propensity score-matched study
  17. Retrospective analysis of crescent score in clinical prognosis of IgA nephropathy
  18. Expression of DNM3 is associated with good outcome in colorectal cancer
  19. Activation of SphK2 contributes to adipocyte-induced EOC cell proliferation
  20. CRRT influences PICCO measurements in febrile critically ill patients
  21. SLCO4A1-AS1 mediates pancreatic cancer development via miR-4673/KIF21B axis
  22. lncRNA ACTA2-AS1 inhibits malignant phenotypes of gastric cancer cells
  23. circ_AKT3 knockdown suppresses cisplatin resistance in gastric cancer
  24. Prognostic value of nicotinamide N-methyltransferase in human cancers: Evidence from a meta-analysis and database validation
  25. GPC2 deficiency inhibits cell growth and metastasis in colon adenocarcinoma
  26. A pan-cancer analysis of the oncogenic role of Holliday junction recognition protein in human tumors
  27. Radiation increases COL1A1, COL3A1, and COL1A2 expression in breast cancer
  28. Association between preventable risk factors and metabolic syndrome
  29. miR-29c-5p knockdown reduces inflammation and blood–brain barrier disruption by upregulating LRP6
  30. Cardiac contractility modulation ameliorates myocardial metabolic remodeling in a rabbit model of chronic heart failure through activation of AMPK and PPAR-α pathway
  31. Quercitrin protects human bronchial epithelial cells from oxidative damage
  32. Smurf2 suppresses the metastasis of hepatocellular carcinoma via ubiquitin degradation of Smad2
  33. circRNA_0001679/miR-338-3p/DUSP16 axis aggravates acute lung injury
  34. Sonoclot’s usefulness in prediction of cardiopulmonary arrest prognosis: A proof of concept study
  35. Four drug metabolism-related subgroups of pancreatic adenocarcinoma in prognosis, immune infiltration, and gene mutation
  36. Decreased expression of miR-195 mediated by hypermethylation promotes osteosarcoma
  37. LMO3 promotes proliferation and metastasis of papillary thyroid carcinoma cells by regulating LIMK1-mediated cofilin and the β-catenin pathway
  38. Cx43 upregulation in HUVECs under stretch via TGF-β1 and cytoskeletal network
  39. Evaluation of menstrual irregularities after COVID-19 vaccination: Results of the MECOVAC survey
  40. Histopathologic findings on removed stomach after sleeve gastrectomy. Do they influence the outcome?
  41. Analysis of the expression and prognostic value of MT1-MMP, β1-integrin and YAP1 in glioma
  42. Optimal diagnosis of the skin cancer using a hybrid deep neural network and grasshopper optimization algorithm
  43. miR-223-3p alleviates TGF-β-induced epithelial-mesenchymal transition and extracellular matrix deposition by targeting SP3 in endometrial epithelial cells
  44. Clinical value of SIRT1 as a prognostic biomarker in esophageal squamous cell carcinoma, a systematic meta-analysis
  45. circ_0020123 promotes cell proliferation and migration in lung adenocarcinoma via PDZD8
  46. miR-22-5p regulates the self-renewal of spermatogonial stem cells by targeting EZH2
  47. hsa-miR-340-5p inhibits epithelial–mesenchymal transition in endometriosis by targeting MAP3K2 and inactivating MAPK/ERK signaling
  48. circ_0085296 inhibits the biological functions of trophoblast cells to promote the progression of preeclampsia via the miR-942-5p/THBS2 network
  49. TCD hemodynamics findings in the subacute phase of anterior circulation stroke patients treated with mechanical thrombectomy
  50. Development of a risk-stratification scoring system for predicting risk of breast cancer based on non-alcoholic fatty liver disease, non-alcoholic fatty pancreas disease, and uric acid
  51. Tollip promotes hepatocellular carcinoma progression via PI3K/AKT pathway
  52. circ_0062491 alleviates periodontitis via the miR-142-5p/IGF1 axis
  53. Human amniotic fluid as a source of stem cells
  54. lncRNA NONRATT013819.2 promotes transforming growth factor-β1-induced myofibroblastic transition of hepatic stellate cells by miR24-3p/lox
  55. NORAD modulates miR-30c-5p-LDHA to protect lung endothelial cells damage
  56. Idiopathic pulmonary fibrosis telemedicine management during COVID-19 outbreak
  57. Risk factors for adverse drug reactions associated with clopidogrel therapy
  58. Serum zinc associated with immunity and inflammatory markers in Covid-19
  59. The relationship between night shift work and breast cancer incidence: A systematic review and meta-analysis of observational studies
  60. LncRNA expression in idiopathic achalasia: New insight and preliminary exploration into pathogenesis
  61. Notoginsenoside R1 alleviates spinal cord injury through the miR-301a/KLF7 axis to activate Wnt/β-catenin pathway
  62. Moscatilin suppresses the inflammation from macrophages and T cells
  63. Zoledronate promotes ECM degradation and apoptosis via Wnt/β-catenin
  64. Epithelial-mesenchymal transition-related genes in coronary artery disease
  65. The effect evaluation of traditional vaginal surgery and transvaginal mesh surgery for severe pelvic organ prolapse: 5 years follow-up
  66. Repeated partial splenic artery embolization for hypersplenism improves platelet count
  67. Low expression of miR-27b in serum exosomes of non-small cell lung cancer facilitates its progression by affecting EGFR
  68. Exosomal hsa_circ_0000519 modulates the NSCLC cell growth and metastasis via miR-1258/RHOV axis
  69. miR-455-5p enhances 5-fluorouracil sensitivity in colorectal cancer cells by targeting PIK3R1 and DEPDC1
  70. The effect of tranexamic acid on the reduction of intraoperative and postoperative blood loss and thromboembolic risk in patients with hip fracture
  71. Isocitrate dehydrogenase 1 mutation in cholangiocarcinoma impairs tumor progression by sensitizing cells to ferroptosis
  72. Artemisinin protects against cerebral ischemia and reperfusion injury via inhibiting the NF-κB pathway
  73. A 16-gene signature associated with homologous recombination deficiency for prognosis prediction in patients with triple-negative breast cancer
  74. Lidocaine ameliorates chronic constriction injury-induced neuropathic pain through regulating M1/M2 microglia polarization
  75. MicroRNA 322-5p reduced neuronal inflammation via the TLR4/TRAF6/NF-κB axis in a rat epilepsy model
  76. miR-1273h-5p suppresses CXCL12 expression and inhibits gastric cancer cell invasion and metastasis
  77. Clinical characteristics of pneumonia patients of long course of illness infected with SARS-CoV-2
  78. circRNF20 aggravates the malignancy of retinoblastoma depending on the regulation of miR-132-3p/PAX6 axis
  79. Linezolid for resistant Gram-positive bacterial infections in children under 12 years: A meta-analysis
  80. Rack1 regulates pro-inflammatory cytokines by NF-κB in diabetic nephropathy
  81. Comprehensive analysis of molecular mechanism and a novel prognostic signature based on small nuclear RNA biomarkers in gastric cancer patients
  82. Smog and risk of maternal and fetal birth outcomes: A retrospective study in Baoding, China
  83. Let-7i-3p inhibits the cell cycle, proliferation, invasion, and migration of colorectal cancer cells via downregulating CCND1
  84. β2-Adrenergic receptor expression in subchondral bone of patients with varus knee osteoarthritis
  85. Possible impact of COVID-19 pandemic and lockdown on suicide behavior among patients in Southeast Serbia
  86. In vitro antimicrobial activity of ozonated oil in liposome eyedrop against multidrug-resistant bacteria
  87. Potential biomarkers for inflammatory response in acute lung injury
  88. A low serum uric acid concentration predicts a poor prognosis in adult patients with candidemia
  89. Antitumor activity of recombinant oncolytic vaccinia virus with human IL2
  90. ALKBH5 inhibits TNF-α-induced apoptosis of HUVECs through Bcl-2 pathway
  91. Risk prediction of cardiovascular disease using machine learning classifiers
  92. Value of ultrasonography parameters in diagnosing polycystic ovary syndrome
  93. Bioinformatics analysis reveals three key genes and four survival genes associated with youth-onset NSCLC
  94. Identification of autophagy-related biomarkers in patients with pulmonary arterial hypertension based on bioinformatics analysis
  95. Protective effects of glaucocalyxin A on the airway of asthmatic mice
  96. Overexpression of miR-100-5p inhibits papillary thyroid cancer progression via targeting FZD8
  97. Bioinformatics-based analysis of SUMOylation-related genes in hepatocellular carcinoma reveals a role of upregulated SAE1 in promoting cell proliferation
  98. Effectiveness and clinical benefits of new anti-diabetic drugs: A real life experience
  99. Identification of osteoporosis based on gene biomarkers using support vector machine
  100. Tanshinone IIA reverses oxaliplatin resistance in colorectal cancer through microRNA-30b-5p/AVEN axis
  101. miR-212-5p inhibits nasopharyngeal carcinoma progression by targeting METTL3
  102. Association of ST-T changes with all-cause mortality among patients with peripheral T-cell lymphomas
  103. LINC00665/miRNAs axis-mediated collagen type XI alpha 1 correlates with immune infiltration and malignant phenotypes in lung adenocarcinoma
  104. The perinatal factors that influence the excretion of fecal calprotectin in premature-born children
  105. Effect of femoral head necrosis cystic area on femoral head collapse and stress distribution in femoral head: A clinical and finite element study
  106. Does the use of 3D-printed cones give a chance to postpone the use of megaprostheses in patients with large bone defects in the knee joint?
  107. lncRNA HAGLR modulates myocardial ischemia–reperfusion injury in mice through regulating miR-133a-3p/MAPK1 axis
  108. Protective effect of ghrelin on intestinal I/R injury in rats
  109. In vivo knee kinematics of an innovative prosthesis design
  110. Relationship between the height of fibular head and the incidence and severity of knee osteoarthritis
  111. lncRNA WT1-AS attenuates hypoxia/ischemia-induced neuronal injury during cerebral ischemic stroke via miR-186-5p/XIAP axis
  112. Correlation of cardiac troponin T and APACHE III score with all-cause in-hospital mortality in critically ill patients with acute pulmonary embolism
  113. LncRNA LINC01857 reduces metastasis and angiogenesis in breast cancer cells via regulating miR-2052/CENPQ axis
  114. Endothelial cell-specific molecule 1 (ESM1) promoted by transcription factor SPI1 acts as an oncogene to modulate the malignant phenotype of endometrial cancer
  115. SELENBP1 inhibits progression of colorectal cancer by suppressing epithelial–mesenchymal transition
  116. Visfatin is negatively associated with coronary artery lesions in subjects with impaired fasting glucose
  117. Treatment and outcomes of mechanical complications of acute myocardial infarction during the Covid-19 era: A comparison with the pre-Covid-19 period. A systematic review and meta-analysis
  118. Neonatal stroke surveillance study protocol in the United Kingdom and Republic of Ireland
  119. Oncogenic role of TWF2 in human tumors: A pan-cancer analysis
  120. Mean corpuscular hemoglobin predicts the length of hospital stay independent of severity classification in patients with acute pancreatitis
  121. Association of gallstone and polymorphisms of UGT1A1*27 and UGT1A1*28 in patients with hepatitis B virus-related liver failure
  122. TGF-β1 upregulates Sar1a expression and induces procollagen-I secretion in hypertrophic scarring fibroblasts
  123. Antisense lncRNA PCNA-AS1 promotes esophageal squamous cell carcinoma progression through the miR-2467-3p/PCNA axis
  124. NK-cell dysfunction of acute myeloid leukemia in relation to the renin–angiotensin system and neurotransmitter genes
  125. The effect of dilution with glucose and prolonged injection time on dexamethasone-induced perineal irritation – A randomized controlled trial
  126. miR-146-5p restrains calcification of vascular smooth muscle cells by suppressing TRAF6
  127. Role of lncRNA MIAT/miR-361-3p/CCAR2 in prostate cancer cells
  128. lncRNA NORAD promotes lung cancer progression by competitively binding to miR-28-3p with E2F2
  129. Noninvasive diagnosis of AIH/PBC overlap syndrome based on prediction models
  130. lncRNA FAM230B is highly expressed in colorectal cancer and suppresses the maturation of miR-1182 to increase cell proliferation
  131. circ-LIMK1 regulates cisplatin resistance in lung adenocarcinoma by targeting miR-512-5p/HMGA1 axis
  132. LncRNA SNHG3 promoted cell proliferation, migration, and metastasis of esophageal squamous cell carcinoma via regulating miR-151a-3p/PFN2 axis
  133. Risk perception and affective state on work exhaustion in obstetrics during the COVID-19 pandemic
  134. lncRNA-AC130710/miR-129-5p/mGluR1 axis promote migration and invasion by activating PKCα-MAPK signal pathway in melanoma
  135. SNRPB promotes cell cycle progression in thyroid carcinoma via inhibiting p53
  136. Xylooligosaccharides and aerobic training regulate metabolism and behavior in rats with streptozotocin-induced type 1 diabetes
  137. Serpin family A member 1 is an oncogene in glioma and its translation is enhanced by NAD(P)H quinone dehydrogenase 1 through RNA-binding activity
  138. Silencing of CPSF7 inhibits the proliferation, migration, and invasion of lung adenocarcinoma cells by blocking the AKT/mTOR signaling pathway
  139. Ultrasound-guided lumbar plexus block versus transversus abdominis plane block for analgesia in children with hip dislocation: A double-blind, randomized trial
  140. Relationship of plasma MBP and 8-oxo-dG with brain damage in preterm
  141. Identification of a novel necroptosis-associated miRNA signature for predicting the prognosis in head and neck squamous cell carcinoma
  142. Delayed femoral vein ligation reduces operative time and blood loss during hip disarticulation in patients with extremity tumors
  143. The expression of ASAP3 and NOTCH3 and the clinicopathological characteristics of adult glioma patients
  144. Longitudinal analysis of factors related to Helicobacter pylori infection in Chinese adults
  145. HOXA10 enhances cell proliferation and suppresses apoptosis in esophageal cancer via activating p38/ERK signaling pathway
  146. Meta-analysis of early-life antibiotic use and allergic rhinitis
  147. Marital status and its correlation with age, race, and gender in prognosis of tonsil squamous cell carcinomas
  148. HPV16 E6E7 up-regulates KIF2A expression by activating JNK/c-Jun signal, is beneficial to migration and invasion of cervical cancer cells
  149. Amino acid profiles in the tissue and serum of patients with liver cancer
  150. Pain in critically ill COVID-19 patients: An Italian retrospective study
  151. Immunohistochemical distribution of Bcl-2 and p53 apoptotic markers in acetamiprid-induced nephrotoxicity
  152. Estradiol pretreatment in GnRH antagonist protocol for IVF/ICSI treatment
  153. Long non-coding RNAs LINC00689 inhibits the apoptosis of human nucleus pulposus cells via miR-3127-5p/ATG7 axis-mediated autophagy
  154. The relationship between oxygen therapy, drug therapy, and COVID-19 mortality
  155. Monitoring hypertensive disorders in pregnancy to prevent preeclampsia in pregnant women of advanced maternal age: Trial mimicking with retrospective data
  156. SETD1A promotes the proliferation and glycolysis of nasopharyngeal carcinoma cells by activating the PI3K/Akt pathway
  157. The role of Shunaoxin pills in the treatment of chronic cerebral hypoperfusion and its main pharmacodynamic components
  158. TET3 governs malignant behaviors and unfavorable prognosis of esophageal squamous cell carcinoma by activating the PI3K/AKT/GSK3β/β-catenin pathway
  159. Associations between morphokinetic parameters of temporary-arrest embryos and the clinical prognosis in FET cycles
  160. Long noncoding RNA WT1-AS regulates trophoblast proliferation, migration, and invasion via the microRNA-186-5p/CADM2 axis
  161. The incidence of bronchiectasis in chronic obstructive pulmonary disease
  162. Integrated bioinformatics analysis shows integrin alpha 3 is a prognostic biomarker for pancreatic cancer
  163. Inhibition of miR-21 improves pulmonary vascular responses in bronchopulmonary dysplasia by targeting the DDAH1/ADMA/NO pathway
  164. Comparison of hospitalized patients with severe pneumonia caused by COVID-19 and influenza A (H7N9 and H1N1): A retrospective study from a designated hospital
  165. lncRNA ZFAS1 promotes intervertebral disc degeneration by upregulating AAK1
  166. Pathological characteristics of liver injury induced by N,N-dimethylformamide: From humans to animal models
  167. lncRNA ELFN1-AS1 enhances the progression of colon cancer by targeting miR-4270 to upregulate AURKB
  168. DARS-AS1 modulates cell proliferation and migration of gastric cancer cells by regulating miR-330-3p/NAT10 axis
  169. Dezocine inhibits cell proliferation, migration, and invasion by targeting CRABP2 in ovarian cancer
  170. MGST1 alleviates the oxidative stress of trophoblast cells induced by hypoxia/reoxygenation and promotes cell proliferation, migration, and invasion by activating the PI3K/AKT/mTOR pathway
  171. Bifidobacterium lactis Probio-M8 ameliorated the symptoms of type 2 diabetes mellitus mice by changing ileum FXR-CYP7A1
  172. circRNA DENND1B inhibits tumorigenicity of clear cell renal cell carcinoma via miR-122-5p/TIMP2 axis
  173. EphA3 targeted by miR-3666 contributes to melanoma malignancy via activating ERK1/2 and p38 MAPK pathways
  174. Pacemakers and methylprednisolone pulse therapy in immune-related myocarditis concomitant with complete heart block
  175. miRNA-130a-3p targets sphingosine-1-phosphate receptor 1 to activate the microglial and astrocytes and to promote neural injury under the high glucose condition
  176. Review Articles
  177. Current management of cancer pain in Italy: Expert opinion paper
  178. Hearing loss and brain disorders: A review of multiple pathologies
  179. The rationale for using low-molecular weight heparin in the therapy of symptomatic COVID-19 patients
  180. Amyotrophic lateral sclerosis and delayed onset muscle soreness in light of the impaired blink and stretch reflexes – watch out for Piezo2
  181. Interleukin-35 in autoimmune dermatoses: Current concepts
  182. Recent discoveries in microbiota dysbiosis, cholangiocytic factors, and models for studying the pathogenesis of primary sclerosing cholangitis
  183. Advantages of ketamine in pediatric anesthesia
  184. Congenital adrenal hyperplasia. Role of dentist in early diagnosis
  185. Migraine management: Non-pharmacological points for patients and health care professionals
  186. Atherogenic index of plasma and coronary artery disease: A systematic review
  187. Physiological and modulatory role of thioredoxins in the cellular function
  188. Case Reports
  189. Intrauterine Bakri balloon tamponade plus cervical cerclage for the prevention and treatment of postpartum haemorrhage in late pregnancy complicated with acute aortic dissection: Case series
  190. A case of successful pembrolizumab monotherapy in a patient with advanced lung adenocarcinoma: Use of multiple biomarkers in combination for clinical practice
  191. Unusual neurological manifestations of bilateral medial medullary infarction: A case report
  192. Atypical symptoms of malignant hyperthermia: A rare causative mutation in the RYR1 gene
  193. A case report of dermatomyositis with the missed diagnosis of non-small cell lung cancer and concurrence of pulmonary tuberculosis
  194. A rare case of endometrial polyp complicated with uterine inversion: A case report and clinical management
  195. Spontaneous rupturing of splenic artery aneurysm: Another reason for fatal syncope and shock (Case report and literature review)
  196. Fungal infection mimicking COVID-19 infection – A case report
  197. Concurrent aspergillosis and cystic pulmonary metastases in a patient with tongue squamous cell carcinoma
  198. Paraganglioma-induced inverted takotsubo-like cardiomyopathy leading to cardiogenic shock successfully treated with extracorporeal membrane oxygenation
  199. Lineage switch from lymphoma to myeloid neoplasms: First case series from a single institution
  200. Trismus during tracheal extubation as a complication of general anaesthesia – A case report
  201. Simultaneous treatment of a pubovesical fistula and lymph node metastasis secondary to multimodal treatment for prostate cancer: Case report and review of the literature
  202. Two case reports of skin vasculitis following the COVID-19 immunization
  203. Ureteroiliac fistula after oncological surgery: Case report and review of the literature
  204. Synchronous triple primary malignant tumours in the bladder, prostate, and lung harbouring TP53 and MEK1 mutations accompanied with severe cardiovascular diseases: A case report
  205. Huge mucinous cystic neoplasms with adhesion to the left colon: A case report and literature review
  206. Commentary
  207. Commentary on “Clinicopathological features of programmed cell death-ligand 1 expression in patients with oral squamous cell carcinoma”
  208. Rapid Communication
  209. COVID-19 fear, post-traumatic stress, growth, and the role of resilience
  210. Erratum
  211. Erratum to “Tollip promotes hepatocellular carcinoma progression via PI3K/AKT pathway”
  212. Erratum to “Effect of femoral head necrosis cystic area on femoral head collapse and stress distribution in femoral head: A clinical and finite element study”
  213. Erratum to “lncRNA NORAD promotes lung cancer progression by competitively binding to miR-28-3p with E2F2”
  214. Retraction
  215. Expression and role of ABIN1 in sepsis: In vitro and in vivo studies
  216. Retraction to “miR-519d downregulates LEP expression to inhibit preeclampsia development”
  217. Special Issue Computational Intelligence Methodologies Meets Recurrent Cancers - Part II
  218. Usefulness of close surveillance for rectal cancer patients after neoadjuvant chemoradiotherapy
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