Discovery and development of Seliciclib. How systems biology approaches can lead to better drug performance

Seliciclib (R-Roscovitine) was identified as an inhibitor of CDKs and has undergone drug development and clinical testing as an anticancer agent. In this review, the authors describe the discovery of Seliciclib and give a brief summary of the biology of the CDKs Seliciclib inhibits. An overview of the published in vitro and in vivo work supporting the development as an anti-cancer agent, from in vitro experiments to animal model studies ending with a summary of the clinical trial results and trials underway is presented. In addition some potential non-oncology applications are explored and the potential mode of action of Seliciclib in these areas is described. Finally the authors argue that optimisation of the therapeutic effects of kinase inhibitors such as Seliciclib could be enhanced using a systems biology approach involving mathematical modelling of the molecular pathways regulating cell growth and division

MMP2 -1306C>T polymorphism in patients with COPD

The remodeling of the bronchial walls is an important process of the pathophysiology of COPD as the matrix metalloproteinase-2 (MMP-2) is shown to play an important role in this process. The aim of the current study was to elucidate the possible role of MMP2 -1306C>T promoter polymorphism as risk factor of COPD. We genotyped by PCR-RFLP 84 patients with COPD and 71 control individuals. The genotype, but not allele distribution, differed between COPD patients and controls (p=0.021 and 0.602, respectively). Carriers of the variant T allele (CT+TT) tended to have 1.64-fold higher risk for COPD (95% CI: 0.82-3.26, p=0.164) than those with CC genotype, as that risk was significant in the subset of older than 65 years individuals (OR=4.24, 95% CI:1.31-13.57, p=0.019). The risk for COPD of T carriers (CT+TT) was significant and even higher in the subset of older individuals (more than 65 years) and in those without diabetes as a co-morbidity. Patients with T genotypes had later onset of the disease (64.1±7.1 years) than those with CC genotype (59.7±9.5 years, p=0.045). In conclusion, our results suggest that the T genotypes of MMP2 -1306C>T SNP may determine a risk for COPD especially in advanced age

Effects of common functional MMP12 gene polymorphisms on PD in a Polish population

The present study investigated associations of two functional MMP12 polymorphisms with PD risk and cognitive impairment in PD. A total of 478 study subjects (241 PD and 237 age and sex matched controls) were included in the study. UPDRS score, Hoehn–Yahr staging and Schwab–England scale were used to assess motor abilities and activity during daily life. All patients were classified into groups with dementia (PDD, n=72) and without dementia (nPDD, n=159) based on the neuropsychological assessment. The two most common functional single nucleotide polymorphisms (SNPs) in MMP12 gene were determined using TaqMan real-time PCR assays. Frequencies of evaluated MMP12 rs2276109 alleles and genotypes were similar in PD and the controls, whereas rs652438G allele genotypes were significantly more frequent among healthy individuals (p=0.013, OR 0.47 (0.26–0.85). The rs2276109 and rs652438 allele and genotype frequencies were not associated with dementia in PD patients. The current results suggest that MMP12 rs652438 but not MMP12 rs2276109 may affect the risk for PD, as the minor G allele genotypes might be a protective factor

The Role of the Molecular Subtypes in the Prognosis of Breast Cancer Patients

BACKGROUND: Understanding the biology of the tumor, by dividing it into molecular subtypes, has made it possible to individualize the therapeutic approach in high-risk patients. AIM: We aimed to determine the importance of established molecular subtypes in the prognosis and the importance of disease-free and overall survival (OS) in patients with non-metastatic breast cancer. MATERIALS AND METHODS: We analyzed 94 patients with non-metastatic breast cancer for the period 2010–2018. The median follow-up time was 60 months. The mean age in the study group was 60.03 years (SD ± 10.52). According to the characteristics of the studied indicators, we divided the group into Luminal A (n-59 [62.7%]), Luminal B/HER2 (−) (n-2 [2.1%]), Luminal B/HER2 (+) (n-8 [8.5%]), HER2 overexpressing (n-3 [3.2%]), and triple-negative subtype (n-22 [23.5%]). In all patients in the study group, we analyzed the 5-year overall survival (OS) and disease-free survival (DFS) and referred it to molecular subtypes, lymphatic status, HER-2 status, the presence or absence of endocrine therapy for the follow-up period, tumor differentiation, and type of surgery. RESULTS: We observed the 5-year OS in 92% of patients identified as Luminal A; at 50% of Luminal B/HER2 (−) neg.; in 62.5% with Luminal B/HER2 (+), in 67% with HER2-overexpressing carcinoma; and in 66.7% of patients with triple-negative subtype. The total cancer-associated mortality rate in the analyzed period reached 15.9% (n = 15). Patients with mastectomy (p = 0.019, p = 0.027), positive axilla with more than 4 lymph node (LN) (p = 0.000; p = 0.000), and Luminal B/HER-2 (+) tumors (p = 0.004; p = 0.003) were the independent prognostic factors for worse DFS and OS in our study group. Histological differentiation and HER-2 expression were in unsatisfactory correlation (p = 0.077; p = 0.044 and p = 0.081; p = 0.055, respectively). CONCLUSION: Molecular subtypes are essential in the prognosis of breast cancer and maybe a criterion for an individualized therapeutic approach

Application of light microscopical and ultrastructural immunohistochemistry in the study of goblet cell carcinoid in the appendix

<p>Abstract</p> <p>Background</p> <p>Goblet cell carcinoids appear less frequently in the appendix than do other carcinoids. In the presented work a case with a goblet cell carcinoid of the appendix is described.</p> <p>Methods</p> <p>Routine histological and histochemical methods were employed, with a combination of histochemistry and immunohistochemistry on one section and light and electron microscopical immunohistochemisty on paraffin-embedded material, were applied to identify the type of the carcinoid and to reveal the fine structure of cell types in the tumour nests of the appendix.</p> <p>Results</p> <p>During the biopsy of a patient who had undergone appendectomy, an infiltration with clusters of goblet cells in the submucosa of the appendix was found. After a second operation of right-sided hemicolectomy, similar clusters of goblet cells were detected in the muscle layers of the caecum. After 18 months the patient died from cirrhosis and had not developed metastases or any recurrence. Immunohistochemically the serotonin-, somatostatin-, chromogranin A- and synaptophysin-positive endocrine cells were basally attached to mucin-secreting cells. The combined staining revealed simultaneously present endocrine cells (chromogranin-A-positive) and mucin-secreting cells (PAS- or alcian blue-positive). The ultrastructural immunohistochemistry showed that chromogranin A-positive cells had discoid and pleomorphic granules and were located in tumour nests or as single cells in the appendiceal wall.</p> <p>Conclusion</p> <p>The combined histochemical and immunohistochemical procedure and the ultrastructural immunohistochemistry on archival material could contribute in clarifying the diagnosis of goblet cell carcinoid.</p

The leukocyte telomere length, single nucleotide polymorphisms near TERC gene and risk of COPD

Chronic obstructive pulmonary disease (COPD) is characterized by irreversible airflow obstruction and is associated with chronic local and systemic inflammation and oxidative stress. The enhanced oxidative stress and inflammation have been reported to affect telomere length (TL). Furthermore, a number of SNPs at loci encoding the main components of the telomerase genes, TERT and TERC have been shown to correlate with TL. We aimed to explore the leukocyte TL and genotypes for single nucleotide polymorphisms, rs12696304 (C > G) and rs10936599 (C > T) near TERC in COPD cases and matched healthy controls using q-PCR technologies. Successful assessment of TL was performed for 91 patients and 88 controls. The patients had shorter TL (17919.36 ± 1203.01 bp) compared to controls (21 271.48 ± 1891.36 bp) although not significant (p = 0.137). The TL did not associate with the gender, age, spirometric indexes, smoking habits but tended to correlate negatively with BMI (Rho = − 0.215, p = 0.076) in the controls, but not in COPD patients. The genotype frequencies of the SNPs rs12696304 and rs10936599 were compared between patients and controls and the odds ratios (OR) for developing COPD were calculated. The carriers of the common homozygous (CC) genotypes of the SNPs had higher risk for COPD, compared to carriers of the variants alleles (rs12696304 CG+GG vs. CC; OR: 0.615, 95% CI [0.424–0.894], p = 0.011 and for rs10936599 CT+TT vs. CC OR = 0.668, 95% CI [0.457–0.976], p = 0.044). Analysis on the combined effects of the TERC rs12696304 (C > G) and rs10936599 (C > T) genotypes, CC/CC genotype combination was associated with higher risk for COPD (p < 0.0001) and marginally lower FEV1% pr. in patients with GOLD II (p = 0.052). There was no association between the SNP genotypes and TL. In summary, our results suggest that COPD patients may have shorter TL, and rs12696304 and rs10936599 near TERC may affect the risk of COPD independently of TL

Matrix metalloproteinases in COVID-19: underlying significance

AbstractThe role of matrix metalloproteinases (MMPs) in pathogenesis and severity of coronavirus disease 2019 (COVID-19) is under extensive exploration. MMPs are a family of extracellular proteases involved in a variety of physiological and pathological processes and conditions. The role of MMPs in COVID-19 stems from the pathogenesis resulting in the release of chemokines and pro-inflammatory markers which cause pulmonary oedema. In addition, the approaches to treatment of COVID-19 often are associated with some complications like acute lung injury due to extracellular matrix remodelling. In this respect, the aim of this review is to summarize, interpret and evaluate the significance of matrix metalloproteinases in SARS-CoV-2 infection in terms of the severity of the condition and delve into potential treatment from this perspective as well as highlighting the physiological and protective role of some MMPs

Possible Role of Serum Leptin as Biomarker in COPD

Leptin is one of the adipokines shown to exert a significant effect in respiratory diseases, including chronic obstructive pulmonary disease (COPD).The aim of the present study was to evaluate the possible role of serum leptin as biomarker in COPD.The serum leptin levels were assessed in 58 patents with stable COPD and 21 controls applying ELISA method.The leptin levels were higher, although not significantly, in COPD patients than in controls (221.52±24.28(SE) vs. 165.04±26.01 pg/ml, p=0.197). This tendency turned out significant when only females were compared (414.60±60.63 vs. 219.40±44.15 pg/ml, p=0.038). The levels of leptin were highly dependent on the BMI both in COPD patients (p<0.001) and in controls (p=0.024): they were the highest in obese individuals and decreased with reducing the BMI.In the COPD group, women had significantly higher leptin levels than men (p<0.0001) independent of the BMI. The non-smoking patients had significantly higher leptin levels than ex-smokers (p=0.007) and current smokers (p=0.007). In patients with BMI above 25, several associations were observed: patients with mild COPD had higher serum leptin level than those with severe or very severe COPD (p=0.038); the leptin levels correlated positively with FEV1% (r= 0.304, p=0.045) and FEV1/FVC ratio (I= 0.348, p=0.021), and tended to correlate negatively with ABCD GOLD groups (Rho=-0.300, p=0.043) and with the CAT points (Rho=-0.258, p=0.091); the leptin levels below 300 ng/ml determined 4.08-fold higher risk for more severe COPD.The results of our study confirm that the serum leptin levels depend significantly on the BMI and are interfered by gender and smoking habits. However, this adipokine cannot be used as a serum biomarker for distinguishing COPD patients, but its decrease might be associated with aggravation of the disease

The Leucocyte Telomere Length, GSTM1 and GSTT1 Null Genotypes and the Risk of Chronic Obstructive Pulmonary Disease

Chronic obstructive pulmonary disease (COPD) is characterized by chronic inflammation and oxidative stress both in the airways and blood and other organs. Elevated oxidative stress and inflammation have been reported to affect leucocyte telomere length (LTL). Glutathione S-transferase (GST) enzymes are a large family of xenobiotic-metabolizing enzymes that utilize different ROS products. We aimed to explore the link between GSTM1 and GSTT1 gene polymorphisms, LTL and COPD risk. For GSTM1, we genotyped 152 COPD patients and 131 non-affected controls; for GSTT1, we genotyped 149 COPD patients and 130 controls. We were able to assess TL for 91 patients and 88 controls. There was a significant difference in the GSTM1 null genotype frequency between the patients and controls (0.59 vs. 0.38, p &le; 0.000), but such was not found for GSTT1 (p = 0.192). When combining both polymorphisms, we obtained a significantly greater presence of at least one null genotype among patients (0.12 vs. 0.05, p = 0.027). An association between GSTT1 and LTL was not found. COPD patients carrying the GSTM1 null genotype had shorter telomeres compared to those carrying the non-null genotype (15,720 bp vs. 22,442 bp, p = 0.008); as for the controls, it was the opposite (31,354 bp vs. 17,800 bp, p = 0.020). The significance in both groups remained when combining GSTM1 and GSTT1 (COPD (at least one null) 16,409 bp vs. COPD (non-null) 22,092 bp, p = 0.029; control (at least one null) 29,666 bp vs. control (non-null) 16,370 bp, p = 0.027). The total glutathione level in GSTM1 non-null controls was higher compared to the null genotype (15.39 ng/mL vs. 5.53 ng/mL, p = 0.002). In COPD patients, we found no association (p = 0.301). In conclusion, according to our results, GSTM1, but not GSTT1, null genotypes might play a role in leucocyte telomere shortening, and thus be involved in the pathogenesis of COPD