Cancer Diagnostics in the Era of Precision Medicine

Advanced diagnostic pathology techniques have become increasingly necessary in the treatment of both cancer and non-neoplastic diseases, as targeted therapy has gained importance in recent years. This emphasizes the importance of developing and utilizing precise diagnostic techniques to identify potential targets for targeted therapy

In Silico Analysis of Differentially Expressed Genes in Colorectal Carcinoma

Background: Colorectal carcinoma (CRC) is a primary cause of morbidity and mortality worldwide. Resistance to therapy contributes to poor patient prognosis. The aim of our study is to identify the key proteins and interaction networks implicated in CRC which may serve as possible therapeutic targets and help in overcoming therapy resistance.Methods: The microarray dataset of 58 cases and 62 controls was used to identify Differentially Expressed Genes (DEGs).After constructing protein-protein interaction networks , Cytoscape analysis was done to identify the hub proteins. Based on sub graph centrality, between-ness and degree (≥10), hub proteins were selected for further literature search and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis.Results: A total of 85 up-regulated genes and 95 down-regulated genes of CRC patients were selected based on criteria of P>0.05 and fold change>2.0. The PPI analysis revealed STAT3, HNRNPA2B1, RBM8A, RBM25, ATM, HIST1H2BK, SRSF5 and HNRNPDLas hub proteins. On the basis of criteria set for cytoscape analysis, STAT3 and HNRNPA2B1 were identified as key hub proteins. KEGG pathway analysis revealed vital role of STAT3 in carcinogenesis.Conclusion: In addition of HNRNPA2B1 activation by STAT3, cross talk of STAT3 with other oncogenic signaling pathways signifies its role in colorectal carcinogenesis. Our study highlights thatSTAT3may be a possible therapeutic target which may help in overcoming the dilemma of resistance to drug treatment in advanced cases.Keywords: STAT3, drug resistance, targeted therapy, bioinformatics    

Predisposing Deleterious Variants in the Cancer-Associated Human Kinases in the Global Populations

Human kinases play essential and diverse roles in the cellular activities of maintaining homeostasis and growth. Genetic mutations in the genes encoding the kinases (or phosphotransferases) have been linked with various types of cancers. In this study, we cataloged mutations in 500 kinases genes in \u3e65,000 individuals of global populations from the Human Genetic Diversity Project (HGDP) and ExAC databases, and assessed their potentially deleterious impact by using the in silico tools SIFT, Polyphen2, and CADD. The analysis highlighted 35 deleterious non-synonymous SNVs in the ExAC and 5 SNVs in the HGDP project. Notably, a higher number of deleterious mutations was observed in the Non-Finnish Europeans (26 SNVs), followed by the Africans (14 SNVs), East Asians (13 SNVs), and South Asians (12 SNVs). The gene set enrichment analysis highlighted NTRK1 and FGFR3 being most significantly enriched among the kinases. The gene expression analysis revealed over-expression of NTRK1 in liver cancer, whereas, FGFR3 was found over-expressed in lung, breast, and liver cancers compared to their expression in the respective normal tissues. Also, 13 potential drugs were identified that target the NTRK1 protein, whereas 6 potential drugs for the FGFR3 target were identified. Taken together, the study provides a framework for exploring the predisposing germline mutations in kinases to suggest the underlying pathogenic mechanisms in cancers. The potential drugs are also suggested for personalized cancer management

Misoprostol for non-alcoholic steatohepatitis: a randomised control trial

Introduction The management of non-alcoholic steatohepatitis (NASH) is an unmet clinical need. Misoprostol, a structural analogue of naturally occurring prostaglandin E1, has been reported to decrease proinflammatory cytokine production and may have a potential role in treating NASH. We aimed to evaluate the efficacy and safety of misoprostol in treating patients with NASH.Methods In this phase 2, double-blind, randomised, placebo-controlled trial, patients with NASH were randomly assigned in a 1:1 ratio to receive 200 µg of misoprostol or placebo thrice daily for 2 months. The primary endpoint was an improvement in liver function tests (LFTs), interleukin-6 (IL-6) and endotoxin levels. The secondary endpoint was improvement in insulin resistance, dyslipidaemia, hepatic fibrosis and hepatic steatosis.Results A total of 50 patients underwent randomisation, of whom 44 (88%) were males. The age range was 25–64 years (mean±SE of mean (SEM) 38.1±1.4). 19 (38%) patients had concomitant type 2 diabetes mellitus. 32 (64%) patients were either overweight or obese. At the end of 2 months’ treatment, a reduction in total leucocyte count (TLC) (p=0.005), alanine aminotransferase (ALT) (p<0.001), aspartate aminotransferase (AST) (p=0.002) and controlled attenuation parameter (CAP) (p=0.003) was observed in the misoprostol group, whereas placebo ensued a decline in ALT (p<0.001), AST (p=0.018), gamma-glutamyl transferase (GGT) (p=0.003), CAP (p=0.010) and triglycerides (p=0.048). There was no diminution in insulin resistance, hepatic fibrosis (elastography) and dyslipidaemia in both groups. However, misoprostol resulted in a significant reduction in CAP as compared with the placebo group (p=0.039). Moreover, in the misoprostol group, pretreatment and post-treatment IL-6 and endotoxin levels remained stable, while in the placebo group, an increase in the IL-6 levels was noted (p=0.049). Six (12%) patients had at least one adverse event in the misoprostol group, as did five (10%) in the placebo group. The most common adverse event in the misoprostol group was diarrhoea. No life-threatening events or treatment-related deaths occurred in each group.Conclusion Improvement in the biochemical profile was seen in both misoprostol and placebo groups without any statistically significant difference. However, there was more improvement in steatosis, as depicted by CAP, in the misoprostol group and worsening of IL-6 levels in the placebo group.Trial registration number NCT05804305

Prevalence Of Blood Groups And Association With Ailments In Pakistani Population: A Review of The Current Literature

The aim of this review is to report studies performed in Pakistan on the prevalence of blood groups among various sections of the population and their association with human diseases.  Google Scholar was searched for the last 20 years based on MESH keywords mentioned below. The inclusion criteria were the studies published in the new millennium that reported either prevalence of blood groups or their association with diseases in the Pakistani population. There were 50 studies in Pakistan which fulfill the inclusion criteria. Among them, twenty- six were from Punjab, seven were from Khyber Pakhtunkhwa (KpK), six from Sindh, four from Kashmir, two from Northern areas, one from Baluchistan and 4 are review articles. This review concludes that blood group B is prevalent among Pakistani population followed by O, A and AB. Studies done in Azad Jammu Kashmir (AJK) and Gilgit- Baltistan reveal that B and A is prevalent in these areas respectively. AB is the least found group and Rh+ve is common among all studies. Moreover, this review also shows that blood groups act as a risk factor for many diseases. Therefore, Pakistani researchers are suggested to work on the genetic makeup of these blood groups to find out the cause of association with systemic ailments in the country

Inflammatory markers and COVID-19 disease progression

Background: The COVID-19 pandemic has resulted in a global humanitarian crisis. Despite ongoing research, transmission risks and many disease characteristics remained unclear. Most patients have displayed elevated levels of certain inflammatory markers, which we sought to investigate further in relation to disease severity. The aim of this study was to examine the correlation between inflammatory markers and the severity of COVID-19 among patients. Methods: We conducted a cross-sectional study from April to September 2020, involving 143 COVID-19 PCR-positive patients from Ziauddin Hospital. Electronic patient records provided data on demographics, clinical status, and laboratory results. Results: The majority of PCR-positive patients were elderly males with comorbidities such as diabetes and hypertension. Almost all patients exhibited increased levels of various inflammatory markers, with procalcitonin (97.2%) being the most common. Statistically significant differences were observed in the levels of TLC (p = 0.005), CRP (p = 0.001), LDH (p = 0.001), Ferritin (p = 0.001), D-dimer (p = 0.001), and procalcitonin (p = 0.028), in relation to COVID-19 severity. Conclusions: The data suggest a significant association between levels of inflammatory markers and COVID-19 severity. All markers, except procalcitonin, demonstrated a significant correlation with disease severity. These results could enhance our understanding of COVID-19 pathogenesis and help predict and manage severe cases

Request for change to authorship.

Human kinases play essential and diverse roles in the cellular activities of maintaining homeostasis and growth. Genetic mutations in the genes encoding the kinases (or phosphotransferases) have been linked with various types of cancers. In this study, we cataloged mutations in 500 kinases genes in >65,000 individuals of global populations from the Human Genetic Diversity Project (HGDP) and ExAC databases, and assessed their potentially deleterious impact by using the in silico tools SIFT, Polyphen2, and CADD. The analysis highlighted 35 deleterious non-synonymous SNVs in the ExAC and 5 SNVs in the HGDP project. Notably, a higher number of deleterious mutations was observed in the Non-Finnish Europeans (26 SNVs), followed by the Africans (14 SNVs), East Asians (13 SNVs), and South Asians (12 SNVs). The gene set enrichment analysis highlighted NTRK1 and FGFR3 being most significantly enriched among the kinases. The gene expression analysis revealed over-expression of NTRK1 in liver cancer, whereas, FGFR3 was found over-expressed in lung, breast, and liver cancers compared to their expression in the respective normal tissues. Also, 13 potential drugs were identified that target the NTRK1 protein, whereas 6 potential drugs for the FGFR3 target were identified. Taken together, the study provides a framework for exploring the predisposing germline mutations in kinases to suggest the underlying pathogenic mechanisms in cancers. The potential drugs are also suggested for personalized cancer management.</div

Gene ontology of the kinome genes.

Majority of the genes are involved in different cellular processes, biological regulation, metabolic processes, response to stimulus, and signaling. (DOCX)</p

List of drugs that target NTRK1.

Human kinases play essential and diverse roles in the cellular activities of maintaining homeostasis and growth. Genetic mutations in the genes encoding the kinases (or phosphotransferases) have been linked with various types of cancers. In this study, we cataloged mutations in 500 kinases genes in >65,000 individuals of global populations from the Human Genetic Diversity Project (HGDP) and ExAC databases, and assessed their potentially deleterious impact by using the in silico tools SIFT, Polyphen2, and CADD. The analysis highlighted 35 deleterious non-synonymous SNVs in the ExAC and 5 SNVs in the HGDP project. Notably, a higher number of deleterious mutations was observed in the Non-Finnish Europeans (26 SNVs), followed by the Africans (14 SNVs), East Asians (13 SNVs), and South Asians (12 SNVs). The gene set enrichment analysis highlighted NTRK1 and FGFR3 being most significantly enriched among the kinases. The gene expression analysis revealed over-expression of NTRK1 in liver cancer, whereas, FGFR3 was found over-expressed in lung, breast, and liver cancers compared to their expression in the respective normal tissues. Also, 13 potential drugs were identified that target the NTRK1 protein, whereas 6 potential drugs for the FGFR3 target were identified. Taken together, the study provides a framework for exploring the predisposing germline mutations in kinases to suggest the underlying pathogenic mechanisms in cancers. The potential drugs are also suggested for personalized cancer management.</div

Additional file 2 of Angiotensin-converting enzyme 2 (ACE2) polymorphisms and susceptibility of severe SARS-CoV-2 in a subset of Pakistani population

Supplementary Table 1: ACE2 haplotypes, haplotype frequency and permutation test for all haplotypes organized in block 1 and block