Exploring the potential of EphA2 receptor signaling pathway: a comprehensive review in cancer treatment.

The protein encoded by the ephrin type-A receptor 2 (EphA2) gene is a member of the ephrin receptor subfamily of the receptor tyrosine kinase family (RTKs). Eph receptors play a significant role in various biological processes, particularly cancer progression, development, and pathogenesis. They have been observed to regulate cancer cell growth, migration, invasion, tumor development, invasiveness, angiogenesis, and metastasis. To target EphA2 activity, various molecular, genetic, biochemical, and pharmacological strategies have been extensively tested in laboratory cultures and animal models. Notably, drugs, such as dasatinib, initially designed to target the kinase family, have demonstrated an additional capability to target EphA2 activity. Additionally, a novel monoclonal antibody named EA5 has emerged as a promising option to counteract the effects of EphA2 overexpression and restore tamoxifen sensitivity in EphA2-transfected MCF-7 cells during in vitro experiments. This antibody mimicked the binding of Ephrin A to EphA2. These methods offer potential avenues for inhibiting EphA2 activity, which could significantly decelerate breast cancer progression and restore sensitivity to certain drugs. This review article comprehensively covers EphA2's involvement in multiple malignancies, including ovarian, colorectal, breast, lung, glioma, and melanoma. Furthermore, we discuss the structure of EphA2, the Eph-Ephrin signaling pathway, various EphA2 inhibitors, and the mechanisms of EphA2 degradation. This article provides an extensive overview of EphA2's vital role in different types of cancers and outlines potential therapeutic approaches to target EphA2, shedding light on the underlying molecular mechanisms that make it an attractive target for cancer treatment.

Expression levels of A disintegrin and metalloproteases (ADAMs), and Th17-related cytokines and their association with Helicobacter pylori infection in patients with gastroduodenal diseases.

Expression levels of A disintegrin and metalloproteases (ADAMs) (10 and 17) and Th17-related cytokines [interleukin (IL) 17A, IL-17F, IL-33, IL-23, IL-23R] were investigated by quantitative real time polymerase chain reaction in gastric biopsies of patients with different gastroduodenal pathologies in the presence and absence of Helicobacter pylori infection. Patients with gastric cancer (GC) (n = 70, intestinal-type 38 and diffuse type 32), peptic ulcer disease [n = 50, duodenal ulcer (DU) 16 and gastric ulcer (GU) 34] and functional dyspepsia (n = 120) were included in the study. Further, the expression levels of ADAMs and Th17 cytokines were correlated with H. pylori cytotoxin-associated genes pathogenicity island (cagPAI) status. Expression levels of ADAMs (10 and 17) and Th17-related cytokines (IL-17A, IL-23, IL-23R) were significantly higher in H. pylori-positive than in H. pylori-negative gastric biopsies. Significant increase in ADAM17 and Th17 cytokines (IL-17A and IL-23) expressions was observed in patients with GU and intestinal-type GC in the presence of H. pylori infection and in strains harbouring intact cagPAI. Expression levels of IL-17A, IL-23 and ADAM17 were strongly correlated with GU and intestinal-type GC and weakly with DU and diffuse-type GC in the presence of H. pylori infection. Higher expression levels of ADAM17 and Th17 cytokines (IL-17A and IL-23), and their strong correlation with GU and intestinal-type GC patients in the presence of H. pylori and its intact cagPAI status, suggest a possible role of strain specificity in the pathogenesis of these diseases.

Prevalence and species spectrum of both pulmonary and extrapulmonary nontuberculous mycobacteria isolates at a tertiary care center.

OBJECTIVE/BACKGROUND: Nontuberculous mycobacteria (NTM) infection associated with pulmonary and extrapulmonary disease has been increasing globally. Despite an increase in incidence rate of NTM infection, its prevalence, species diversity, and circulation pattern in India is largely unknown. This study sought to investigate the overall burden and diversity of NTM among both pulmonary and extrapulmonary clinical isolates from a Northern Indian population. METHODS: The study was conducted in the Department of Microbiology, from January 2013 to December 2015. A total of 4620 clinical samples were collected from patients suspected to have pulmonary and extrapulmonary tuberculosis. Preliminary diagnosis was performed using Ziehl-Neelsen staining followed by liquid culture in BacT/ALERT three-dimensional system. A total of 906 positive cultures obtained were differentiated as either NTM or Mycobacterium tuberculosis complex using a biochemical and MPT64 antigen test. Further identification of NTM species was confirmed with a line probe assay. RESULTS: Out of 906 cultures isolates, 263 (29.0%) were confirmed as NTM and 643 (71.0%) were identified as Mycobacterium tuberculosis complex. A total of 79.4% of the NTM were recovered from pulmonary and 18.2% from extrapulmonary specimens. The diversity of NTM species was high (13 species) and predominated by Mycobacterium abscessus (31.3%) followed by Mycobacterium fortuitum (22%), Mycobacterium intracellulare (13.6%), Mycobacterium chelonae (9.1%), however, M. abscessus and M. fortuitum were the predominant species in both types of clinical isolates. Men (60.4%) and older patients aged greater than 55years were the predominated risk group for NTM infection. CONCLUSION: The high prevalence and species diversity of NTM suggests the need for immediate and accurate characterization of NTM for proper treatment and management of patients.

Role of Helicobacter pylori in gastric cancer: Updates.

Helicobacter pylori (H. pylori) infection is highly prevalent in human, affecting nearly half of the world's population; however, infection remains asymptomatic in majority of population. During its co-existence with humans, H. pylori has evolved various strategies to maintain a mild gastritis and limit the immune response of host. On the other side, presence of H. pylori is also associated with increased risk for the development of various gastric pathologies including gastric cancer (GC). A complex combination of host genetics, environmental agents, and bacterial virulence factors are considered to determine the susceptibility as well as the severity of outcome in a subset of individuals. GC is one of the most common cancers and considered as the third most common cause of cancer related death worldwide. Many studies had proved H. pylori as an important risk factor in the development of non-cardia GC. Although both H. pylori infection and GC are showing decreasing trends in the developed world, they still remain a major threat to human population in the developing countries. The current review attempts to highlight recent progress in the field of research on H. pylori induced GC and aims to provide brief insight into H. pylori pathogenesis, the role of major virulence factors of H. pylori that modulates the host environment and transform the normal gastric epithelium to neoplastic one. This review also emphasizes on the mechanistic understanding of how colonization and various virulence attributes of H. pylori as well as the host innate and adaptive immune responses modulate the diverse signaling pathways that leads to different disease outcomes including GC.

Transforming growth factor beta 1 (TGF-ß1) modulates Epstein-Barr virus reactivation in absence of Helicobacter pylori infection in patients with gastric cancer.

BACKGROUND: Transforming growth factor-beta 1 (TGF-ß1), a multifunctional cytokine, acts as a key factor for Epstein-Barr virus (EBV) reactivation. We investigated the role of TGF-ß1 in latent and lytic stages of EBV in relation to Helicobacter pylori infection among patients with gastric cancer (GC) and peptic ulcer disease (PUD). METHOD: Gastric mucosal TGF-ß1 expression was determined in 95 EBV positive patients with gastroduodenal pathology [GC 40, PUD 19 and non-ulcer dyspepsia (NUD) 36] by quantitative real time PCR. Presence of H. pylori infection was diagnosed when either culture or any two of three tests (RUT, histopathology and specific ureA PCR) were positive. Serum level of TGF-ß1 was detected among 60 patients using ELISA. RESULTS: Mucosal TGF-ß1 mRNA expression was detected in 85 of 95 EBV positive patients and it was significantly higher in patients with GC (p=0.042). TGF-ß1 expression tended to be higher among H. pylori non-infected than infected patients (3.80±6.24 vs. 2.07±2.50, p=0.085). Both mRNA and serum level had significant association with lytic stage of EBV in absence of H. pylori infection when compared with its presence (5.21±4.00 vs. 2.29±2.89, p=0.040 and 842.00 [669.55] vs. 662.63 [628.76], p=0.049; respectively). CONCLUSION: TGF-ß1 expression was significantly associated with GC. TGF-ß1 was higher both at expression and translational levels in lytic EBV infection without H. pylori suggests that H. pylori infection might play important role in preventing EBV reactivation through attenuated TGF-ß1 expression. This might be a "wise host defense against EBV reactivation".

Toll-like receptors TLR4 (Asp299Gly and Thr399Ile) and TLR2 (Arg677Trp and Arg753Gln) gene polymorphisms in end-stage renal disease patients on peritoneal dialysis.

BACKGROUND: Toll-like receptors (TLRs), expressed on cells of the innate immune system, are the first line of host defense. Recognition of bacterial pathogens by the peritoneum is mediated in part by TLR. In this study, we investigated the role of TLR4 (Asp299Gly and Thr399Ile) and TLR2 (Arg677Trp and Arg753Gln) gene polymorphisms in end-stage renal disease (ESRD) patients on peritoneal dialysis (PD). METHOD: A total of 100 ESRD patients on PD and 150 healthy controls were enrolled in the study. The patients were divided into two groups: ESRD patients on PD with peritonitis (n = 38) and without peritonitis (n = 62). Genotyping of TLR4 (Asp299Gly and Thr399Ile) and TLR2 (Arg677Trp and Arg753Gln) genes were performed by polymerase chain reaction-restriction fragment-length polymorphism (PCR-RFLP). RESULTS: Heterozygous variant of TLR4 (Thr399Ile) Thr/Ile genotype showed significant association with both groups of patients (patients with and without peritonitis) with no difference between the groups. Overall, TLR4 (Thr399Ile) Thr/Ile genotype demonstrated an association with ESRD on PD (OR 3.9). Further, TLR4 (Thr399Ile) polymorphism showed significant association with PD patients having two or more episodes of peritonitis compared to patients with no peritonitis. No such association of increased risk of ESRD was observed with TLR4 (Asp299Gly) Asp/Gly genotype and TLR2 polymorphisms. Haplotype frequencies, Gly/Ile and Asp/Ile, conferred 2.46- and 4.62-fold increased risk of ESRD, respectively. CONCLUSIONS: TLR4 Thr399Ile genotype was associated with ESRD patients on PD; however, the genotype frequency was similar in PD patients with and without peritonitis.

Immune response to Taenia solium cysticerci after anti-parasitic therapy.

Albendazole is the drug of choice for Taenia solium infection. Concomitant administration of steroid has been advocated to avoid adverse reactions to albendazole therapy in neurocysticercosis. Some T. solium cysticerci (larvae) respond to albendazole therapy while others do not and the reasons remain unexplained. We hypothesise that the immune response differs between treatment responder and non-responder cysticerci and this may determine the outcome. Twenty swine naturally infected with T. solium were purchased from the market and the infection was confirmed by magnetic resonance imaging. Swine were divided into two groups; swine in group 1 were treated with albendazole and those in group 2 were treated with albendazole plus steroid (prednisolone). All the animals underwent follow-up MRIs at 6 and 12 weeks after start of therapy and were then sacrificed. Tissues surrounding the cysticerci were collected and studied for the expression of different cytokines by reverse transcriptase PCR and ELISA. Albendazole therapy was found to be more effective in parasite killing than albendazole plus steroid (94.11% versus 70.96%, P=0.011). Albendazole therapy provoked a pro-inflammatory, Th1 (IFN-γ) and pleiotropic (IL-6) cytokine response around the dead cysticerci. Despite a heavy parasite burden in the brain, all the pigs treated with albendazole plus steroid survived. In this group of animals, a mixed pro-inflammatory Th1, Th2 (IL-4) and regulatory cytokine (IL-10) response was associated with responder cysticerci. Further, Th2 and regulatory cytokine responses were associated with non-responder cysticerci.

Helicobacter pylori cagL amino acid polymorphisms and its association with gastroduodenal diseases.

CagL is a pilus protein of Helicobacter pylori that interacts with host cellular α5ß1 integrins through its arginine-glycine-aspartate (RGD) motif, guiding proper positioning of the T4SS and translocation of CagA. Deletion or sequence variations of cagL significantly diminished the ability of H. pylori to induce secretion of IL-8 by the host cell. Therefore, this study was undertaken to investigate the association of cagL and its amino acid sequence polymorphisms with gastric cancer (GC), peptic ulcer disease (PUD), and non-ulcer dyspepsia (NUD) as there are no such studies from India. In total, 200 adult patients (NUD 120, PUD 30, GC 50) who underwent an upper gastrointestinal endoscopy were enrolled. H. pylori infection was diagnosed by rapid urease test, culture, histopathology, and PCR. The collected isolates were screened for cagL genotype by PCR and assessed for amino acid sequence polymorphisms using sequence translation. The prevalence of H. pylori infection in study population was 52.5%. Most of the isolates were cagL genopositive (86.6%), and all had RGD motif in their amino acid sequences. D58 and K59 polymorphisms in cagL-genopositive strains were significantly higher in GC patients (P < 0.05). Combined D58K59 polymorphism was associated with higher risk of GC (3.8-fold) when compared to NUD. In conclusion, H. pylori cagL amino acid polymorphisms such as D58K59 are correlated with a higher risk of GC in the Indian population. Further studies are required to know the exact role of particular cagL amino acid polymorphisms in the pathogenicity of H. pylori infection.