Biology subjects

Bali, P.

Publications and source records attributed to Bali, P..

5 recordsLinked to original sources

bioRxiv2025

Gastric cancer treatment target identified from an accelerated Helicobacter-induced gastric cancer mouse model

Helicobacter pylori (H. pylori) infection and consequent inflammation leads to gastric cancer (GC). Despite the prevalence of this bacterium and availability of genomic data, targeted therapies for GC are still early in development. Previously in our accelerated Helicobacter-induced gastric cancer mouse model we identified several differentially expressed genes (DEGs), including PSMB8 (proteasome subunit beta type 8, also called LMP7); one of the immune subunits of the immunoproteasome, which has been associated with disease severity in multiple cancers. We observed elevated expression of PSMB8 in our accelerated gastric cancer model, in the human gastric cancer cell line (MKN45), and in gastric cancer patient samples. Moreover, we identified carfilzomib as a potential drug that targets PSMB8. Therefore, to test its efficacy against gastric cancer, nude mice were subcutaneously implanted with MKN45 derived tumors and treated with carfilzomib, alone or in combination with 5-fluorouracil (5-FU), the standard care drug. The effectiveness of drug treatment was measured by tumor growth, cell proliferation, and apoptosis. We observed that carfilzomib retarded tumor growth, inhibited cell proliferation and induced apoptosis. These results strongly suggest that carfilzomib has a robust anti-tumor activity and is a suitable drug candidate for targeted therapy in gastric cancer.

cancer biology↗

bioRxiv2024

Human APOE allelic variants suppress the formation of diffuse and fibrillar Aβ deposits relative to mouse Apoe in transgenic mouse models of Alzheimer amyloidosis

BackgroundApolipoprotein E (apoE) modulates the deposition of amyloid {beta} (A{beta}) aggregates in Alzheimers disease (AD) in an isoform-dependent manner. In transgenic mouse models of AD-amyloidosis, replacing mouse Apoe alleles with human APOE variants suppresses fibrillar A{beta} deposits. In the PD-APP transgenic mouse model, deletion of the Apoe gene led to selective reduction of fibrillar deposits with increased diffuse deposits. This finding suggested that apoE may have differential effects on different types of amyloid pathology. MethodsHere, we investigated the interaction between the type of A{beta} pathology in the brain and human apoE isoforms in different transgenic mouse models. ResultsIn the APPsi model that develops predominantly diffuse A{beta} plaques late in life, we determined that replacing mouse Apoe with human APOE3 or APOE4 genes potently suppressed diffuse amyloid formation, with apoE3 exhibiting a greater activity relative to apoE4. Relative to apoE4, apoE3 appeared to suppress A{beta} deposition in the cerebral vasculature. In a second cohort, we accelerated the deposition of diffuse A{beta} pathology by seeding, finding that seeded APPsi mice harboring APOE4 or APOE3 developed equal burdens of diffuse parenchymal A{beta}. Finally, in the recently developed SAA-APP model that has a mix of dense-core and fibrous A{beta} plaques, we found that replacing mouse apoE with human apoE suppressed deposition significantly, with the amyloid burden following the trend of Apoe>>APOE4> APOE3[~]APOE2. In the SAA-APP and seeded APPsi models, we found evidence of apoE protein associated with A{beta} plaques. ConclusionsOverall, these observations demonstrate a capacity for human apoE to suppress the deposition of both diffuse and fibrillar-cored deposits, relative to mouse apoE. Notably, in the seeded paradigm, the suppressive activity of human apoE3 and apoE4 appeared to be overwhelmed. Taken together, this study demonstrates that APOE genotype influences the deposition of both cored-fibrillar and diffuse amyloid.

neuroscience↗

bioRxiv2023

Activation of the TRIF pathway and downstream targets results in the development of precancerous lesions during infection with Helicobacter.

Helicobacter pylori (H. pylori) infection is an established cause of many digestive diseases, including gastritis, peptic ulcers, and gastric cancer. However, the mechanism by which infection with H. pylori causes these disorders is still not clearly understood. This is due to insufficient knowledge of pathways that promote H. pylori-induced disease progression. We have established a Helicobacter-induced accelerated disease progression mouse model, which involves infecting mice deficient in the myeloid differentiation primary response 88 gene (Myd88-/-) with H. felis. Using this model, we report here that that progression of H. felis-induced inflammation to high-grade dysplasia was associated with activation of type I interferon (IFN-I) signaling pathway and upregulation of related downstream target genes, IFN-stimulated genes (ISGs). These observations were further corroborated by the enrichment of ISRE motifs in the promoters of upregulated genes. Further we showed that H. felis-induced inflammation in mice deficient in Toll/interleukin-1 receptor (TIR)-domain-containing adaptor inducing interferon-{beta} (TRIF, TrifLps2) did not progress to severe gastric pathology, indicating a role of the TRIF signaling pathway in disease pathogenesis and progression. Indeed, survival analysis in gastric biopsy samples from gastric cancer patients illustrated that high expression of Trif was significantly associated with poor survival in gastric cancer.

cancer biology↗

bioRxiv2020

Microbiome signatures in a fast and slow progressing gastric cancer murine model and their contribution to gastric carcinogenesis

Gastric cancer is the third most common cancer in the world and Helicobacter spp. being one of the main factors responsible for development of cancer. Alongside Helicobacter the microbiota of the stomach mucosa may also play an important role in gastric cancer progression. Previously we had established that MyD88 deficient mice rapidly progressed to neoplasia when infected with H. felis. Thus, in order to assess the role of microbiota in gastric cancer progression we measured the changes in microbial diversity of the stomach in mice with different genotypic backgrounds (Wild type (WT), MyD88 deficient (MyD88-/-), mice deficient in the Toll/IL-1R (TIR) domain-containing adaptor-inducing interferon-{beta} (TRIF, Triflps2), and MyD88 and Trif deficient (MyD88-/- and Trif-/-)double knockout (DKO) mice), both in uninfected and Helicobacter infected mice and its correlation of these changes with gastric cancer progression. We observed that there was an overall reduction in microbial diversity post infection with H. felis across all genotypes. Campylobacterales were observed in all infected mice, with marked reduction in abundance at 3 and 6 months in MyD88-/- mice. This low abundance of H. pylori could facilitate dominance of other organisms of microbiome like Lactobacilliales. A sharp increase in Lactobacilliales in infected MyD88-/- and DKO mice at 3 and 6 months was observed as compared to Trif-/- and WT mice suggesting its possible role in gastric cancer progression. This was further reinforced upon comparison of Lactobacillus ratio with histological data suggesting that Lactobacillales is closely associated with Helicobacter infection and gastric cancer progression. Thus, this study firstly suggests that difference in genotypes could define the stomach microbiome and make it more susceptible to development of gastric cancer upon Helicobacter infections. Secondly the increase in Lactobacillales could contribute to faster development of gastric cancer and serve as a probable bio marker for fast progressing form of gastric cancer.

cancer biology↗

bioRxiv2020

Early detection of biomarkers for circulating tumor cells in Bone marrow and Peripheral blood in a fast-progressing gastric cancer model.

Helicobacter pylori poses one of the greatest risks for development of gastric cancer. We previously established a crucial role for myeloid differentiation primary response 88 (MyD88) in the regulation of Helicobacter-induced gastric cancer. Mice deficient in Myd88 rapidly progressed to neoplasia when infected with H. felis, a close relative of H. pylori. For this study we examined circulating tumor cells (CTCs) by measuring expression of cytokeratins, epithelial to mesenchymal transition (EMT) and cancer stem cell (CSC) markers in in the bone marrow and peripheral blood of gastric cancer models we termed fast (Myd88-/-)- and slow (WT)-"progressors". We detected cytokeratins CK8/18 as early as 3 months post infection in the fast "progressors". In contrast, cytokeratins were not detected in slow "progressor" gastric cancer model even after 7 months post infection. Expression of MUC1 was observed in both bone marrow and peripheral blood at different time points suggesting its role in gastric cancer metastasis. Snail, Twist and ZEB were expressed at different levels in bone marrow and peripheral blood. Expression of these EMT markers suggests manifestation of cancer metastasis in the early stages of disease development. Lgr5, CD44 and CD133 were the most prominent CSC markers detected. Detection of CSC and EMT markers along with cytokeratins does reinforce their use as biomarkers for gastric cancer metastasis. This early detection of markers suggests that CTCs leave primary site even before cancer is well established. Thus, cytokeratins, EMT, and CSCs could be used as biomarkers to detect aggressive forms of gastric cancers. This information will be important in stratifying patients for treatment before the onset of severe disease characteristics.

cancer biology↗