Biology subjects

Sibai, M.

Publications and source records attributed to Sibai, M..

7 recordsLinked to original sources

bioRxiv2026

Convergent stromal and immune remodeling defines spatial tumor dynamics in PARP inhibitor-resistant high-grade serous ovarian cancer

Acquired resistance to poly(ADP-ribose) polymerase inhibitors (PARPi) remains a major barrier to durable clinical benefit in patients with high-grade serous ovarian cancer (HGSOC), yet the profiles of tumors at resistance remain poorly understood. We profiled longitudinal HGSOC patient tumors spanning diagnosis, post-neoadjuvant therapy, and progression on PARPi with complementary spatial transcriptomics platforms, integrating single-cell-resolution Xenium analysis in paired longitudinal cases with cohort-level Visium profiling. PARPi failure was associated with spatial remodeling of the tumor microenvironment, marked by hypoxia-associated malignant transcriptional programs, increased stromal compartmentalization, and exclusion of effector immune cells. Together, these findings indicate that PARPi resistance in HGSOC is accompanied by reproducible spatial niche remodeling, underscoring the tumor microenvironment as a key contextual determinant of therapeutic failure.

cancer biology↗

bioRxiv2023

CompCorona: A Web Portal for Comparative Analysis of the Host Transcriptome of PBMC and Lung SARS-CoV-2, SARS-CoV, and MERS-CoV

MotivationUnderstanding the host response to SARS-CoV-2 infection is crucial for deciding on the correct treatment of this epidemic disease. Although several recent studies reported the comparative transcriptome analyses of the three coronaviridae (CoV) members; namely SARS-CoV, MERS-CoV, and SARS-CoV-2, there is yet to exist a web-tool to compare increasing number of host transcriptome response datasets against the pre-processed CoV member datasets. Therefore, we developed a web application called CompCorona, which allows users to compare their own transcriptome data of infected host cells with our pre-built datasets of the three epidemic CoVs, as well as perform functional enrichment and principal component analyses (PCA). ResultsComparative analyses of the transcriptome profiles of the three CoVs revealed that numerous differentially regulated genes directly or indirectly related to several diseases (e.g., hypertension, male fertility, ALS, and epithelial dysfunction) are altered in response to CoV infections. Transcriptome similarities and differences between the host PBMC and lung tissue infected by SARS-CoV-2 are presented. Most of our findings are congruent with the clinical cases recorded in the literature. Hence, we anticipate that our results will significantly contribute to ongoing studies investigating the pre-and/or post-implications of SARS-CoV-2 infection. In addition, we implemented a user-friendly public website, CompCorona for biomedical researchers to compare users own CoV-infected host transcriptome data against the built-in CoV datasets and visualize their results via interactive PCA, UpSet and Pathway plots. AvailabilityCompCorona is freely available on the web at http://compcorona.mu.edu.tr Contacttugbasuzek@mu.edu.tr

bioinformatics↗

bioRxiv2022

Charting the Spatial Landscape of Cancer Hallmarks

Tumors are complex ecosystems with dozens of interacting cell types. The concept of Cancer Hallmarks distills this complexity into a set of underlying principles that govern tumor growth. Here, we exploit this abstraction to explore the physical distribution of Cancer Hallmarks across 63 primary untreated tumors from 10 cancer types using spatial transcriptomics. We show that Hallmark activity is spatially organized-with 7 out of 13 Hallmarks consistently more active in cancer cells than within the non-cancerous tumor microenvironment (TME). The opposite is true for the remaining six Hallmarks. Additionally, we discovered that genomic distance between tumor subclones correlates with differences in Cancer Hallmark activity, even leading to clone-Hallmark specialization in some cases. Finally, we demonstrate interdependent relationships between Cancer Hallmarks at the junctions of TME and cancer compartments. In conclusion, including the spatial dimension, particularly through the lens of Cancer Hallmarks, can improve our understanding of tumor ecology. SignificanceWe explored Cancer Hallmarks in 63 primary untreated tumors from 10 cancer types using spatial transcriptomics. This study unveiled spatial patterns in Hallmark activity, with some being more active in cancer cells and others in the non-cancerous tumor environment. Genomic distance impacted Hallmark activity, and we identified interdependencies at the TME-cancer junctions, improving our understanding of tumor ecology.

cancer biology↗

bioRxiv2021

Pan-ErbB inhibition protects from SARS-CoV-2 replication, inflammation, and injury

Targeting host factors exploited by multiple viruses could offer broad-spectrum solutions for pandemic preparedness. Seventeen candidates targeting diverse functions emerged in a screen of 4,413 compounds for SARS-CoV-2 inhibitors. We demonstrated that lapatinib and other approved inhibitors of the ErbB family receptor tyrosine kinases suppress replication of SARS-CoV-2, Venezuelan equine encephalitis virus (VEEV), and other emerging viruses with a high barrier to resistance. Lapatinib suppressed SARS-CoV-2 entry and later stages of the viral life cycle and showed synergistic effect with the direct-acting antiviral nirmatrelvir. We discovered that ErbB1, 2 and 4 bind SARS-CoV-2 S1 protein and regulate viral and ACE2 internalization, and they are required for VEEV infection. In human lung organoids, lapatinib protected from SARS-CoV-2-induced activation of ErbB-regulated pathways implicated in non-infectious lung injury, pro-inflammatory cytokine production, and epithelial barrier injury. Lapatinib suppressed VEEV replication, cytokine production and disruption of the blood-brain barrier integrity in microfluidic-based human neurovascular units, and reduced mortality in a lethal infection murine model. We validated lapatinib-mediated inhibition of ErbB activity as an important mechanism of antiviral action. These findings reveal regulation of viral replication, inflammation, and tissue injury via ErbBs and establish a proof-of-principle for a repurposed, ErbB-targeted approach to combat emerging viruses.

microbiology↗

bioRxiv2021

Infection and vaccine-induced neutralizing antibody responses to the SARS-CoV-2 B.1.617.1 variant

SARS-CoV-2 has caused a devastating global pandemic. The recent emergence of SARS-CoV-2 variants that are less sensitive to neutralization by convalescent sera or vaccine-induced neutralizing antibody responses has raised concerns. A second wave of SARS-CoV-2 infections in India is leading to the expansion of SARS-CoV-2 variants. The B.1.617.1 variant has rapidly spread throughout India and to several countries throughout the world. In this study, using a live virus assay, we describe the neutralizing antibody response to the B.1.617.1 variant in serum from infected and vaccinated individuals. We found that the B.1.617.1 variant is 6.8-fold more resistant to neutralization by sera from COVID-19 convalescent and Moderna and Pfizer vaccinated individuals. Despite this, a majority of the sera from convalescent individuals and all sera from vaccinated individuals were still able to neutralize the B.1.617.1 variant. This suggests that protective immunity by the mRNA vaccines tested here are likely retained against the B.1.617.1 variant. As the B.1.617.1 variant continues to evolve, it will be important to monitor how additional mutations within the spike impact antibody resistance, viral transmission and vaccine efficacy.

immunology↗

bioRxiv2019

Comparison of Gene Expression During Early Phases of Limb Regeneration Between Regeneration-permissive Neotenic and Regeneration-deficient Metamorphic Axolotl

The axolotl (Ambystoma Mexicanum) salamander, an urodele amphibian, has an exceptional regenerative capacity to fully restore an amputated limb throughout the life-long lasting neoteny. By contrast, when axolotls are experimentally induced to metamorphosis, attenuation of the limbs regenerative competence is noticeable. Here, we sought to discern the proteomic profiles of the early stages of blastema formation of neotenic and metamorphic axolotls after limb amputation by means of LC-MS/MS technology. We quantified a total of 714 proteins having an adjusted p < 0.01 with FC greater or equal to 2 between two conditions. Principal component analysis revealed a conspicuous clustering between neotenic and metamorphic samples at 7 days post-amputation. Different set of proteins was identified as differentially expressed at all of the time points (1, 4, and 7 days post-amputations against day0) for neotenic and metamorphic stages. Although functional enrichment analyses underline the presence of common pathways between regenerative and nonregenerative stages, cell proliferation and its regulation associated pathways, immune system related pathways and muscle tissue and ECM remodeling and degradation pathways were represented at different rate between both stages. To validate the proteomics results and provide evidence for the putative link between immune system activity and regenerative potential, qRT-PCR for selected genes was performed.

molecular biology↗

bioRxiv2019

Integrative Analysis of Axolotl Gene Expression data from Regenerative and Wound Healing Tissues

Axolotl (Ambystoma mexicanum) is a urodele amphibian endowed with remarkable regenerative capacities manifested in scarless wound healing and full restoration of amputated limbs. Several regenerative cues of the axolotl limb were successfully unraveled due to the advent of high-throughput technologies and their employment in tackling research questions on several OMICS levels. The field of regenerative biology and medicine has therefore utilized the axolotl as a major and powerful experimental model. Studies which have previously unraveled differentially expressed (DE) genes en masse in different phases of the axolotl limb regeneration have primarily used microarrays and RNA-Seq technologies. However, as different labs are conducting such experiments, sufficient consistency may be lacking due to statistical limitations arising from limited number of sample replicates as well as possible differences in study designs. This study, therefore, aims to bridge such gaps by performing an integrative analysis of publicly available microarray and RNA-Seq data from axolotl limb samples having comparable study designs. Three biological groups were conceived for the analysis; homeostatic tissues (control group), from amputation/injury timepoint up to around 50 hours post amputation (wound healing group), and from 50 hours to 28 days post amputation/injury (regenerative group). Integrative analysis was separately carried out on the selected microarray and RNA-Seq data from axolotl limb samples using the \"merging\" method. Differential expression analysis was separately implemented on the processed data from both technologies using the R/Bioconductor \"limma\" package. A total of 1254 genes (adjusted P < 0.01) were found DE in regenerative samples compared to the control, out of which 351 showed magnitudes of Log Fold Changes (LogFC) > 1 and were identified as the top DE genes from data of both technologies. Downstream analyses illustrated consistent correlations of the logFCs of DE genes distributed among the biological comparisons, within and between both technologies. Gene ontology annotations demonstrated concordance with the literature on the biological process involved in the axolotl limb regeneration. qPCR analysis validated the observed gene expression level differences between regenerative and control samples for a set of five genes. Future studies may benefit from the utilized concept and approach for enhanced statistical power and robust discovery of biomarkers of regeneration.

bioinformatics↗