Identification of Topological Features in Renal Tumor Microenvironment Associated with Patient Survival

Motivation As a highly heterogeneous disease, the progression of tumor is not only achieved by unlimited growth of the tumor cells, but also supported, stimulated, and nurtured by the microenvironment around it. However, traditional qualitative and/or semi-quantitative parameters obtained by pathologist’s visual examination have very limited capability to capture this interaction between tumor and its microenvironment. With the advent of digital pathology, computerized image analysis may provide a better tumor characterization and give new insights into this problem. Results We propose a novel bioimage informatics pipeline for automatically characterizing the topological organization of different cell patterns in the tumor microenvironment. We apply this pipeline to the only publicly available large histopathology image dataset for a cohort of 190 patients with papillary renal cell carcinoma obtained from The Cancer Genome Atlas project. Experimental results show that the proposed topological features can successfully stratify early- and middle-stage patients with distinct survival, and show superior performance to traditional clinical features and cellular morphological and intensity features. The proposed features not only provide new insights into the topological organizations of cancers, but also can be integrated with genomic data in future studies to develop new integrative biomarkers

GPU-accelerated subgraph enumeration on partitioned graphs

Ministry of Education, Singapore under its Academic Research Funding Tier

Limitations of radiosensitization by direct telomerase inhibition to treat high-risk medulloblastoma

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Previous studies have elucidated the genomic landscape of MB leading to the recognition of four core molecular subgroups (WNT, SHH, group 3 and group 4) with distinct clinical outcomes. Group 3 has the worst prognosis of all MB. Radiotherapy (RT) remains a major component in the treatment of poor prognosis MB but is rarely curative alone and is associated with acute and long-term toxicities. A hallmark of cancer cells is their unlimited proliferative potential which correlates closely with telomere length. The vast majority of malignant tumors activate telomerase to maintain telomere length, whereas this activity is barely detectable in most normal human somatic tissues, making telomerase inhibition a rational therapeutic target in the setting of cancer recurrence and therapy resistance. We and others have previously shown that short telomeres confer sensitivity to ionizing radiation (IR) suggesting that telomerase inhibition mediated telomere shortening will improve the efficacy of RT while minimizing its side effects. Here, we investigated the efficacy of the combination of IR with IMT, a potent telomerase inhibitor, in an in vivo model of group 3 MB. Our results indicate that although IMT inhibited MB telomerase activity resulting in telomere shortening and delayed tumor growth, the combination with IR did not prevent tumor recurrence and did not improve survival compared to the treatment with IR alone. Together, these findings suggest that the radiosensitization by direct telomerase inhibition is not an effective approach to treat high-risk pediatric brain tumors

Canonical and Atypical E2Fs Regulate the Mammalian Endocycle

SUMMARY The endocycle is a variant cell cycle consisting of successive DNA synthesis and Gap phases that yield highly polyploid cells. Although essential for metazoan development, relatively little is known about its control or physiologic role in mammals. Using novel lineage-specific cre mice we identified two opposing arms of the E2F program, one driven by canonical transcription activation (E2F1, E2F2 and E2F3) and the other by atypical repression (E2F7 and E2F8), that converge on the regulation of endocycles in vivo. Ablation of canonical activators in the two endocycling tissues of mammals, trophoblast giant cells in the placenta and hepatocytes in the liver, augmented genome ploidy, whereas ablation of atypical repressors diminished ploidy. These two antagonistic arms coordinate the expression of a unique G2/M transcriptional program that is critical for mitosis, karyokinesis and cytokinesis. These results provide in vivo evidence for a direct role of E2F family members in regulating non-traditional cell cycles in mammals

M-CSF Induces Monocyte Survival by Activating NF-κB p65 Phosphorylation at Ser276 via Protein Kinase C

Macrophage colony-stimulating factor (M-CSF) promotes mononuclear phagocyte survival and proliferation. The transcription factor Nuclear Factor-kappaB (NF-κB) is a key regulator of genes involved in M-CSF-induced mononuclear phagocyte survival and this study focused at identifying the mechanism of NF-κB transcriptional activation. Here, we demonstrate that M-CSF stimulated NF-κB transcriptional activity in human monocyte-derived macrophages (MDMs) and the murine macrophage cell line RAW 264.7. The general protein kinase C (PKC) inhibitor Ro-31-8220, the conventional PKCα/β inhibitor Gö-6976, overexpression of dominant negative PKCα constructs and PKCα siRNA reduced NF-κB activity in response to M-CSF. Interestingly, Ro-31-8220 reduced Ser276 phosphorylation of NF-κBp65 leading to decreased M-CSF-induced monocyte survival. In this report, we identify conventional PKCs, including PKCα as important upstream kinases for M-CSF-induced NF-κB transcriptional activation, NF-κB-regulated gene expression, NF-κB p65 Ser276 phosphorylation, and macrophage survival. Lastly, we find that NF-κB p65 Ser276 plays an important role in basal and M-CSF-stimulated NF-κB activation in human mononuclear phagocytes

The Application of Metabolomics in Recent Colorectal Cancer Studies: A State-of-the-Art Review

Colorectal cancer (CRC) is a highly prevalent disease with poor prognostic outcomes if not diagnosed in early stages. Current diagnosis techniques are either highly invasive or lack sufficient sensitivity. Thus, identifying diagnostic biomarkers of CRC with high sensitivity and specificity is desirable. Metabolomics represents an analytical profiling technique with great promise in identifying such biomarkers and typically represents a close tie with the phenotype of a specific disease. We thus conducted a systematic review of studies reported from January 2012 to July 2021 relating to the detection of CRC biomarkers through metabolomics to provide a collection of knowledge for future diagnostic development. We identified thirty-seven metabolomics studies characterizing CRC, many of which provided metabolites/metabolic profile-based diagnostic models with high sensitivity and specificity. These studies demonstrated that a great number of metabolites can be differentially regulated in CRC patients compared to healthy controls, adenomatous polyps, or across stages of CRC. Among these metabolite biomarkers, especially dysregulated were certain amino acids, fatty acids, and lysophosphatidylcholines. Additionally, we discussed the contribution of the gut bacterial population to pathogenesis of CRC through their modulation to fecal metabolite pools and summarized the established links in the literature between certain microbial genera and altered metabolite levels in CRC patients. Taken together, we conclude that metabolomics presents itself as a promising and effective method of CRC biomarker detection

AAV-BDNF gene therapy ameliorates a hypothalamic neuroinflammatory signature in the Magel2-null model of Prader-Willi syndrome

Individuals with Prader-Willi syndrome (PWS) exhibit several metabolic and behavioral abnormalities associated with excessive food-seeking activity. PWS is thought to be driven in part by dysfunctional hypothalamic circuitry and blunted responses to peripheral signals of satiety. Previous work described a hypothalamic transcriptomic signature of individuals with PWS. Notably, PWS patients exhibited downregulation of genes involved in neuronal development and an upregulation of neuroinflammatory genes. Deficiencies of brain-derived neurotrophic factor (BDNF) and its receptor were identified as potential drivers of PWS phenotypes. Our group recently applied an adeno-associated viral (AAV)-BDNF gene therapy within a preclinical PWS model, Magel2-null mice, to improve metabolic and behavioral function. While this proof-of-concept project was promising, it remained unclear how AAV-BDNF was influencing the hypothalamic microenvironment and how its therapeutic effect was mediated. To investigate, we hypothalamically injected AAV-BDNF to wild type and Magel2-null mice and performed mRNA sequencing on hypothalamic tissue. Here, we report that (1) Magel2 deficiency is associated with neuroinflammation in the hypothalamus and (2) AAV-BDNF gene therapy reverses this neuroinflammation. These data newly reveal Magel2-null mice as a valid model of PWS-related neuroinflammation and furthermore suggest that AAV-BDNF may modulate obesity-related neuroinflammatory phenotypes through direct or indirect means

Risk Factors Associated with Survival Following Ganciclovir Prophylaxis through Day +100 in Cytomegalovirus At-Risk Pediatric Allogeneic Stem Cell Transplantation Recipients: Development of CMV Viremia Associated with Significantly Decreased One-Year Survival

Cytomegalovirus (CMV) reactivation is a major cause of morbidity and nonrelapse mortality (NRM) in pediatric allogeneic stem cell transplantation (alloSCT) recipients. Approximately 80% of CMV seropositive alloHCT recipients will experience CMV reactivation without prophylaxis. The impacts of ganciclovir prophylaxis and subsequent CMV viremia on 1-year survival and 1-year NRM are unknown. The primary objective of this study was to determine the effect of CMV viremia on the probability of 1-year survival and 1-year NRM in pediatric alloSCT recipients receiving 100 days of ganciclovir prophylaxis. The secondary objective was to determine the effect of other risk factors on 1-year survival and 1-year NRM. All patients age 0 to 26 years who underwent alloSCT between June 2011 and May 2020 and received ganciclovir prophylaxis for 100 days at Westchester Medical Center, an academic medical center, were analyzed. Ganciclovir was administered to at-risk alloSCT recipients (donor and or recipient CMV serostatus) as 5 mg/kg every 12 hours from the first day of conditioning through day -1 (recipient CMV only) followed by 6 mg/kg every 24 hours on Monday through Friday beginning on the day of an absolute neutrophil count \u3e750/mm and continuing through day +100. National Cancer Institute Common Terminology Criteria for Adverse Events 5.0 criteria were used to grade toxicity. NRM was analyzed using competing survival analysis with relapse death as a competing event. The log-rank and Gray tests were performed to compare the 1-year survival probabilities and NRM cumulative incidence between patients who experienced CMV viremia post-alloSCT and those who did not. Univariate Cox regression analysis was performed for the following risk factors: CMV viremia, donor source, sex, malignant disease, disease risk index, conditioning intensity, receipt of rabbit antithymocyte globulin (rATG)/alemtuzumab, graft-versus-host disease (GVHD) prophylaxis, CMV donor/recipient serostatus, grade II-IV acute GVHD, and grade 3/4 neutropenia necessitating discontinuation of ganciclovir, treating the last 3 factors as time-dependent covariates. Those with P values \u3c .2 were included in the multivariate Cox regression analysis. Eighty-four alloSCT recipients (41 males, 43 females; median age, 10.8 years [range, .4 to 24.4 years]) were analyzed. Multivariate analysis showed significantly lower 1-year survival and significantly higher 1-year NRM in patients who developed CMV viremia compared to those who did not (P = .0036). No other risk factors were significantly associated with 1-year survival or 1-year NRM. One-year survival was significantly decreased and 1-year NRM was significantly increased in pediatric alloSCT recipients who developed CMV viremia following ganciclovir prophylaxis. No other risk factors were found to be associated with 1-year survival or 1-year NRM. Alternative CMV prophylaxis regimens that reduce CMV viremia should be investigated in pediatric alloSCT recipients at risk for CMV infection