Diabetes-associated breast cancer is molecularly distinct and shows a DNA damage repair deficiency.

Diabetes commonly affects patients with cancer. We investigated the influence of diabetes on breast cancer biology using a 3-pronged approach that included analysis of orthotopic human tumor xenografts, patient tumors, and breast cancer cells exposed to diabetes/hyperglycemia-like conditions. We aimed to identify shared phenotypes and molecular signatures by investigating the metabolome, transcriptome, and tumor mutational burden. Diabetes and hyperglycemia did not enhance cell proliferation but induced mesenchymal and stem cell-like phenotypes linked to increased mobility and odds of metastasis. They also promoted oxyradical formation and both a transcriptome and mutational signatures of DNA repair deficiency. Moreover, food- and microbiome-derived metabolites tended to accumulate in breast tumors in the presence of diabetes, potentially affecting tumor biology. Breast cancer cells cultured under hyperglycemia-like conditions acquired increased DNA damage and sensitivity to DNA repair inhibitors. Based on these observations, we conclude that diabetes-associated breast tumors may show an increased drug response to DNA damage repair inhibitors.

Chromatin Accessibility Landscape of Human Triple-negative Breast Cancer Cell Lines Reveals Variation by Patient Donor Ancestry.

African American (AA) women have an excessive risk of developing triple-negative breast cancer (TNBC). We employed Assay for Transposase-Accessible Chromatin using sequencing to characterize differences in chromatin accessibility between nine commonly used TNBC cell lines derived from patients of European and African ancestry. Principal component and chromosome mapping analyses of accessibility peaks with the most variance revealed separation of chromatin profiles by patient group. Motif enrichment and footprinting analyses of disparate open chromatin regions revealed differences in transcription factor activity, identifying 79 with ancestry-associated binding patterns (FDR < 0.01). AA TNBC cell lines exhibited increased accessibility for 62 transcription factors associated with epithelial-to-mesenchymal transition, cancer stemness/chemotherapeutic resistance, proliferation, and aberrant p53 regulation, as well as KAISO, which has been previously linked to aggressive tumor characteristics in AA patients with cancer. Differential Assay for Transposase-Accessible Chromatin signal analysis identified 1,596 genes located within promoters of differentially open chromatin regions in AA-derived TNBC, identifying DNA methyltransferase 1 as the top upregulated gene associated with African ancestry. Pathway analyses with these genes revealed enrichment in several pathways, including hypoxia. Culturing cells under hypoxia showed ancestry-specific stress responses that led to the identification of a core set of AA-associated transcription factors, which included members of the Kruppel-like factor and Sp subfamilies, as well as KAISO, and identified ZDHHC1, a gene previously implicated in immunity and STING activation, as the top upregulated AA-specific gene under hypoxia. Together, these data reveal a differential chromatin landscape in TNBC associated with donor ancestry. The open chromatin structure of AA TNBC may contribute to a more lethal disease. SIGNIFICANCE: We identify an ancestry-associated open chromatin landscape and related transcription factors that may contribute to aggressive TNBC in AA women. Furthermore, this study advocates for the inclusion of diversely sourced cell lines in experimental in vitro studies to advance health equity at all levels of scientific research.

How Comorbidities Shape Cancer Biology and Survival.

Comorbid chronic diseases affect cancer patients with an increasing frequency as populations get older. They negatively and disproportionately impact underserved populations and influence cancer diagnosis, tumor biology and metastasis, and choice of treatment. Many comorbidities are associated with a delayed cancer diagnosis. Although the relationship between comorbidities and cancer risk and survivorship has been studied extensively, we still lack knowledge on how they affect tumor biology and the metastatic process. Here, we will discuss our current understanding of mechanisms linking comorbidities to an adverse tumor biology and lethality and introduce thoughts of how we can close existing gaps in this knowledge. We argue that research into comorbidity-induced alterations in cancer metastasis, immunity, and metabolism should be prioritized.

Association between children death and consumption of Cassia occidentalis seeds: clinical and experimental investigations.

Recently, children with high mortality rate have been observed in northern parts of India, for which the etiology is still not established, although a case control study has been linked to the consumption of Cassia occidentalis (CO) seeds. In the present investigation toxicity of CO seeds (0.5, 1 and 2% w/w) in diet were carried out in wistar rats. After 28 days it was observed that CO seeds caused significant increases in the serum markers viz transaminases, alkaline phosphatase and lactate dehydrogenase along with histopathological lesions in hepatic tissue. CO consumption also showed decrease in grip strength, vacuolization and myopathy of skeletal muscles along with increases in serum creatinine and creatinine phosphokinase suggesting muscular damage in animals. Neuronal damage in CO treated animals was evident by a marked increase in glial fibrilar acidic protein and decrease in ß-tubulin III. The experimental findings of CO consumption showed liver, muscles and brain to be the target organs, which were similar to that of the clinical data of poisoning cases as observed in the present study. Overall, the study suggests that CO seed consumption is the main etiological factor in children population suffering from hepatomyoencephalopathy in India.

Molecular characterization of distinct YMV (Yellow mosaic virus) isolates affecting pulses in India with the aid of coat protein gene as a marker for identification.

The present study was carried out to find out the variations present in different isolates of yellow mosaic virus (YMV) causing yellow mosaic disease of pulses in southern parts of India. The coat protein gene of YMV was amplified using gene specific and deng universal primers with DNA isolated from YMV infected samples. Further, cloning and DNA sequencing of CP gene was carried out. CP gene decrypt sequences revealed that YMV infected samples of Black gram, Cowpea and Green gram were similar to the MYMV-Tamil Nadu isolates. Whereas the YMV infected sample of Horse gram was found to be similar with HYMV. Hence, in the present study, two distinct YMV infecting pulses in Tamil Nadu (MYMV and HYMV species) were identified and it was observed that there exists considerable genetic variation among these species. In addition, Cowpea crop which was earlier supposed not to be susceptible for YMV infection also showed the presence of this virus similar to the MYMV. Overall, the findings of the present study indicate that the CP region is efficient enough to provide a simple, rapid, and reliable method for early detection of YMV infections in pulses, which would help to develop proper management strategies to control these viruses.

Preparative thin-layer chromatographic separation followed by identification of antifungal compound in Cassia laevigata by RP-HPLC and GC-MS.

BACKGROUND: Several species of the genus Cassia are known for their antioxidant, antimicrobial and antidiabetic activities, but some of the lesser-known Cassia species, e.g. C. renigera, C. biflora and C. laevigata have not been studied for their biological activities. RESULTS: Methanol extract of C. laevigata was fractionated by preparative thin-layer chromatography. The resulting six different fractions were tested against Fusarium oxysporum and Aspergillus niger for their antifungal activity. Due to higher antifungal activity of fraction 1 of C. laevigata, this was further analyzed by reversed-phase high-performance liquid chromatography (RP-HPLC), resulting in distinct separation of one compound at a retention time of 7.2 min with an absorbance of 252 nm. Further, this compound was analyzed by gas chromatography-mass spectrometry (GC-MS) for its putative structural identification. Mass spectra of this compound resembled the spectra of anthraquinone 1-carboxylic acid by NIST library search. The genomic-level expression of chalcone synthase, a key enzyme involved in the biosynthesis of polyketides, was increased in C. laevigata when compared to other Cassia species. CONCLUSIONS: This study provides an insight into the higher antifungal activity of C. laevigata, including the identification of anthraquinone 1-carboxylic acid, which may be responsible for the antifungal activity.