Biology subjects

Shrestha, G.

Publications and source records attributed to Shrestha, G..

3 recordsLinked to original sources

bioRxiv2021

Novel temporal and spatial patterns of metastatic colonization from rapid-autopsy tumor biopsies

BackgroundMetastatic breast cancer is a deadly disease with a low 5-year survival rate. Tracking metastatic spread in living patients is difficult, and thus poorly understood. ResultsVia rapid autopsy, we have collected 30 tumor samples over 3 timepoints and across 8 organs from a triple-negative metastatic breast cancer patient. The large number of sites sampled, together with deep whole genome sequencing and advanced computational analysis, allowed us to comprehensively reconstruct the tumors evolution at subclonal resolution. The most unique, previously not reported aspect of the tumors evolution we observed in this patient was the presence of "subclone incubators", i.e. already metastatic sites where substantial tumor evolution occurred before colonization of additional sites and organs by subclones that evolved at the incubator site. Overall, we identified four discrete waves of metastatic expansions, each of which resulted in a number of new, genetically similar metastasis sites that also enriched for particular organs (e.g. abdominal vs bone and brain). The lung played a critical role in facilitating metastatic spread in this patient: the lung was the first site of metastatic escape from the primary breast lesion; subclones at this site were the source of all four subsequent metastatic waves; and multiple sites in the lung acted as subclone incubators. Finally, functional annotation revealed that many known driver or metastasis-promoting tumor mutations in this patient were shared by some, but not all metastatic sites, highlighting the need for more comprehensive surveys of a patients metastases for effective clinical intervention. ConclusionsOur analysis revealed the presence of substantial tumor evolution at metastatic incubator sites, with potentially important clinical implications. Our study demonstrated that sampling of a large number of metastatic sites affords unprecedented detail for studying metastatic evolution.

cancer biology↗

bioRxiv2020

Experiences of cervical cancer survivors in Chitwan, Nepal: a qualitative study

Introduction Cervical cancer is a global leading cause of morbidity and mortality. The majority of cervical cancer deaths occur in developing countries including Nepal. Though knowledge of cervical cancer is an important determinant of women’s participation in prevention and screening for cervical cancer, little is known about this topic in Nepal. This study explores the experiences of cervical cancer survivors and assesses the attitude of family and community towards it and stigma related to this disease in Bharatpur, Nepal.Methods The study design is qualitative methods involving two focus-group discussions. A total of 17 cervical cancer survivors were selected purposively from Chitwan. All qualitative data were transcribed and translated into English and were thematically analyzed.Results Majority of the participants had scant knowledge about cervical cancer, its causative agent, showed less cervical cancer screening, delayed healthcare-seeking behavior despite having persistent symptoms before the diagnosis. The main reasons identified for not uptaking the cervical screening methods are an embarrassment and having no symptoms at all. Most of them endured social stigma related to cervical cancer in the form of physical isolation and verbal abuse.Conclusions There is an urgent need for interventions to make women and the public aware of cervical cancer and launch effective health education campaigns, policies for cervical cancer prevention programs. This implementation can save the lives of hundreds of women and help them avoid going through all the negative experiences related to cervical cancer. More studies are required to gain the perspectives, knowledge, experiences, and attitudes of cervical cancer survivors to add to the research.View Full Text

scientific communication and education↗

bioRxiv2020

Circulating immune cell phenotype dynamics reflect the strength of tumor-immune cell interactions in patients during immunotherapy

The extent that immune cell phenotypes in the peripheral blood reflect within-tumor immune activity prior to and early in cancer therapy is unclear. To address this question, we studied the population dynamics of tumor and immune cells, and immune phenotypic changes, using clinical tumor and immune cell measurements and single cell genomic analyses. These samples were serially obtained from a cohort of advanced gastrointestinal cancer patients enrolled on a trial with chemotherapy and immunotherapy. Using an ecological population model, fitted to clinical tumor burden and immune cell abundance data from each patient, we find evidence of a strong tumor-circulating immune cell interaction in responder patients, but not those patients that progress on treatment. Upon initiation of therapy, immune cell abundance increased rapidly in responsive patients, and once the peak level is reached, tumor burden decreases, similar to models of predator-prey interactions; these dynamic patterns were absent in non-responder patients. To interrogate phenotype dynamics of circulating immune cells, we performed single cell RNA sequencing at serial time points during treatment. These data show that peripheral immune cell phenotypes were linked to the increased strength of patients tumor-immune cell interaction, including increased cytotoxic differentiation and strong activation of interferon signaling in peripheral T-cells in responder patients. Joint modeling of clinical and genomic data highlights the interactions between tumor and immune cell populations and reveals how variation in patient responsiveness can be explained by differences in peripheral immune cell signaling and differentiation soon after the initiation of immunotherapy. One sentence summaryPeripheral immune cell differentiation and signaling, upon initiation of immunotherapy, reflects tumor attacking ability and patient response. Significance statementThe evolution of peripheral immune cell abundance and signaling over time, as well as how these immune cells interact with the tumor, may impact a cancer patients response to therapy. By developing an ecological population model, we provide evidence of a dynamic predator-prey like relationship between circulating immune cell abundance and tumor size in patients that respond to immunotherapy. This relationship is not found either in patients that are non-responsive to immunotherapy or during chemotherapy. Single cell RNA-sequencing (scRNAseq) of serial peripheral blood samples from patients show that the strength of tumor-immune cell interactions is reflected in T-cells interferon activation and differentiation early in treatment. Thus, circulating immune cell dynamics reflect a tumors response to immunotherapy.

cancer biology↗