tbuckley/cabot-search huggingface dataset:
A global overview of genetically interpretable multimorbidities among common diseases in the UK Biobank
Authors: Guiying Dong, Jianfeng Feng, Fengzhu Sun, Jingqi Chen, Xing-Ming Zhao
Journal: Genome Medicine (2021)

Abstract Background Multimorbidities greatly increase the global health burdens, but the landscapes of their genetic risks have not been systematically investigated. Methods We used the hospital inpatient data of 385,335 patients in the UK Biobank to investigate the multimorbid relations among 439 common diseases. Post-GWAS analyses were performed to identify multimorbidity shared genetic risks at the genomic loci, network, as well as overall genetic architecture levels. We conducted network decomposition for the networks of genetically interpretable multimorbidities to detect the hub diseases and the involved molecules and functions in each module. Results In total, 11,285 multimorbidities among 439 common diseases were identified, and 46% of them were genetically interpretable at the loci, network, or overall genetic architecture levels. Multimorbidities affecting the same and different physiological systems displayed different patterns of the shared genetic components, with the former more likely to share loci-level genetic components while the latter more likely to share network-level genetic components. Moreover, both the loci- and network-level genetic components shared by multimorbidities converged on cell immunity, protein metabolism, and gene silencing. Furthermore, we found that the genetically interpretable multimorbidities tend to form network modules, mediated by hub diseases and featuring physiological categories. Finally, we showcased how hub diseases mediating the multimorbidity modules could help provide useful insights for the genetic contributors of multimorbidities. Conclusions Our results provide a systematic resource for understanding the genetic predispositions of multimorbidities and indicate that hub diseases and converged molecules and functions may be the key for treating multimorbidities. We have created an online database that facilitates researchers and physicians to browse, search, or download these multimorbidities ( https://multimorbidity.comp-sysbio.org ).
Abstract 10372: Human Cardiomyocyte Protection From Apoptosis by Cardiac Progenitor Cell Secreted Factors
Authors: Chrystalla Constantinou, Michela Noseda, Patricia Chaves, Antonio M Miranda, Mohamed Bellahcene, Kevin Cheng, Sian Harding, Michael D Schneider
Journal: Circulation (2019)

Myocardial infarction is the foremost cause of death globally, and progression to heart failure is proportional to infarct size. Prevention of cardiomyocyte loss is vital to halt cardiac damage. Ou...
Показники ферокінетики та регуляція метаболізму заліза у хворих на хронічні запальні захворювання кишечника
Authors: T.Y. Boiko, S.Yu. Yehorova, H.S. Paranko, O.V. Sorochan, I.A. Klenina, O.P. Petishko
Journal: GASTROENTEROLOGY (2014)

У статті наведено дані параметрів метаболізму заліза та цитокінів (IL-6 і TNF-α) у хворих на хронічні запальні захворювання кишечника (ХЗЗК). Матеріалом для дослідження була кров 69 пацієнтів із ХЗЗК з анемією та 26 — без анемії. Вивчено особливості основних показників ферокінетики (заліза, загальної залізозв’язуючої здатності сироватки, насичення трансферину залізом, феритину, трансферинового рецептора, еритропоетину, гепсидину) залежно від рівня гемоглобіну та типу анемії. Показано взаємозв’язок порушень обміну заліза з рівнем прозапальних цитокінів (IL-6 та TNF-α).
Plasma Lipids, Lipoproteins, and Apolipoproteins and Incident Ischemic Stroke:
Authors: Eyal Shahar, Lloyd E Chambless, Wayne D Rosamond, Lori L Boland, Christie M Ballantyne, Paul G McGovern, A. Richey Sharrett
Journal: Circulation (2001)

P63 The role of plasma lipids, lipoproteins, and apolipoproteins in the pathogenesis of ischemic stroke is unclear. We examined the association of incident hospitalized ischemic stroke with baseline plasma measurements of LDL-cholesterol, apoB, HDL-cholesterol, apoA-1, and triglycerides in a population-derived sample of 14,175 middle-aged men and women. Over an average follow up of 8.2 years, we documented 233 incident ischemic strokes (120 in men; 113 in women). After multivariable adjustment for stroke risk factors, categorical analysis revealed weak, inconsistent, and statistically non-significant associations between ischemic stroke and the five analytes. For example, the adjusted hazard ratios (95% CI) of ischemic stroke for the top fourth versus the bottom fourth were 1.17 (0.81-1.68) for LDL-cholesterol; 1.29 (0.90-1.87) for apoB; 0.90 (0.57-1.41) for HDL-cholesterol; 0.83 (0.55-1.26) for apoA-1; and 1.25 (0.82-1.92) for triglycerides. Sex-specific analysis (supported by evidence of statistical interaction) indicated lack of any association in men. In women, however, we observed moderate associations of ischemic stroke with LDL-cholesterol, apoB, and triglycerides, primarily restricted to the right tail of their distributions. Hazard ratios of ischemic stroke in women are shown in the table below. These findings are compatible with the following hypotheses: 1) The effect of LDL-cholesterol, apoB, and triglycerides on ischemic stroke might differ qualitatively between men and women; 2) The pathogenesis of a substantial proportion of ischemic strokes (e.g., lacunar strokes) does not involve classical atherosclerotic mechanisms. Table 1.
Abstract 556: Highly complex DNA sequencing library preparation for cfDNA enrichment panels using a single-stranded approach
Authors: Charles J. Vaske, Chris Troll, Camille Schwartz, Colin Naughton, Abdullah Mahmood Ali, Azra Raza, Varsha Rao, Kelly Harkins-Kincaid, Richard Edward Green
Journal: Cancer Research (2021)

Abstract DNA sequencing library preparation is a crucial step for next-generation sequencing of cell free DNA of plasma for cancer diagnostics. We present SRSLY, a robust single-stranded DNA library preparation method, that generates libraries with unique molecule identifiers (UMIs), with advantages over traditional double-stranded DNA preparations. Using 5 ng of plasma-derived cfDNA from acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), and gastrointestinal cancer cases, we prepared both SRSLY and double-stranded DNA (dsDNA) sequencing libraries with UMIs. The libraries were enriched using a Twist Biosciences custom hybridization probe set for an 800 kilobase cancer mutation panel. We sequenced to a panel depth of 1000x to 2000x, after correcting UMI sequences and removing duplicate reads. With comparable fold enrichment and on-target percentages, we observe complexities of 11-21 million unique molecules with SRSLY. This is approximately four times higher than dsDNA complexity of 2.8-4.9 million unique molecules. Using duplicate reads from the same unique molecule, we perform error correction on template read bases and are able to call low-variant allele frequency mutations. In particular, we show an increase in KRAS p.G12D variant allele fraction during progression from MDS to AML. SRSLY shows increased recovery of small fragments over dsDNA preparations and retains the native lengths and termini of all fragments. Apart from improved library complexity, we show that MDS and AML samples can be distinguished from healthy samples by their disrupted genomic profile of short to long fragments, which has been previously demonstrated in solid tumors but not for MDS or AML. Citation Format: Charles J. Vaske, Chris Troll, Camille Schwartz, Colin Naughton, Abdullah Mahmood Ali, Azra Raza, Varsha Rao, Kelly Harkins-Kincaid, Richard Edward Green. Highly complex DNA sequencing library preparation for cfDNA enrichment panels using a single-stranded approach [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 556.
Abstract 1325: Overexpression of Tribbles 2 enhances prostate cancer cell growth and contributes to enzalutamide resistance
Authors: Jitender Monga, Parshva Sanghvi, Jagadananda Ghosh
Journal: Cancer Research (2021)

Abstract Background: Enzalutamide, an FDA-approved androgen receptor blocker, is commonly prescribed for advanced prostate cancer which slows down prostate tumor growth. However, therapeutic benefit of enzalutamide is temporary because enzalutamide-resistant prostate cancer (ERPC) invariably develops which is incurable, primarily because currently available therapies cannot effectively kill ERPC cells. Molecular basis behind enzalutamide-resistance is not clearly understood, which is delaying progress towards development of new therapies. Thus, proper molecular characterization of ERPC cells is an urgent and unmet medical need to find appropriate targets to improve the current state of ERPC therapy. Methods: We developed an ERPC model by chronically treating prostate cancer cells to mimic the clinical conditions of Enzalutamide resistance. These ERPC cells were used for comprehensive gene expression analysis by Illumina Hi-Seq whole genome gene-expression array. Hits were confirmed by RT-PCR and Western blot. Regulation of expression and pro-cancer effects of new hits were determined by overexpression and/or treating cells with shRNA and analyzing cell viability, soft-agar colony formation, apoptosis, and effects on downstream targets. Results: Transcriptional profiling revealed that Tribbles 2 (Trib2), a pseudokinase, is overexpressed in ERPC cells. Elevated level of Trib2 was also observed in enzalutamide treated PDX tumors in mice, and in prostate tumors from patients who were treated with enzalutamide. Inhibition of Trib2 by shRNA effectively kills ERPC cells, suggesting that Trib2 plays an important role in ERPC. We found that the Trib2 protein level is especially higher in prostate cancer cells where the AR activity is either low, or absent due to genetic changes. Moreover, transfection and re-expression of the AR gene in AR-negative cells decreases Trib2 protein level, indicating that the expression of Trib2 is negatively regulated by androgenic signaling. Interestingly, forced overexpression of Trib2 results in faster prostate cancer cell growth and makes the cells completely resistant to enzalutamide, and inhibition of Trib2 by shRNA or chemical inhibitor decreases viability and re-sensitizes these cells to enzalutamide. Conclusion: Collectively, our findings reveal that Trib2 is overexpressed in ERPC cells and tumors, and suggest that Trib2 may turn out to be a novel, promising molecular target for therapy of enzalutamide-resistant, lethal prostate cancer. Citation Format: Jitender Monga, Parshva Sanghvi, Jagadananda Ghosh. Overexpression of Tribbles 2 enhances prostate cancer cell growth and contributes to enzalutamide resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1325.
Indocyanine green guidance during 3D augmented reality robot assisted partial nephrectomy: A step towards the “automatic” overlapping
Authors: F. Porpiglia, D. Amparore, F. Piramide, E. Checcucci, P. Verri, G. Volpi, S. De Cillis, A. Piana, P. Piazzolla, A. Bellin, M. Manfredi, E. Vezzetti, C. Fiori
Journal: European Urology (2021)
Abstract 3041: ASPSCR1-TFE3 gene fusion in transgenic mouse as a new pediatric kidney cancer model
Authors: Aylin Alasonyalilar-Demirer, James L. Miller, Erin E. Miller, Justyna J. Gleba, Han W. Tun, John A. Copland
Journal: Cancer Research (2021)

Abstract A novel genetically engineered mouse (GEM) model for pediatric kidney cancer expressing proximal tubule specific ASPSCR1 :TFE3 fusion gene has been developed. The Rosa26 knock-in ASPSCR1 :TFE3 mouse was crossed with SGLT2-Cre mouse that expresses Cre recombinase in the proximal tubules of the kidney. The ASPSCR1 :TFE3 fusion gene retains the DNA binding and activation domain of TFE3, whereas the N-terminal region of TFE3 is replaced with ASPSCR1 sequences. ASPSCR1 :TFE3 is known to up-regulate the Met receptor tyrosine kinase gene and induce oncogenic phenotypes such as uncontrolled cell proliferation, invasion, and metastasis. However, the molecular roles of ASPSCR1 :TFE3 are poorly understood and no standard of care (SOC) exists for pediatric TFE3 fusion renal cell carcinoma (RCC). Ultrasound (US) and histological analyses of the kidneys of 5, 6 and 7 month old mice revealed bilateral cysts and tumors, while 6-week-old mouse kidney appears normal. At gross inspection, 5-month-old mouse had cysts with a diameter of 1-2 mm while 7-month-old mouse had a polycystic kidney and in the end stage disease. Histopathology revealed neoplastic changes in initial stages in the 5-month-old mouse whereas the neoplasia was predominantly a papillary cystic renal carcinoma; solid tumor formations were observed in the 7-month-old mouse. Neoplastic cells seen in within the blood vessel walls of the 7-month-old mouse indicated future metastasis. This new TFE3 fusion GEM will provide an avenue to understand molecular events of tumorigenesis and progression as well as a model for testing novel therapeutics with survival benefit for a cancer with no current SOC. Citation Format: Aylin Alasonyalilar-Demirer, James L. Miller, Erin E. Miller, Justyna J. Gleba, Han W. Tun, John A. Copland. ASPSCR1-TFE3 gene fusion in transgenic mouse as a new pediatric kidney cancer model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3041.
Abstract 3011: Cancer of Unknown Primary: novel therapeutic opportunities from patient-derived cell cultures and in vivo models
Authors: Noemi Laprovitera, Claudia Fumarola, Elisa Porcellini, Stefano Cairo, Giulia Gallerani, Francesco Gelsomino, Irene Salamon, Maria Naddeo, Andrea Ardizzoni, Andrea Cavazzoni, Manuela Ferracin
Journal: Cancer Research (2021)

Abstract Patients with occult primary cancer or cancer of unknown primary (CUP) carry the double burden of an aggressive disease and reduced access to therapies, which are typically tumor-type oriented. Moreover, experimental in-vitro and in-vivo models summing up CUP features and heterogeneity are currently unavailable. We derived and expanded two CUP cell lines, and corresponding patient-derived xenografts (PDXs), from ascites tumor cells. CUP cell lines, one spontaneously growing as organoid, and PDXs were subjected to histological, immune-phenotypical, molecular and genomic (CNV and target sequencing) characterization to show their ability to recapitulate the original tumor. MicroRNA profile and genomic information were used to identify a possible primary site and patient-specific therapeutic approaches. Data on CUP most frequently altered genes were used to design a custom CUP-specific, 92-gene panel for target NGS analysis with Sure Select XS technology (Agilent Technology). Drug-screening assays were performed in vitro and in vivo on two models targeting the most promising actionable pathways. We obtained unexpected and promising results on drug combinations efficacy. This study brings personalized therapy closer to CUP patients and paves the way to future applications of personalized medicine for metastatic patients with adverse prognosis. This work was supported by grants from the Italian Association for Cancer Research (AIRC) to MF (IG 18464). Citation Format: Noemi Laprovitera, Claudia Fumarola, Elisa Porcellini, Stefano Cairo, Giulia Gallerani, Francesco Gelsomino, Irene Salamon, Maria Naddeo, Andrea Ardizzoni, Andrea Cavazzoni, Manuela Ferracin. Cancer of Unknown Primary: novel therapeutic opportunities from patient-derived cell cultures and in vivo models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3011.
Abstract 1664: Inhibition of arginase in combination with radiation therapy shows increased immune-activation and anti-tumor activity in syngeneic tumor models
Authors: Alwin Schuller, Aatman Doshi, Susan Cantin, Matt Griffin, Maryann San Martin, Theresa Proia, Corinne Reimer, Scott Mlynarski, Ray Finlay, Wenlin Shao
Journal: Cancer Research (2021)

Abstract The tumor microenvironment (TME) has multiple mechanisms of immune-suppression including recruitment of arginase (ARG) expressing myeloid cells. ARG is an enzyme that catalyzes hydrolysis of L-arginine into urea and L-ornithine. Given L-arginine is essential for optimal function of both T cells and natural killer (NK) cells, inhibition of ARG has been recognized as a potential therapeutic approach to reverse immune-suppression and optimize anti-tumor immunity. We recently presented development of a novel ARG inhibitor, AZD0011, and demonstrated immune activation and anti-tumor activity as single agent and in combination with a-PD-L1 in various tumor models. We now expand these findings demonstrating combination benefit with radiation therapy. Radiation therapy (5 gray on day 6 and 9 after tumor cell implant) demonstrated an increase of both the number of arginase expressing myeloid cells, and NK cells in the TME of Lewis Lung (LL) tumors. Immuno-histochemistry also demonstrated a redistribution of the location of ARG positive myeloid cells with a marked increase at the edge of the tumor. LL tumor bearing mice receiving either AZD0011 (30 mg/kg twice daily), or radiation therapy as monotherapy did not show a significant anti-tumor response reaching 0.3% and 28% tumor growth inhibition (TGI) respectively (p&amp;gt;0.05 versus vehicle). In contrast, combination treatment showed a marked increased efficacy averaging 60% TGI (p&amp;lt;0.05 versus either monotherapy). Combination treatment also further increased several markers of immune activation including a doubling of the number of IL2+ or IFNg+ CD4+ and CD8+ T-cells in tumor draining lymph nodes. In summary, our pre-clinical data demonstrates that radiation therapy increases the number and location of intra-tumoral ARG expression myeloid cells and increased anti-tumor activity when combining the ARG inhibitor AZD0011 with radiation therapy. Citation Format: Alwin Schuller, Aatman Doshi, Susan Cantin, Matt Griffin, Maryann San Martin, Theresa Proia, Corinne Reimer, Scott Mlynarski, Ray Finlay, Wenlin Shao. Inhibition of arginase in combination with radiation therapy shows increased immune-activation and anti-tumor activity in syngeneic tumor models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1664.
Abstract 2873: Comparison of metastatic and nonmetastatic breast cancer cell survival in glutamine depleted extracellular matrix detached conditions
Authors: Kanika K. Garg, Madeline Sheeley, Dorothy Teegarden
Journal: Cancer Research (2021)

Abstract For women, breast cancer is the most diagnosed cancer, with metastasis being the primary cause of most breast cancer-related deaths. During metastasis, cells detach from the extracellular matrix (ECM) to move to a secondary site. Unlike normal cells, metastatic cells are resistant to cell death upon ECM detachment. The amino acid glutamine is used as an energy source during metastatic progression via replenishing the TCA cycle. Breast cancer cells have decreased viability in the absence of glutamine, but the effect of glutamine in ECM detached conditions in metastatic cells is not known. We hypothesize that metastatic and non-metastatic cells have a decreased viability in ECM detachment in glutamine deprived conditions. In this study, metastatic MCF10CA1a cells and non-metastatic Harvey-ras oncogene transfected MCF10A-ras cells were employed. As expected, in ECM detached conditions, the MCF10A-ras cells had a greater decrease in viability (58.4%) in comparison to the MCF10CA1a cells (32.7%). However, in glutamine deprived conditions, the MCF10CA1a cells decrease in viability was 15.2% greater compared to the MCF10A-ras cells. mRNA expression of the major glutamine transporter, SLC1A5, was decreased in detached conditions in both cell lines, but to a greater extent in the MCF10A-ras cells (70.04%) compared to the MCF10CA1a cells (20.15%). Additionally, mRNA expression in detached conditions of glutamate dehydrogenase, the enzyme that metabolizes the downstream glutamine metabolite glutamate to α-ketoglutarate (αKG), was decreased by 77% in the non-metastatic cells, but increased by 23% in the metastatic cells. Additionally, mRNA expression of GOT1, a gene which encodes for the transaminase enzyme which synthesizes αKG and aspartate from glutamate and oxaloacetate, decreased 73% in detached conditions in the non-metastatic cells but was unchanged in the metastatic cells. Moreover, following detachment the glutamine synthesizing enzyme, glutamine synthetase mRNA expression was increased by 81.92% in the non-metastatic cells and 88.43% in the metastatic cells. In summary, the greater effect of glutamine depletion on viability, and the maintained expression of glutamine metabolizing enzymes in the metastatic cells suggest greater dependence on glutamine metabolism in ECM detached conditions compared to non-metastatic cells. Comparison of metastatic and non-metastatic breast cancer cells will provide insights to direct the development of new targets for the prevention of breast cancer metastasis. Citation Format: Kanika K. Garg, Madeline Sheeley, Dorothy Teegarden. Comparison of metastatic and nonmetastatic breast cancer cell survival in glutamine depleted extracellular matrix detached conditions [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2873.
Novel volumetric and morphologic parameters derived from 3D virtual modelling to improve comprehension of tumour’s anatomy in patients with renal cancer
Authors: L. Bianchi, B. Bortolani, A. Mottaran, L. Cercenelli, S. Boschi, M. Droghetti, E. Molinaroli, F. Chessa, E. Balestrazzi, C. Gaudiano, A. Rustici, A. Cappelli, R. Golfieri, E. Marcelli, R. Schiavina, E. Brunocilla
Journal: European Urology (2021)