tbuckley/cabot-search huggingface dataset:
Relationship Between Diabetic Retinopathy Stages and Risk of Major Lower-Extremity Arterial Disease in Patients With Type 2 Diabetes
Authors: Ninon Foussard, Pierre-Jean Saulnier, Louis Potier, Stéphanie Ragot, Fabrice Schneider, Elise Gand, Marie Monlun, Laurence Baillet-Blanco, Gilberto Velho, Michel Marre, Ronan Roussel, Vincent Rigalleau, Kamel Mohammedi, Samy Hadjadj
Journal: Diabetes Care (2020)

OBJECTIVE We evaluated the association between diabetic retinopathy stages and lower-extremity arterial disease (LEAD), its prognostic value, and the influence of potential contributors to this relationship in a prospective cohort of patients with type 2 diabetes. RESEARCH DESIGN AND METHODS Diabetic retinopathy was staged at baseline as absent, nonproliferative, or proliferative. A Cox regression model was fitted in order to compute the hazard ratio (HR) (95% CI) for major LEAD (lower-limb amputation or revascularization) during follow-up by baseline retinopathy stages. The retinopathy-LEAD association was assessed in subgroups by age, sex, diabetes duration, HbA1c, systolic blood pressure, diabetic kidney disease, smoking, and macrovascular disease at baseline. The performance of retinopathy in stratifying LEAD risk was assessed by using the C statistic, integrated discrimination improvement (IDI), and net reclassification improvement (NRI). RESULTS Among 1,320 participants without a history of LEAD at baseline, 94 (7.1%) developed a major LEAD during a 7.1-year median follow-up (incidence rate 9.6 per 1,000 person-years [95% CI 7.8–11.7]). The LEAD incidence rate (per 1,000 person-years) increased as retinopathy worsened: it was 5.5 (95% CI 3.9–7.8) in participants in whom retinopathy was absent, 14.6 (11.1–19.3) in those with nonproliferative retinopathy, and 20.1 (11.1–36.3) in those with proliferative retinopathy. Nonproliferative retinopathy (adjusted HR 2.31 [95% CI 1.43–3.81], P = 0.0006) and proliferative retinopathy (3.14 [1.40–6.15], P = 0.007) remained associated with major LEAD. No heterogeneity was observed across subgroups. Retinopathy enhanced the C statistic (+0.023 [95% CI 0.003–0.044], P = 0.02), IDI (0.209 [0.130–0.321], P &amp;lt; 0.001), and NRI (0.562 [0.382–0.799], P &amp;lt; 0.001) values for risk of LEAD, beyond traditional risk factors. CONCLUSIONS An independent dose-response relationship was identified between diabetic retinopathy stages and major LEAD. Retinopathy yielded incremental prognostic information for stratifying risk of LEAD, suggesting its usefulness as a predictor of LEAD.
Abstract 1682: Epithelial-mesenchymal heterogeneity of high-grade serous ovarian carcinoma samples correlates with let-7 levels and predicts tumor growth and metastasis
Authors: Juli Unternaehrer, Evgeny Chirshev, Nozomi Hojo, Antonella Bertucci, Linda Sanderman, Anthony Nguyen, Hanmin Wang, Tise Suzuki, Emmanuel Brito, Shannalee Martine, Christine Castañón, Saied Mirshahidi, Marcelo Vazquez, Kerby C. Oberg, Yevgeniya J. Ioffe
Journal: Cancer Research (2020)

Abstract Objective: Patient-derived samples present an advantage over current cell line models of high grade serous ovarian cancer (HGSOC), which are flawed in terms of being reliable and phenotypically faithful models of in vivo HGSOC. To improve upon cell line models of HGSOC, we characterized a panel of patient-derived cells to determine their epithelial and mesenchymal characteristics, invasiveness, proliferation, stemness, and in vivo growth. Experimental procedures: Patient-derived xenograft (PDX) models of HGSOC were analyzed in vitro for phenotypic (RNA, let-7 miRNA, and protein expression, flow cytometry) and functional aspects including growth in spheroids, wound healing assays, invasion assays and in vivo (orthotopic PDX) growth characteristics. Results: Samples fell along the spectrum from epithelial to mesenchymal, and all had hybrid characteristics. Those toward the more epithelial end of the spectrum were most active in self-renewal assays, and grew most robustly in orthotopic xenograft models. Chemoresistance correlated both with the mesenchymal state and with BRCA2 wild type status. Loss of microRNA let-7 (lethal-7) is an important component of the cancer stem cell phenotype, and we observed an inverse association between let-7 expression and the epithelial state. We observed lower levels of let-7, more efficient spheroid and tumor formation, and increased sensitivity to platinum-based chemotherapy in cells with the most epithelial phenotype. Conclusions: Surprisingly, in these HGSOC cells, stemness could be dissociated from invasiveness: epithelial cells (those with least let-7 expression) were less migratory, but more tumorigenic, than the mesenchymal cells with higher let-7 expression. We conclude that epithelial/mesenchymal state and let-7 expression are valuable predictors of HGSOC proliferation, in vitro self-renewal, and tumor burden in vivo. Citation Format: Juli Unternaehrer, Evgeny Chirshev, Nozomi Hojo, Antonella Bertucci, Linda Sanderman, Anthony Nguyen, Hanmin Wang, Tise Suzuki, Emmanuel Brito, Shannalee Martine, Christine Castañón, Saied Mirshahidi, Marcelo Vazquez, Kerby C. Oberg, Yevgeniya J. Ioffe. Epithelial-mesenchymal heterogeneity of high-grade serous ovarian carcinoma samples correlates with let-7 levels and predicts tumor growth and metastasis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1682.
Access to intensive care in 14 European countries: a spatial analysis of intensive care need and capacity in the light of COVID-19
Authors: Jan Bauer, Dörthe Brüggmann, Doris Klingelhöfer, Werner Maier, Lars Schwettmann, Daniel J. Weiss, David A. Groneberg
Journal: Intensive Care Medicine (2020)

The coronavirus disease 2019 (COVID-19) poses major challenges to health-care systems worldwide. This pandemic demonstrates the importance of timely access to intensive care and, therefore, this study aims to explore the accessibility of intensive care beds in 14 European countries and its impact on the COVID-19 case fatality ratio (CFR). We examined access to intensive care beds by deriving (1) a regional ratio of intensive care beds to 100,000 population capita (accessibility index, AI) and (2) the distance to the closest intensive care unit. The cross-sectional analysis was performed at a 5-by-5 km spatial resolution and results were summarized nationally for 14 European countries. The relationship between AI and CFR was analyzed at the regional level. We found national-level differences in the levels of access to intensive care beds. The AI was highest in Germany (AI = 35.3), followed by Estonia (AI = 33.5) and Austria (AI = 26.4), and lowest in Sweden (AI = 5) and Denmark (AI = 6.4). The average travel distance to the closest hospital was highest in Croatia (25.3 min by car) and lowest in Luxembourg (9.1 min). Subnational results illustrate that capacity was associated with population density and national-level inventories. The correlation analysis revealed a negative correlation of ICU accessibility and COVID-19 CFR (r = − 0.57; p < 0.001). Geographical access to intensive care beds varies significantly across European countries and low ICU accessibility was associated with a higher proportion of COVID-19 deaths to cases (CFR). Important differences in access are due to the sizes of national resource inventories and the distribution of health-care facilities relative to the human population. Our findings provide a resource for officials planning public health responses beyond the current COVID-19 pandemic, such as identifying potential locations suitable for temporary facilities or establishing logistical plans for moving severely ill patients to facilities with available beds.
Abstract 1277: SPARCL1 exhibits different expression pattern between left- and right- sided colon cancer and it was down-regulated via DNA methylation
Authors: Dehao Wu, Wen Cai, Junxi Xu, Xue Liu, Rui Bai, Shu Zheng, Weiting Ge, Hanguang Hu
Journal: Cancer Research (2020)

Abstract Background: We previously identified SPARC-like 1 (SPARCL1) as a suppressor for colon cancer metastasis. Recent studies confirmed its epigenetic modification in prostate cancer and osteosarcoma. Here we conducted in vivo and in vitro studies to investigate the mechanism of SPARCL1 epigenetic regulation and the relationship with clinicopathological features. Method: Tissue array (271 left- [LCC] and 257 right-sided colon cancer [RCC]) and immunohistochemistry were performed to measure SPARCL1 expression. Methylation status was compared by bisulfite sequencing PCR between 17 LCC and 16 RCC. Epigenetic alteration and rescue experiment were performed in colon cancer cell lines (HCT-116, RKO and HT-29) using decitabine, panobinostat, or siRNA. Transwell assay was employed to compare cell mobility. Chi-square test, Mann-Whitney U test were used for comparing SPARCL1 expression or other clinical characteristics, and t-test for cell motility. Result: RCC significantly lower expressed SPARCL1 protein than LCC (P =0.007). High methylated CpG site of SPARCL1 enriched in RCC not in LCC (56.25% vs. 29.41%). In vitro studies confirmed that decitabine could up regulate SPARCL1 transcription by 72-fold. Transwell assays further revealed that significant inhibition of decitabine in decreasing cells invasion and migration properties, which could be rescued by siRNA against SPARCL1. In addition, we didn't observe transcriptional alteration with panobinostat treatment. Conclusion: DNA methylation not histone acetylation modulated SPARCL1 expression and suppress tumor metastasis, which may contribute to aberrant expression pattern and different clinical outcomes varying in left and right-colon cancer. Citation Format: Dehao Wu, Wen Cai, Junxi Xu, Xue Liu, Rui Bai, Shu Zheng, Weiting Ge, Hanguang Hu. SPARCL1 exhibits different expression pattern between left- and right- sided colon cancer and it was down-regulated via DNA methylation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1277.
Long-Term Survival of Older Patients with Myelodysplastic Syndromes Treated with Hypomethylating Agent Therapy: A Large Population-Based Analysis
Authors: Maximilian Stahl, Xin Hu, Rong Wang, Xiaomei Ma, Scott Huntington, Nikolai A. Podoltsev, Steven D. Gore, Gregory A. Abel, Amy J. Davidoff, Amer M. Zeidan
Journal: Blood (2017)
OP0063 Three months results of a double-blind placebo controlled, phase-iii clinical trial of infliximab in active ankylosing spondylitis
Authors: J Brandt, R Alten, G Burmester, E Gromnica-Ihle, H Kellner, M Schneider, H Sörensen, H Zeidler, W Thriene, J Sieper, J Braun
Journal: Annals of the Rheumatic Diseases (2001)

<h3>Background</h3> Recently, patients with severe ankylosing spondylitis (AS) significantly improved upon treatment with the anti-tumour necrosis factor a (TNFa) antibody infliximab (RemicadeR) in an open pilot study (A&amp;R June 2000). Therefore, a placebo-controlled trial was designed to prove that the administration of infliximab has a beneficial effect on the short and long term course of severe AS. <h3>Objectives</h3> <h3>Methods</h3> Seventy patients (47 men, 23 women) with a mean age of 39.2 years and proven AS (1984 New York criteria) in an active stage of disease were included in the study. Active disease was defined as a Bath AS Disease Activity Index (BASDAI) &gt; 4 and pain &gt; 4 on a numeric rang scale (NRS). The patients were randomised into two groups of 35 patients each which received either infliximab in a dosage of 5 mg/kg i.v. or placebo. Infusions were given at week 0, 2 and 6 and then every 6 weeks until week 48. The BASDAI, BASFI (Functional Index), BASMI (Metrology Index), pain on a NRS, quality of life by the SF36 and CRP were measured. Patients with &gt; 50% improvement of BASDAI was defined as a responder. The study started on August 15th 2000; the last patient was included on 19th October 2000. <h3>Results</h3> The last patient has finished the placebo-controlled part of the study on January 25th 2001. Sixty-six patients have completed the three-months placebo-controlled period. One patient developed tuberculosis. The three-months-follow up data which are just being analysed are presented at the EULAR-Meeting in June 2001. <h3>Conclusion</h3> The subjective therapeutic efficacy in some of the patients was impressive but the results of the ongoing analysis have to be awaited.
Abstract 2491: Targeted next generation sequencing identifies somatic variants in Egyptian breast cancer patients
Authors: Auhood Nassar, Mohamed abouelhoda, Abeer Bahnassy, Amira Salah El-Din Youssef, Mai M. Lotfy, ola S. Ahmed, Hoda Ismail, Abdel-Rahman N. Zekri
Journal: Cancer Research (2020)

Abstract Breast cancer (BC) is the leading cause of cancer-related death in women worldwide and its incidence is progressively increasing in Egypt. Recent advances in next generation sequencing have been used to detect the acquired somatic mutations driving BC. However, there is insufficient knowledge of the acquired somatic mutations in Egyptian BC patients which limit our understanding of disease progression. Up to our knowledge, this is the first Egyptian cohort to sequence a multiple-gene panel of cancer related genes on BC patients. 409 cancer related genes were sequenced in 46 fresh breast tumors of Egyptian BC patients to identify somatic mutations and their frequencies, using the Ion Ampliseq Comprehensive Cancer Panel based on the Ion torrent DNA sequencing technology. The identified sequences were mapped to the human reference genome (hg19) and the detected genetic variants were annotated against different reference databases. The average depth of coverage is 668X and the average of the aligned reads which cover the target regions is 99.6%. Our results showed that TP53 and PIK3CA were the most top two frequently mutated genes. We detected 15 different somatic mutations in TP53 and 8 different ones in PIK3CA, each in 27 samples (58.7%). Most of the detected somatic mutations in TP53 and PIK3CA are pathogenic and well established in known hotspot regions. According to Clinvar database; we found 19 pathogenic somatic mutations: 7 in p53, 5 in PIK3CA, and single variants of VHL, STK11, AKT1, KRAS, IDH2, PTEN and ERBB2. We also identified 5 variants with uncertain significance (4 in TP53 and 1 in CEBPA) and 4 variants with conflicting interpretations of pathogenicity (2 in TP53 and 1 in each of APC and JAK3). Moreover, 4 novel variants were identified in JAK2, MTOR, KIT and EPHB. In this cohort, we shed the light on the most frequently detected somatic mutations in Egyptian BC patients which allows for more knowledge about BC progression. Citation Format: Auhood Nassar, Mohamed abouelhoda, Abeer Bahnassy, Amira Salah El-Din Youssef, Mai M. Lotfy, ola S. Ahmed, Hoda Ismail, Abdel-Rahman N. Zekri. Targeted next generation sequencing identifies somatic variants in Egyptian breast cancer patients [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2491.
Abstract 5166: <i>In silico</i> identification of specific inhibitor(s) of tumor associated Vacuolar ATPase ‘a2' isoform: A critical target for anti-cancer drug development
Authors: Arpita Kulshrestha, Gajendra K. Katara, Awanish Kumar, Kenneth D. Beaman
Journal: Cancer Research (2020)

Abstract The discovery of effective anti-cancer therapies has immense consequences on global health. Vacuolar (H+)-ATPases (V-ATPases) are multi-subunit nano-motors that acidify the lumen of intracellular organelles in normal physiology. In cancer cells, the plasma membrane V-ATPases acidify the extracellular space. This is critical in tumor invasion, metastasis, and chemo-resistance. The `a2` isoform of V-ATPase (a2V) is the major pH sensing unit of this complex and is distinctly overexpressed on the surface of cancer cells making it an excellent drug target. The chemical inhibitors such as bafilomycin/concanamycin target V-ATPase subunits also critical in normal cell function. Currently, there are no selective a2V inhibitors commercially available as anti-cancer agents. Here, we employed in silico molecular modeling to analyze specific a2V binding sites in order to design targeted small molecules a2V inhibitors. We have identified several natural compounds as a2V ligands which inhibit specifically a2V in cancer. Employing human ovarian and breast epithelial cells (normal or tumor), in vitro studies measured each a2V ligand(s) effects on cancer cell proliferation. We selected five a2V ligands showing the most potent anti-proliferative activity in cancer cells and were least toxic to normal cells. We further measured each ligand(s) effects on specific ATPase activity in vitro by determining the decrease in inorganic phosphate levels. Next, the two most potent a2v ligands (KDB001, KDB002) which belonged to alkaloid and mono-terpenoid phenol groups, were selected to measure the changes in cytosolic and extracellular pH- SNARF assay and pH of cell supernatants. KDB001 induced cytosolic pH acidification in a dose-dependent manner indicating inhibition of V-ATPase activity. Based on the above experiments, the best ligand with most prominent effect on a2V activity (KDB-001) was further validated in vivo for anti-ovarian cancer efficacy in an athymic nude mouse model. KDB001 administration resulted in a significant delay in in vivo ovarian tumor growth. Studies are underway to design and synthesize more efficient analogs for KDB001 molecular modelling, toxicity assessment and chemical synthesis approach. In conclusion, the study has discovered new inhibitors of V-ATPase-a2V, positioning these promising compounds to enter the anti-cancer drug development pipeline. Citation Format: Arpita Kulshrestha, Gajendra K. Katara, Awanish Kumar, Kenneth D. Beaman. In silico identification of specific inhibitor(s) of tumor associated Vacuolar ATPase ‘a2' isoform: A critical target for anti-cancer drug development [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5166.
Advances in synthetic lethality for cancer therapy: cellular mechanism and clinical translation
Authors: Win Topatana, Sarun Juengpanich, Shijie Li, Jiasheng Cao, Jiahao Hu, Jiyoung Lee, Kenneth Suliyanto, Diana Ma, Bin Zhang, Mingyu Chen, Xiujun Cai
Journal: Journal of Hematology & Oncology (2020)

Abstract Synthetic lethality is a lethal phenomenon in which the occurrence of a single genetic event is tolerable for cell survival, whereas the co-occurrence of multiple genetic events results in cell death. The main obstacle for synthetic lethality lies in the tumor biology heterogeneity and complexity, the inadequate understanding of synthetic lethal interactions, drug resistance, and the challenges regarding screening and clinical translation. Recently, DNA damage response inhibitors are being tested in various trials with promising results. This review will describe the current challenges, development, and opportunities for synthetic lethality in cancer therapy. The characterization of potential synthetic lethal interactions and novel technologies to develop a more effective targeted drug for cancer patients will be explored. Furthermore, this review will discuss the clinical development and drug resistance mechanisms of synthetic lethality in cancer therapy. The ultimate goal of this review is to guide clinicians at selecting patients that will receive the maximum benefits of DNA damage response inhibitors for cancer therapy.
Eighteen Coral Genomes Reveal the Evolutionary Origin of <i>Acropora</i> Strategies to Accommodate Environmental Changes
Authors: Chuya Shinzato, Konstantin Khalturin, Jun Inoue, Yuna Zayasu, Miyuki Kanda, Mayumi Kawamitsu, Yuki Yoshioka, Hiroshi Yamashita, Go Suzuki, Noriyuki Satoh
Journal: Molecular Biology and Evolution (2020)

The genus Acropora comprises the most diverse and abundant scleractinian corals (Anthozoa, Cnidaria) in coral reefs, the most diverse marine ecosystems on Earth. However, the genetic basis for the success and wide distribution of Acropora are unknown. Here, we sequenced complete genomes of 15 Acropora species and 3 other acroporid taxa belonging to the genera Montipora and Astreopora to examine genomic novelties that explain their evolutionary success. We successfully obtained reasonable draft genomes of all 18 species. Molecular dating indicates that the Acropora ancestor survived warm periods without sea ice from the mid or late Cretaceous to the Early Eocene and that diversification of Acropora may have been enhanced by subsequent cooling periods. In general, the scleractinian gene repertoire is highly conserved; however, coral- or cnidarian-specific possible stress response genes are tandemly duplicated in Acropora. Enzymes that cleave dimethlysulfonioproprionate into dimethyl sulfide, which promotes cloud formation and combats greenhouse gasses, are the most duplicated genes in the Acropora ancestor. These may have been acquired by horizontal gene transfer from algal symbionts belonging to the family Symbiodiniaceae, or from coccolithophores, suggesting that although functions of this enzyme in Acropora are unclear, Acropora may have survived warmer marine environments in the past by enhancing cloud formation. In addition, possible antimicrobial peptides and symbiosis-related genes are under positive selection in Acropora, perhaps enabling adaptation to diverse environments. Our results suggest unique Acropora adaptations to ancient, warm marine environments and provide insights into its capacity to adjust to rising seawater temperatures.
Controlling the COVID-19 pandemic in Brazil: a challenge of continental proportions
Authors: Mayra Monteiro de Oliveira, Trevon L. Fuller, Patricia Brasil, Claudia R. Gabaglia, Karin Nielsen-Saines
Journal: Nature Medicine (2020)

Five months into the
COVID-19 epidemic, as of 19 August
2020, Brazil reported a total of 3,407,354
PCR-confirmed cases and 109,888 deaths
due to COVID-19, a case fatality rate (CFR)
of 3.2%.
These numbers likely reflect a
massive underestimate as individuals who
are asymptomatic, pauci-symptomatic
or pre-symptomatic are often not tested,
while contact tracing remains limited.

The rapid spread of COVID-19 in Brazil is
attributable to many factors, including urban
density, timing of the implementation and
maintenance of social distancing policies,
and limited testing capacity. Furthermore, as
of late June 2020, as a result of economic and
political pressures, many Brazilian states have
lifted restrictions on businesses and shared
spaces despite increasing numbers of cases.