tbuckley/cabot-search huggingface dataset:
Landscape of somatic DNA damage repair (DDR) gene mutations in genitourinary cancer in China.
Authors: Kaiwei Yang, Qi Tang, Yue Mi, Wei Yu, Yi Song, Yanrui Zhang, Huina Wang, Feng Lou, Shanbo Cao, Zhisong He
Journal: Journal of Clinical Oncology (2020)

e17516 Background: DDR gene alterations(GAs) are prevalent in cancer and play key roles in tumorigenesis, progression and therapeutic response. However, the molecular profile of DDR in genitourinary cancer is still lacking in Asian. In this study, we assessed DDR GAs for better understanding therapeutic implications. Methods: Patients(pts) diagnosed with genitourinary cancer were enrolled. Tumors and plasma samples were collected for next-generation sequencing with Acornmed panel(2.0 Mbp) containing 808 cancer-related genes, including 34 DDR genes(Jonathan, et al.). OncoKB and COSMIC were used to identify GAs status including deleterious, unknown significance, and wild type(wt). Results: A total of 140 pts were enrolled with 56 pts of prostate cancer(PC), 55 pts of renal cell cancer(RCC) and 29 pts of urothelial cancer(UC). Metastatic diseases were accounted for 33.5%. A total of 127 tumor tissues and 109 baseline plasma samples were collected, including 96 matched tissue/plasma samples. A total of 109 pts(77.9%) harbored at least one GA in DDR pathway. UC carried the most DDR GAs(93.1 %), followed by PC(75%) and RCC(72.7%). After stratifying GA status, the most commonly deleterious GAs were ATM(n = 5); FANCA(n = 4); ERCC2, BRCA1, ATR, CHEK2(n = 2 each); MSH6, ERCC4, BRCA2, PALB2(n = 1 each).Tumor mutation burden(TMB) was significantly different among pts with deleterious, unknown significance and wt in PC(Mean: 17.8 vs 9.065 vs 4.468; p = 0.0003). Notably, DDR GAs were more likely to present in pts with metastatic disease(80.95% vs 62.50%), deleterious DDR GAs as well(14.29% vs 8.33%). Conclusions: DDR pathways are frequently altered in genitourinary cancer, especially UC in China. DDR GAs were significantly associated with higher TMB in PC. A higher prevalence was identified in metastatic disease. Comprehensive genomic profiling of DDR GAs highlights the clinical and therapeutic implication. Further exploration of the deleterious nature and alterations of unknown significance are required. [Table: see text]
Relative and absolute risk of second primary neoplasms of the central nervous system.
Authors: Elisa Liu, Cheongeun Oh, Erik P. Sulman
Journal: Journal of Clinical Oncology (2020)

1593 Background: Cranial radiation is known to increase the relative risk for developing a second primary neoplasm, but existing analyses do not take into account differential survival or follow-up. The absolute risk, or true incidence, of developing a second primary neoplasm in the central nervous system (CNS) is not well characterized. Methods: Patients diagnosed with cancer from between 1976 and 2016 were sampled using the Surveillance, Epidemiology, and End Results (SEER) Program. Relative risks were estimated using standardized incidence ratios (SIRs) and absolute risks were estimated using cumulative incidence (CI) functions with death as a competing risk. Among CNS primaries, comparison groups were matched by age, sex, year of diagnosis, primary histology, and lesion location. Results: Over 3.8 million patient records, including 13,167 second primary CNS tumors, were extracted from SEER. The relative risk of developing a second primary CNS neoplasm is elevated in all patients diagnosed with a CNS primary cancer (SIR = 9.6), but higher in those who received radiation (SIR = 13.1) or chemotherapy (SIR = 12.6). The absolute risk of developing a second primary CNS neoplasm at 25-years is highest in CNS and endocrine cancers (CI 1.0% and 0.50%, respectively). Among long-term ( &gt; 10-year) survivors of CNS primaries, the 25-year CI of a second primary CNS neoplasm was 4.4%. Cranial radiation increased the incidence of second primary tumors in pediatric patients (25-year CI 4.8% vs 1.2%, p = 0.007), but not adults (25-year CI 5.1% vs 4.9%, p = 0.85). Chemotherapy did not increase CI in either pediatric (25-year CI 7.0% vs 5.4%, p = 0.87) or adult (25-year CI 3.6% vs 5.8%, p = 0.11) populations. Meningiomas (39.3% vs 22.0%, p = 1e-6) and glioblastomas (21.1% vs 14.6%, p = 0.03) represent a greater proportion of the second primary CNS tumors in those who received cranial irradiation. Conclusions: The risk of developing a second primary CNS neoplasm is elevated in patients with a prior CNS cancer. Cranial irradiation increased the CI of second primary tumors in pediatric patients but did not affect adult patients. The association between radiation therapy and risk for subsequent cancers may be limited to the pediatric population.
生后使用苯巴比妥钠预防早产儿脑室周围-脑室内出血的临床价值
Authors: 陈妍华, 朱立春, 李坚, 古梅, 秦桂莲, 孙平, 刘敬
Journal: BMJ (2006)

为探讨生后常规应用苯巴比妥钠对早产儿脑室周围-脑室内出血的预防价值,将112例早产儿随机分为苯巴比妥钠预防组和对照组,对两组脑室周围-脑室内出血的发生率及重度出血发生率进行比较.结果显示苯巴比妥钠预防组和对照组颅内出血发生率分别为52.0%和56.4%(χ.2= 0.221,P=0.638),重度出血发生率分别为4.0%和17.7%(χ.2= 5.09,P=0.024).产后注射苯巴比妥钠虽不能使早产儿脑室周围-脑室内出血总的发生率降低,但可减少重度出血的发生及减少轻度出血转化为重度出血,因而有较重要的临床实用价值。
Mitochondrial peroxiredoxin 3 is oxidized during Fas and TNF-α mediated apoptosis
Authors: Andrew Cox, Juliet Pullar, Gillian Hughes, Elizabeth Ledgerwood, Mark Hampton
Journal: Cancer Research (2007)

3579  Stimulation of cellular death receptors is proposed to generate oxidants that contribute to the process of apoptosis. Oxidation of the peroxiredoxins and glyceraldehyde phosphate dehydrogenase are two sensitive cellular markers of increased H2O2 production and disruption of thiol homeostasis. We found that of these proteins only peroxiredoxin 3 was oxidised in Jurkat T lymphoma cells treated with anti-Fas antibody. Oxidation was detected at a similar time as activation of effector caspases. Interestingly, all of the peroxiredoxin 3 was captured as a disulfide-linked dimer rather than the overoxidised form, indicative of a disruption of the mitochondrial thioredoxin system rather than increased H2O2 production. Peroxiredoxin 3 oxidation was also observed in U937 cells stimulated with TNF-α, suggesting that this phenomenon may be a general feature of death receptor activated apoptosis. We propose that peroxiredoxin-3 oxidation is indicative of selective disruption of the mitochondrial redox environment, which leads to increased H2O2 production that contributes to apoptosis.
Post-marketing safety surveillance of tumor treating fields (TTFields) in patients with high-grade glioma in clinical practice.
Authors: Wenyin Shi, Deborah T. Blumenthal, Nancy Ann Oberheim Bush, Seid Kebir, Rimas Vincas Lukas, Yoshihiro Muragaki, Jay-Jiguang Zhu, Martin Glas
Journal: Journal of Clinical Oncology (2020)

2542 Background: Tumor Treating Fields (TTFields) are an antineoplastic treatment delivering low intensity, intermediate frequency, alternating electric fields through two pairs of transducer arrays locoregionally applied to tumor bed. TTFields are FDA-approved for glioblastoma (GBM; 200 kHz) and mesothelioma (150 kHz). Safety and effectiveness were demonstrated in the phase III EF-11 and EF-14 trials in recurrent GBM (rGBM) and in newly diagnosed GBM (ndGBM), respectively. The main TTFields-related adverse event (AE) was array-associated manageable skin irritation. We report AEs from TTFields-treated patients in the real-world, clinical practice setting. Methods: Unsolicited, global, post-market surveillance data from TTFields-treated patients (October 2011–February 2019) were retrospectively analyzed using MedDRA v21.1, stratified by region (US, EMEA [Europe, Middle East, Africa], or Japan), diagnosis (ndGBM, rGBM, anaplastic astrocytoma and anaplastic oligodendroglioma, or other brain tumors that includes brain metastases from different cancer types), and years of age (&lt;18, pediatric; 18 to 64, adults; or ≥65, elderly). Results: Of 11,029 patients, 53% had ndGBM, 39% had rGBM (at any line of recurrence), 6% had anaplastic astrocytoma/oligodendroglioma, and 1% had other brain tumors. Most were adults (73%) and 26% were elderly (≥65 years of age). The majority of patients were males (66.3%) compared to females (33.7%), with a ratio representative of a typical GBM population. The most reported TTFields-related AE was array-associated local skin reaction, with an incidence of 38% in ndGBM, 29% in rGBM, 38% in anaplastic astrocytoma/oligodendroglioma, 31% in other brain tumors, 37% in pediatric, 34% in adults, and 36% in elderly patients. Most skin AEs were mild to moderate and resolved with no treatment or over the counter topical ointments. Incidence of other TTFields-related AEs in patients with ndGBM and rGBM, respectively, included heat sensation (under-array warmth; 11%, 10%), electric sensation (under-array tingling; 11%, 9%), and headache (7%, 6%). Conclusions: This retrospective, global, TTFields safety surveillance analysis revealed no new safety signals, with favorable safety and tolerability comparable to published TTFields/GBM trials. The most common TTFields-related AE was array-associated local skin reaction. The safety profile remained consistent among subgroups (diagnosis, age, or region) and total cohort, indicating feasibility in multiple subpopulations, including elderly patients.
An amphipathic peptide targeting the gp41 cytoplasmic tail kills HIV-1 virions and infected cells
Authors: Qian Wang, Shan Su, Jing Xue, Fei Yu, Jing Pu, Wenwen Bi, Shuai Xia, Yu Meng, Cong Wang, Wenqian Yang, Wei Xu, Yun Zhu, Qinwen Zheng, Chuan Qin, Shibo Jiang, Lu Lu
Journal: Science Translational Medicine (2020)

HIV-associated morbidity and mortality have markedly declined because of combinational antiretroviral therapy, but HIV readily mutates to develop drug resistance. Developing antivirals against previously undefined targets is essential to treat existing drug-resistant HIV strains. Some peptides derived from HIV-1 envelope glycoprotein (Env, gp120-gp41) have been shown to be effective in inhibiting HIV-1 infection. Therefore, we screened a peptide library from HIV-1 Env and identified a peptide from the cytoplasmic region, designated F9170, able to effectively inactivate HIV-1 virions and induce necrosis of HIV-1-infected cells, and reactivated latently infected cells. F9170 specifically targeted the conserved cytoplasmic tail of HIV-1 Env and effectively disrupted the integrity of the viral membrane. Short-term monoadministration of F9170 controlled viral loads to below the limit of detection in chronically SHIV-infected macaques. F9170 can enter the brain and lymph nodes, anatomic reservoirs for HIV latency. Therefore, F9170 shows promise as a drug candidate for HIV treatment.
Real-world data on liquid biopsies utilization in lung cancer patients in the community setting: The Mount Sinai experience.
Authors: Kathrin Dvir, Gliceida Galarza Fortuna, Joel M. Haines, Leylah Drusbosky, Christopher Febres-Aldana, Paulina Gines, Estelamari Rodriguez
Journal: Journal of Clinical Oncology (2020)

e21502 Background: Liquid biopsy describes the extraction of circulating tumor DNA (ctDNA) from peripheral blood via next-generation-sequencing (NGS). The yield of adding plasma-based NGS to tissue NGS for the detection of Actionable Mutations (AM) have been reported scarcely and additional “real world” data is needed. Methods: In this retrospective data review, we included patients with non-small cell lung cancer (NSCLC) who had plasma NGS genomic testing ordered between Nov 2014 and July 2019, as part of routine management. Plasma testing was performed using Guardant360 commercial platform and was analyzed for therapeutically AM in: EGFR, ALK, MET, BRCA1, BRCA2, KRAS, ROS1, RET, ERBB2, BRAF, and NTRK2. Results: Over a period of 5 years, 337 samples taken from 279 patients were sent for ctDNA NGS testing. The median age at diagnosis was 73 years [range 36-93, SD:10.4], 51% (N=141) were males and 49% (N=138) were females. Excluding synonymous mutations and variants of unknown significance, 239 samples (71%) and 201 patients (72%) had 705 somatic mutations. Of them, 36% (N=254) were therapeutically actionable and were detected in 139 samples (58%), taken from 106 patients (53%). Commonly detected AM were EGFR (N=127; 50%), KRAS (N=61; 24%), BRAF (N=24; 9.5%), MET (N=23; 9%), RET (N=5; 1.9%), BRCA1 (N=5; 1.9%), BRCA2 (N=4; 1.6%), ERBB2 (N=4; 1.6%) and ALK (N=1, 0.4%). None of the samples had mutations in ROS1, NTRK2. One patient had Microsatellite instability (MSI). Common co-occurring mutations were EGFR and BRAF (N=14), EGFR and MET (N=13) and MET and BRAF (N=10) (p&lt;0.001). Common mutually exclusive mutations were KRAS and EGFR (p&lt;0.001). Tissue NGS analysis was performed in 62/106 patients (58%), with AM found in 45 patients (72%). Concordance agreement in AM between plasma and tissue NGS modalities was detected in 39/45 patients (87%) and was demonstrated in EGFR (N=25), KRAS (N=11), BRAF (N=2) and MET (N=1). In the reminder 6 patients (13%), tissue NGS was discordant from their plasma NGS results. In 44/106 patients, for whom tissue sampling was not performed, utilizing plasma NGS increased AM detection yield by 41%. Conclusions: Integration of plasma NGS testing into the routine management of NSCLC patients demonstrated substantial yield of therapeutically targetable mutations detection rate, when tissue NGS was not available.
First-line PD-1/PD-L1 inhibitor monotherapy for advanced renal cell carcinoma (aRCC): A multi-institutional cohort.
Authors: Whitley Hatton, Arnab Basu, Vadim S Koshkin, Deepak Kilari, Ellen Jaeger, Elisa Marie Ledet, Patrick Cotogno, Charlotte Manogue, Brian E. Lewis, Jodi Lyn Layton, Spencer Krane, Oliver A. Sartor, Mehmet Asim Bilen, Arpita Desai, Pedro C. Barata
Journal: Journal of Clinical Oncology (2020)

e17109 Background: Combination regimens containing a programmed cell death protein 1 (PD-1) or a programmed cell death ligand 1 (PD-L1) inhibitor improve the clinical outcomes of previously untreated aRCC. These regimens are clinically active but are associated with adverse events (AEs). One prospective study (KEYNOTE-427) has shown clinical activity of pembrolizumab monotherapy in aRCC. We aimed to describe the utilization and outcomes of single-agent PD-1/PD-L1 in previously untreated aRCC patients (pts). Methods: Consecutive pts treated with front-line PD-1/PD-L1 monotherapy for aRCC were included. Descriptive statistics were used to analyze outcomes including overall response rate (ORR), progression-free survival (PFS) and safety. Results: A total of 28 pts (median age 60; 32% ECOG 2/3; intermediate/poor risk 86%/14%; 35% non-clear cell aRCC) were identified. Common sites of metastases included lung (57%), lymph nodes (39%), bone (21%) and brain (21%). Pts received pembrolizumab (n = 9), avelumab (n = 1) or nivolumab (n = 18) due to pt/physician’s decision (46%), poor performance status (29%) or clinical trial (21%). In evaluable pts (n = 24), the ORR was 33% in ccRCC and 30% in nccRCC. With a median follow up of 13 months (mo), the median PFS was 6.3 mo (CI 95%, 1.5-11.1) and 16 pts progressed on therapy. Frequent AEs (57%) included fatigue (21%), myalgias/arthralgias (11%) and hypothyroidism (7%). No significant grade AEs (G3+) were noted. After progression on PD-1/PD-L1 (n = 16), 39% received a subsequent anti-VEGF (cabozantinib n = 6; sunitinib n = 4; pazopanib n = 1), 42% went to hospice or died and 21% were lost to follow up. Conclusions: First-line single-agent treatment with PD-1/PD-L1 inhibitors showed a favorable safety profile and clinical activity in patients with clear cell and non-clear cell aRCC who were not considered for a combination regimen. [Table: see text]
Tolerability and durable respones of the PI3Kδ inhibitor ME-401 administered on an intermittent schedule in relapsed/refractory (R/R) follicular lymphoma (FL) and other B-cell malignancies.
Authors: Andrew David Zelenetz, Nishitha Reddy, Deepa Jagadeesh, Anastasios Stathis, Huda S. Salman, Jacob D. Soumerai, Vaishalee Padgaonkar Kenkre, Adam Steven Asch, Judith Llorin-Sangalang, Joanne Li, Igor Gorbatchevsky, John M. Pagel
Journal: Journal of Clinical Oncology (2020)

8016 Background: ME-401, a potent, selective, and structurally differentiated oral PI3kδ inhibitor was evaluated in a dose escalation/expansion Phase 1b study, and previously demonstrated a high objective response rate (ORR) in FL and chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL) when given on a continuous (CS) or an intermittent schedule (IS). IS appeared to significantly reduce the incidence of immune-mediated adverse events of special interest (AESI) associated with PI3kδ inhibitors (diarrhea, rash, transaminase elevation, pneumonitis). We report maturing data from patients treated on the IS in this study. Methods: Eligible patients (pts) had FL, CLL/SLL, marginal zone lymphoma (MZL) and diffuse large B-cell lymphoma (DLBCL), at least 1 prior therapy, adequate bone marrow and organs function, ECOG status ≤2, and no prior PI3K therapy. IS dosing: ME-401 at 60 mg/day for two 28-day cycles, followed by 7 days of therapy every 28-day cycle until disease progression or intolerance. Pts received ME-401 monotherapy (n = 21) or a combination with rituximab (n = 36) given at 375 mg/m 2 for 8 doses in Cycles 1-6. Results: Total of 57 pts treated with IS: 35 FL, 10 CLL/SLL, 4 MZL, and 8 DLBCL with 38 (67%) currently still ongoing. Median age: 66 years (range 38-94) and median prior therapies: 2 (range 1-8). As of January 2020, median follow-up = 9.7 mo (range 0.6-25.4+). Grade 3 AESI reported in 7 pts: 2 diarrhea (3.5%), 2 colitis (3.5%), 1 rash (2%), 1 ALT increased (2%), and 1 pneumonitis (2%). No Grade 3 AESI reported beyond Cycle 3. Discontinuation for AE in 3 pts (5%). There were no discernable safety differences between the monotherapy and rituximab combination groups. ORR was 83% in FL (76% in monotherapy group, 88% in combination group) and 89 % in CLL/SLL (100%, 83%), with median duration of response not reached. Median PFS was not reached in all patients with FL and CLL (combined analysis of both single agent and with rituximab). ORR was 100% (4/4) in MZL and 25 % (2/8) in DLBCL (in combination group only). Conclusions: ME-401 administered on an IS was well-tolerated, with a low-rate of Grade 3 class-related AESI and achieved a high-rate of durable objective responses in R/R indolent B-cell malignancies. These results may differentiate ME-401 and support further evaluation as a single-agent and in combination regimens. An ongoing global trial is evaluating ME-401 by IS in pts with FL after failure of ≥2 prior therapies (NCT03768505). Clinical trial information: NCT02914938 .
Prevalence of erectiledysfunction and it's related factors in type 2 diabetic patients
Authors: 柳林, 逄力男, 刘长山, 邵静波
Journal: BMJ (2007)

目的 了解2型糖尿病患者勃起功能障碍(DED)发生情况,分析相关危险因素.方法用无记名问卷形式,根据国际勃起功能指数表(IIEF-5)自我评分,对904例已婚男性2型糖尿病患者的年龄、病程、糖化血红蛋白(HbA1c)、血压、吸烟史、饮酒史、应用降压药物等因素进行调查,并分析其与DED的关系.结果DED患病率为67.7%(612/904),Logistic逐步回归分析显示,年龄、病程、HbA1c、收缩压、吸烟、饮酒与DED发生独立相关,病程每增加5年、年龄每增加10岁、HbA1c每增加2%、收缩压每增加30mm Hg(1 mm Hg=0.133 kPa)、吸烟史优势比(OR值)分别为1.96、1.25、2.32、1.12和1.67(P＜0.05),饮酒史OR值为4.37(P＜0.01).结论DED患病率较高,年龄、病程、HbA1c、收缩压、吸烟、饮酒与其发生独立相关。
Improve effectively the level of prevention and control for common chronic respiratory diseases
Authors: 何权瀛
Journal: BMJ (2006)

随着社会前进,我国许多慢性呼吸道疾病,如慢性阻塞性肺疾病、支气管哮喘等的患病率逐年上升,成为我国人群主要死因之一和造成重要社会负担的原因.至今许多人还没有充分认识到这一点,因而没有广泛采取有效的医疗服务模式来解决这个问题。
T-Cell receptor repertoire and genomic analysis of tracheal adenoid cystic carcinoma.
Authors: Fei Wang, Chengzhi Zhou, Xiaohong Xie, Ming Liu, Xinqing Lin, Yinyin Qin, Zhanhong Xie, Jiexia Zhang, Ming Ouyang, Mengmeng Song, Pansong Li, Yan-Fang Guan, Xuefeng Xia
Journal: Journal of Clinical Oncology (2020)

e18576 Background: Tracheal adenoid cystic carcinoma (TACC) is the second type of cancer in bronchial tumors, has a high rate of postoperative recurrence and poor prognosis for which therapeutic targets are unavailable. Currently, studies were mostly about ACC of salivary gland. Our study is aim to elucidate genomic landscape and predict clinical biomarker of TACC. Methods: We performed whole-exome sequencing (WES), T cell repertoire sequencing (TCR) and immunohistochemistry (IHC) on tumor tissue samples and matched peripheral blood (PB) samples from TACC patients. All patients were followed up for their disease-free survival. Results: 13 cases were enrolled from 2010 to 2019. Median age of 13 TACCs was 35 yrs. 7 patients were female. 12 patients were stage I. In 8 WES samples, TCEB3CL (62%, 5/8), LPAR3 (50%, 4/8), ALPI (38%, 3/8), ARID1A (38%, 3/8) and BCOR (38%, 3/8) mutated most frequently. The median TMB was 3.67 (1.37-6.77) mutations/Mb. 1 patient showed microsatellite instability high (MSI-H). 2 patients with the highest TMB both had POLE mutations. We compared frequency of most mutated genes in our 8 samples with three different ACC types, including 935 ACC of salivary gland cancer, 76 ACC of the lung, and 38 ACC of breast cancer. 7 mutated frequently genes were found both in TACC and other types of ACCs, including ARID1A, BCOR, ARID1B, KMT2C, KMT2D, CREBBP and FAT3. 6 of them were more frequent in TACC. 7 FFPE tumors and 13 PB samples from 13 TACCs were used to investigate immune microenvironment. In 13 PB samples, TCR diversity (shannon index) and clonality was negatively associated with age (Pearson, r = -0.53, p = 0.06; r = 0.53, p = 0.06, respectively). There was no significant association between the other clinical characteristics (gender and smoking history) and any TCR parameter (clonality, clonotype, shannon index). Patients with lower clonotype number had longer DFS than those with higher clonotype number (15.0 vs 9.5 months, p &lt; 0.001, 95% CI, 0.23-675.66, HR, 12.46), while shannon index and clonality was not significantly associated with DFS. Conclusions: The genetic mutations associated with TACC are different from those implicated in non-small cell lung cancer. TCR analysis as a useful of indicator of disease development and prognosis in TACC may be utilized to direct further immunotherapy.