tbuckley/cabot-search huggingface dataset:
Functional analysis of patient-derived PALB2 missense variants of uncertain significance.
Authors: Shijie Wu, Jiaojiao Zhou, Yiding Chen
Journal: Journal of Clinical Oncology (2020)

1531 Background: Inherited PALB2 pathogenic variants are associated with an increased lifetime risk for breast cancer development. However, the interpretation of numerous PALB2 missense variants of uncertain significance (VUS) identified in germline genetic testing remains a challenge. Here, we assessed the impact of breast cancer patient-derived VUS on PALB2 function and identified pathogenic PALB2 missense variants that may increase cancer risk. Methods: A total of seven potentially pathogenic PALB2 VUS identified in 2,279 breast cancer patients were selected for functional analysis. All these selected VUS were assessed by SIFT, Align-GVGD, and PolyPhen2 in silico and were predicted to be deleterious by at least two in silico algorithms. The p.L35P [c.104T &gt; C] variant was also included, for which pathogenicity has been recently confirmed. The effects of the VUS on the homologous recombination (HR) activity of PALB2 were tested by U2OS/DR-GFP reporting system. Functional characterization was further validated by protein co-immunoprecipitation and RAD51 recruitment assay. Results: PALB2 variants p.L24F [c.72G &gt; C] and p.L35P [c.104T &gt; C] showed the most significant disruption to the HR activity of PALB2 relative to the wild-type condition, retaining only 52.2% ( p = 0.0013) and 8.5% ( p &lt; 0.0001) of HR activity respectively. Moderate but statistically significant HR deficiency was observed for four other variants (p.P405A [c.1213C &gt; G], p.T1012I [c.3035C &gt; T], p.E1018D [c.3054G &gt; C], and p.T1099M [c.3296C &gt; T]). We found no statistical differences for the p.K628N [c.1884G &gt; T] and p.R663C [c.1987C &gt; T] in the HR activity compared to wild-type PALB2. The p.L24F and p.L35P variants compromised the BRCA1-PALB2 interaction and reduced RAD51 foci formation in response to DNA damage. Conclusions: We have identified a novel patient-derived pathogenic PALB2 missense variant, p.L24F [c.72G &gt; C], that compromises PALB2-mediated HR activity. We suggest the integration of the identified pathogenic variants into breast cancer genetic counseling and individualized treatment regimens for better clinical outcomes.
多巴反应性肌张力不全二例
Authors: 杨兴仁, 李梅, 石小芳, 张平安, 王晓华, 李军玲
Journal: BMJ (2004)

例1 患者女,7岁.6岁时右下肢呈划弧样行走,病情逐渐加重,并出现双下肢僵硬,双脚尖着地,走路困难,晨起轻,午后重,休息后减轻,运动后加重,既往史、个人史无特殊.查体:患者神志清楚,智能、发育正常,无角膜色素环,颅神经检查正常,下颌反射阴性,四肢肌力正常,肌张力呈齿轮样增高,双手快复轮替动作欠灵活.双膝反射、跟腱反射亢进,双侧踝阵挛阳性,双侧病理征阴性,胸腹段MRI正常.口服多巴丝肼62.5 mg2 h后可行走,治疗10 d后症状基本消失.遂诊断为多巴反应性肌张力不全(dopa-responsive dystonia , DRD)。
Phase 3, Randomized, Double-Blind, Active-Comparator (Darbepoetin Alfa) Study of Oral Roxadustat in CKD Patients with Anemia on Hemodialysis in Japan
Authors: Tadao Akizawa, Manabu Iwasaki, Yusuke Yamaguchi, Yoshikatsu Majikawa, Michael Reusch
Journal: Journal of the American Society of Nephrology (2020)

Roxadustat is an oral hypoxia-inducible factor prolyl hydroxylase inhibitor approved in China for dialysis-dependent CKD anemia.This phase 3, 24-week, double-blind, double-dummy study evaluated roxadustat's noninferiority to darbepoetin alfa for hemodialysis-dependent CKD anemia. We randomly assigned Japanese patients to oral roxadustat three times weekly or to darbepoetin alfa injections once weekly, titrating doses to maintain hemoglobin between 10-12 g/dl. The primary end point was change of average hemoglobin from baseline to weeks 18-24 (∆Hb18-24). Secondary end points were average hemoglobin and proportion of patients with hemoglobin between 10-12 g/dl (maintenance rate) at weeks 18-24, and iron parameters. Safety assessments included treatment-emergent adverse events and adjudicated ophthalmologic findings.We randomly assigned 303 patients to roxadustat (n=151) or darbepoetin alfa (n=152). The difference between roxadustat and darbepoetin alfa in ∆Hb18-24 was -0.02 g/dl (95% confidence interval, -0.18 to 0.15), confirming roxadustat's noninferiority to darbepoetin alfa. Average hemoglobin at weeks 18-24 with roxadustat was 10.99 g/dl (95% confidence interval: 10.88 to 11.10), confirming its efficacy. Among patients with one or more hemoglobin value during weeks 18-24, the maintenance rate was 95.2% with roxadustat and 91.3% with darbepoetin alfa. Serum iron, ferritin, and transferrin saturation remained clinically stable with roxadustat; transferrin and total iron binding capacity increased through week 4 before stabilizing. Common treatment-emergent adverse events were nasopharyngitis, shunt stenosis, diarrhea, contusion, and vomiting. The proportion of patients with new or worsening retinal hemorrhage was 32.4% with roxadustat and 36.6% with darbepoetin alfa. We observed no clinically meaningful changes in retinal thickness groups.Roxadustat maintained hemoglobin within 10-12 g/dl in patients on hemodialysis and was noninferior to darbepoetin alfa. Treatment-emergent adverse events were consistent with previous reports.A Study of Intermittent Oral Dosing of ASP1517 in Hemodialysis Chronic Kidney Disease Patients with Anemia, NCT02952092 (ClinicalTrials.gov).
Multigene mutation signatures in colorectal cancer patients: Predict for the diagnosis, pathological classification, staging and prognosis.
Authors: Yan Zhuang, Hailong Wang, Da Jiang, Ying Li, Caijuan Tian, Zanmei Xu, Meina Su, Xiaowei Wang, Jiangyan Zhang, Yuanjing Hu, Pengfei Liu
Journal: Journal of Clinical Oncology (2020)

e16113 Background: Like most cancers, early diagnosis of colorectal cancer (CRC) contributes to a good prognosis. Recently, some studies indicated that mutation gene signatures have good performances in predicting the treatment and prognosis in CRC patients. However, incomplete understanding of the genotype is not conducive to proper treatment. The objective was to give further genetic insights into CRC and provide more comprehensive references for clinical practice. Methods: In the training group, the whole genome sequencing (WGS), clinical, and demographic data of 531 patients were downloaded from The Cancer Genome Atlas (TCGA). The validation group contained 53 patients, which were collected in Tianjin Medical University Cancer Institute and Hospital (Tianjin, China) from April 2014 to November 2018. The fresh tissues collected within 24 hours after operation were used to extract genomic DNA, and then sequenced with targeted next-generation sequencing (NGS) technology to examine somatic mutations and analyze relevant gene concerning clinical indicators. The correlation between gene variation distribution and various indexes such as cancer species, stage, total survival period, sex, age and race were evaluated. Results: A total of 44 mutant genes with mutation frequencies above 5% were found in both TCGA cases and validated cases. Mutations of TP53, APC, KRAS, BRAF and ATM covered 97.55% of TCGA population and 83.02% validation patients, which were proved to be associated with the development of CRC and could be used as a diagnostic signature. Importantly, mutations of TP53, PIK3CA, FAT4, FMN2 and TRRAP had a remarkable difference between early (I/II) and advanced (III/IV) stage patients (P &lt; 0.0001). Besides, we also confirmed that PIK3CA, LRP1B, FAT4 and ROS1 were a mutated gene signature for the prognosis, LRP1B portended to a higher of recurrence and shorter progression-free survival (PFS); mutation of FAT4 portended to a lower of recurrence and longer PFS, which could predict the recurrence and survival of CRC patients. Conclusions: We have indicated gene mutation signatures related to the diagnosis, pathological classification, staging and prognosis in CRC, which provides further insights into the study of CRC genotype. It is helpful to further improve the personalized diagnosis and treatment.
Outcomes of patients with metastatic castration resistant prostate cancer according to somatic sequencing of domage DNA repair genes.
Authors: Zoé Neviere, Agathe Ricou, Dominique Vaur, Etienne Muller, Sophie Krieger, Flavie Boulouard, Laurent Castera, Alexandra Leconte, Isabelle Bonnet, Laura Moise, Elodie Coquan, Emeline Meriaux, Pierre-Emmanuel Brachet, Idlir Licaj, Justine Lequesne, Florence Joly
Journal: Journal of Clinical Oncology (2020)

e17595 Background: More than 20% of mCRPC present somatic DNA damage repair gene mutation (DDR). If some data are available for germline mutations, there are few studies describing the relation between somatic alterations and response to standard therapies in mCRPC. Methods: To describe outcomes of mCRPC patients treated with standard therapies according to somatic DDR status.A retrospective somatic analysis on a 69-gene panel was conducted among mCRPC patients. Progression-free survival (PFS) of first-line treatment was analyzed according to somatic DDR mutation as primary endpoint. First exposition to taxanes chemotherapy and PFS2 (time to the second event of disease progression) depending on therapeutic sequences (new-generation hormonotherapy [NGHT]/taxanes chemotherapy) were also analyzed. Results: Among 83 patients tested, 33 (40%) had a somatic DDR mutation, including 10 ATM, 5 BRCA2, 4 CHEK2, 3 CDK12, 3 FANCG, 1 BLM, 1 CHEK1, 1 FANCF, 1 FANCI, 1 FANCM, 1 MDC1, 1 MRE11A and 1 PALB2. In first-line treatment, 20 patients received taxanes and 63 NGHT. Median PFS was 9.8 months for mutated patients and 8.4 months for non-mutated patients (p = 0.9). For mutated patients, median PFS was 12.3 months in taxanes group and 9.8 months in NGHT group, (p = 0.74). One BRCA2-mutated patient treated by docetaxel was particularly long responder (PFS = 39.2 months). PFS of first exposition to taxanes was 8.2 months among mutated patients and 5.7 months among non-mutated patients (p = 0.31). Patients with BRCA1/BRCA2/ATM mutations had longer PFS compared to the others patients (10.6 months versus 5.5 months, p = 0.04). Ten patients received the chemotherapy-NGHT sequence (CHS) and 28 the NGHT-chemotherapy sequence (HCS). PFS2 were 16.5 months for mutated patients, whatever the sequence, and 11.7 months among non-mutated patients (p = 0.07). The 3 mutated patients (1 BRCA1, 1 BRCA2, 1 ATM mutation) had long PFS2 in the CHS (49.8 months). PFS2 of mutated patients in HCS was 15.6 months. Conclusions: Mutated mCRPC patients benefit from standard therapies, with long responders to taxanes among patients with BRCA1/2 and ATM mutations.
A new criteria for obesity-clinical significance of waist circumference index
Authors: 何秉贤, 郭艳英, 严卫丽, 王坤, 赵蕾
Journal: BMJ (2006)

目的 提出并评价将腰围指数作为判断腹型肥胖的一个简易指标的可行性及价值.方法 从2004年新疆博尔塔拉州高血压流行病学基线调查资料中,抽取资料完整且为空腹的样本3 300例列入本次研究.肥胖的诊断根据亚洲成人超重和肥胖标准,代谢综合征的诊断根据国际糖尿病联盟标准.应用受试者工作特性曲线(receiver operating characteristic,ROC)评价WI诊断成人腹型肥胖的准确性和最佳切点.结果 控制性别、民族因素后,与身高的偏相关系数,腰围为0.17,腰围指数为-0.10,体重指数为0.04;与腰围的偏相关系数,腰围指数为0.72,体重指数为0.62.根据亚洲成人超重和肥胖标准,男女腰围指数诊断肥胖阈值在0.50～0.52时特异度为75%～89%、灵敏度为95%～97%,男女肥胖患者腰围指数诊断的ROC曲线下面积比较差异无统计学意义.以腰围指数≥0.5为腹型肥胖的诊断阈值,依据国际糖尿病联盟的代谢综合征标准,诊断代谢综合征的灵敏度为97.3%、特异度为97.8%.结论 在新疆博尔塔拉州30岁以上人群中,采用腰围指数预测腹型肥胖简单易行。
Application of quantitative ultrasound in evaluation bone strength in early infants
Authors: Yumei Wang, Lan Lu, Li Zhang, Zhaojun Pan, Yuehong Wang
Journal: BMJ (2014)

A total of 4 982 healthy infants were recruited from our child health clinic during July 2011 to June 2012.There were 2 769 males and 2 213 females with an age range of 31-59 days.Then an ultrasound bone sonometer Omnisense™ 7000P was employed to acquire their values of speed of sound (SOS) in bones for Asian.The values of SOS for 1-month-old infants were (2 919.77±129.16)m/s (males) and (2 929.67±124.19) m/s (females) respectively.SOS in summer and autumn was significantly higher than that in spring and winter (P 0.05). The values of SOS has remarkable difference in different seasons and latitudes and increase with age.Therefore it is necessary to establish its reference criterion for local children.


Key words: 
Quantitative ultrasound; Bone development
发热-胸背部疼痛
Authors: 于微, 王玉, 曾学军
Journal: BMJ (2007)

患者女,69岁.主因发热、胸背部疼痛1个月余于2006年10月23日入院.患者1个月前无明显诱因出现发热,体温最高38.9℃,伴有畏寒及胸背部疼痛,以深呼吸、咳嗽、变换体位时为著;伴有右侧肩部疼痛.无明显寒战,无流涕,咽痛,无咳嗽、咳痰,不伴腹痛、腹泻等,左氧氟沙星治疗3 d效果不佳。
A call for food system change
Authors: Marion Nestle
Journal: The Lancet (2020)

In shutting down entire societies, the COVID-19 pandemic has exposed the fundamental inequities and inadequacies of market-driven economies that prioritise profits over human welfare. Inequities show up in businesses that furlough employees while paying high salaries and bonuses to executives. They are also revealed by the dependence of food systems on poorly paid workers and cheap global supply chains. The COVID-19 crisis demonstrates how current food systems fail to protect populations from hunger and diet-influenced non-communicable diseases and why the poor, disenfranchised, discriminated against, and chronically ill are those most vulnerable to this disease.
Response to: ‘Physician global assessment in systemic lupus erythematosus: can we rely on its reliability?’ by Chessa<i>et al</i>
Authors: Anca Askanase, Shereen Oon, Molla Huq, Alicia Calderone, Eric F Morand, Mandana Nikpour, Cynthia Aranow
Journal: Annals of the Rheumatic Diseases (2020)

Response to: 'Physician global assessment in systemic lupus erythematosus: can we rely on its reliability?' by Chessa et alWe thank Chessa et al for their interest in our article on lupus Physician's Global Assessment (PGA). 1 Their correspondence discusses the measurement used to determine PGA scoring reliability and suggests that the intraclass correlation coefficient (ICC) used, ICC2,k, with a two-way random effect model based on mean scorings may have increased the reliability estimates reported, compared with a two-way random effect models based on individual data points (ICC2,1). 2Indeed correlation coefficients were approximately 39% lower for the pre-lab PGA and 27% lower for the post-labPGA when computed with the ICC2,1 compared with the ICC2,k.We used the ICC2,k to assess inter-rater reliability as our study was designed to evaluate and compare mean PGA scores before and after receipt of laboratory values from multiple (k=50) raters. 3 Additionally, mean-based models (ICC2,k) are conventionally used to report ICC.Which of these models is more mathematically or conceptually correct remains debated.Importantly, both models showed increased agreement when laboratory values are available (post-lab PGA) compared with the pre-lab PGA.We wholeheartedly agree that further standardisation and precise guidelines for its scoring will likely improve the performance of the PGA when used by lupus experts and practising rheumatologists.
Methodology, results, and publication of oncology clinical trials: Insights from all the world’s randomized controlled trials (RCTs) 2014-2017.
Authors: Shubham Sharma, Connor Wells, Joey C. Del Paggio, Wilma M. Hopman, Bishal Gyawali, C S. Pramesh, Richard Sullivan, Christopher M. Booth
Journal: Journal of Clinical Oncology (2020)

2019 Background: Clinical cancer research is now a global effort. Most published overviews of oncology trials are restricted to a specific disease site or cohort of high-profile journals. Here we describe authorship, trial characteristics, design, and results of all oncology RCTs published globally during 2014-2017. Methods: A structured literature search was designed using PUBMED to identify all RCTs evaluating anti-cancer therapies published during 2014-2017. Data were captured regarding authorship, participants, study characteristics, design, and results. Among superiority RCTs that met the primary endpoint (i.e. statistically “positive”), we calculated the ESMO-MCBS to identify trials with substantial clinical benefit (MCBS scores 4/5 or A/B). Outcomes were compared with Chi Square or Fisher’s Exact tests. Results: The study cohort included 694 RCTs. The most common cancers evaluated were breast (17%, 121/694), lung (15%, 104/694) and colorectal (8%, 58/694). Treatment intent was curative, adjuvant/neoadjuvant, and palliative in 10% (68/694), 25% (176/694), and 65% (448/694) of trials respectively. Median sample size was 443 (IQR 246-718). Seventy percent (488/694) of RCTs were supported by industry; 87% (601/694) of experimental arms tested systemic therapy. Ninety-two percent (636/694) of RCTs were led by investigators in 28 high-income countries; the most common countries leading these trials were US (27%, 174/636), France (10%, 64/636), Germany (10%, 62/636), Japan (9%, 59/636), and UK (9%, 57/636). The most common primary endpoints were PFS (32%, 220/694), OS (31%, 215/694), and DFS (11%, 79/694); Forty-six percent of all trials (318/694) met their primary endpoint. Among superiority trials with “positive” results, 33% met ESMO-MCBS threshold for substantial clinical benefit. The median impact factor (IF) of journals which published the overall study cohort of trials was 21 (IQR 7-27); trials meeting their primary endpoint were published in higher profile journals (median IF 25 vs 18, p &lt; 0.001). Conclusions: At the global level, oncology clinical trials are dominated by high-income countries and study diseases which do not necessarily reflect the global burden of cancer. The vast majority of trials are funded by industry and only one third of “positive” trials meet ESMO-MCBS threshold for substantial clinical benefit.
Correlation of serum cystatin C with left ventricular hypertrophy in maintenance hemodialysis patients
Authors: Xiao-yun Si, Xiao-hong Bi, Ying Yao, Ping Le, Xiao-yan Wu
Journal: BMJ (2009)

The clinical data and routine biochemical parameters of 64 maintenance hemodialysis (MHD)patients and 20 controls were analyzed in the study.Serum cystatin C levels were detected by latex particle enhalice inununo-turbidimetry:and the cardial structure and function were assessed by echocardiography.As MHD time extended,the levels of semm cystatin C increased gradually,accompanied with high incidence of left ventricular hypertrophy(LVH).The LVH-positive patients had higher systolic blood pressure and left veHtricular mass index,and had higher serum cystatin C than tllose in LVH-negative patients.The serum cystatin C levels were positively correlated with left yentricular mass index(r=0.633,P<0.01)and systolic blood pressure(r:0.397,P<0.01).The results suggest that serum cystatin levels may be an influencing factor for long-term cardiacvascular complication in MHD patients.

Key words: 
Hemodialysis; Cystatin C; Hypertrophy,left ventricular
Phase I pilot study of RRx-001 + nivolumab in patients with traditionally non-checkpoint inhibitor-responsive cancers (PRIMETIME).
Authors: Corey Carter, Scott Caroen, Bryan Oronsky, Mary Flanagan Quinn, Jeannie Williams, Christina E. Brzezniak
Journal: Journal of Clinical Oncology (2020)

e15119 Background: RRx-001 is a minimally toxic small molecule that downregulates CD47 via Myc inhibition and repolarizes tumor-associated macrophages (TAMs). A phase 1 pilot study was undertaken to determine the safety and feasibility of RRx-001 and nivolumab in patients with advanced traditionally non-immunogenic cancers and no standard options. Methods: This single arm, open-label pilot study (NCT02518958) was designed to evaluate the safety profile of RRx-001 + nivolumab in patients with advanced malignancies. A 3+3 trial design was used to establish safety of the combination at each dose level and guide the decision to escalate dose. RRx-001 is infused once weekly while nivolumab is given at 3mg/kg once every 2 weeks. RRx-001 starting dose was 2 mg IV weekly with 4 dose level escalations up to 16 mg IV weekly. From January 2015 to November 2015, 12 patients received treatment for 4 cycles (total 12 weeks) with the combination due to unavailability of nivolumab, which was not supplied to the Sponsor. Treatment-emergent (all cause, TEAEs) and treatment-related (TRAEs) adverse events occurring within 16 weeks of the first dose of RRx-001 + nivolumab were characterized according to CTCAE v4.03. Results: 12 patients received &gt; 1 dose of RRx-001 and nivolumab. One discontinuation occurred due to pneumonitis and one to voluntary withdrawal after a post-procedural infection. There were no dose-limiting toxicities. The main adverse event related to RRx-001 was pain on infusion (33.3%). The main adverse event related to the combination was pseudoprogression (larger tumors in symptomatically improved patients) (25%). The most common immune-related treatment-emergent AEs were pneumonitis (8.3%), and hypothyroidism (8.3%). Objective response rate at 12 weeks was 25% and the disease control rate (DCR) consisting of &gt; SD was 67% by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. 25% of the patients progressed on the combination. Conclusions: RRx-001 + nivolumab was well-tolerated with preliminary evidence of anti-cancer activity in non-immunogenic cancers. Further analyses with a larger sample size are required to confirm activity. Clinical trial information: NCT02518958 .
潍坊市乳母有关知识行为的调查分析
Authors: 董素花, 迟慧, 郭良玉
Journal: BMJ (2004)

母乳喂养有利于婴幼儿的生长发育和母亲产后康复,世界卫生组织近年来倡导对4个月以内的婴儿实行纯母乳喂养,对满4个月的婴儿才需要合理添加必要的辅食.乳汁中各种营养成分全部来自母体,良好的乳母营养供给是保证乳汁的正常分泌并维持乳汁质量恒定的必要条件.本次研究通过对乳母的营养知识、态度、行为进行调查,了解乳母的营养状况。
Trial in progress: A phase I/II, open-label, dose-escalation, safety and tolerability study of NC318 in subjects with advanced or metastatic solid tumors.
Authors: Martin Gutierrez, Omid Hamid, Elaine Shum, David R Wise, Arjun Vasant Balar, Jeffrey S. Weber, Patricia LoRusso, Saba Shafi, David L. Rimm, Anthony W. Tolcher, Debashree Basudhar, Melanie Elizabeth Dujka, Kevin N. Heller
Journal: Journal of Clinical Oncology (2020)

TPS3166 Background: Siglec-15 (S15) is a member of the Siglec family (Sialic acid-binding Immunoglobulin Lectins), a distinct subgroup of immunoglobulin (Ig) superfamily proteins involved in discriminating self from non-self-immune regulation (Macauley MS et al. 2014). Nonclinical models demonstrate S15 mediates suppression of T cell proliferation and negatively regulates T cell function. NC318 is a first-in-class monoclonal antibody that blocks S15-mediated immune suppression and prevents tumor growth by normalizing T cell function and restoring anti-tumor immunity in the tumor microenvironment (Wang J et al. 2019). The clinical hypothesis of this study is that NC318 targeting of S15 can improve anti-tumor immune response and provide benefit in multiple oncology indications. Methods: This is a multi-center, first in human, phase 1/2, open-label, non-randomized study to determine the safety and tolerability, define maximum tolerated dose and/or pharmacologically active dose, assess preliminary efficacy, and explore predictive and pharmacodynamic biomarkers of NC318 in subjects with advanced or metastatic solid tumors. Key eligibility criteria included measurable disease based on RECIST v1.1 and consent for collection of biopsies at screening and on treatment (optional for phase 1). Phase 1 used a 3+3 dose escalation design to determine the recommended phase 2 dose (RP2D) and schedule of NC318 while identifying drug related toxicities (DLTs). Phase 2 enrollment is limited to non-small cell lung, ovarian, head and neck, and triple negative breast cancer subjects with PD-L1 tumor proportion scores &lt;50% (additional tumor types are being evaluated for inclusion). Ongoing exploratory analyses include the assessment of predictive biomarkers associated with treatment benefit, and pharmacodynamic markers associated with study drug activity (e.g. evaluation of tumor biopsies and peripheral markers of inflammation). Phase 1 enrollment began October 2018 and completed in August 2019. The RP2D was defined and the phase 2 opened to enrollment October 2019. Clinical trial information: NCT03665285 .