tbuckley/cabot-search huggingface dataset:
Tumor detection rates in screening carriers with <i>SDHx</i>-related hereditary paraganglioma-pheochromocytoma syndrome based on prior tumor history.
Authors: Samantha Greenberg, Michelle Jacobs, Heather Wachtel, Amanda Anson, Luke Buchmann, Debbie Cohen, Maria Bonnani, Bonita Bennett, Anne Naumer, Amanda Schaefer, Wendy Kohlmann, Katherine Nathanson, Tobias Else, Lauren Fishbein
Journal: Journal of Clinical Oncology (2020)

1545 Background: Patients with germline pathogenic variants (PVs) in the SDHx genes have increased risk for paragangliomas/pheochromocytomas (PGL/PCC), renal cell carcinomas, and gastrointestinal stromal tumors. Expert recommendation suggests individuals with SDHx PVs undergo biennial whole-body imaging and annual biochemical testing. This study aimed to evaluate tumor detection rate using standard biochemical and imaging protocols for individuals with SDHx PVs, particularly in those with and without SDHx-related tumor history, and in those with biochemical testing data. Methods: A retrospective longitudinal observational study at the Universities of Michigan, Pennsylvania, and Utah Huntsman Cancer Institute was conducted from the start of each center’s screening program through March 1, 2018. Individuals with SDHx PVs had clinical imaging with whole body MRI/CT and biochemical testing per expert recommendation. SDHx-related tumors identified during clinical screening were measured. Results: A total of 263 individuals with SDHx PVs completed 491 screens. Individuals with SDHB PVs were the most prevalent (n = 188, 71.5%). The average number of screens per subject was 1.87 (range 1-7). A majority (n = 194, 73.7%) of individuals did not have a prior history of PGL/PCC. Overall, SDHx-related tumors were detected in 17.1% (n = 45) of the cohort. Of the 46 scans that identified an SDHx-related tumor, 85% of them (n = 39) were baseline scans. SDHx-related tumors were identified in 18.6% (n = 36/194) of individuals that did not have a prior history of PGL/PCC, whereas they were identified in 13.0% (n = 9/69) of individuals that did have a prior history of PGL/PCC (p = 0.39). Biochemical testing was available for 70% (n = 343) of imaging screens, of which 18% (n = 61) had positive biochemistry. Of those with positive biochemistry, 19 tumors were identified on imaging (6%). Sixteen tumors were identified on imaging with negative biochemistry (5%) with a sensitivity of 54% and a specificity of 94%. Utilizing a cut-off of two times the upper limit of normal, 9.91% (n = 34) biochemical tests were positive, and 15 (44.12%) had an SDHx-related tumor on corresponding imaging. Conclusions: Current SDHx screening protocols are effective at identifying SDHx-related tumors. Tumors were detected in subjects with a prior history of PGL/PCC and those with no prior history. This suggests life-long screening is important for all SDHx carriers. Imaging is a crucial piece of SDHx screening given biochemical testing’s sensitivity and specificity.
Characterization of patients (pts) with long-term responses to rucaparib in recurrent ovarian cancer (OC).
Authors: Elizabeth M. Swisher, Rebecca Sophie Kristeleit, Amit M. Oza, Anna Tinker, Isabelle Laure Ray-Coquard, Ana Oaknin, Robert L. Coleman, Howard A. Burris III, Carol Aghajanian, David M. O'Malley, Alexandra Leary, Stephen Welch, Diane M. Provencher, Geoffrey Shapiro, Lee-may Chen, Ronnie Shapira-Frommer, Sandra Goble, Lara Maloney, Kevin K. Lin, Iain A. McNeish
Journal: Journal of Clinical Oncology (2020)

6015 Background: Pts who derive durable benefit from PARP inhibitor treatment may provide insights into improving outcomes. Here we describe long-term responders from Study 10 (NCT01482715) and ARIEL2 (NCT01891344), studies of the PARP inhibitor rucaparib for the treatment of high-grade recurrent OC. Methods: This analysis included pts enrolled in Study 10 (Part 2A: BRCA1 or BRCA2 [ BRCA]-mutant OC, platinum sensitive, 2–4 prior chemotherapies; Part 2B: any platinum status, 3–4 prior chemotherapies) and ARIEL2 (Part 1: BRCA-mutant or wild-type OC, platinum sensitive; Part 2: any platinum status, 3–4 prior chemotherapies). Final results from Study 10 (n = 54) and ARIEL2 (n = 491) were pooled. Long-term responders were defined as pts with duration of response (DOR) &gt; 1 y, and short-term responders as pts with DOR ≤ 20 weeks; responses were evaluated using RECIST. Targeted next-generation sequencing was used to detect deleterious mutations and loss of heterozygosity (LOH) in tumors. BRCA1 methylation was quantified by digital droplet PCR. Results: Overall, 25% (138/545) of enrolled pts were responders. Of these, 29% (40/138) had long-term responses, including 16/138 (12%) with DOR &gt; 2 y; 21% (29/138) were short-term responders. Both groups received a median of 3 prior anticancer therapies. Among patients with BRCA mutations, BRCA homozygous deletion or rearrangement was detected in 15% (4/27) of long-term responders vs 0% (0/15) of short-term responders. In an expanded analysis of the 95 pts with BRCA mutations and confirmed response, pts with BRCA homozygous deletion or rearrangement had significantly longer DOR than pts with other mutation types (median 3.5 vs 0.6 y; HR = 0.30; p = 0.024). There was no apparent difference in BRCA gene or mutation location for long- vs short-term responders. Ten of the 13 long-term responders with BRCA wild-type OC had high genome-wide LOH (≥16% LOH), a genomic scar indicative of homologous recombination deficiency, including OC associated with BRCA1 hypermethylation (n = 2) and RAD51C/D mutations (n = 2). Conclusions: Long-term responders to rucaparib include OC with BRCA mutation, particularly homozygous deletion or rearrangements, which would not be susceptible to somatic reversion mutations, as well as BRCA1 hypermethylation, and RAD51C/D mutations. Clinical trial information: NCT01482715; NCT01891344.
Economic evaluation of SP142 IHC assay versus 22C3 IHC assay in patients with unresectable locally advanced or metastatic triple-negative breast cancer in the Brazilian private healthcare system.
Authors: Rodrigo Shimabukuro Ho, Mariana Mioti Sebastião, Joao Carvalho, Tomás Neves, Micha Nussbaum
Journal: Journal of Clinical Oncology (2020)

e13097 Background: The IMpassion130 trial has demonstrated that atezolizumab plus nab-paclitaxel results in significant clinical benefits for patients with unresectable locally advanced or metastatic (aTNBC). The SP142 IHC assay is a clinically validated and FDA-approved PD-L1 test to identify patients with aTNBC for treatment with atezolizumab plus nab-paclitaxel. A post hoc analysis of IMpassion130 evaluated two other PD-L1 IHC assays, 22C3 and SP263, for analytical and clinical concordance with SP142 and the PD-L1 prevalence by each assay. The prevalence of PD-L1+ per SP142 (tumor-infiltrating immune cells 1%), 22C3 (combined positive score1) and SP263 (tumor-infiltrating immune cells 1%), were 46%, 81% and 75%, respectively. The study compared only SP142 assay with 22C3 assay because patients with SP142 negative and 22C3 positive did not demonstrate a significant clinical benefit for progression-free survival (PFS) and overall survival (OS). Therefore the study aimed to demonstrate the economic impact of these assays in the treatment with atezolizumab plus nab-paclitaxel. Methods: Data of PFS and OS from the post hoc analysis of Impassion130 were extracted to develop a Markov model to simulate the clinical and economic impact of the patient with atezolizumab plus nab-paclitaxel guided by SP142 and 22C3 assays. The analysis considered the cost of atezolizumab+nab-paclitaxel, the cost associated with the management of the adverse events and the cost of the assay. The costs were based on CBHPM (Classificação Brasileira Hierarquizada de Procedimentos Médicos), CMED PF18% (Câmara de Regulação do Mercado de Medicamentos) and local publications. An univariate sensitivity analysis was performed. Results: The study demonstrated that SP142 assay has the potential to save 175,917 BRL (45,595 USD) with atezolizumab plus nab-paclitaxel per patients with aTNBC in three years. Conclusions: The SP142 assay can optimize the use of atezolizumab plus nab-paclitaxel avoiding its use in patient who will not have a significant clinical improvement.
Application of motivational interview techniques in receiving diabetes patients with poor compliance
Authors: Yuhuan Zhao, Yue Jiang, Yue Sha
Journal: BMJ (2019)

对于依从性不好的糖尿病患者，应充分运用全科医学的理念，探索患者真正的问题，采用动机性访谈技术引导患者配合治疗，与患者共同制定个体化的治疗方案和管理计划，最后取得令患者及家属满意的疗效。
Abstract 15728: Real-Time Noninvasive Intra-Cardiac Pressure Estimation Using Subharmonic Signals From Ultrasound Contrast Agents
Authors: Cara Esposito, Priscilla Machado, Maureen McDonald, Praveen Mehrotra, Michael P Savage, David L Fischman, Ira Cohen, Nicholas J Ruggiero, Paul Walinsky, Oleg Vishnevsky, Andrew Boyle, Marguerite Davis, Flemming Forsberg, Kristopher Dickie, Jaydev K Dave
Journal: Circulation (2019)

Introduction: Subharmonic aided pressure estimation (SHAPE) utilizes subharmonic signals from ultrasound contrast agents to estimate ambient pressures. The purpose of this study was to evaluate the...
Missed Opportunities to Save Lives—Treatments for Opioid Use Disorder After Overdose
Authors: Elizabeth M. Schoenfeld, Lauren M. Westafer, William E. Soares
Journal: JAMA Network Open (2020)

Austin S. Kilaru, MD, MSHP; Aria Xiong, MS; Margaret Lowenstein, MD, MPhil; Zachary F. Meisel, MD, MPH, MSHP; Jeanmarie Perrone, MD; Utsha Khatri, MD; Nandita Mitra, PhD; M. Kit Delgado, MD, MS
The role of circCNIH4 in the adipocyte's effects on metastasis of breast cancer cells.
Authors: Xiu Chen, Jinhai Tang
Journal: Journal of Clinical Oncology (2020)

e13086 Background: Obesity is associated with the risk of breast cancer(BCa) incidence and development. However, biological changes in obesity BCa individuals are still uncertain. Nowadays, circCNIH4, one of novel non-coding RNAs, was found to be a non-invasive biomarker in cancers. Methods: We verified the cancer-promoting role of obesity in BCa patients by comparing BMI indexes of 33 BCa and 44 benign tumor patients. Then we cocultured viscera adipose cells(HPA-v) and BCa cells(MCF-7/H and MDA-MB-231/H) to confirm the function of adipocytes on metastasis of BCa cells through wound healing, transwell assays. In vivo experiments were also performed. We analyzed the expression level of circCNIH4 in MCF-7/H, MDA-MB-231/H and different subtypes of BCa cells by quantitative polymerase chain reaction. Simultaneously, we identified inhibited effects of circCNIH4 on metastasis of BCa cells by wound healing, transwell assays and verified the location of circCNIH4 by FISH. Luciferase Assay was used to detect harbored miRNA. Rescue experiments were then applied. Results: We found the BMI of BCa patients(24.37±2.51) was much higher than benign patients(22.97±2.91). Metastasis of BCa cells were obviously promoted after in vitro and in vivo experiments. Then we found the expression of circCNIH4 in MCF-7/H and MDA-MB-231/H were down-regulated 0.71 and 0.52 than that in MCF-7 and MDA-MB-231. Also, circCNIH4 was positively correlated with less aggressive types of BCa cells. Overexpression of circCNIH4 in MDA-MB-231 could suppress cell invasion and migration, while silencing of it in MCF-7 promoted cell invasion and migration. The FISH assay demonstrated that circCNIH4 mainly located in the cytoplasm and might function as a “sponge” for miRNA. MiR-135b functioned as a tumor promoter gene from data of 93 BCa patients (HR = 2.27; 1.01 − 5.12), and it could be captured by circCNIH4 via luciferase and rescued assays. Conclusions: In this study, we revealed that BMI or viscera adipocytes could deteriorate prognosis of BCa and circCNIH4 could be a novel biomarker for non-invasive BCa. In details, circCNIH4 mainly suppressed the adipocyte's pro-metastasis effects on BCa by capturing miR-135b.
改善病情抗风湿药在类风湿关节炎治疗中的应用
Authors: 马丽
Journal: BMJ (2005)

根据世界卫生组织的定义,将具有阻止类风湿关节炎(RA)病情发展的一类药物统称改善病情抗风湿药(disease modifying anti-rheumatic drugs,DMARDs),或病情缓解药(remission-inducing drugs).作为风湿病专科医生或全科医生都非常有必要对此类药物进行较深入的了解。
Effect of an lncRNA-associated ceRNA regulatory network in MVI-positive hepatocellular carcinoma on their sensitivity to sorafenib.
Authors: Zhiwen Luo, Xinyu Bi
Journal: Journal of Clinical Oncology (2020)

e16615 Background: Microvascular invasion (MVI) is a histological feature of hepatocellular carcinoma (HCC) related to aggressiveness. But different sensitivity to first line targeted drug, sorafenib, in MVI + HCC has been observed. Long noncoding RNAs (lncRNAs) can act as microRNA (miRNA) sponges to regulate protein-coding gene expression; so lncRNAs are considered as a major part of competitive endogenous RNA (ceRNA) network and have attracted growing attention. We explored the regulatory mechanisms and functional roles of lncRNAs as ceRNAs in MVI + HCC, and ceRNA network’s potential impact on prognosis and sensitivity to sorafenib in MVI + HCC patient. Methods: We studied the expression profiles, prognostic value of lncRNA, miRNA, and mRNA from MVI + HCC patients, established a prognosis-related network of dysregulated ceRNAs and analyzed its role in sensitivity to sorafenib and radiomics features by bioinformatics methods. Results: A ceRNA network including 13 lncRNAs, 3 miRNAs, and 2 mRNAs specific to MVI+ HCC was established. 6 lncRNAs ( ARHGEF7-AS1, ATP2B2-IT1, LINC00330, MUC2, TLR8-AS1 and ZNF385D-AS1), 2 miRNAs ( hsa-mir-206 and hsa-mir-373) and two mRNAs ( PAX3, SIK1) were prognostic biomarkers for MVI + HCC. PAX3 was an unfavorable prognostic gene (HR = 1.9, 95%CI 1.01 ~ 3.60), while SIK1 favored the prognosis (HR = 0.4, 95%CI 0.19 ~ 0.85). PAX3 as a stratification in recurrence predicting model was used to identify MVI + HCC with high or low recurrence risk. Datamining into the dataset of phase 3 STORM trial showed no difference in the influence of PAX3 level on the outcome between sorafenib HCC group and placebo HCC group. However, deep datamining into GDSC dataset revealed our high PAX3 group in MVI + HCC related to resistance to sorafenib ( P = 0.0039). Radiomics features were extracted from CT of MVI + HCC, and texture analysis in MVI + HCCs is ongoing. Conclusions: The proposed ceRNA network may help elucidate the regulatory mechanism by which lncRNAs function as ceRNAs and contribute to the pathogenesis of MVI in HCC. Importantly, the candidate lncRNAs, miRNAs, and mRNAs involved in the ceRNA network have shown to be potential therapeutic targets and prognostic biomarkers for MVI + HCC. PAX3 might play a vital role in the mechanism of sorafenib resistance in MVI + HCC, exclusively, this aggressive HCC subtype. The ongoing experiments on radiomics might add potent supports to identify sorafenib sensitive MVI + HCC.
A machine learning approach predicts future risk to suicidal ideation from social media data
Authors: Arunima Roy, Katerina Nikolitch, Rachel McGinn, Safiya Jinah, William Klement, Zachary A. Kaminsky
Journal: npj Digital Medicine (2020)

Machine learning analysis of social media data represents a promising way to capture longitudinal environmental influences contributing to individual risk for suicidal thoughts and behaviors. Our objective was to generate an algorithm termed "Suicide Artificial Intelligence Prediction Heuristic (SAIPH)" capable of predicting future risk to suicidal thought by analyzing publicly available Twitter data. We trained a series of neural networks on Twitter data queried against suicide associated psychological constructs including burden, stress, loneliness, hopelessness, insomnia, depression, and anxiety. Using 512,526 tweets from N = 283 suicidal ideation (SI) cases and 3,518,494 tweets from 2655 controls, we then trained a random forest model using neural network outputs to predict binary SI status. The model predicted N = 830 SI events derived from an independent set of 277 suicidal ideators relative to N = 3159 control events in all non-SI individuals with an AUC of 0.88 (95% CI 0.86-0.90). Using an alternative approach, our model generates temporal prediction of risk such that peak occurrences above an individual specific threshold denote a ~7 fold increased risk for SI within the following 10 days (OR = 6.7 ± 1.1, P = 9 × 10-71). We validated our model using regionally obtained Twitter data and observed significant associations of algorithm SI scores with county-wide suicide death rates across 16 days in August and in October, 2019, most significantly in younger individuals. Algorithmic approaches like SAIPH have the potential to identify individual future SI risk and could be easily adapted as clinical decision tools aiding suicide screening and risk monitoring using available technologies.
Correlation of PI3K upregulation with <i>NOTCH2</i> mutations in ibrutinib-resistant mantle cell lymphoma.
Authors: Krystle Nomie, Preetesh Jain, Nikita Kotlov, Vitaly Segodin, Qingsong Cai, Yang Liu, Lucy Navsaria, Viktor Svekolkin, Alexander Bagaev, Felix Frenkel, Ravshan Ataullakhanov, Nathan Hale Fowler, Michael Wang
Journal: Journal of Clinical Oncology (2020)

e20065 Background: PI3K dysregulation has been linked to ibrutinib resistance in mantle cell lymphoma (MCL); however, the investigation of PI3K signaling as an important ibrutinib resistance mechanism has been rarely assessed in clinical samples. Therefore, we sought to more fully characterize PI3K dysregulation in ibrutinib-sensitive and -resistant MCL clinical samples at the genomic and transcriptomic levels. Methods: Whole exome sequencing (WES; n = 41) and RNA-seq (n = 93) were performed on fresh peripheral blood, apheresis, or biopsy patient primary samples. All analysis was performed using the BostonGene automated pipeline. Results: To evaluate ibrutinib resistance in MCL, we compared the activity of 11 cellular pathways calculated by PROGENy between ibrutinib-sensitive and -resistant MCL. The PI3K pathway was the most differentially expressed between the two groups (q &lt; 0.005; &gt; 1 median absolute deviation in ibrutinib-resistant MCL). Increased PI3K pathway expression in the ibrutinib-resistant MCL tumors strongly correlated with hyperproliferation (r = 0.49; p = 6e-07). Both hyperproliferation and enriched PI3K expression associated with more frequent NOTCH2 somatic mutations (~22% ibrutinib-resistant MCL with high PI3K expression (p = 0.004) and hyperproliferation (p = 0.003)) that generate a premature stop codon in the PEST domain, likely resulting in hyperactive NOTCH2. Frequent TP53 mutations were identified in ibrutinib-resistant MCL tumors (58%; 3-fold greater vs ibrutinib-sensitive tumors; p = 0.02) based on our cohort and the Agarwal et al., 2019, Nature Medicine cohort. PI3K signaling is a known p53 activator, which may lead to a compensatory tumor suppressive mechanism, indicating that PI3K activation may induce mutational pressure on TP53 to promote MCL survival. V H gene usage variability of the B-cell receptor (BCR), the inducer of PI3K signaling, was not different between ibrutinib-sensitive and -resistant MCL, suggesting that diverse BCR expression does not underlie enriched ibrutinib-resistant MCL PI3K expression. Conclusions: PI3K inhibitors have resulted in underwhelming MCL clinical outcomes; yet, the advent of next-generation PI3K inhibitors such as copanlisib with potentially greater efficacy and less toxicity warrants the continued investigation of PI3K signaling in ibrutinib-resistant MCL. We identified a strong correlation between gain-of-function NOTCH2 mutations and enriched PI3K signaling, suggesting that dual inhibition of NOTCH and PI3K may overcome ibrutinib resistance in MCL.
骨关节炎患者治疗时的风险评估与用药策略(二)
Authors: 韩斌, 邓磊
Journal: BMJ (2009)

韩斌:骨关节炎(osteoarthritis,OA)是最常见的慢性退行性关节病损,以缓慢发展的关节疼痛、僵硬、关节肥大畸形伴活动受限等为主要特点,又称退行性骨关节病、肥大性关节炎或老年性骨关节病.病因尚不明确,它的发生与年龄、肥胖、炎症、创伤及遗传因素等有关.非甾体类抗炎药(NSAIDS)是目前治疗骨关节炎的主要手段,很多人需要长期服用。
Improvement of subcutaneous CDX model of lung cancer using A549 cell line.
Authors: Tatiana P. Protasova, Anna S. Goncharova, Marina A. Gusareva, Elena A. Karnaukhova, Igor A. Leyman, Anastasia O. Sitkovskaya, A. V. Volkova, M. V. Mindar, Sergey Yu. Tkachev, Ekaterina V. Zaikina, D. V. Khodakova, Ekaterina A. Lukbanova, Irina V. Mezhevova, Liubov Yu Vladimirova, Aleksey Yu. Maksimov, Oleg I. Kit
Journal: Journal of Clinical Oncology (2020)

e15618 Background: Lung cancer is a challenging cancer problem, despite significant progress in its therapy. The search of drugs for the treatment of lung cancer is an urgent task. The creation of animal models of lung cancer plays a key role in preclinical trials and in understanding the mechanisms of tumor pathogenesis. The purpose of the study was to create a subcutaneous cell line-derived xenograft (CDX) model of lung cancer using the human lung cancer cells A459 and to compare results of subcutaneous injections of a cell suspension with different numbers of cells in two groups of animals. Methods: A CDX model of lung cancer was created using the human lung cancer cells A459 and male BALB/c Nude mice divided into two groups (n = 4 and n = 6) with subcutaneous injections of a mix of a cell suspension with Matrigel (200 μl). The injection mix contained 5*10 6 cells in 100 μl of serum-free RPMI-1640 medium and 100 μl of Matrigel (n = 4) and 10*10 6 cells in 100 μl of serum-free RPMI-1640 medium and 100 μl of Matrigel (n = 6). Results: Animal models receiving a suspension of 10*10 6 cells in 100 μl of serum-free RPMI-1640 medium and 100 μl of Matrigel were characterized by a higher tumor growth index compared to animals receiving 5*10 6 cells in 100 μl of serum-free RPMI-1640 medium and 100 μl of Matrigel. Models created with the injections of 10*10 6 cells showed a larger volume of tumor nodes: 65.33±1, 39.2±1, 41.79±1, 36.64±1, 75.87±1 and 43.13±1 mm 3 . CDX models created with the injections of 5*10 6 cells were characterized by a division of the single tumor node by the 30th day of the experiment which complicated the measurement. Conclusions: The creation of a CDX model with injections of 5*10 6 cells is undesirable due to the nonlinear growth of the xenograft and its division into several tumor nodes. Subcutaneous CDX models of lung cancer created with injections of 10*10 6 cells showed the linear growth and the formation of the single tumor node.