tbuckley/cabot-search huggingface dataset:
Abstract 5808: Examination of clinically relevant inhibitor selectivity in live cells across the CDK family
Authors: James Vasta, Carrow Wells, Cesear Corona, Jennifer Wilkinson, Chad Zimprich, Morgan Ingold, Domenic Ogno, Marie Schwinn, Thomas Machleidt, Mei Cong, Frank Fan, Kristin Huwiler, Amy Landreman, Julie E. Pickett, Kilian Huber, Matthew Robers
Journal: Cancer Research (2020)

Abstract Cyclin-dependent kinases (CDK) play key roles in diverse cellular functions including cell cycle control, cell proliferation, and transcriptional regulation. Due to these important roles, CDKs have been targeted for cancer therapeutic development, which has resulted in hundreds of small molecule inhibitors. However, conflicting data of CDK inhibitor potency has been reported and a rigorous comparison of inhibitor affinity and selectivity for intracellular CDKs is lacking. To address this need, we have developed a panel of cell-permeable energy transfer probes or tracers to enable comprehensive quantitation of inhibitor target occupancy and affinity for CDKs in live cells via a bioluminescent energy transfer (BRET) method. Specifically, the quantitative BRET-based capability is achieved via energy transfer from cell-permeable fluorescent tracers reversibly engaged to NanoLuc luciferase-tagged CDK proteins expressed in live cells. An untagged cyclin can be introduced into the cells at the same time as the NanoLuc-CDK, allowing for the interrogation of a specific CDK-cyclin pair. The BRET-based method can be used in equilibrium binding analysis. In addition, time-dependent target-compound occupancy (or residence time) can also be obtained with this method. We will present a comprehensive evaluation of intracellular isozyme potency and selectivity for a collection of clinically-advanced CDK inhibitors and chemical probes across the CDK family. We observed unexpected intracellular activity profiles for some clinically-advanced CDK inhibitors. We further evaluated mechanisms for achieving target selectivity through target residence time under non-equilibrium cell culture conditions. This BRET-based method is broadly applicable for evaluating the occupancy, affinity, and selectivity of chemical matter for CDKs in live cells. Citation Format: James Vasta, Carrow Wells, Cesear Corona, Jennifer Wilkinson, Chad Zimprich, Morgan Ingold, Domenic Ogno, Marie Schwinn, Thomas Machleidt, Mei Cong, Frank Fan, Kristin Huwiler, Amy Landreman, Julie E. Pickett, Kilian Huber, Matthew Robers. Examination of clinically relevant inhibitor selectivity in live cells across the CDK family [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 5808.
Expansion of Private Equity Involvement in Women’s Health Care
Authors: Joseph D. Bruch, Alexander Borsa, Zirui Song, Sarah S. Richardson
Journal: JAMA Internal Medicine (2020)

with ISCHEMIA trial criteria) had a minimal association with the proportion of patients with PCIs classified as appropriate, maybe appropriate, and rarely appropriate.Discussion | In a national registry of patients undergoing nonacute PCI, we found that approximately 1 in 6 patients were asymptomatic at the time of PCI.If the AUC were modified to incorporate randomized clinical trials, such as COURAGE 5 and the recent ISCHEMIA trial, 2 and considered these PCIs to be rarely appropriate for SIHD, the rates of rarely appropriate PCI may be nearly 7-fold higher compared with current AUC ratings.Given that we were unable to assess whether optimal antianginal therapy had failed before PCI in the current or modified AUC, the proportion of patients with PCIs classified as rarely appropriate with either AUC could be even higher than we estimate.As PCIs in patients with SIHD are estimated to cost $2.8 billion annually 6 and are associated with risks for bleeding, infection, and death, these findings underscore the importance of updating clinical guidelines and AUC to be consistent with the robust evidence base.
Five-year relapse-free survival and predictors of relapse following preoperative docetaxel and mitoxantrone for high-risk localized prostate cancer
Authors: B. L. Rademacher, M. Garzotto, C. S. Higano, C. A. O'Brien, N. Janeba, L. Fazli, P. H. Lange, S. Lieberman, T. M. Beer
Journal: Journal of Clinical Oncology (2009)

5121 Background: Efforts to incorporate systemic therapy with activity against castration-resistant prostate cancer into the early management of high-risk disease are motivated by persistent risk of relapse when neoadjuvant androgen suppression therapy (AST) is combined with surgery. As docetaxel and mitoxantrone exert anti-tumor effects through distinct cellular mechanisms, this combination has the potential for synergistic activity against prostate cancer. Here we report the 5-year outcomes of patients treated with a novel regimen that combines these agents without AST prior to prostatectomy. We also examined pathologic, biomarker and clinical predictors of early relapse. Methods: 57 high-risk prostate cancer patients were enrolled in a phase I/II study of weekly docetaxel 35 mg/m 2 and escalating mitoxantrone to 4 mg/m 2 delivered weekly for 3 of every 4 weeks per cycle for 4 cycles over 16 weeks followed by radical prostatectomy. A tissue micro-array constructed from the prostatectomy specimens served to facilitate the exploratory evaluation of biomarkers. The primary end point was relapse-free survival. Relapse was defined as a confirmed serum PSA &gt; 0.4 ng/mL. Results: 54 of 57 pts received all 4 cycles of docetaxel and mitoxantrone prior to radical prostatectomy. Grade 4 toxicities were limited to leucopenia, neutropenia and hyperglycemia. Serum testosterone levels remained stable after chemotherapy. Negative surgical margins were attained in 67% of cases. Lymph node involvement was detected in 18.5% of cases. With a median follow-up of 63 months (range 7 to 86 months), 27 of 57 (47.4%) patients recurred. The Kaplan-Meier progression-free survival at 2 years was 65.5% (95% CI 53.0% to 78.0%) and 49.8% at 5 years (95% CI 35.5% to 64.1%). Pretreatment serum PSA, lymph node involvement, and post-chemotherapy tissue VEGF expression were independent predictors of early relapse. Conclusions: Preoperative combination chemotherapy with docetaxel and mitoxantrone is safe. Approximately half of the high risk pts remain relapse free at 5 years and clinical and molecular predictors of early relapse in this population have been identified. [Table: see text]
Alison Galvani—a modeller whose career has flourished early
Authors: Tony Kirby
Journal: The Lancet Infectious Diseases (2020)

Alison Galvani experienced tragedy at an early age, losing her mother at 5 years old, which fractured her family life and led to her being sent away from home in San Francisco, CA, USA, to boarding school in the UK. Ever since those difficult early years, she has immersed herself firstly in her education, and now in her career and family life. Today, she is the director of the Center for Infectious Disease Modeling and Analysis (CIDMA) and the Burnett and Stender Families Professor of Epidemiology at Yale University, School of Public Health.
High-Density Lipoprotein Carries Markers That Track With Recovery From Stroke
Authors: Deanna L. Plubell, Alex M. Fenton, Sara Rosario, Paige Bergstrom, Phillip A. Wilmarth, Wayne M. Clark, Neil A. Zakai, Joseph F. Quinn, Jessica Minnier, Nabil J. Alkayed, Sergio Fazio, Nathalie Pamir
Journal: Circulation Research (2020)

Prospective cohort studies question the value of HDL-C (high-density lipoprotein cholesterol) for stroke risk prediction.Investigate the relationship between long-term functional recovery and HDL proteome and function.Changes in HDL protein composition and function (cholesterol efflux capacity) in patients after acute ischemic stroke at 2 time points (24 hours, 35 patients; 96 hours, 20 patients) and in 35 control subjects were measured. The recovery from stroke was assessed by 3 months, the National Institutes of Health Stroke Scale and modified Rankin scale scores. When compared with control subject after adjustments for sex and HDL-C levels, 12 proteins some of which participate in acute phase response and platelet activation (APMAP [adipocyte plasma membrane-associated protein], GPLD1 [phosphate inositol-glycan specific phospholipase D], APOE [apolipoprotein E], IHH [Indian hedgehog protein], ITIH4 [inter-alpha-trypsin inhibitor chain H4], SAA2 [serum amyloid A2], APOA4 [apolipoprotein A-IV], CLU [clusterin], ANTRX2 [anthrax toxin receptor 2], PON1 [serum paraoxonase/arylesterase], SERPINA1 [alpha-1-antitrypsin], and APOF [apolipoprotein F]) were significantly (adjusted P<0.05) altered in stroke HDL at 96 hours. The first 8 of these proteins were also significantly altered at 24 hours. Consistent with inflammatory remodeling, cholesterol efflux capacity was reduced by 32% (P<0.001) at both time points. Baseline stroke severity adjusted regression model showed that changes within 96-hour poststroke in APOF, APOL1, APMAP, APOC4 (apolipoprotein C4), APOM (apolipoprotein M), PCYOX1 (prenylcysteine oxidase 1), PON1, and APOE correlate with stroke recovery scores (R2=0.38-0.73, adjusted P<0.05). APOF (R2=0.73) and APOL1 (R2=0.60) continued to significantly correlate with recovery scores after accounting for tPA (tissue-type plasminogen activator) treatment.Changes in HDL proteins during early acute phase of stroke associate with recovery. Monitoring HDL proteins may provide clinical biomarkers that inform on stroke recuperation.
Evaluation of known risk factors for breast cancer in Venezuelan patients with breast cancer, benign breast diseases, and without breast pathology
Authors: D. E. Hernandez, A. E. Hernandez, G. C. Garcia
Journal: Journal of Clinical Oncology (2009)

1531 Background: Breast cancer (BC) represents the second cause of death from cancer in Venezuelan women, therefore, it is important to study the known risk factors for developing BC in Venezuelan patients. Also, little is known about the importance of these risk factors in patients with benign breast diseases (BBD). Due to this we carried out a prospective case-control study of known risk factors for developing BC in a group of female patients with BC and BBD with the purpose of defining clinical criteria which can be used to orient physicians and patients about the conducts to be followed not only by the patients, but also by their family group. Methods: We included 515 patients with BC, 507 with BBD, and 505 without breast pathology.The following risk factors were identified through a personal interview with each patient: family history of breast and ovary cancer, exposure to female hormones (exogenous and endogenous), and previous history of BBD. Results: The significant results when comparing the BC group with the BBD group were the following: strong family history of BC (p = 0.004), ingestion of oral contraceptives (p = 0.035), lactation (p = 0.00013), hormone replacement therapy (p = 0.000001), and previous history of BBD (p = 0.0000032). The significant results when comparing the BC group with the group without breast pathology were the following: family history of BC (p = 0.0000001), family history of ovary cancer (p = 0.0000001), nulliparity (p = 0.00009), age of first terminal pregnancy (p = 0.000001), number of abortion (p = 0.024), lactation (p = 0.03), and previous history of BBD (p = 0.0000001). A logistic regression model showed that the variables with the highest impact were lactation (p = 0.0001), family history of breast cancer (p = 0.0001), and family history of ovary cancer (p = 0.0001). Conclusions: Even though several hormonal factors were important, lactation and family history of breast and ovary cancer were the most important risk factors. No significant financial relationships to disclose.
Hyperphosphatemia Secondary to the Selective Fibroblast Growth Factor Receptor 1–3 Inhibitor Infigratinib (BGJ398) Is Associated with Antitumor Efficacy in Fibroblast Growth Factor Receptor 3–altered Advanced/Metastatic Urothelial Carcinoma
Authors: Yung Lyou, Petros Grivas, Jonathan E. Rosenberg, Jean Hoffman-Censits, David I. Quinn, Daniel P. Petrylak, Matthew Galsky, Ulka Vaishampayan, Ugo De Giorgi, Sumati Gupta, Howard Burris, Jessica Rearden, Ai Li, Hao Wang, Maribel Reyes, Susan Moran, Siamak Daneshmand, Dean Bajorin, Sumanta K. Pal
Journal: European Urology (2020)
Management of a necrosed bile duct by combination of a fully covered metal biliary stent and endoscopic ultrasound-guided gastrojejunostomy
Authors: Christopher J. DiMaio, Antonio R. Cheesman, Satish Nagula, Nikhil A. Kumta
Journal: Endoscopy (2020)

Endoscopic ultrasound-guided gastrojejunostomy (EUS-GJ) is an emerging procedure in the management of gastric outlet obstruction [1] [2] [3] [4] [5]. One potential application of EUS-GJ is to divert luminal contents away from a luminal defect in order to minimize infection and/or facilitate healing.
Life, learning, and medicine: advice to new medical students from a junior doctor
Authors: Laith Alexander
Journal: BMJ (2020)

Starting out at medical school is challenging. It isn’t just the work: it’s the prospect of meeting new people, adapting to a different place, and managing your independence. It’s normal to feel apprehensive. I could reel off some practical things you should do to prepare for medical school, but that’s been done many times before. Instead, I want to offer you some of my reflections. Call it what you will—wisdom, hindsight, or nostalgia from a seasoned medical school graduate—but perhaps you can take away something useful for your own journey.

You’re committing several years of your life to medical school, and it’s natural that you will oscillate between times that are good, great, and difficult. Being at medical school will be one of the most formative experiences of your life, so embrace it. Your friendship group—medics and non-medics alike—will become your rock. Friends will be with you to enjoy the highs and to help you stay resilient during …
No Easy Answers in Allocating Unapproved COVID-19 Drugs Outside Clinical Trials
Authors: Jaime Webb, Lesha Shah, Holly Fernandez Lynch
Journal: The American Journal of Bioethics (2020)

Click to increase image sizeClick to decrease image sizeThis article refers to:Ethically Allocating COVID-19 Drugs Via Pre-approval Access and Emergency Use Authorization DISCLOSURE STATEMENTJamie D. Webb has no competing interests to disclose. Lesha D. Shah is a member of the NYU Grossman School of Medicine Working Group on Compassionate Use and Preapproval Access (CUPA). Holly Fernandez Lynch is the founder and co-chair of the Advancing Effective Research Ethics Oversight Consortium (AEREO), a member of a subcommittee of the U.S. Department of Health and Human Services Secretary?s Advisory Committee for Human Research Protections (SACHRP), a board member of Public Responsibility in Medicine and Research (PRIM&R) and the American Society of Law, Medicine and Ethics (ASLME), and a member of the NYU Grossman School of Medicine Working Group on Compassionate Use and Preapproval Access (CUPA). She received travel costs and honorarium for a lecture to WCG Clinical in 2017 and consulting fees from Hueston Hennigan in 2019 on matters related to research compliance.Additional informationFundingHolly Fernandez Lynch receives research funding from the Greenwall Foundation.
The study of FDG PET-CT on the value in predicting of patient outcome after treatment of stage III non-small cell lung cancer
Authors: H. Zhang, J. Yu
Journal: Journal of Clinical Oncology (2009)

7572 Background: Up to the present study, the value of FDG PET-CT in patients of non-small cell lung cancer (NSCLC) before and after treatment has been approved. However, the significance of FDG PET-CT during the treatment has not been confirmed. The objective of this study was to evaluate 18 FDG PET-CT for assessment of therapy response and prediction of patient outcome after concurrent chemo-radiotherapy (CCRT) of NSCLC. Methods: Forty six patients with histologically proven stage III NSCLC had two repeated FDG PET-CT scans either one week before therapy and at the dose of 40∼50Gy, the SUVmax and Changes of the two group after completion of NARCT were compared with (1) the therapy response and (2) treatment results and long-term survival. Results: Of the 46 eligible patients, the pretreatment SUVmax of the responding and nonresponding groups was7.59±3.14 and 14.72±4.67 respectively. The midtreatment SUVmax of the two groups was 2.89±1.39 and 9.82±3.31 respectively. Significantly difference (t= 4.74,P=0.001; t=7.23,P=0.001) in SUVmax were observed either before and during treatment. Furthermore, the percent change of SUVmax of pretreatment and midtreatment was ΔSUVmax=61.91±86.69 and ΔSUVmax=33.56±90.37, difference between the two groups was also significantly (t=2.83, P=0.007). In addition, the 1 year survival rate of the the respond and non-respond group were 73% and 69% respectively, the 2-year survival rate of the two groups were 40% and 37% respectively, significant difference was observed between the two groups (P=0.001; P=0.001). Conclusions: 18 FDG PET-CT is highly effective in detecting therapy response in stage III NSCLC patients, the analysis of percent change of SUVmax provides incremental value in early prediction of therapy response and patient outcome. No significant financial relationships to disclose.
Correction: Bone marrow plasma cells 20% or greater discriminate presentation, response, and survival in AL amyloidosis
Authors: Eli Muchtar, Morie A. Gertz, Taxiarchis V. Kourelis, Surbhi Sidana, Ronald S. Go, Martha Q. Lacy, Francis K. Buadi, David Dingli, Suzanne R. Hayman, Prashant Kapoor, Nelson Leung, Amie Fonder, Miriam Hobbs, Yi Lisa Hwa, Wilson Gonsalves, Rahma Warsame, Stephen Russell, John A. Lust, Yi Lin, Steven Zeldenrust, S. Vincent Rajkumar, Robert A. Kyle, Shaji K. Kumar, Angela Dispenzieri
Journal: Leukemia (2020)
Abstract 6374: Novel RAS inhibitors
Authors: Geoffrey Justin Clark
Journal: Cancer Research (2020)

Abstract The Ras oncoprotein may participate in driving half of human tumors and as such remains the single most significant therapeutic target in cancer. Attempts to develop targeted inhibitors of RAS have proved extremely challenging. We have developed a novel Ras binding molecule that blocks the ability of Ras to interact with its downstream effector components and thus down-regulates Ras signaling. We have also developed the first direct inhibitor of the RAS effector RALGDS. Both compounds suppresses the transforming activity of mutant forms of Ras as well as the wild type protein when it is over-active due to defects in the NF1 protein. The compounds have no detectable toxicity in animals and readily crosses the blood-brain barrier. They are potently active in xenograft models of Ras mediated transformation and can eradicate the ability of Ras addicted tumor cells to form tumors in animals. We propose the compounds may serve as the basis for the development of new treatments for oncogenic RAS driven tumors and for many Rasopathy symptoms. Citation Format: Geoffrey Justin Clark. Novel RAS inhibitors [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 6374.
Multicenter randomized controlled phase III clinical trial using TNFerade (TNF) with chemoradiation (CRT) in patients with locally advanced pancreatic cancer (LAPC): Interim analysis (IA) of overall survival (OS)
Authors: K. J. Chang, W. Fisher, D. Kenady, J. Klapman, M. Posner, T. Reid, A. Rosemurgy, R. Shah, E. Zervos, D. Laheru
Journal: Journal of Clinical Oncology (2009)

4605 Intro: Local control of LAPC with CRT has historically demonstrated survival benefit vs. RT alone. TNF is a nonreplicating adenovirus vector delivering human tumor necrosis factor (TNF-α). Results from a phase II study with TNF in LAPC indicated a possible survival advantage. To confirm these findings, a randomized, open-label, controlled Pancreatic Cancer Trial with TNF (PACT) study was developed. Methods: The TNF arm received a 5 wk treatment of qw intratumoral inj of 4x10 11 PU TNF, cont. iv 5-FU and 50.4Gy radiation. The standard of care (SOC) arm received CRT alone. Both groups received adjuvant gemcitabine(G) with the option of erlotinib(E). An IA of OS (primary efficacy endpoint) was planned after the first third (92) of the expected 276 total death events (from a total patient n=330). Nonparametric logrank of OS was planned; in addition, a lognormal model was used to account for an evident separation of the survival curves after the median. Results: 185 pts were available for OS analysis (117-TNF+SOC and 68-SOC). Survival in the TNF+SOC group demonstrated a HR of 0.753 (CI [0.494 - 1.15]) relative to SOC. Best fit parametric lognormal analysis indicated a median survival of 11.1 mo with TNF+SOC and 8.7 mo with SOC; nonparametric methods indicated a MS of 9.9 mo for both arms, with a pronounced “late effect” (75th percentile 19.4 mo with TNF+SOC and 11.8 mo with SOC). Prognostic information (G and E use, stage, etc) indicated equivalent distribution between groups. Conclusions: HR results of the OS IA indicate an encouraging trend in favor of the TNF treated group. Parametric medians may better reflect the true HR than nonparametric methods since the latter do not reflect the shape of the OS distribution. A second IA is planned after 2/3 total events. [Table: see text]