tbuckley/cabot-search huggingface dataset:
First-In-Human Effects of PPT1 Inhibition Using the Oral Treatment with GNS561/Ezurpimtrostat in Patients with Primary and Secondary Liver Cancers
Authors: James J. Harding, Ahmad Awada, Gael Roth, Thomas Decaens, Philippe Merle, Nuria Kotecki, Chantal Dreyer, Christelle Ansaldi, Madani Rachid, Soraya Mezouar, Agnes Menut, Eloïne Nadeige Bestion, Valérie Paradis, Philippe Halfon, Ghassan K. Abou-Alfa, Eric Raymond
Journal: Liver Cancer (2022)

&lt;b&gt;&lt;i&gt;Introduction:&lt;/i&gt;&lt;/b&gt; GNS561/Ezurpimtrostat is a first-in-class, orally bioavailable, small molecule that blocks cancer cell proliferation by inhibiting late-stage autophagy and dose-dependent build-up of enlarged lysosomes by interacting with the palmitoyl-protein thioesterase 1 (PPT1). &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; This phase I, open-label, dose-escalation trial (3 + 3 design) explored two GNS561 dosing schedules: one single oral intake 3 times a week (Q3W) and twice daily (BID) continuous oral administration in patients with advanced hepatocellular carcinoma, cholangiocarcinoma, and pancreatic adenocarcinoma or colorectal adenocarcinomas with liver metastasis. The primary objective was to determine GNS561 recommended phase II dose (RP2D) and schedule. Secondary objectives included evaluation of the safety/tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity of GNS561. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; Dose escalation ranged from 50 to 400 mg Q3W to 200–300 mg BID. Among 26 evaluable patients for safety, 20 were evaluable for efficacy and no dose-limiting toxicity was observed. Adverse events (AEs) included gastrointestinal grade 1–2 events, primarily nausea and vomiting occurred in 13 (50%) and 14 (54%) patients, respectively, and diarrhea in 11 (42%) patients. Seven grade 3 AEs were reported (diarrhea, decreased appetite, fatigue, alanine aminotransferase, and aspartate aminotransferase increased). Q3W administration was associated with limited exposure and the BID schedule was preferred. At 200 mg BID GNS561, plasma and liver concentrations were comparable to active doses in animal models. Liver trough concentrations were much higher than in plasma a median time of 28 days of administration with a mean liver to plasma ratio of 9,559 (Min 149–Max 25,759), which is in accordance with rat preclinical data observed after repeated administration. PPT1 expression in cancer tissues in the liver was reduced upon GNS561 exposure. There was no complete or partial response. Five patients experienced tumor stable diseases (25%), including one minor response (−23%). &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; Based on a favorable safety profile, exposure, and preliminary signal of activity, oral GNS561 RP2D was set at 200 mg BID. Studies to evaluate the antitumor activity of GNS561 in hepatocarcinoma cells and intrahepatic cholangiocarcinoma are to follow NCT 03316222.
The Heart and Digitalis
Authors: J. McMichael
Journal: BMJ (1963)

In the early part of the scientific period of human history, which is now only in its fourth century, progress of ideas in medicine was made by discrete steps, each marked by the significant contribution of a single individual.Thus we have the physiological landmarks created by William Harvey, Malpighi, and Stephen Hales, and the clinical progress of such astute observers as Morgagni, Heberden, and, in the same century, William Withering, whose remarkable account of the effects of the foxglove was published in 1785.It was Withering's profound collateral studies in botany (he was known as the British Linnaeus) which enabled him in 1775, when aged 34, to identify digitalis leaves as the potent agent in a hotchpotch of herbs used in Midland folk medicine.Withering exemplifies " the beauty and power of a liberal education . . .having reached out into the world of ideas and brought together in himself, self- taught, a large number of fields of interests" (Alan Gregg).He was physician, botanist, chemist, and geologist.It has been suggested that new drugs should never be used until their pharmacological effects are fully under- stood.Had this proscription been effective, digitalis would be prohibited even to-day, nearly 180 years after Withering's monograph, for we still fall considerably short of full understanding of the mode of action of this remark- able remedy.To commemorate your greatest historical medical figure in this city I can only express pride in your invitation tempered with humility.The text of my discourse is based on Withering's own final inference based on his precise clinical studies, that digitalis "has a power over the motion of the heart to a degree yet unobserved in any medicine and . . .this power may be converted to salutary ends."My first lecture deals with the motion of the heart.I venture to think that we stand to-day on the threshold of new conceptions of cardiac physiology, much of it appre- ciated only in the last decade, revealing new problems and a wide vista of investigative possibilities.I shall try to review our present knowledge in the light of personal experience.Starling's Law Let us take as our starting-point Starling's law.Fifty years ago Knowlton and Starling (1912) perfected what was for its time a magnificent technical physiological feat in isolating the dog heart and lungs for recirculation experiments.The heart, cut off from nervous and hormonal influences, responded to an increased inflow of blood, resulting from elevation of the filling pressure, by elongation of the ventricular myocardium, which responded to the stretch by a substantially increased stroke output.This was really a demonstration on the heart itself of a fundamental property of striated muscle which, within certain limits, is in an improved functional state with
Window-of-opportunity clinical trial platform for evaluation of novel treatment strategies in renal cell cancer (WIRE).
Authors: Jamal A N Sipple, Martin G Thomas, Helen Mossop, James Wason, Ferdia Gallagher, Anita Chhabra, Anne Warren, John Stone, Balaji Venugopal, Grenville Oades, Sarah Joanne Welsh, Grant D. Stewart
Journal: Journal of Clinical Oncology (2022)

TPS406 Background: Renal cell cancer (RCC) is the 7 th commonest cancer in the UK. The WIRE trial ‘exploits’ a window-of-opportunity between clear cell RCC diagnosis and nephrectomy to use vascular endothelial growth factor tyrosine kinase inhibitors, PARP inhibitors, and immune checkpoint inhibitor therapies in isolation and in combination. WIRE aims to provide biological proof-of-mechanism of these therapies, and build on encouraging pre-clinical evidence of DNA damage response inhibition to be an effective future therapeutic strategy in RCC. Methods: WIRE is a phase II, multi-IMP, multi-arm, non-randomised clinical trial featuring a Bayesian adaptive design with five treatment arms, and three recruitment stages per arm. The treatment groups: cediranib, cediranib and olaparib, olaparib, durvalumab, and durvalumab and olaparib form the initial set of therapy options with the opportunity for additional treatments to be deployed on this platform-trial in future. The primary endpoint for the first three arms is tumour capillary permeability, measured using multiparametric MRI, defined as a 30% reduction in K trans compared to pre-treatment. Whereas in the remaining two arms the primary endpoint is changed to intra-tumoural CD8 positive T cells, defined as an increase of 30% cell count compared to pre-treatment. Up to 76 evaluable participants will be recruited. Monotherapy arms will recruit a maximum of 12 participants each, whereas a maximum of 20 participants will be recruited into each dual-therapy arm. Participants are assigned to the current recruiting arm for treatment lasting between 14 and 28 days before proceeding with standard-of-care nephrectomy. Participants will undergo a biopsy and imaging before and after treatment for primary endpoint analysis, alongside blood and urine collections for translational endpoints. A final two follow-up visits are scheduled before concluding the trial pathway. Rapid interim analysis will follow at the end of a recruitment stage to determine whether to cease recruitment to the current treatment arm due to biological response, or due to futility – defined as lacking in promising evidence for proof of mechanism. Alternatively, if more data is required, recruitment will continue within the same treatment arm until the next interim analysis, where endpoints are re-examined. This highly-efficient design accelerates the exploration of multiple therapies with a strong emphasis on determining early proof-of-mechanism. Promising therapies can then be taken forward to later phase trials in RCC with greater confidence. Clinical trial information: NCT03741426.
Systems-based approaches to study immunometabolism
Authors: Vinee Purohit, Allon Wagner, Nir Yosef, Vijay K. Kuchroo
Journal: Cellular and Molecular Immunology (2022)

Abstract Technical advances at the interface of biology and computation, such as single-cell RNA-sequencing (scRNA-seq), reveal new layers of complexity in cellular systems. An emerging area of investigation using the systems biology approach is the study of the metabolism of immune cells. The diverse spectra of immune cell phenotypes, sparsity of immune cell numbers in vivo, limitations in the number of metabolites identified, dynamic nature of cellular metabolism and metabolic fluxes, tissue specificity, and high dependence on the local milieu make investigations in immunometabolism challenging, especially at the single-cell level. In this review, we define the systemic nature of immunometabolism, summarize cell- and system-based approaches, and introduce mathematical modeling approaches for systems interrogation of metabolic changes in immune cells. We close the review by discussing the applications and shortcomings of metabolic modeling techniques. With systems-oriented studies of metabolism expected to become a mainstay of immunological research, an understanding of current approaches toward systems immunometabolism will help investigators make the best use of current resources and push the boundaries of the discipline.
House Decides Major Policy
Journal: JAMA (1966)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA HomeNew OnlineCurrent IssueFor Authors Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA journal
Digital Health Emergency Management—Pandemics and Beyond
Authors: Lennart Reifels, Virginia Murray
Journal: JAMA Network Open (2022)

Bandar Al Knawy, MD; Mollie Marian McKillop, MPH; Joud Abduljawad, MD; Sasu Tarkoma, PhD; Mahmood Adil, MD; Louise Schaper, PhD; Adam Chee, PhD; David W. Bates, MD; Michael Klag, MD; Uichin Lee, PhD; Zisis Kozlakidis, PhD; George Crooks, MBChB; Kyu Rhee, MD, MPP
President's Address
Authors: J. Paget
Journal: BMJ (1881)

Continuous epidural blockade with lidocaine was used for the management of acute pancreatitis in eighty-three patients. Pain relief and alteration in the course of the disease were obtained as evidenced by relief of ileus, improvement of renal function, relaxation of the sphincter of Oddi and reduction in pulmonary complications. Mortality rate was improved over earlier methods of treatment.
Abstract 17160: Quantitative Characterization of Porcine Peripheral Artery Disease Models
Authors: Juline Deppen, Lanfang Wang, Deqiang Qiu, Christopher Leatherday, John N Oshinski, Rebecca Levit
Journal: Circulation (2018)

Introduction: Peripheral artery disease (PAD) is a significant age-related medical condition affecting over 200 million patients worldwide. PAD cell therapy clinical trials have shown minimal benefits, and questions remain regarding the optimal cell type, dose, and delivery method. A large animal preclinical PAD model has not been standardized nor quantitatively characterized, potentially contributing to the lack of success in these trials. Hypothesis: We hypothesize that a durable model of PAD can be created in swine to test cell therapy efficacy as determined through quantitative measurements of microvascular muscle perfusion and limb functionality while walking. Methods: Swine were divided into three cohorts and underwent unilateral ligation of 1) the external iliac and circumflex iliac arteries, 2) the external, internal, and circumflex iliac arteries, or 3) distal hind limb arteries to create models of PAD. Automated gait analysis with a pressure-sensitive walkway was performed at various time points pre- and post-model creation to quantify functional deficits of trotting animals. Objective calculation of various gait parameters was performed by walkway software. A pulsed arterial spin labeling (ASL) MRI sequence was used to measure perfusion in pig hind limbs during cuff-induced reactive hyperemia. Fluoroscopy-based angiography was performed during model creation and sixth week terminal procedures, and fluorescent microsphere perfusion measurements were obtained for limb muscles at study conclusions. Results: The most severe, durable functional deficits were exhibited in Cohort 2. Cohort 1 exhibited transient functional abnormalities in ischemic vs. non-ischemic hind limbs that returned to baseline in one week. Animals in Cohort 3 also displayed slight deficits early that quickly resolved. ASL MRI successfully quantified microvascular perfusion in hind limb skeletal muscle. Extensive collateral formation in ischemic hind limbs was detected at the end of each study. Conclusions: External and internal iliac artery ligation is a promising strategy to establish a durable model of hind limb ischemia in which to test the efficacy of cell and other therapeutics, better facilitating the transition of PAD therapies from bench to bedside.
Trensesophageal 3-dimensional echocardiographic study of coronary arteries: methodology, feasibility and location of coronary artery stenosis
Authors: J. Yao, M.A. Taams, P.J. de Feijter, F.J. Ten Cate, L.A. van Herwerden, J.R.T.C. Roelandt
Journal: Journal of the American College of Cardiology (1998)
Characterizing IMDC prognostic groups in contemporary first-line combination therapies for metastatic renal cell carcinoma (mRCC).
Authors: Matthew Scott Ernst, Vishal Navani, J Connor Wells, Frede Donskov, Naveen S. Basappa, Chris Labaki, Sumanta K. Pal, Luis A Meza, Lori Wood, D. Scott Ernst, Bernadett Szabados, Rana R. McKay, Francis Parnis, Cristina Suárez, Takeshi Yuasa, Anil Kapoor, Ajjai Shivaram Alva, Georg A. Bjarnason, Toni K. Choueiri, Daniel Yick Chin Heng
Journal: Journal of Clinical Oncology (2022)

308 Background: The combination of immuno-oncology agents (IO) ipilimumab and nivolumab (IPI-NIVO) and combinations of IO with vascular endothelial growth factor targeted therapies (IOVE) have demonstrated efficacy in clinical trials for the first-line treatment of mRCC. This study seeks to establish real-world clinical benchmarks based on the International mRCC Database Consortium (IMDC) criteria using vascular endothelial growth factor targeted therapy (VEGF-TT) treated patients for context. Methods: The IMDC database (IMDConline.com) was used to identify patients with mRCC who received first-line IPI-NIVO, IOVE (axitinib/pembrolizumab, lenvatinib/pembrolizumab, cabozantinib/nivolumab, or axitinib/avelumab) and VEGF-TT (sunitinib or pazopanib) from 2002-2021. The primary endpoint was overall survival (OS) and was calculated from time of initiation of first-line therapy to death or last follow up. Log-rank tests were conducted to compare favorable, intermediate, and poor risk OS outcomes within treatment groups. Overall response rates (ORR) and complete response (CR) rates were calculated based on physician assessment of best clinical response. Results: In total, 692 patients received IPI-NIVO, 244 received IOVE, and 7152 received VEGF-TT. Baseline characteristics for IPI-NIVO, IOVE, and VEGF-TT, respectively, were as follows: median age (interquartile range) 63 (56-69), 64 (57-70), and 63 (56-70); male 72%, 74%, and 72% (p=0.74); non-clear cell histology 15%, 10%, and 13% (p=0.15); sarcomatoid features 24%, 15%, and 13% (p&lt;0.0001); brain metastasis 8%, 4%, and 8% (p=0.04); liver metastasis 18%, 14%, and 18% (p=0.17); underwent nephrectomy 61%, 79% and 80% (p&lt;0.0001). OS and ORR are reported in the table. P-values (log rank) for OS between risk groups were significant for IPI-NIVO (p&lt;0.0001), IOVE (p=0.0005), and VEGF-TT (p&lt;0.0001). Conclusions: These findings provide real-world survival and response benchmarks for contemporary first-line mRCC treatments and could be helpful for patient counselling. In addition, these findings mirror the efficacy of combination therapies established in clinical trials against VEGF-TT monotherapy. IMDC criteria continue to risk stratify patients in these novel combination therapies.[Table: see text]
Predictive factors for effectiveness from novel androgen-receptor-axis-targeted agents in patients with metastatic prostate cancer.
Authors: Koshiro Nishimoto, Kenichi Nakajima, Masafumi Oyama, Go Kaneko, Satoru Takahashi, Hideyasu Matsuyama, Hiroaki Shiina, Tomohiko Ichikawa, Hiroyuki Horikoshi, Katsuyoshi Hashine, Yutaka Sugiyama, Takeshi Miyao, Manabu Kamiyama, Kenichi Harada, Akito Ito, Atsushi Mizokami
Journal: Journal of Clinical Oncology (2022)

33 Background: About a half of men with prostate cancer progress to metastatic castration-resistant prostate cancer (mCRPC) one year after the initiation of androgen-deprivation therapy (ADT), whereas approximately 20 % of men keep the sensitivity to ADT more than 5 years. Several novel androgen-receptor-axis-targeted agents (ARATAs) were developed for the treatment of mCRPC, and improved overall survival (OS) in patients with mCRPC; however, to which patients these ARATAs were more beneficial is yet to be determined. We conducted this study to identify factors that predict effectiveness from ARATAs for mCRPC. Methods: We previously performed a multicenter study to determine prognostic factors including bone scan index (BSI) in patients with metastatic hormone sensitive prostate cancer (n = 148) and mCRPC (n = 99), which showed that BSI was one of the significant determinants of 3-year OS (PROSTAT-BSI study). The patients with mHSPC progressed to mCRPC (n = 101). Among these mCRPC patients, 69 patients received treatments with or without ARATAs, because the patients were recruited before and after approval of ARATAs in Japan. We used the data of the 69 patients to identify predictors for effective use of ARTA. The cohort was divided into two groups according to patient factors by several thresholds, and these two cohorts were further divided into two subgroups: those who received and did not receive ARATAs (abiraterone or enzalutamide). OS was compared between these two cohort groups to evaluate contribution of each factor. Categorical values were analyzed in the same way, although no threshold setting was required. Results: Factors, in which the significant treatment effect from ARATAs was observed between subgroups in only one group (eg. age &lt; 71.4 vs age ≥ 71.4), were age ( &lt; 71.4 years); serum levels of C-reactive protein (≥0.16 ng/mL), alkaline phosphatase (≥548 U/L), and type 1 collagen C-terminal telopeptide ( &lt; 6.4 ng/mL); time to PSA progression after ADT ( &lt; 8.9 months); lowest PSA level (≥1 ng/mL) after ADT; and rate of PSA decline 3 month after ADT ( &lt;.987). Whereas, no significant difference was observed between two groups in cohorts divided by hemoglobin level, PSA before ADT, Gleason score, and BSI. Conclusions: This study identified the predictors of the effectiveness from ARATAs. In addition, the number of bone metastases (corresponding to BSI) and Gleason score, which were considered as high-risk factors in the LATITUDE study and disease volume in the CHAARTED criteria, may not be useful for predicting the effectiveness from ARATAs.
Abstract 262: Hemodynamically-Guided Optimum Chest Compression Point in a Rat Model of Cardiopulmonary Resuscitation
Authors: Davide Olivari, Daria De Giorgio, Deborah Novelli, Aurora Magliocca, Laura Ruggeri, Giuseppe Ristagno
Journal: Circulation (2018)

Introduction: CPR aims to re-establish blood flow by chest compression (CC), achieving threshold levels of coronary perfusion pressure (CPP). For this, current guidelines recommend the lower sternal half as optimum CC point. However, this point might be not optimal for every individual. We investigated the hemodynamics generated by CC performed on different chest points in a rat model of CPR. We hypothesized that a CC point hemodynamically-identified would be a better approach compared to the lower sternal half. Methods: Ten male rats were anesthetized and arterial and right atrial pressures monitored. Ventricular fibrillation was induced and untreated for 8 min. CPR, including mechanical CC, ventilation, and epinephrine, was then performed for 8 min. Animals were divided to receive CC performed either on the lower sternal half (standard (STD), n=5) or on an optimum point identified as the one able to generate the maximum CPP (MaxCPP group, n=5). Cardiac districts involved in CC were subsequently identified by computed tomography (CT). Results: STD CC produced a CPP that was constantly below the threshold for successful resuscitation and trended to decrease over time. When the optimum CC point was identified hemodynamically, the CPP generated was constantly &gt; 20 mmHg. Indeed, CPP was significantly higher in the MaxCPP group compared to the STD one for the whole 8 min of CPR (p&lt;0.01, Fig). Moreover, administration of epi rapidly further improved CPP (p&lt;0.01 vs. pre-epi) in the group with an optimized CC point, while no drug effect was observed in the STD one. CT scan showed that the lower sternal half did not correspond to the LV maximum diameter, known to account for a maximum stroke volume generation during CC (Fig). Conclusion: Standard lower sternal half CC point is not able to maximize hemodynamics during CPR, making ineffective CC efforts and vasopressor administration. The quality of CPR may improve if the optimum CC point is identified as a reflection of CPP generated.
Marshaling macrophages against metastases
Authors: M. L. Zoler
Journal: JAMA (1983)

The frequent failure of attempts to treat metastatic cancer may stem in part from the heterogenous nature of malignant neoplasms which leads to the rapid emergence of metastases resistant to conventional therapy (<i>JAMA</i>[MEDICAL NEWS] 1982;247:417). However, observes Isaiah J. Fidler, DVM, PhD, there now is "evidence that activated macrophages can recognize and destroy neoplastic cells in vitro without regard to their phenotypic diversity." As a result, a number of laboratories are investigating the mechanisms by which macrophages destroy tumor cells, ways in which this process can be enhanced, and the best ways to incorporate macrophage therapy into conventional anticancer treatments. These investigations have utilized a wide array of in vitro, animal, and clinical systems, although none of the macrophage-enhancing protocols are yet ready for large-scale use in patients, nor is it probable that they will be for some time. The "mononuclear phagocyte" system of the human body consists of