tbuckley/cabot-search huggingface dataset:
Tivozanib (T) as first-line (1L) treatment of metastatic renal cell carcinoma (mRCC): A real-world outcome review in North-West of England (NWE), UK.
Authors: Jonathan Heseltine, Jennifer Allison, Sam Wong, Kellati Prasad, Helen Wong, Zhu Oong, Natalie Charnley, Andrea Law, Omi Parikh, Manon Rhys Pillai, Tom Waddell, Richard Griffiths, Shien Chow
Journal: Journal of Clinical Oncology (2022)

335 Background: The TIVO-1 study demonstrated improved PFS in mRCC patients (pts) undergoing 1L treatment with T compared with sorafenib. We previously presented outcomes of our experience of T in 4 cancer centres in NWE. Here we present updated outcomes with longer follow-up (FU). Methods: mRCC pts commencing 1L T March 2017- May 2019 were identified. Outcomes of interest included overall response rate (ORR), survival (OS, PFS) and toxicity. Data cut off for this update was 30/11/2020. Results: 113 pts were identified with characteristics as in the table. Median FU was 25.9 mo (18.3-44.7mo), 18% pts remain on treatment at data cut-off. 88.5% commenced T at full dose, of which 67% maintained dose intensity. 11.5% commenced T with dose reduction due to prior TKI toxicities or comorbidities. Median number of cycles was 7 (1-33). In terms of efficacy, ORR was 29% (CR 0%, PR29%, SD39%, PD26%, NE 6%) and median PFS was 9.0 months (95% C.I. 6.0-12.1mo). Median PFS by IMDC risk group was: F= 23.0 months (95% C.I. 7.6-38.4mo); I= 10.0 months (95% C.I. 6.3-13.7mo); P= 3.0 months (95% C.I. 1.5.- 4.5mo), p value&lt;0.0001. Median OS was 25.0 months (95% C.I. 15.4-34.6mo). Median OS by IMDC risk group was: F= NR with 72% alive at data cut-off; I= 26.0 months (95% C.I. 17.9-34.1mo); P= 7.0 months (95% C.I. 4.4-9.6mo), p value&lt;0.0001. Adverse events (AEs) of any grade occurred in 77% (≥G3 13%) including fatigue 42% (≥G3 0%), diarrhoea 19% (≥G3 &lt; 1%), mucositis 24% ( ≥G3 2%), anorexia 12% (≥G3 &lt; 1%); and hypertension 7% (≥G3 2%). Notable ≥G3 events included abnormal liver function 3%; vascular events 2% and seizure &lt; 1%. 18% of patients discontinued treatment due to toxicity with no treatment-related deaths. Conclusions: Our real world experience of 1L T suggests comparable activity with randomized data and other TKIs, particularly in F and I IMDC risk groups. The low incidence of serious AEs makes it an attractive option if unsuitable for combination therapies. [Table: see text]
The oesophagus.
Authors: D A Edwards
Journal: Gut (1971)

end expiratory' or maximum 'mean sphincter'.Greater excitement occurred when the pressure recorded by continuously perfused tubes within the sphincter of subjects suffering from reflux was found to be less than that in people without reflux4"7,910 and careful studies began to claim that there was no overlap between the sphincter pressures of those with and those without reflux.The difficulty was still the large discrepancy between the pressure 948 on August 20, 2023 by guest.
Notes and Observations on Diseases of the Heart and Lungs
Authors: T. Shapter
Journal: BMJ (1872)

This communication may be considered as the abstract of two papers.One of them was read to the Royal Society last April; and the other, at the meetilng of the British Association at Edinburgh in August of last year.* There is more soda present in muscular tissue than is required for the formation of chloride of sodium with the chlorine.The determinations yielded on 200 gra7nmnes.Mean in health.
Oral Contraceptives and Myocardial Infarction
Authors: M. F. Oliver
Journal: BMJ (1970)

During 1965-9 22 women aged 41 years or less have been seen with myocardial infarction. Eleven had been taking oral contraceptives. This prevalence of oral contraception (50%) is appreciably greater than that estimated for women of the same age in the general population. Nine of these 11 women had an independent increased risk of developing ischaemic heart disease because of hyperlipidaemia, hypertension, or excessive cigarette smoking. Ten of the 11 not taking an oral contraceptive also had a readily identifiable predisposing factor. None of the 22 showed carbohydrate intolerance. The similarity of the two groups is the striking finding. Details of 15 women of comparable age seen during 1960-4 before oral contraceptives were widely used are also presented, and they had similar characteristics. Oral contraceptives do not appear on their own to increase the risk of developing myocardial infarction, but they may do so in women otherwise prone to ischaemic heart disease. Suggestions are made for the identification of these women.
ABC of blood pressure reduction.
Authors: L T Bannan, D G Beevers, N Wright
Journal: BMJ (1980)

About 0.5% of the middle-aged population have Middte-aged adults diastolic blood pressures of 130 mm Hg or more.If left untreated they have a prognosis worse than if they had cancer.A further 4% have diastolic t / °050/0 pressures of 110 to 129 mm Hg, and about 20% of these will die in five years if left untreated.The
Tumor Drug Concentration and Phosphoproteomic Profiles After Two Weeks of Treatment With Sunitinib in Patients with Newly Diagnosed Glioblastoma
Authors: Myra E. van Linde, Mariette Labots, Cyrillo G. Brahm, Koos E. Hovinga, Philip C. De Witt Hamer, Richard J. Honeywell, Richard de Goeij-de Haas, Alex A. Henneman, Jaco C. Knol, Godefridus J. Peters, Henk Dekker, Sander R. Piersma, Thang V. Pham, William P. Vandertop, Connie R. Jiménez, Henk M.W. Verheul
Journal: Clinical Cancer Research (2022)

Tyrosine kinase inhibitors (TKIs) have poor efficacy in patients with glioblastoma (GBM). Here, we studied whether this is predominantly due to restricted blood-brain barrier penetration or more to biological characteristics of GBM.Tumor drug concentrations of the TKI sunitinib after 2 weeks of preoperative treatment was determined in 5 patients with GBM and compared with its <em>in vitro</em> inhibitory concentration (IC50) in GBM cell lines. In addition, phosphotyrosine (pTyr) directed mass spectrometry(MS)-based proteomics was performed to evaluate sunitinib-treated versus control GBM tumors.The median tumor sunitinib concentration of 1.9 µM (range 1.0 - 3.4) was 10-fold higher than in concurrent plasma, but 3 times lower than sunitinib IC50s in GBM cell lines (median 5.4 µM, 3.0-8.5; p=0.01). pTyr-phosphoproteomic profiles of tumor samples from 4 sunitinib-treated versus 7 control patients revealed 108 significantly up- and 23 downregulated (p&lt;0.05) phosphopeptides for sunitinib-treatment, resulting in an EGFR-centered signaling network. Outlier analysis of kinase activities as a potential strategy to identify drug targets in individual tumors identified 9 kinases, including MAPK10 and INSR/IGF1R.Achieved tumor sunitinib concentrations in patients with GBM are higher than in plasma, but lower than reported for other tumor types and insufficient to significantly inhibit tumor cell growth <em>in vitro</em>. Therefore, alternative TKI dosing to increase intratumoral sunitinib concentrations might improve clinical benefit for patients with GBM. In parallel, a complex profile of kinase activity in GBM was found, supporting the potential of (phospho)proteomic analysis to identify targets for (combination) treatment.
Abstract 301: Reasons for Death Following In- and Out-of-Hospital Cardiac Arrest
Authors: Lise Witten, Ryan Gardner, Mathias J Holmberg, Sebastian Wiberg, Ari Moskowitz, Michael W Donnino, Katherine M Berg
Journal: Circulation (2018)

Introduction: There is no standard method for reporting reasons for death in cardiac arrest patients. Categorizing reasons for death is important for comparing outcomes across cardiac arrest trials, assessing the benefits of targeted interventions in in-hospital (IHCA) and out-of-hospital (OHCA) cardiac arrest patients, and developing quality-improvement initiatives. We developed and tested a method for categorizing reasons for death in post-cardiac arrest patients, assessed inter-rater reliability, and compared reasons for death between IHCA and OHCA. Methods: Single-center, retrospective, cohort study of patients who had return of spontaneous circulation (ROSC) after an OHCA or IHCA between 2008 and 2017, but died before hospital discharge. Traumatic arrests and patients with a “do-not-resuscitate” order prior to their initial arrest were excluded. Two independent investigators reviewed medical records and assigned each patient to one of five predefined categories of reasons for death. Inter-rater reliability was assessed using Fleiss Kappa. For final categorization, discrepancies were resolved by discussion with a third investigator. Categorical data was compared by Fisher’s Exact Test, and continuous data by Wilcoxon Rank-Sum Test. Results: There were 182 IHCA and 227 OHCA included, with the initial rhythm being non-shockable in 77% and 69% of cases (p=0.07), respectively. Median time to ROSC was shorter in IHCA compared to OHCA (10 [IQR: 6-20] vs 30 [IQR: 21-42] min, p&lt;0.01). Median time to death was 3.3 (IQR: 1.4-8.7) days in IHCA vs 3.5 (IQR: 1.8-5.9) days in OHCA (p=0.92). The Kappa for reasons for death was 0.62 for IHCA and 0.61 for OHCA. Reasons for death for IHCA and OHCA were: neurological withdrawal of care (28% vs 72%, p&lt;0.01), comorbid withdrawal of care (36% vs 4%, p&lt;0.01), refractory hemodynamic shock 24% vs 18%, p=0.11), respiratory failure (1% vs 2%, p=0.47), and sudden cardiac death (11% vs 4%, p&lt;0.01). Conclusion: Five categories for reasons for death in post-cardiac arrest patients were developed. The primary reason for death was neurological withdrawal of care after OHCA and comorbid withdrawal of care after IHCA. Categorizing reasons for death may be important for investigators when targeting an IHCA vs an OHCA population.
Don't Compromise Myeloma Care Due to COVID-19 Pandemic!
Authors: Nikhil C. Munshi, Kenneth C. Anderson
Journal: Blood Cancer Discovery (2020)

Patients with active myeloma, especially with earlier stages of the disease, are susceptible to COVID-19 infection and can have adverse outcomes, even in those on first-line treatment. Importantly, myeloma therapy can be safely administered, and optimal control of myeloma is associated with improved outcome.
Socioeconomic functioning in patients with brain abscess – a nationwide, population-based cohort study in Denmark
Authors: Lars Haukali Omland, Jacob Bodilsen, Jannik Helweg-Larsen, Jens Otto Jarløv, Morten Ziebell, Svend Ellermann-Eriksen, Ulrik Stenz Justesen, Niels Frimodt-Møller, Niels Obel
Journal: Journal of Infection (2022)
Neurological Pathophysiology
Authors: Charles M. Poser
Journal: JAMA (1978)

This book remains a unique contribution to the neurologic literature in that it manages to convey to the intellectually curious physician and student a superb balance between basic sciences and their clinical applications. It also manages the rare feat of avoiding most zebras and concentrating on horses. It retains the clarity of exposition that was so apparent in the first edition and continues the useful practice of pointing out which hypotheses and procedures remain controversial. Two somewhat disappointing features need to be mentioned. The chapter on disorders of cerebral circulation is curiously lacking in a discussion of transient ischemic attacks and the bases for therapeutic considerations. Second, the short bibliographies are not as up to date as they might be. In general, however, this book is recommended with enthusiasm.
Abstract 17015: PGC-1alpha/Arhgap6 Axis Mediates Diabetic Vascular Dysfunction Through Diminution of Endothelial Glycolytic Flux
Authors: Makoto Ariyoshi, Mariko Aoyagi-Keller, Zolt Arany, Naoki Sawada
Journal: Circulation (2018)

Introduction: Aberrant angiogenesis in diabetes (DM) is caused by failure of local endothelial cells (ECs) to properly undergo VEGF-driven migration, and leads to a high propensity to develop critical limb ischemia. We recently showed that type 1 and 2 DM induce PGC-1α in ECs, which in turn strongly blocks EC migration and angiogenesis. Despite this therapeutic potential, PGC-1α may not be “druggable” due to the diverse distribution and functions in non-vascular tissues. Thus, understanding EC PGC-1α effectors is critical, which may involve bioenergetics since PGC-1α broadly induces mitochondrial OxPhos. Although ECs show high rate of glycolytic flux and synthesis of lactate, a burgeoning angiogenic mediator, this is blunted in DM via mechanisms still ill-defined. We hypothesized that a novel PGC-1α target in DM mediates blunted EC glycolysis and migration. Methods and Results: By leveraging NRF1/2-binding defective PGC-1α, we show that PGC-1α blocks glycolysis, through PPARgamma-driven Notch induction independent of mitochondrial activation, which fully accounts for PGC-1α inhibition of EC migration in DM. mRNA microarray identified ARHGAP6, a Rho-GAP and actin cytoskeletal modulator, as a DM-inducible main effector of PGC-1α axis to inhibit EC lactate synthesis and migration. Data suggest the causal role for ARHGAP6 in the reduced migration and glycolysis (Seahorse XF analyzer) of STZ-induced DM mouse ECs. Impaired migration of DM ECs and ECs overexpressing PPARgamma or ARHGAP6 was associated with decreased activity of Rac1 and rescued by addition of lactate. Reduced GTP-Rac1 in ECs overexpressing PGC-1α was restored by knockdown of ARHGAP6. Positive feedback loop between Rac1 and LDHA was demonstrated, suggesting a cytoskeletal-metabolic module to mediate EC migration and dysfunction. Conclusions: PGC-1α/ ARHGAP6 inhibition of EC glycolysis and lactate synthesis is a key mechanism of impaired EC migration in DM angiopathy. Our data provide important insights into the mechanistic link between EC actin cytoskeleton and bioenergetics mediated by ARHGAP6, and opportunities to restore diminished glycolysis in DM ECs by targeting PGC-1α axis component ARHGAP6 to develop safe and efficacious therapeutic since it is dispensable for health.
MOTOR NOTES FOR MEDICAL MEN
Authors: H. M. Buist
Journal: BMJ (1919)

go lg'tgj I KZDl0"J0vAKAL~~~~~~~~~~~x-ray evidence, while the gynaecological and dental conse- quences of intestinal stasis are set forth by Mr. Chapple and Mr. Forsyth.The whole book, well printed and illustrated, deserves careful study.It is the outcome of much thought, observation, and experience on the part of experts.Some of the results of the operative treatment whiclh it advocates have been remarkable, but the actual proportion of success and failure is not recorded.OCCUPATIONAL DISEASES.So many acute and chronic diseases are connected with various industrial occupations, and so many ipcreasing disabilities of every sort arise therefrom, that the massive textbook on Diseases of Occ-upation and Vocational HIygiene,2 edited by KOBER and HANSON, may be accepted witlh gratitude as a work of reference on the problems of industrial otganization.The editors contribute a most interesting historical review of the subject as preface to the volume.As all writers must, they begin with Professor Ramazzini of Padua, who wrote the first systematic treatise on diseases of occupation in 1700.It was translated into English and into French a few years later, and was the forerunner of many books in both languages, but particu- larly in our own.Tle volume now before us is so full of facts and figures of importance as to preclude anything like a systematic review in the space at our disposal.It is divided into three sections.The first is mainly medical, and deals with the specific and systemic diseases of occupation, fatigue, and the neuroses; the second section is devoted to the causation and prevention of occupational diseases and accidents, and will repay study by employers and con- trollers of labour.The third and shortest section gives an account of Professor Devoto's clinic for occupational diseases at Milan, oDened ten years ago; it contains statistical and legislational studies in the prevention of these diseases.We commend the book very warmly to all medical practitioners who are concerned with the subject of occupational diseases and their prevention.
BOOK REVIEW
Authors: C. K. CLIFFORD
Journal: JNCI Journal of the National Cancer Institute (1993)

BOOK REVIEW Macronutrients: Investigating Their Role in Cancer Marc S. Micozzi , Thomas E. Moon , eds. New York : Marcel Dekker , 1992 , 479 pp., illus. $155. ISBN 0-8247-8593-2 CAROLYN K. CLIFFORD, PH.D CAROLYN K. CLIFFORD, PH.D Diet and Cancer Branch Division of Cancer Prevention and Control National Cancer Institute BethesdaMaryland 20892 Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 85, Issue 13, 7 July 1993, Page 1086, https://doi.org/10.1093/jnci/85.13.1086 Published: 07 July 1993
Randomized controlled trial of GnRH antagonist monotherapy versus GnRH agonist plus bicalutamide (CAB) for patients with metastatic hormone-sensitive prostate cancer (mHSPC) (KYUCOG-1401).
Authors: Akira Yokomizo, Futoshi Morokuma, Masatoshi Eto, Masaki Shiota, Hideyasu Matsuyama, Hiroaki Matsumoto, Toshiyuki Kamoto, Naoki Terada, Kazuya Kawahara, Hideki Enokida, Shuichi Tatarano, Naohiro Fujimoto, Katsuyoshi Higasijima, Hideki Sakai, Tomoaki Hakariya, Tsukasa Igawa, Shigetaka Suekane, Tomomi Kamba, Yutaka Sugiyama, Seiji Naito
Journal: Journal of Clinical Oncology (2022)

99 Background: To investigate a clinical response of GnRH antagonist monotherapy against CAB therapy for mHSPC. Methods: Histopathological confirmed mHSPC patients were randomly assigned to GnRH antagonist monotherapy group (Group A) and CAB group (Group B). A deferred CAB therapy by adding bicalutamide to GnRH antagonist was performed in Group A after PSA progression. The primary endpoint was PSA progression free survival (PSA-PFS). The secondary endpoints were time to CAB treatment failure (CAB-TTF), radiographic progression free survival (rPFS), overall survival (OS), change of PSA, effect on hormone dynamics, change of bone metabolic markers, effect on lipid metabolism, adverse events (AE). This trial was registered with UMIN-CTR (UMIN000014243). Results: A total of 200 patients (101 patients in Group A and 99 in Group B) were registered from June 2014 to June 2017. The PSA-PFS was significantly better in Group B (HR (95% CI) =1.40 (1.01-1.95), p=0.041) as shown in the table. Time to CAB treatment failure (TTF) tended to be better in Group A, but there was no statistically significant difference in CAB-TTF between two groups (Table). rPFS and OS were also not statistically significant difference (Table). Time to PSA nadir was significantly shorter in Group B (HR (95% CI) = 0.72 (0.54 - 0.97), p = 0.028). The proportion of patients whose serum testosterone did not reach or maintain the castration level was more frequent in Group A (significant difference at 60 weeks, p = 0.046). There was no significant difference in the effect of bone metabolic markers and lipid metabolism between two groups. In terms of AE, injection-site-reaction was more frequent in Group A. Conclusions: LH-RH agonist CAB therapy (Group B) prolonged PSA-PFS compared to LH-RH antagonist monotherapy (Group A), probably due to the higher frequency of insufficient achievement of castration level in Group A. However, a deferred CAB therapy by adding bicalutamide to GnRH antagonist resulted in no difference in CAB-TTF, rPFS and OS. Clinical trial information: UMIN000014243.[Table: see text]
Structure-based discovery of orally efficient inhibitors via unique interactions with H-pocket of PDE8 for the treatment of vascular dementia
Authors: Xu-Nian Wu, Qian Zhou, Ya-Dan Huang, Xi Xie, Zhe Li, Yinuo Wu, Hai-Bin Luo
Journal: Acta Pharmaceutica Sinica B (2022)

Our previous study demonstrated that phosphodiesterase 8 (PDE8) could work as a potential target for vascular dementia (VaD) using a chemical probe 3a. However, compound 3a is a chiral compound which was obtained by chiral resolution on HPLC, restricting its usage in clinic. Herein, a series of non-chiral 9-benzyl-2-chloro-adenine derivatives were discovered as novel PDE8 inhibitors. Lead 15 exhibited potent inhibitory activity against PDE8A (IC50 = 11 nmol/L), high selectivity over other PDEs, and remarkable drug-like properties (worthy to mention is that its bioavailability was up to 100%). Oral administration of 15 significantly improved the cAMP level of the right brain and exhibited dose-dependent effects on cognitive improvement in a VaD mouse model. Notably, the X-ray crystal structure of the PDE8A-15 complex showed that the potent affinity and high selectivity of 15 might come from the distinctive interactions with H-pocket including T-shaped π-π interactions with Phe785 as well as a unique H-bond network, which have never been observed in other PDE-inhibitor complex before, providing new strategies for the further rational design of novel selective inhibitors against PDE8.
From the NIH
Authors: J. B. Wyngaarden
Journal: JAMA (1986)

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 Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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) 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
Controversies About Advance Care Planning—Reply
Authors: R. Sean Morrison, Diane E. Meier, Robert M. Arnold
Journal: JAMA (2022)

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 Journals 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