tbuckley/cabot-search huggingface dataset:
Abstract 17038: <i>Twist1</i> Modulates Smooth Muscle Cell Phenotypes in Atherosclerosis
Authors: Marie A Guerraty, Sylvia T Nurnberg, Vraj Shah, Daniel J Rader
Journal: Circulation (2018)

Introduction: Genome-wide association studies have identified rs2107595, a non-coding locus on chromosome 9 between HDAC9 and Twist1 genes, as a risk allele for several vascular phenotypes, including Coronary Artery Disease (CAD). Rs2107595 has, more specifically, been associated with stable CAD over myocardial infarction phenotypes. Recent work has shown that rs2107595 risk allele increases Twist1 expression in smooth muscle cells (SMCs) by creating an RBPJ binding site. In other cell types, Twist1 is known to maintain cells in a de-differentiated state and to promote epithelial to mesenchymal transformation, driving tumor progression and metastasis. Hypothesis: Twist1 modulates SMC differentiation to promote an immature proliferative state over a differentiated (osteoblastic) state. This shift in phenotype promotes features of plaque stability in vivo . Methods: Twist1 expression plasmid (pCMV6-TWIST1) was transfected into A7r5 rat smooth muscle cells. To assess proliferation, cells were counted at 24, 48, 72, and 96 hours. To assess calcification, A7r5 cells were cultured in calcification media (2mM NaPhos) for 10 days and stained with Alizarin Red. In vivo studies were performed in Twist1 fl/fl tamoxifen-inducible MYH11-Cre C57BL/6 mice on ApoE-/- background fed a Western diet for 16 weeks to induce atherosclerotic lesions. Immunohistochemistry with SM22a identified lesion SMCs, and alizarin red was used to identify calcifications. Results: Ectopic overexpression of Twist1 in A7r5 SMCs decreased proliferation at 48h and 72h (80%, p=0.014). Twist 1 overexpression also decreased the total area of calcification (33% reduction, p=0.007). In vivo , both control and Twist 1 KO mice show similar burden of atherosclerosis. However, there is a decrease in sub-endothelial SMCs in atherosclerotic lesions by SM22a staining in the Twist1 KO. Additionally, Twist1 KO mice have more prominent and larger focal calcifications. Conclusions: Twist1 promotes SMC proliferation and decreases calcification in vitro , and may affect the presence of subendothelial SMCs and calcification in vivo . This provides a compelling link that rs2107595 may promote plaque stability in CAD by increasing Twist1 to modulate SMC phenotypes.
Curare
Authors: M. Dawkins
Journal: BMJ (1947)

IIhead cold.I advised him to suck some of the penicillin lozenges.Two days later his left knee was swollen, with fluid in and around the joint.It was tender but not red, and his temperature was normal.The penicillin lozenges were continued, and by the next day his right knee was mildly affected in the same way, and hydrarthrosis of the joints of the fingers prevented full flexion.The penicillin was stopped and within twenty-four hours the joints appeared normal.A skin test showed a sensitivity equal to that of his son.This record shows once more how indiscriminate use of penicillin can produce startling results.It also points out the benefit of kpowing about a patient's sensitivity to penicillin, so that an attempt may be made to desensitize him in preparation for a possible future sudden need for penicillin.-Iam, etc., Leeds.
ORCHID: A phase II study of olaparib in metastatic renal cell carcinoma patients harboring a BAP1 or other DNA repair gene mutations.
Authors: Yasser Ged, Irina Rifkind, Amber Michalik, Michael Anthony Carducci, Mark Christopher Markowski
Journal: Journal of Clinical Oncology (2022)

TPS400 Background: Metastatic renal cell carcinoma (RCC) comprises a wide set of heterogenous tumors, many of which are increasingly recognized with alterations that affect genomic instability. Several studies demonstrated that DNA repair pathways are frequently disrupted in RCC. Recent In vitro studies have shown that RCC cells are sensitive to PARP inhibitors, with subsequent increased DNA replication stress, DNA synthesis suppression and eventual increased cell cycle arrest. In addition, other studies demonstrated reduced repair of double stranded DNA (dsDNA) breaks following conditional knockout of BAP-1 suggesting that PARP inhibitors may result in synthetic lethality in the setting of BAP-1 inactivation. In light of this we have initiated a phase 2 clinical trial to examine the activity of the PAPR inhibitor olaparib in metastatic RCC with BAP-1 and select DNA repair gene alterations. Methods: This is an open-label, single-arm, investigator-initiated phase II trial of olaparib in patients with metastatic RCC (NCT03786796). Eligibility criteria include age ≥18 years; histologically confirmed, unresectable, locally advanced or mRCC; disease progression after at least one VEGF targeted therapy or immune-checkpoint inhibitor, evidence of deleterious somatic or germline DDR gene alteration ( BAP1, ATM, BRCA1, BRCA2, PALB2, CHEK2, BRIP1, RAD51C, BARD1, CDK12, CHEK1, FANCL, PP2R2A, RAD51B, RAD51D, or RAD54L). A total of 20 patients will be enrolled with the primary endpoint of disease control rate (defined as complete response [CR], partial response [PR], or stable disease [SD]) at six months of treatment) according to RECIST version 1.1. Patients will be treated with olaparib at an initial dose of 150mg by mouth twice daily. If olaparib is tolerated without any grade &gt; 3 adverse events after one month, the dose will be increased to the FDA-approved dose of 300mg by mouth twice daily. Patients will be followed monthly with clinic visits, safety labs, and toxicity assessments. Treatment will be continued until radiographic progression (RECIST version 1.1) or unmanageable toxicity requiring drug cessation. Secondary endpoints include progression-free survival, best overall response, and safety. The study is currently open to enrollment. Clinical trial information: NCT03786796.
St. George's Hospital
Authors: T. Jones
Journal: BMJ (1864)

ing, as she said, tumours per vaginam.The catamenia, when present, were very copious.In April 1844, they stopped, only a few drops passing away.This suppression was followed by lumbar and inguinal pains, colicky pains, and vertigo.In July, pains like labour-pains supervened.A medical man now con- sulted diagnosed a polypus uteri.Next month, the breasts began to enlarge as well as the abdomen.The movements of a child were felt internally by her- self and could be felt externally by the hand.In February 1845, there was recurrence of labour-pains, constipation, and difficult micturition.Eight days subsequently, a kind of membrane (decidua?)came away per vaginam, followed by catamenia for three days.From this time, all fcetal movements ceased.The general pains and other symptoms recurred from time to time.The tumour had moved apparently from the median line to the left side.An eminent Parisian accoucheur, now consulted, diagnosed a fibroid tumour in the uterus or ovarian disease.On June 3, the catamenia recurred, and lasted six days.On admission, the following were the symptoms observed.By Palpation, etc.: Large abdomen; round hemispheric tumour, more on the right than on the left side; percussion dull anteriorly, clear in the lum- bar regions, extending from six centimitres below the xiphoid cartilage to the pubes over a space of thirty centitetetres; circumference, seventy-five centimitres; no uterus to be felt, nor fluctuation; external veins not enlarged.When she was placed on her side, the tumour fell to such side, but without pain.There was no souffle.Vaginal Examination: The cervix lay rather to the left side, and hypertrophied, behind the pubes; flattened from before backwards.The os was open, admitting the index finger.Between the vagina and rectum, in the posterior cul-de-sac, a tumour filled the cavity.There was no feeling of a foetus.M. Jobert diagnosed extrauterine pregnancy and a dead fretus.
Abstract 149: Role of Pre and Intra-Arrest Hemodynamics in Evolution of the Ventricular Fibrillation Electrocardiogram Waveform
Authors: Caelie E Kern, David D Salcido
Journal: Circulation (2018)

Purpose: Quantitative waveform measures (QWM) of the ventricular fibrillation (VF) waveform have been shown in laboratory and clinical studies to be predictive of return of spontaneous circulation (ROSC) and survival to hospital discharge. During resuscitation, QWM are responsive to hemodynamic changes resulting from CPR. It is not known whether the trajectory of QWM are affected by pre-arrest hemodynamics or intra-arrest arterio-venous pressure equilibration. We sought to investigate the role of hemodynamics on the evolution of VF before and during prolonged VF. Methods: We pooled data from six previous porcine experiments. Each modeled prolonged VF and included electrical induction of VF which was left untreated for up to 10 minutes, followed by attempted resuscitation. All animals were instrumented with pressure transducers (Millar, MikroTip) placed via femoral cutdown in the aorta and right atrium, as well as Lead II surface ECG. Signals were recorded continuously at 1000Hz with a data acquisition unit (PowerLab, ADInstruments). Mean baseline central arterial (CAP) and central venous pressure (CVP) were calculated from 1- minute of immediate pre-VF pressure traces. Coronary perfusion pressure (CPP) during untreated VF was calculated as the continuous difference between the CAP and CVP channels. Median slope (MS), a QWM, was calculated in 1-second windows and interpolated to the full length of the intra-arrest ECG. For trajectory analysis, CPP and MS traces were normalized on a 0-1 scale and grouped by morphological similarity. Pearson’s Correlation coefficient was calculated between corresponding CPP and MS traces. Results: A total of 141 experiments were included in the analysis. Overall mean (SD) correlation between CPP and MS was 0.56 (0.29). CPP-MS correlation strength did not correlate with baseline pressures. However, trajectory analysis revealed multiple patterns of hemodynamic and QWM evolution through untreated VF, with the most well-defined (mean coeff. = 0.58) indicating a shared bimodality temporally offset between CPP and MS. Conclusions: Hemodynamics during untreated VF show some correlation with the trajectory of QWM of the VF signal. More work is needed to understand the mechanism of this relationship.
CABOSEQ: The efficacy of cabozantinib post up-front immuno-oncology combinations in patients with advanced renal cell carcinoma: Results from the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC).
Authors: Vishal Navani, Connor Wells, Devon J. Boyne, Winson Y. Cheung, Darren Brenner, Bradley Alexander McGregor, Chris Labaki, Andrew Lachlan Schmidt, Rana R. McKay, Sumanta K. Pal, Luis A Meza, Frede Donskov, Benoit Beuselinck, Matthew Scott Ernst, Maxwell Otiato, Lisa Ludwig, Thomas Powles, Bernadett Szabados, Toni K. Choueiri, Daniel Yick Chin Heng
Journal: Journal of Clinical Oncology (2022)

318 Background: There are limited data to understand the activity of cabozantinib (CABO) as second line (2L) therapy post standard of care ipilimumab-nivolumab (IPI-NIVO) or immuno-oncology(IO)/vascular endothelial growth factor (VEGF) inhibitor combinations (IOVE). The activity of subsequent 3L approved therapies post CABO has not been established. Methods: Using the IMDC dataset, we examined all patients who received 2L CABO. We sought to identify the overall response rate (ORR), time to treatment failure (TTF) and overall survival (OS) of 2L CABO after IPI-NIVO, approved IOVE combinations and other 1L approaches. Additionally, we examined these outcomes for patients that received an approved 3L treatment post 2L CABO. Hazard ratios were adjusted for IMDC risk groups. Results: 346 patients were identified who had all received 2L CABO (78 post 1L IPI NIVO, 46 post 1L IOVE, 222 post 1L other). Of the entire cohort, 12.6%, 62.6% and 24.8% were IMDC favourable, intermediate and poor risk, respectively. 84% had clear cell histology, 18.5% had a sarcomatoid component and 38.3% had bone metastases at diagnosis. Outcomes for patients that received 2L CABO, stratified by 1L therapy are outlined in the table, followed by outcomes for patients that received subsequent 3L therapy post 2L CABO. After adjustment for IMDC criteria, the HR for 2L CABO OS and TTF for IOVE vs IPI-NIVO were 1.73 (95% CI 0.83-3.62 p = 0.14) and 1.62 (0.89-2.95 p = 0.11), respectively. Conclusions: There is clinically meaningful activity of CABO post IPI-NIVO, IOVE and other standard 1L approved therapies. Broadly, time to event endpoints and response rates are similar irrespective of 1L therapy. Approved systemic therapies post CABO, mainly single agent VEGF inhibitors also have activity, though as expected this is diminished compared to earlier lines of therapy. These are real world benchmarks with which to counsel our patients when using single agent CABO.[Table: see text]
Grams, not Grains.
Journal: JAMA (1963)

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
Colistimethate Toxicity
Authors: R. M. Gabrielson
Journal: JAMA (1969)

<h3>To the Editor:—</h3> Publication of case reports calling attention to drug toxicity is certainly worthwhile. We, therefore, fully endorse publication of "Colistimethate Toxicity: Report of a Fatal Case in a Previously Healthy Child" (<b>207</b>:2099, 1969). However, we feel that the title was poorly chosen because it fails to convey the key concept of "overdosage" or "misuse." Neither word appears in the title which leaves a false impression with the casual reader who may be only scanning headlines. Serious reactions to colistimethate sodium rarely, if ever, occur when our current recommendations are followed, and these are revised as experience indicates. The authors report the colistimethate sodium dose as 30 mg/kg every six hours. This is 120 mg/kg/ day whereas the maximum recommended dose is only 5 mg/kg/day! Thus, the dosage in this case was 24 times the maximum recommended dose.
Controversies About Advance Care Planning
Authors: Michael J. Rigby, Tosha B. Wetterneck, George M. Lange
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
Hepatitis.
Authors: G C Turner
Journal: BMJ (1973)

Delayed HIV-1 disease progression is associated with a single nucleotide polymorphism upstream of the <i>HLA-C</i> gene that correlates with differential expression of the HLA-C Ag. This polymorphism was recently shown to be a marker for a protective variant in the 3′UTR of <i>HLA-C</i> that disrupts a microRNA binding site, resulting in enhanced HLA-C expression at the cell surface. Whether individuals with “high” HLA-C expression show a stronger HLA-C–restricted immune response exerting better viral control than that of their counterparts has not been established. We hypothesized that the magnitude of the HLA-C–restricted immune pressure on HIV would be greater in subjects with highly expressed HLA-C alleles. Using a cohort derived from a unique narrow source epidemic in China, we identified mutations in HIV proviral DNA exclusively associated with HLA-C, which were used as markers for the intensity of the immune pressure exerted on the virus. We found an increased frequency of mutations in individuals with highly expressed HLA-C alleles, which also correlated with IFN-γ production by HLA-C–restricted CD8<sup>+</sup> T cells. These findings show that immune pressure on HIV is stronger in subjects with the protective genotype and highlight the potential role of HLA-C–restricted responses in HIV control. This is, to our knowledge, the first in vivo evidence supporting the protective role of HLA-C–restricted responses in nonwhites during HIV infection.
Albumin metabolism targeted peptide-drug conjugate strategy for targeting pan-KRAS mutant cancer
Authors: Young Seok Cho, Gui Chul Kim, Hye Min Lee, Byoungmo Kim, Ha Rin Kim, Seung Woo Chung, Hyo Won Chang, Yoon Gun Ko, Yoon Se Lee, Seong Who Kim, Youngro Byun, Sang Yoon Kim
Journal: Journal of Controlled Release (2022)

Despite recent breakthroughs in the development of direct KRAS inhibitors and modulators, no drugs targeting pan-KRAS mutant cancers are clinically available. Here, we report a novel strategy to treat pan-KRAS cancers using a caspase-3 cleavable peptide–drug conjugate that exploits enhanced albumin metabolism in KRAS altered cancers to deliver a cytotoxic agent that can induce a widespread bystander killing effect in tumor cells. Increased albumin metabolism in KRAS mutant cancer cells induced apoptosis via the intracellular uptake of albumin-bound MPD1. This allowed caspase-3 upregulation activated MPD1 to release the payload and exert the non-selective killing of neighboring cancer cells. MPD1 exhibited potent and durable antitumor efficacy in mouse xenograft models with different KRAS genotypes. An augmentation of anti-cancer efficacy was achieved by the bystander killing effect derived from the caspase-3 mediated activation of MPD1. In summary, albumin metabolism-induced apoptosis, together with the bystander killing effect of MPD1 boosted by caspase-3 mediated activation, intensified the efficacy of MPD1 in KRAS mutant cancers. These findings suggest that this novel peptide-drug conjugate could be a promising breakthrough for the treatment in the targeting of pan-KRAS mutant cancers.
Paracentesis Thoracis
Authors: W. A. I'Anson
Journal: BMJ (1872)

AT this time, wlien the subject of hydrophobia is being discuissed not only in the public press, but also in the medical journals, the following notes taken from my private note-book of a case which occurred at St. Thomas's Hospital during the time when I was house-surgeon may be in- teresting, especially as I saw the man from beginning to end-that is, at the time when he was bitten, and also when the symptoms to be pre- sently detailed occurred.John Wells, a working engineer, aged 57, a somewhat pale but hearty-looking man, who had always been temperate, applied for
Pathological and oncological outcomes of off-criteria radical prostatectomy in patients opting for active surveillance: From PRIAS-JAPAN.
Authors: Yoichiro Tohi, Takuma Kato, Masaki Nakamura, Ryuji Matsumoto, Hiroshi Sasaki, Koji Mitsuzuka, Junichi Inokuchi, Katsuyoshi Hashine, Akira Yokomizo, Hidefumi Kinoshita, Isao Hara, Norihiko Kawamura, Kohei Hashimoto, Masaharu Inoue, Jun Teishima, Hidenori Kanno, Hiroshi Fukuhara, Satoru Maruyama, Shinichi Sakamoto, Mikio Sugimoto
Journal: Journal of Clinical Oncology (2022)

250 Background: Trigger for definitive treatment in active surveillance (AS) is strictly criteria-based, but some patients might be surgically treated without adherence to the criteria. We aimed to evaluate whether oncological outcomes differ depending on adherence to the criteria in patients who opting for AS. Methods: We retrospectively reviewed data of 1,035 patients enrolled in a prospective cohort of PRIAS-JAPAN. Of 162 patients underwent radical prostatectomy, 136 patients were analyzed, excluding those with Gleason score 3+4 at diagnosis, RP within one year of enrollment. Triggers for RP due to pathological reclassification on repeat biopsy was defined as on-criteria. We compared pathological findings on RP and prostate specific antigen (PSA) recurrence-free survival of on-criteria with off-criteria. Results: Off-criteria was 35 patients (24.7%). There were significant differences in the median time to RP (16 vs. 18.5 months, p&lt;0.001) and median PSA before RP (6.1 vs. 8.3 ng/mL, p=0.007) when comparing patients with on-criteria and off-criteria. Fifty percent of off-criteria received RP within 35 months. On pathological findings of RP, pathological T3≤ (10.5 vs. 9.4%, p=0.183), Gleason score 4+3≤ (33 vs. 28.6%, p=0.679), and pathological N positive (4.3 vs. 0%, p&gt;0.999) were not significantly different. At a median postoperative follow-up of 36 months, no significant difference in PSA recurrence-free survival was found (log-rank p = 0.828). Conclusions: Although half of off-criteria patients underwent RP within 3 years of starting AS, their oncological outcomes were not different from on-criteria. Our result suggested the potential for tailoring the inclusion criteria of AS within the strict protocol. Clinical trial information: 000002874. [Table: see text]