tbuckley/cabot-search huggingface dataset:
Midostaurin therapy for advanced systemic mastocytosis: Mayo Clinic experience in 33 consecutive cases
Authors: Amritpal Singh, Aref Al‐Kali, Kebede H. Begna, Mark R. Litzow, Jeremy T. Larsen, Taimur Sher, Maymona G. Abdelmagid, Faiqa Farrukh, Kaaren K. Reichard, Naseema Gangat, Animesh Pardanani, Ayalew Tefferi
Journal: American Journal of Hematology (2022)

We retrospectively examined our experience with midostaurin therapy in 33 consecutive patients (median age 68 years; 58% females) with advanced systemic mastocytosis (adv-SM): aggressive SM (ASM; n = 17), SM associated with another hematologic neoplasm (SM-AHN; n = 14) and mast cell leukemia (MCL; n = 2). KITD816V mutation was detected in 84% of the patients and C findings in 91%. Eleven (33%) patients were previously treated with other cytoreductive drugs, including cladribine (n = 4) and imatinib (n = 3). Median time from diagnosis to initiation of midostaurin therapy was 2.2 months (range 0.3-41). Using modified valent criteria, overall response was 42% (53% ASM, 29% SM-AHN, 50% MCL; p = .22), all classified as being major. Responses included ≥50% reduction in bone marrow mast cells in 40% and normalization of serum tryptase in 29%, of evaluated cases. After a median follow-up of 14.6 months from initiation of midostaurin therapy, 7 (21%) deaths, 1 (3%) leukemic progression, and 18 (55%) treatment discontinuations were documented; median duration of midostaurin treatment was 7.9 months (range 0.5-123) and response duration 21.5 months (range 2.9-123). Most frequent side effect was gastrointestinal (51%) while grade 3/4 neutropenia or thrombocytopenia occurred in 12% of patients. Response to treatment was not predicted by KIT mutation (p = .67) or exposure to prior cytoreductive therapy (p = .44). Median survival was longer in midostaurin responders but not significantly (median 26.5 vs. 16 months; p = .15). Findings from the current study are broadly consistent with previously published clinical trial observations.
Degradation pathways of PCB upon gamma irradiation
Authors: F Lépine, R Massé
Journal: Environmental Health Perspectives (1990)

In order to understand the modifications of the chromatographic profile of Aroclor 1260 upon gamma irradiation, a total of 14 pure polychlorinated biphenyl (PCB) congeners were separately irradiated in solution.Dechlorination was observed, and the generated products were investigated by gas chromatography and mass spectrometry.Degradation proceeds more rapidly in methanol/water mixture than in petroleum ether, but the relative amount of ortho-dechlorinated congeners formed upon irradiation was smaller in the former solvent.Ortho chlorines are preferentially lost in petroleum ether except when they are involved in a 2,5 (or 3,6) substi- tution pattern, in which case para dechlorination becomes predominant.The precursors of some toxicologically important congeners such as congeners 77, 118, 167, and 189 have been identified.These data are useful to rationalize the modifications of the chromatographic profile of PCB complex mixture upon gamma irradiation.
Abstract 194: Public Perception Towards Out-of-Hospital Cardiac Arrest Victims: Potential Reasons Influencing the Decision to Perform Bystander Cardiopulmonary Resuscitation
Authors: Sarah S Gul, Torben K Becker, Carolina B Maciel, Travis Murphy, Teddy S Youn, Scott A Cohen, Emmett Martin, Joseph A Tyndall, Carlos L Alviar
Journal: Circulation (2018)

Background: Bystander cardiopulmonary resuscitation (CPR) after out-of-hospital cardiac arrest (OHCA) improves survival and neurological outcomes. Unfortunately many OHCA victims do not receive bystander CPR during a witnessed arrest. It is known that gender disparities play a role with lower rates of bystander CPR in women suffering OHCA in public places. Our aim was to identify potential factors influencing the decision to perform bystander CPR. Methods: Participants at CPR training events were surveyed prior to training. Using different scenarios, subjects were asked about their comfort level performing CPR on female, geriatric, and pediatric victims. Anonymous responses were collected and transformed into categorical variables by a psychometrist. Results: Of the 677 participants, 585 (86.4%) responded the survey, with 87.5% between 18-29 years of age, 58.8% without prior CPR training and 93.3% without prior CPR experience. Reasons to hesitate starting bystander CPR in women included concern about exposing the victim (12.9%), being accused of sexual assault (6.1%), and possible pregnancy (6.5%). In participants with prior CPR training, 61.1% reported concerns about performing CPR on women, with 18.9% having concerns about performing chest compressions in relation to breast location. In participants without prior CPR training, 73.2% reported having concerns about performing CPR on women. Causing injury and exposing the patient were top concerns to perform CPR in women amongst participants who were uncomfortable (30.5% and 17.5% respectively) and comfortable (14.5% and 9.8% respectively) performing CPR in public. Causing injury was the top concern in performing CPR on geriatric (45.4%) and pediatric patients (41.7%), followed by fragility (18.1% and 10.2% respectively). Lack of skills to perform CPR on children was reported in 22% of CPR-trained participants. Conclusion: Public perception of OHCA victims influences willingness to perform bystander CPR. Factors such as age, gender, fear of injury, pregnancy status and sexual assault concerns can negatively impact this life saving intervention. Awareness of the importance of bystander CPR on any cardiac arrest victim must be improved.
Relative power of ammunition
Authors: R. G. Schipf
Journal: JAMA (1979)

<h3>To the Editor.—</h3> In his review of an apparent suicide attempt (241:2265, 1979), Bernard P. Wolff, MD, mentioned the use of "a .32-caliber revolver" and reported that the bullets barely got through the skin over the skull. He called this a "remarkably minor injury resulting from a powerful weapon." I would guess that the ammunition involved here is either the .32 S&amp;W or the .32 S&amp;W long (these are standard designations), most likely the former. If so, the injury is not remarkable at all as these "calibers" are notorious for their poor results on humans, especially when bone penetration is necessary. Either caliber is an excellent squirrel- or rabbit-getter, especially the latter, but any decent ballistician or knowledgeable gun buff will discourse at length on the ineffectiveness of this kind of stuff as man-stoppers. Surely, such ammunition can kill, but that is not the point here or in most cases. There are, of
Abstract 251: Comparison of Ischemia-Reperfusion Injury in Langendorff-Prepared Hearts From Zucker Diabetic Fatty and Lean Rats
Authors: William J Cleveland, Claudius Balzer, Michele M Salzman, Matthias L Riess
Journal: Circulation (2018)

Introduction: The Zucker Diabetic Fatty (ZDF) rat is a relevant model for assessing ischemia-reperfusion (IR) injury, due to it having comorbidities associated with a higher risk for cardiac arrest and poorer outcomes following cardiopulmonary resuscitation in humans. Hypothesis: Based on previous studies in the literature, we hypothesize that ZDF rats would have similar outcomes to lean rats subjected to IR when accounting for perfusion buffer osmolarity. Methods: ZDF (n=4) and lean control (n=6) rats were anesthetized with pentobarbital, intubated, and mechanically ventilated and monitored for 3-hours, with blood glucose (BG) readings taken before and after ventilation. They were then decapitated and a thoracotomy performed to isolate the Langendorff-prepared hearts. Krebs buffer with the osmolarity adjusted to each rat’s BG level using glucose was used to perfuse the hearts. Following a 20-minute stabilization period, the hearts were subjected to a 30-minute period of global no-flow ischemia followed by 120-minutes of reperfusion. Spontaneous heart rate, isovolumetric left ventricular pressure (LVP), and mitochondrial redox state were measured continuously. Data are mean ± SD. Statistics: two-tailed t-test, p&lt;0.05 Results: There was no significant difference in average body weight between the two groups; however, ZDF rats showed significantly higher BG levels (504±52 vs 174±14 mg/dl) than their lean littermates. ZDF rats had a greater percent change from baseline systolic LVP upon reperfusion than lean rats (133±33.3 vs 84.9±16.5 %), with the lean rats never returning to baseline. Diastolic contracture occurred more in lean rats during ischemia, but trended towards a lower contracture during reperfusion. No significant difference was seen in developed LVP, rate pressure products, or mitochondrial redox states, although lean rats trended towards better diastolic contractility and relaxation. Conclusion: Lean rats showed marginally better outcomes in heart function than their ZDF littermates. Future studies will focus on potential mechanisms of Type 2 diabetes that may exacerbate IR injuries.
Artificial Pneumothorax
Authors: J. Crocket
Journal: BMJ (1937)

The value of artificial pneumothorax treatment for pul- monary tuberculosis is now well established, and the time has come to consider whether the method can be more fully utilized.To render a patient's sputum negative to tubercle bacilli, to arrest the disease, in any case, is a service not merely to the individual but to the community and the State.It deals with a centre and source of infec- tion.I would like to put in a plea to-day for (1) a more widespread use of the treatment in the early and acute types of the disease; (2) ambulatory artificial pneumo- thorax; (3) bilateral artificial pneumothorax; with special reference to the last-mentioned.1. Early and Acute Forms of Pulmonary Tuberculosis and Artificial Pneumothorax
Charting a Path Forward: Assessing the Science of Chemical Risk Evaluations under the Toxic Substances Control Act in the Context of Recent National Academies Recommendations
Authors: Jennifer McPartland, Rachel M. Shaffer, Mary A. Fox, Keeve E. Nachman, Thomas A. Burke, Richard A. Denison
Journal: Environmental Health Perspectives (2022)

In 2016, Congress enacted the Frank R. Lautenberg Chemical Safety for the 21st Century Act ("the Lautenberg Act"), which made major revisions to the main U.S. chemical safety law, the 1976 Toxic Substances Control Act (TSCA). Among other reforms, the Lautenberg Act mandates that the U.S. Environmental Protection Agency (U.S. EPA) conduct comprehensive risk evaluations of chemicals in commerce. The U.S. EPA recently finalized the first set of such chemical risk evaluations.We examine the first 10 TSCA risk evaluations in relation to risk science recommendations from the National Academies to determine consistency with these recommendations and to identify opportunities to improve future TSCA risk evaluations by further implementing these key approaches and methods.Our review of the first set of TSCA risk evaluations identified substantial deviations from best practices in risk assessment, including overly narrow problem formulations and scopes; insufficient characterization of uncertainty in the evidence; inadequate consideration of population variability; lack of consideration of background exposures, combined exposures, and cumulative risk; divergent approaches to dose-response assessment for carcinogens and noncarcinogens; and a flawed approach to systematic review. We believe these deviations result in underestimation of population exposures and health risks. We are hopeful that the agency can use these insights and have provided suggestions to produce chemical risk evaluations aligned with the intent and requirements of the Lautenberg Act and the best available science to better protect health and the environment-including the health of those most vulnerable to chemical exposures. https://doi.org/10.1289/EHP9649.
TET2 Suppresses VHL Deficiency-Driven Clear Cell Renal Cell Carcinoma by Inhibiting HIF Signaling
Authors: Xinchao Zhang, Shuyan Li, Jing He, Yunjie Jin, Ruonan Zhang, Wenjing Dong, Mingen Lin, Yajing Yang, Tongguan Tian, Yuefan Zhou, Yixin Xu, Qun-Ying Lei, Jing Zhang, Qing Zhang, Yanping Xu, Lei Lv
Journal: Cancer Research (2022)

Abstract Inactivating mutations of von Hippel–Lindau (VHL) are highly prevalent in clear cell renal cell carcinoma (ccRCC). Improved understanding of the vulnerabilities of VHL-deficient ccRCC could lead to improved treatment strategies. The activity of DNA dioxygenase ten-eleven translocation (TET)2 is significantly reduced in multiple cancers by different mechanisms, but its role in ccRCC progression remains unclear. Here, we report that increased expression of TET2, but not TET1 and TET3, is negatively associated with tumor metastasis and advanced tumor stage and is positively associated with good prognosis uniquely in ccRCC among all 33 types of cancer in The Cancer Genome Atlas datasets. TET2 restrained glycolysis and pentose phosphate pathway metabolism in a VHL deficiency–dependent manner, thereby suppressing ccRCC progression. Notably, TET2 and VHL mutations tended to cooccur in ccRCC, providing genetic evidence that they cooperate to inhibit the progression of ccRCC. Mechanistically, TET2 was recruited by transcription factor HNF4α to activate FBP1 expression, which antagonized the function of hypoxia-inducible factor-1/2α (HIF1/2α) in metabolic reprogramming to impede ccRCC growth. Stimulating the TET2-FBP1 axis with vitamin C repressed the growth of VHL-deficient ccRCC with wild-type TET2 and increased the sensitivity to glycolysis inhibitors. Moreover, combined expression levels of the HNF4α–TET2-FBP1 axis served as a biomarker of prognosis in patients with ccRCC. This study reveals a unique function of TET2 in the suppression of tumor metabolism and HIF signaling, and it also provides therapeutic targets, potential drugs, and prognostic markers for the management of ccRCC. Significance: The identification of TET2-mediated inhibition of HIF signaling and tumor metabolic reprogramming provides insights for new therapeutic strategies for VHL-deficient ccRCC.
Severe insulin resistance syndromes
Authors: Angeliki M. Angelidi, Andreas Filippaios, Christos S. Mantzoros
Journal: Journal of Clinical Investigation (2021)

Severe insulin resistance syndromes are a heterogeneous group of rare disorders characterized by profound insulin resistance, substantial metabolic abnormalities, and a variety of clinical manifestations and complications. The etiology of these syndromes may be hereditary or acquired, due to defects in insulin potency and action, cellular responsiveness to insulin, and/or aberrations in adipose tissue function or development. Over the past decades, advances in medical technology, particularly in genomic technologies and genetic analyses, have provided insights into the underlying pathophysiological pathways and facilitated the more precise identification of several of these conditions. However, the exact cellular and molecular mechanisms of insulin resistance have not yet been fully elucidated for all syndromes. Moreover, in clinical practice, many of the syndromes are often misdiagnosed or underdiagnosed. The majority of these disorders associate with an increased risk of severe complications and mortality; thus, early identification and personalized clinical management are of the essence. This Review aims to categorize severe insulin resistance syndromes by disease process, including insulin receptor defects, signaling defects, and lipodystrophies. We also highlight several complex syndromes and emphasize the need to identify patients, investigate underlying disease mechanisms, and develop specific treatment regimens.
Comprehensive Pediatrics
Authors: Hugh A. Carithers
Journal: JAMA (1990)

<b>Nelson Essentials of Pediatrics,</b>by Richard E. Behrman and Robert Kliegman, 743 pp, with illus, $34.95, ISBN 0-7216-2229-1, Philadelphia, Pa, WB Saunders Co, 1990. Textbooks in the field of clinical medicine have expanded greatly, and in some instances a single subject requires volumes. Some texts have become unwieldy, not comfortable to use and disagreeable because of small print. Physicians, medical students, and those in the paramedical professions may feel the need for a book in each discipline but are discouraged because of the overwhelming size of the volumes as well as their cost. Appearance within a few months of two condensed textbooks in pediatrics indicates a probable need for this kind of book. Both are of exceptionally fine quality, and editing, printing, and binding are praiseworthy. Appearing first was<i>Comprehensive Pediatrics</i>, a high-quality textbook and successor to the deservedly popular<i>Synopsis of Pediatrics</i>by James G. Hughes, MD, which rests
Translating science to medicine: The case for physician-scientists
Authors: Paul J. Utz, Mukesh K. Jain, Vivian G. Cheung, Brian K. Kobilka, Robert Lefkowitz, Tadataka Yamada, Victor J. Dzau
Journal: Science Translational Medicine (2022)

As the number of physician-scientists continues to decline, action must be taken to support them as they embark on their careers.
Pelvic pain.
Authors: T. N. Jeffcoate
Journal: BMJ (1969)

The third McCurrich oration delivered at a meeting of the Regional Hospitals' Consultants and Specialists Association at the Royal College of Obstetricians and Gynaecologists, London, on 9 May 'An exception to this rule is any operation which tightens the internal urethral sphincter for the purpose of curing stress incontinence, but the mechanism of retention is then different.
The Molecular and Genetic Basis of Neurological Disease
Authors: Roger L. Albin
Journal: JAMA (1997)

This is a successful revision of a multiauthor text designed to serve as a reference on neurogenetic disorders and the molecular basis of neurologic diseases. The editors have done an excellent job of assembling a collection of expert authors, and the quality of individual chapters is high. The majority of chapters are devoted to monogenic entities and summarize succinctly the clinical features, biochemistry, and genetics of the disorders under discussion. In the great majority of these chapters, the quality of writing is excellent, and the reference lists are extensive. These chapters are valuable reviews of their topics and are the core of the book. A number of chapters move beyond discussion of monogenic disorders. There are excellent sections on mitochondrial disorders and prion diseases. Some effort is made to discuss the genetic and molecular basis of common disorders such as Alzheimer disease, schizophrenia, mood disorders, alcoholism, and multiple sclerosis. These
Biomarkers for Locally Advanced Hepatocellular Carcinoma Patients Treated with Liver-Directed Combined Radiotherapy
Authors: Seung Yeun Chung, Kyoung-Jin Kim, Jinsil Seong
Journal: Liver Cancer (2022)

In the era of biomarker-driven cancer therapy, robust biomarkers for hepatocellular carcinoma (HCC) have not been well-defined. In this hypothesis-generating study, we investigated biomarkers that can be incorporated to predict treatment outcomes in patients with locally advanced HCC who are administered liver-directed combined radiotherapy (LDCRT).Ninety-nine patients with HCC who were treated with conventional fractionation LDCRT between July 2016 and October 2018 were enrolled in this prospective single-arm study. Clinical outcomes and possible serum biomarkers, including soluble programmed cell death ligand-1 (sPD-L1), interleukin (IL)-10, IL-6, cell-free DNA (cfDNA), inter-alpha inhibitor H4, and interferon-gamma, were analyzed. The primary endpoint was disease progression, and additional endpoints were local failure-free rate, intrahepatic failure-free rate, and lung metastasis-free rate.The median follow-up period was 18.7 months. The 1-year progression-free rate was 38.2%. Increasing baseline sPD-L1 per pg/mL, previous treatment history, protein induced by vitamin K absence-II >1,629 mAU/mL, and multiple tumors were the adverse factors for progression based on multivariate analysis. Survival tree analysis revealed three prognostic groups for progression, in which patients with multiple lesions and baseline sPD-L1 ≥41.07 pg/mL showed the worst outcomes. For dynamic changes in biomarker levels, sPD-L1 fold change and cfDNA fold-change values were unfavorable factors for progression.Baseline sPD-L1, sPD-L1 fold change, and cfDNA fold-change values showed the highest potential as biomarkers for predicting post-treatment progression after LDCRT in HCC patients. By incorporating clinical factors, these biomarkers may be useful for devising a biomarker-driven treatment paradigm in locally advanced HCC.
Excitotoxicity, calcium and mitochondria: a triad in synaptic neurodegeneration
Authors: Manish Verma, Britney N. Lizama, Charleen T. Chu
Journal: Translational Neurodegeneration (2022)

Abstract Glutamate is the most commonly engaged neurotransmitter in the mammalian central nervous system, acting to mediate excitatory neurotransmission. However, high levels of glutamatergic input elicit excitotoxicity, contributing to neuronal cell death following acute brain injuries such as stroke and trauma. While excitotoxic cell death has also been implicated in some neurodegenerative disease models, the role of acute apoptotic cell death remains controversial in the setting of chronic neurodegeneration. Nevertheless, it is clear that excitatory synaptic dysregulation contributes to neurodegeneration, as evidenced by protective effects of partial N -methyl- D -aspartate receptor antagonists. Here, we review evidence for sublethal excitatory injuries in relation to neurodegeneration associated with Parkinson’s disease, Alzheimer’s disease, amyotrophic lateral sclerosis and Huntington’s disease. In contrast to classic excitotoxicity, emerging evidence implicates dysregulation of mitochondrial calcium handling in excitatory post-synaptic neurodegeneration. We discuss mechanisms that regulate mitochondrial calcium uptake and release, the impact of LRRK2, PINK1, Parkin, beta-amyloid and glucocerebrosidase on mitochondrial calcium transporters, and the role of autophagic mitochondrial loss in axodendritic shrinkage. Finally, we discuss strategies for normalizing the flux of calcium into and out of the mitochondrial matrix, thereby preventing mitochondrial calcium toxicity and excitotoxic dendritic loss. While the mechanisms that underlie increased uptake or decreased release of mitochondrial calcium vary in different model systems, a common set of strategies to normalize mitochondrial calcium flux can prevent excitatory mitochondrial toxicity and may be neuroprotective in multiple disease contexts.
Books Received
Authors: Gen Kanayama, James I. Hudson, Harrison G. Pope Jr., Misari Oe, Ulrich Schnyder, Sonja Schumacher, Christoph Mueller-Pfeiffer, Frank H. Wilhelm, Nilüfer Kalebasi, Daniel Roos, Martin Hersberger, Chantal Martin-Soelch, Maurizio Fava, David Mischoulon, Dan Iosifescu, Janet Witte, Michael Pencina, Martina Flynn, Linda Harper, Michael Levy, Karl Rickels, Mark Pollack, Martin Franklin, Edna B. Foa, Helen Blair Simpson, Michael J. Maher, John S. Ogrodniczuk, Carlos Sierra Hernandez, Ingrid Sochting, Anthony S. Joyce, William E. Piper, M.E. Beutel, J. Wiltink, Y. Till, P.S. Wild, T. Münzel, F.M. Ojeda, T. Zeller, R.B. Schnabel, K. Lackner, M. Blettner, I. Zwiener, M. Michal, Anna Ogliari, Marco Battaglia, Elizabeth Maloney, Jin-Mann S. Lin, Christine Heim, William C. Reeves, Urs M. Nater, Zoltan Kozinszky, Robert B. Dudas, Iván Devosa, Sarolta Csatordai, Éva Tóth, Dávid Szabó, János Sikovanyecz, Katalin Barabás, Attila Pál, Elena Tomba, A.M.M. De Vries, V. Forni, R. Voellinger, Yuanjia Wang, Allan Zuckoff, Melanie M. Wall, F. Stiefel, Satz Mengensatzproduktion, Druck Reinhardt Druck Basel, Druck Reinhardt Druck Basel
Journal: Psychotherapy and Psychosomatics (2012)

This volume is rich in detail that helps implementing group therapies for a variety of psychiatric conditions such as depression and social phobia.Clinical material can also be downloaded.