tbuckley/cabot-search huggingface dataset:
Clinical and biological characteristics and prognostic impact of somatic GATA2 mutations in myeloid malignancies: a single institution experience
Authors: Ahmad Nanaa, David Viswanatha, Zhuoer Xie, Dragan Jevremovic, Phuong Nguyen, Mohamad E. Salama, Patricia Greipp, Kurt Bessonen, Naseema Gangat, Mrinal Patnaik, Animesh Pardanani, Hassan B. Alkhateeb, Mithun Shah, William Hogan, Ayalew Tefferi, Mark Litzow, Rong He, Aref Al-Kali
Journal: Blood Cancer Journal (2021)
Spinal Inhibitory Dysfunction in Patients With Painful or Painless Diabetic Neuropathy
Authors: Anne Worthington, Alise Kalteniece, Maryam Ferdousi, Luca D'Onofrio, Shaishav Dhage, Shazli Azmi, Clare Adamson, Shaheen Hamdy, Rayaz A. Malik, Nigel A. Calcutt, Andrew G. Marshall
Journal: Diabetes Care (2021)

OBJECTIVE Impaired rate-dependent depression of the Hoffman reflex (HRDD) is a marker of spinal inhibitory dysfunction and has previously been associated with painful neuropathy in a proof-of-concept study in patients with type 1 diabetes. We have now undertaken an assessment of HRDD in patients with type 1 or type 2 diabetes. RESEARCH DESIGN AND METHODS A total of 148 participants, including 34 healthy control subjects, 42 patients with painful diabetic neuropathy, and 62 patients with diabetic neuropathy without pain, underwent an assessment of HRDD and a detailed assessment of peripheral neuropathy, including nerve conduction studies, corneal confocal microscopy, and thermal threshold testing. RESULTS Compared with healthy control subjects (P &amp;lt; 0.001) and patients without pain (P &amp;lt; 0.001), we found that HRDD is impaired in patients with type 1 or type 2 diabetes with neuropathic pain. These impairments are unrelated to diabetes type and the presence or severity of neuropathy. In contrast, patients without neuropathic pain (P &amp;lt; 0.05) exhibited enhanced HRDD compared with control subjects. CONCLUSIONS We suggest that loss or impairment of HRDD may help to identify a subpopulation of patients with painful diabetic neuropathy mediated by impaired spinal inhibitory systems who may respond optimally to therapies that target spinal or supraspinal mechanisms. Enhanced RDD in patients without pain may reflect engagement of spinal pain–suppressing mechanisms.
Fitness to practise: Plan would class doctors investigated for health reasons as lacking in competence
Authors: Abi Rimmer
Journal: BMJ (2021)

The government has set out proposals to remove health issues as a reason for a doctor to be investigated over their fitness to practise. The General Medical Council has disagreed with the suggestion, which it said would mean describing doctors who face investigation for reasons related to health as lacking competence.

Currently, a question about a doctor’s fitness to practise can arise if a doctor’s health is compromising the safety of patients or poses a risk to the public’s confidence in the profession.1

In a consultation on the regulation of healthcare professionals the government proposed that all healthcare regulators should have the same grounds for action that could lead them to undertake an investigation over fitness to practise.2 These grounds would include lack of competence, which in turn would include a “lack of the necessary knowledge of English, or a health …
Abstract 18888: Long-Term (10 Years) Experience of Implantable Cardioverter-Defibrillator Implantation in Patients with Hypertrophic Cardiomyopathy
Authors: Christopher P Kolibash, M. F Jan, Naoyo Mori, Imran Niazi, M. E Mortada, A. J Tajik, Jasbir Sra
Journal: Circulation (2012)

Introduction: Sudden cardiac death (SCD) in patients with hypertrophic cardiomyopathy (HCM) is unpredictable and the most frequent cause of premature death. Implantable cardioverter-defibrillator (ICD) therapy is an effective strategy for both primary and secondary SCD prevention in select HCM populations. However, limited data exist on the long-term follow-up of HCM patients with ICD for prevention of SCD. Methods: We examined consecutive patients with HCM who underwent ICD implantation at our tertiary care institution. Patients were grouped into two cohorts (A and B) based on established clinical risk markers for SCD in HCM. Patients in group A had 2 or more major risk factors (≥2RF); patients in group B had 1 or fewer risk factors (≤1RF) for SCD. The number of appropriate and inappropriate ICD shocks, all-cause mortality and early and late ICD-related complications were compared between the two groups. Results: Over a 10-year period, we identified 60 consecutive HCM patients (median age 52 years [interquartile range = 45-62]; 47% female) who underwent ICD implantation. Of these, 26 patients had ≥2RF (group A); 34 patients had ≤1 RF (group B). Median follow-up was 62 months for both groups. In group A, 30.8% of HCM patients (8 of 26) received an appropriate ICD shock compared to 2.9% of patients in group B (1 of 34) (p= 0.004). Also, only 2 patients (7.7%) in group A received an inappropriate ICD shock compared with 6 patients (17.6%) in group B (p=0.446). The predominant risk predictors for ICD shocks in both groups were nonsustained ventricular tachycardia on Holter monitor and history of syncope. There were no differences between groups for early and late ICD-related complications of pneumothorax, pocket hematoma, infection, lead revisions, symptomatic upper-extremity deep venous thrombosis, new atrial arrhythmias and generator changes. All-cause mortality was not statistically significant between the groups (15.4% in group A compared to 12.1% in group B (p=0.717). Conclusion: Hypertrophic cardiomyopathy patients with 2 or more risk factors for SCD are more likely to receive an appropriate ICD shock compared to patients with 1 or fewer risk factors. This study validates that HCM patients with at least two risk factors for SCD benefit most with ICD implantation.
Abstract 313: Assessment of Arrest Procedures, Hospital Care and Functional Survival of Initial VT/VF Arrest Patients Shocked by a Bystander AED vs Patients Shocked by EMS
Authors: Myron L Weisfeldt, Siobhan Brown, Brittany Sanchez, Tom Aufderheide, Jim Christenson, Mohamud Daya, Michelle Gaudio, Peter Kudenchuk, Sean Marquis, Thomas Rea, Katy Sims, Christian Vaillancourt, Lynn Wittwer, George Sopko, Joseph Ornato, Laurie Morrison
Journal: Circulation (2013)

Introduction: Although one randomized trial and a prospective cohort study suggest that survival to hospital discharge doubles if a bystander uses an AED to defibrillate vs waiting for an EMS provider to defibrillate, there has been no comprehensive comparison of functional survival outcomes or resuscitation treatment differences for these two resuscitation strategies. METHODS: Population based data from the ROC Registry (Epistry) provided a comparison of public, witnessed initial VT/VF arrests treated with bystander AED shock (n=77) vs EMS shock (n=328) during 2010. Modified Rankin score (MRS) was determined from the hospital record and MRS &lt;3 at discharge was considered to be good functional survival. Results: The two groups were similar in EMS response time, age, and sex. More of the bystander AED vs. EMS shocked patients had bystander CPR (98.7 vs. 62.5%, p&lt;0.001) and fewer received epinephrine (42.9 vs. 72.6%, p&lt;0.001) or amiodarone (9.1 vs. 29.3%, p&lt;0.001). In-hospital care was not different in use of hypothermia (31-32%) but median hospitalization was shorter for bystander AED shocked patients who survived to discharge (10 days vs 13.5 days, ns) Survival to discharge for bystander AED vs. EMS shocked patients was 68% vs. 46% (p=0.001) and survival with MRS &lt; 3 was 53% vs. 33% (p=0.001). The functional survival advantage for bystander AED shocked patients persisted after adjustment for age, sex, bystander CPR and study site: OR of 2.17 (95% CI 1.26, 3.75 p=0.006). CONCLUSIONS: Thus AED shock by bystanders for initial VT/VF arrests is associated with greater survival with good to excellent functional recovery and results in less use of medications to achieve stable hemodynamics after arrest.
Features of cytokine balance with the progression of structural changes in the gastric mucosa in patients with atrophic gastritis
Authors: L.M. Mosyichuk, O.M. Tatarchuk, O.V. Simonova, O.P. Petishko
Journal: GASTROENTEROLOGY (2021)

Background. Until now, the issue of the correlation between the cytokine balance and the progression of structural changes in the gastric mucosa remain completely uncertain. At the same time, the determination of the role of cytokine balance as a component of gastric carcinogenesis will make it possible to substantiate new approaches to managing patients with atrophic gastritis. The purpose was to assess the level of pro- and anti-inflammatory cytokines, vascular endothelial growth factor (VEGF) at the stages of progression of structural changes in the gastric mucosa of patients with atrophic gastritis. Materials and methods. The study included 79 individuals with atrophic gastritis who underwent narrow band imaging endoscopic examination. The patients were divided into groups taking into account the revealed structural changes in the gastric mucosa: group I— 7 people with gastric mucosal atrophy without intestinal metaplasia (IM); group II— 16 individuals with gastric mucosal atrophy with IM limited by the antrum; group III— 45 people with diffuse IM against the background of gastric mucosal atrophy; group IV— 10 individuals with gastric mucosal dysplasia. In all patients, we assessed the level of interleukins (IL-8, IL-10, IL-18), tumor necrosis factor alpha (TNF-α), VEGF. Results. In patients of group IV, the concentration of IL-8 in the blood serum was 18.6 (11.3; 23.9) pg/ml that was significantly higher than in group I (by 5.0 times, p&lt;0.05), group II (by 3.6 times, p&lt;0.05) and group III (by 3.4 times, p&lt;0.05). According to the results of the Kruskal-Wallis test, the probability of a difference in the IL-8 level between the groups was 0.0260. The level of VEGF in the blood serum of patients with gastric mucosal dysplasia was significantly increased compared to that in people with gastric mucosal atrophy without IM (by 1.8 times, p&lt;0.05) and those with gastric mucosal atrophy with IM (by 1.7times, p&lt;0.05). Changes in the cytokine balance towards proinflammatory cytokines were most pronounced in patients of groups III and IV; according to the results of the Kruskal-Wallis test, the probability of a difference in the IL-8/IL-10 ratio between the groups was 0.0207. Conclusions. With the progression of structural changes in the gastric mucosa of patients with atrophic gastritis, an increase in the level of proinflammatory cytokines (IL-8, IL-18 and TNF-α) in the blood serum does not induce the secretion of anti-inflammatory cytokines (IL-10). According to the results of the ROC analysis, the diagnostic criteria for the formation of the risk group for detecting dysplastic changes in the gastric mucosa are VEGF level of more than 341.4 mU/ml (sensitivity— 90.0%, specificity— 77.2%) and the level of IL-8 above 14.4 pg/ml (sensitivity— 80.0%, specificity— 78.3%).
Abstract 204: Serine Threonine Kinase-35 Regulates Diabetes-induced Endothelial Progenitor Cells Dysfunction
Authors: Darukeshwara Joladarashi, Rajarajan A. Thandavarayan, Sahana Suresh Babu, Prince Jeyabal, Raj Kishore, Prasanna Krishnamurthy
Journal: Circulation Research (2016)

The completion of the sequencing of the human genome has revealed that up to ~20% of the human genes encode proteins involved in signal transduction. Among these, there are &gt;500 protein kinases. Protein kinases play a central role in the intracellular signal transduction systems involved in cell proliferation, differentiation, metabolism, and other responses to external stimuli. Serine Threonine Kinase 35 (STK35), a novel kinase that binds to nuclear actin, has been shown to regulate important cellular functions such as cell migration, proliferation, survival, and angiogenesis. However, the role of STK35 in Endothelial Progenitor Cells (EPC) function and in cardiac regeneration under diabetic condition is unknown. The purpose of this study was to determine the role of STK35 in diabetes-induced EPC dysfunction. The expression of STK35 in response to high glucose was measured by RT-PCR. STK35 expression was assessed in myocardial tissue from both human patients and mice with diabetes. To enable detailed study of STK35 biological effects in EPCs, we performed loss-of-function experiments by STK35 inhibition in EPCs. EPC from bone marrow of mice and exposed to high glucose level, showed decreased STK35 expression (vs normoglycemia-treated cells). In addition, STK35 knockdown in EPCs reduces their migration and vascular tube formation. Moreover, STK35 knockdown in EPCs have shown decreased in the expression of proangiogenic cytokines and growth factors. Results from both diabetic human heart and diabetic mice heart have also shown lower STK35 expression as compared to respective non-diabetic hearts. Taken together, these data suggest that diabetes decreases STK35 expression in EPCc thereby impairs EPC function under diabetic condition. Our future studies will test whether ex-vivo STK35-overexpression in EPCs rescues diabetes-induced dysfunction and whether their transplantation into myocardium of diabetic mice promotes angiogenesis and cardiac repair after injury.
Abstract 424: Effector T Cells Induce Cardiac Fibroblasts Transition to Myofibroblasts &amp; Contribute to Pressure Overload Induced Cardiac Fibrosis
Authors: Tania A Nevers, Ane Salvador, Francisco Velazquez, Mark Aronovitz, Robert Blanton
Journal: Circulation Research (2016)

Background: Cardiac fibrogenesis is a major pathogenic factor that occurs in heart failure (HF) and results in contractile dysfunction and ventricular dilation. Recently, we showed that T cell deficient mice (TCRα -/- ) do not develop cardiac fibrosis (CF) and have preserved cardiac function in the thoracic aortic constriction (TAC) mouse model of pressure overload (PO). Specifically, CD4 + T cells are activated in the cardiac draining lymph nodes and infiltrate the LV, where the Th1 and Th17 effector T cell signature transcription factors are significantly upregulated as compared with control mice. However, the T cell subsets involved and the mechanisms by which they contribute to CF and pathogenesis of non-ischemic HF remains to be determined. Thus, we hypothesize that heart infiltrated effector T cells perpetuate the fibrotic response by regulating the differentiation and activation of extracellular matrix-producing cardiac myofibroblasts. Methods and Results: Naïve or effector T cells differentiated in vitro or isolated from mice undergoing TAC or Sham surgery were co-cultured with adult C57BL/6 cardiac fibroblasts (CFB). In contrast with naïve T cells, effector T cells and PO activated T cells strongly adhered to CFB and mediated fibroblast to myofibroblasts transition as depicted by immunofluorescence expression of SMAα. Effector T cell supernatants only slightly mediated this transition, indicating that effector T cells direct contact with CFB, rather than cytokine release is required to mediate CFB transformation. Adoptive transfer of effector, but not naïve T cells, into TCRα -/- recipient mice in the onset of TAC resulted in T cells infiltration into the left ventricle and increased CF. Conclusions: Our data indicate that CD4+ effector T cells directly interact with CFB to induce CF in response to PO induced CF. Future studies will determine the adhesion mechanisms regulating this crosstalk and evaluate the pro-fibrotic mechanisms induced and whether this is a T effector cell specific subset. These results will provide an attractive tool to counteract the inflammatory/fibrotic process as an alternative option for the treatment of CF in non- ischemic HF.
Evolution of mouse circadian enhancers from transposable elements
Authors: Julius Judd, Hayley Sanderson, Cédric Feschotte
Journal: Genome biology (2021)

Transposable elements are increasingly recognized as a source of cis-regulatory variation. Previous studies have revealed that transposons are often bound by transcription factors and some have been co-opted into functional enhancers regulating host gene expression. However, the process by which transposons mature into complex regulatory elements, like enhancers, remains poorly understood. To investigate this process, we examined the contribution of transposons to the cis-regulatory network controlling circadian gene expression in the mouse liver, a well-characterized network serving an important physiological function.ChIP-seq analyses reveal that transposons and other repeats contribute ~ 14% of the binding sites for core circadian regulators (CRs) including BMAL1, CLOCK, PER1/2, and CRY1/2, in the mouse liver. RSINE1, an abundant murine-specific SINE, is the only transposon family enriched for CR binding sites across all datasets. Sequence analyses and reporter assays reveal that the circadian regulatory activity of RSINE1 stems from the presence of imperfect CR binding motifs in the ancestral RSINE1 sequence. These motifs matured into canonical motifs through point mutations after transposition. Furthermore, maturation occurred preferentially within elements inserted in the proximity of ancestral CR binding sites. RSINE1 also acquired motifs that recruit nuclear receptors known to cooperate with CRs to regulate circadian gene expression specifically in the liver.Our results suggest that the birth of enhancers from transposons is predicated both by the sequence of the transposon and by the cis-regulatory landscape surrounding their genomic integration site.
Prognostic relevance of acute graft-versus-host disease (agvhd) on outcome in patients transplanted with hla-identical sibling transplants for chronic myeloid leukemia (cml) in first chronic phase
Authors: A. Gratwohl, R. Brand, J. Apperley, A. V. Biezen, A. Devergie, T. De Witte, F. Frassoni, C. Guglielmi, M. Michallet, H. Kolb, T. Ruutu, D. Niederwieser
Journal: Blood (2000)
Rates of Bronchopulmonary Dysplasia Following Implementation of a Novel Prevention Bundle
Authors: Maria Fe B. Villosis, Karine Barseghyan, Ma. Teresa Ambat, Kambiz K. Rezaie, David Braun
Journal: JAMA Network Open (2021)

Bronchopulmonary dysplasia (BPD) rates in the United States remain high and have changed little in the last decade.To develop a consistent BPD prevention bundle in a systematic approach to decrease BPD.This quality improvement study included 484 infants with birth weights from 501 to 1500 g admitted to a level 3 neonatal intensive care unit in the Kaiser Permanente Southern California system from 2009 through 2019. The study period was divided into 3 periods: 1, baseline (2009); 2, initial changes based on ongoing cycles of Plan-Do-Study-Act (2010-2014); and 3, full implementation of successive Plan-Do-Study-Act results (2015-2019).A BPD prevention system of care bundle evolved with a shared mental model that BPD is avoidable.The primary outcome was BPD in infants with less than 33 weeks' gestational age (hereafter referred to as BPD <33). Other measures included adjusted BPD <33, BPD severity grade, and adjusted median postmenstrual age (PMA) at hospital discharge. Balancing measures were adjusted mortality and adjusted mortality or specified morbidities.The study population included 484 infants with a mean (SD) birth weight of 1070 (277) g; a mean (SD) gestational age of 28.6 (2.9) weeks; 252 female infants (52.1%); and 61 Black infants (12.6%). During the 3 study periods, BPD <33 decreased from 9 of 29 patients (31.0%) to 3 of 184 patients (1.6%) (P < .001 for trend); special cause variation was observed. The standardized morbidity ratio for the adjusted BPD <33 decreased from 1.2 (95% CI, 0.7-1.9) in 2009 to 0.4 (95% CI, 0.2-0.8) in 2019. The rates of combined grades 1, 2, and 3 BPD decreased from 7 of 29 patients (24.1%) to 17 of 183 patients (9.3%) (P < .008 for trend). Grade 2 BPD rates decreased from 3 of 29 patients (10.3%) to 5 of 183 patients (2.7%) (P = .02 for trend). Adjusted median PMA at home discharge decreased by 2 weeks, from 38.2 (95% CI, 37.3-39.1) weeks in 2009 to 36.8 (95% CI, 36.6-37.1) weeks during the last 3 years (2017-2019) of the full implementation period. Adjusted mortality was unchanged, whereas adjusted mortality or specified morbidities decreased significantly.A sustained low rate of BPD was observed in infants after the implementation of a detailed BPD system of care.
Abstract LB116: Prostaglandin F2 Receptor Negative Regulator (PTGFRN) is a novel target to inhibit tumor growth via antibody drug conjugate
Authors: Jorge Marquez, Jianping Dong, Chun Dong, Ginette Serrero
Journal: Cancer Research (2021)

Abstract Introduction: Antibody-drug conjugates (ADC) are effective antibody-based therapeutics for a growing number of cancers, particularly hematopoietic and lymphoid tumors. There is need to identify new targets for ADCs, particularly for cancers with unmet needs. Methods: Our strategy has been to develop hybridoma libraries developed against cancer cells surface proteins and select antibody able to bind and internalize in cancer cell lines. Selected antibody can then be used for identification of the cancer cell surface target by immunoprecipitation (IP) and mass spectrometric analysis (Mass-spec), followed by target validation. After target validation, binding and target positivity can be tested by flow cytometry and western blot analysis on several cancer cell lines. The in vitro and in vivo efficacy of the antibody conjugated to a cytotoxic payload as ADC can then be evaluated with the target positive cancer cell lines.Results: Using the strategy described above, we have selected a monoclonal antibody named 33B7 able to bind and internalize in several cancer cell lines. The cell surface target binding 33B7 was identified by IP/Mass-spec as Prostaglandin F2 Receptor Negative Regulator (PTGFRN), a transmembrane protein in the Tetraspanin family. This target was then validated by showing that cells transfected with PTGFRN cDNA bound and internalized the antibody. Screening by Flow bidning and by western blot identified several human cancer cells lines expressing PTGFRN. In vitro treatment of these cell lines with the 33B7-saporin ADC inhibited their proliferation in a dose-dependent fashion. 33B7 conjugated to saporin was also able to block tumor growth in vivo in mouse xenografts when compared to a control ADC. Conclusion: These findings show that screening antibody libraries for internalizing antibodies in cancer cell lines is a good approach to identify new cancer targets for ADC development. These results suggest PTGFRN is a possible therapeutic target via antibody-based approach for certain cancers. The elucidation of PTGFRN role in cancer cells, particularly in possibly mediating metastasis is presently being carried out. Citation Format: Jorge Marquez, Jianping Dong, Chun Dong, Ginette Serrero. Prostaglandin F2 Receptor Negative Regulator (PTGFRN) is a novel target to inhibit tumor growth via antibody drug conjugate [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB116.
A variant in human AIOLOS impairs adaptive immunity by interfering with IKAROS
Authors: Motoi Yamashita, Hye Sun Kuehn, Kazuki Okuyama, Satoshi Okada, Yuzaburo Inoue, Noriko Mitsuiki, Kohsuke Imai, Masatoshi Takagi, Hirokazu Kanegane, Masahiro Takeuchi, Naoki Shimojo, Miyuki Tsumura, Aditya K. Padhi, Kam Y. J. Zhang, Bertrand Boisson, Jean-Laurent Casanova, Osamu Ohara, Sergio D. Rosenzweig, Ichiro Taniuchi, Tomohiro Morio
Journal: Nature Immunology (2021)