tbuckley/cabot-search huggingface dataset:
Dominant-negative IKZF1 mutations cause a T, B, and myeloid cell combined immunodeficiency
Authors: David Boutboul, Hye Sun Kuehn, Zoé Van de Wyngaert, Julie E. Niemela, Isabelle Callebaut, Jennifer Stoddard, Christelle Lenoir, Vincent Barlogis, Catherine Farnarier, Frédéric Vely, Nao Yoshida, Seiji Kojima, Hirokazu Kanegane, Akihiro Hoshino, Fabian Hauck, Ludovic Lhermitte, Vahid Asnafi, Philip Roehrs, Shaoying Chen, James W. Verbsky, Katherine R. Calvo, Ammar Husami, Kejian Zhang, Joseph Roberts, David Amrol, John Sleaseman, Amy P. Hsu, Steven M. Holland, Rebecca Marsh, Alain Fischer, Thomas A. Fleisher, Capucine Picard, Sylvain Latour, Sergio D. Rosenzweig
Journal: Journal of Clinical Investigation (2018)

Ikaros/IKZF1 is an essential transcription factor expressed throughout hematopoiesis. IKZF1 is implicated in lymphocyte and myeloid differentiation and negative regulation of cell proliferation. In humans, somatic mutations in IKZF1 have been linked to the development of B cell acute lymphoblastic leukemia (ALL) in children and adults. Recently, heterozygous germline IKZF1 mutations have been identified in patients with a B cell immune deficiency mimicking common variable immunodeficiency. These mutations demonstrated incomplete penetrance and led to haploinsufficiency. Herein, we report 7 unrelated patients with a novel early-onset combined immunodeficiency associated with de novo germline IKZF1 heterozygous mutations affecting amino acid N159 located in the DNA-binding domain of IKZF1. Different bacterial and viral infections were diagnosed, but Pneumocystis jirovecii pneumonia was reported in all patients. One patient developed a T cell ALL. This immunodeficiency was characterized by innate and adaptive immune defects, including low numbers of B cells, neutrophils, eosinophils, and myeloid dendritic cells, as well as T cell and monocyte dysfunctions. Notably, most T cells exhibited a naive phenotype and were unable to evolve into effector memory cells. Functional studies indicated these mutations act as dominant negative. This defect expands the clinical spectrum of human IKZF1-associated diseases from somatic to germline, from haploinsufficient to dominant negative.
Incidence of long-term hair loss (LHL) following docetaxel (D)-containing non-anthracycline (A) adjuvant chemotherapy (Adj) of early stage breast cancer (ESB).
Authors: John Crown, Janice Maria Walshe, David William Fennelly, Jessica-Clare Long, Josephine Ballot, Deirdre McDonnell, Susan Cairney, Therese Lyons, Aileen O'Meara, Conor Buckley, John Gannon, Mary Quinn, Giuseppe Gullo
Journal: Journal of Clinical Oncology (2018)

e12522 Background: Taxane-containing Adj is an accepted life-prolonging component of modern multi-modal ESB therapy. One of the most distressing complications of Adj is alopecia. While patients (pts) are usually reassured that this is temporary, there have been troubling reports of LHL, generally with regimens that include D and A. We attempted to define the incidence of LHL in a large cohort of patients who received Adj which contained D without A. Methods: Pts who received Adj/neo-Adj which contained D but not A for ESB in clinical trials, or as standard of care in our single academic institution were identified. Pts had completed Adj more than one year. Trials pts were contacted directly, non-trials pts assessed during clinic visits. LHL was graded as 0,1 or 2 (CTCAE). Results: We identified 368 pts, with a median follow-up of >5 years. Pts received DC4 or DC6 (D/cyclophosphamide 75/600 mg/2 iv 3-weekly 4 or 6 times); or DPH (D 75 mg/m2, carboplatin AUC 6 and trastuzumab given 3-weekly iv). LHL occurred in 15%, 37% and 31% of DC4, DC6 and DPH (Table). Adj endocrine therapy (given to 85%) did not correlate with LHL, nor did companion drugs (C or P). Conclusions: D-non-A Adj regimens pose a substantial dose-related risk of LHL, independently of endocrine therapy. While D-non-A Adj offers other toxicity advantages (e.g. decreased cardiotoxicity) versus A regimens, clinicians and pts need to be aware of the risk of this devastating and relatively common sequel of Adj with D. The incidence of LHL with paclitaxel non-A needs study. There is an urgent need to assess the impact of scalp cooling on LHL with D. Table Total LHL and grade 2 LHL were significantly (p<0.001) more common with DC6+DPH6 than with DC4 (p=.001). TCx4 TCx6 TPHx6 Total n. of Patients 140 96 132 Grade of Hairloss #pts LHL(%) #pts LHL(%) #pts LHL(%) Grade 0 119 (85%) 60 (63%) 91 (69%) Grade 1 17 (12%) 26 (27%) 31 (23%) Grade 2 4 (3%) 10 (10%) 10 (8%)
Gorab is a Golgi protein required for structure and duplication of Drosophila centrioles
Authors: Levente Kovacs, Jennifer Chao-Chu, Sandra Schneider, Marco Gottardo, George Tzolovsky, Nikola S. Dzhindzhev, Maria Giovanna Riparbelli, Giuliano Callaini, David M. Glover
Journal: Nature Genetics (2018)
Cancer survivorship in the rural U.S. Columbia Pacific: A pilot study.
Authors: Jennifer L. Lycette, Paulina Cockrum, Venus Fromwiller, Kerri M. Winters-Stone
Journal: Journal of Clinical Oncology (2018)

106 Background: We provide the only fully staffed cancer center in the rural Columbia Pacific, serving multiple counties in OR and WA. Rural areas can lack resources to provide comprehensive survivorship care. Higher rates of medical comorbidities and socioeconomic barriers add challenges to rural survivorship. We conducted a pilot study to 1) develop a program for lifestyle and behavior modifications to fit the needs of our rural community and 2) determine feasibility and preliminary efficacy of a survivorship program for breast cancer patients. Methods: : 9 women with stage I-III breast cancer completed a 12-week program consisting of 1:1 meetings every 2 weeks with a physical therapist and registered dietician; health coach support; and access to a social worker. The following pre-post measures of physical health were taken: fasting lipids and glucose, HbA1C, waist circumference, blood pressure, BMI, 3-day physical activity log and food journal, joint range of motion, and muscle strength. Pre-post well-being was assessed by EORTC QLQC30 and focus groups. Results: Decreases in systolic BP, weight, waist circumference, fasting glucose, and HbA1c were seen in a majority of participants; however, only decreases in waist circumference reached statistical significance (p = .043). On post-program survey using a 0-10 rating scale, program acceptability was rated at an average of 7, and likelihood to continue at an average of 9.4; however, overall QOL rating had no change. Focus group feedback indicated participants valued dietician visits, but requested more social work support, exercise customization, and group support to foster mentoring, education, and sense of community. Conclusions: Developing a rural comprehensive survivorship care program is feasible. More work is needed to translate physical health goals into enhancement of well-being and improved QOL. As of 10/2/17 we have opened a comprehensive cancer center housing medical oncology and radiation oncology services in one facility. We now have a full-time dietitian, resource coordinator, and social worker. This unique facility is well poised to deliver long-term care to rural cancer survivors, and we believe could serve as a model for other rural regions.
The Calcium-Sensing Receptor Increases Activity of the Renal NCC through the WNK4-SPAK Pathway
Authors: Silvana Bazúa-Valenti, Lorena Rojas-Vega, María Castañeda-Bueno, Jonatan Barrera-Chimal, Rocío Bautista, Luz G. Cervantes-Pérez, Norma Vázquez, Consuelo Plata, Adrián R. Murillo-de-Ozores, Lorenza González-Mariscal, David H. Ellison, Daniela Riccardi, Norma A. Bobadilla, Gerardo Gamba
Journal: Journal of the American Society of Nephrology (2018)

Background Hypercalciuria can result from activation of the basolateral calcium-sensing receptor (CaSR), which in the thick ascending limb of Henle's loop controls Ca2+ excretion and NaCl reabsorption in response to extracellular Ca2+ However, the function of CaSR in the regulation of NaCl reabsorption in the distal convoluted tubule (DCT) is unknown. We hypothesized that CaSR in this location is involved in activating the thiazide-sensitive NaCl cotransporter (NCC) to prevent NaCl loss.Methods We used a combination of in vitro and in vivo models to examine the effects of CaSR on NCC activity. Because the KLHL3-WNK4-SPAK pathway is involved in regulating NaCl reabsorption in the DCT, we assessed the involvement of this pathway as well.Results Thiazide-sensitive 22Na+ uptake assays in Xenopus laevis oocytes revealed that NCC activity increased in a WNK4-dependent manner upon activation of CaSR with Gd3+ In HEK293 cells, treatment with the calcimimetic R-568 stimulated SPAK phosphorylation only in the presence of WNK4. The WNK4 inhibitor WNK463 also prevented this effect. Furthermore, CaSR activation in HEK293 cells led to phosphorylation of KLHL3 and WNK4 and increased WNK4 abundance and activity. Finally, acute oral administration of R-568 in mice led to the phosphorylation of NCC.Conclusions Activation of CaSR can increase NCC activity via the WNK4-SPAK pathway. It is possible that activation of CaSR by Ca2+ in the apical membrane of the DCT increases NaCl reabsorption by NCC, with the consequent, well known decrease of Ca2+ reabsorption, further promoting hypercalciuria.
Myeloid Cells Remodel the Mitral Valve
Authors: Sebastian Cremer, Matthias Nahrendorf
Journal: Circulation (2018)

itral valve disease is a degenerative cardiac pathology that increases markedly with age in the Western Hemisphere.Rheumatic heart disease is another frequent cause of valve pathology, in particular, in developing countries.In this condition, valvular damage arises from autoimmune responses after group A streptococcal infection, leading first to mitral valve insufficiency and, at later stages, to stenosis.Once the disease is established, therapeutic options are currently limited to either symptomatic treatment or invasive surgical procedures. 1 The central importance of the adaptive immune response for developing rheumatic heart disease is well known: B cells produce antibodies directed against streptococcal epitopes.Those antibodies cross-react with antigens such as laminin in the valve endocardium, ultimately leading to endothelial cell activation and vascular cell adhesion molecule expression.This promotes the entry of T cells, which likely destroy valvular tissue by secretion of proinflammatory cytokines. 1n this issue of Circulation, Meier et al 2 describe for the first time the causal involvement of innate immune cells in the pathogenesis of mitral valve disease.The authors conducted their studies in K/B.g7 T-cell receptor transgenic mice (TCR mice) that express a T-cell receptor that recognizes the self-peptide glucose-6-phosphate isomerase.The resulting autoantibody production causes erosive polyarthritis and mitral valve inflammation.Mitral valves become fibrotic and accumulate myeloid cells that express the fractalkine receptor CX3CR1.Genetic deletion of CX3CR1 protects mice from valve fibrosis and inflammation, likely because this receptor regulates myeloid cell migration and survival. 3sing multicolor flow cytometry, the authors identify a CD301b/MGL2 mononuclear cell population as a key protagonist of mitral valve disease in TCR mice.They characterize this population as CXC3CR1 + CD64 + CD301b + mononuclear phagocytes and ascribe to them the characteristics of macrophages and dendritic cells.The authors report that ablation of CD301b + cells in TCR mice reduces valve inflammation and fibrosis significantly, suggesting a causal pathogenic role for cells expressing this receptor in autoantibody-triggered pathologies of the mitral valve.Using intracellular flow cytometry, the authors found that CD301b + myeloid cells produce the inflammatory cytokines interleukin-6 and tumor necrosis factor-α.These preclinical data are accompanied by identification of CD301 + macrophages in human rheumatic valves that were obtained during valve replacement surgery.Mechanistically, using several genetic mouse models, the authors report that cell type-specific ablation of the small tyrosine kinase Syk in mononuclear phagocytes using CX3CR1-cre prevents mitral valve fibrosis and inflammation, including reduced infiltration of CD301b + myeloid cells, which express less interleukin-6 and tumor necrosis factor-α after Syk deletion.Interleukin-1β is an important inflam-
Feasibility of concurrent weekly paclitaxel and radiotherapy in adjuvant treatment of breast cancer: An experience from India.
Authors: Mohan Kumar Somashekar, Murali Subramanian V, Nirmala Srikantaiah S, Arul Ponni TR, Rajeev A G, Kirthi Koushik AS, Janaki M G, Nalini Kilara R, Ramesh Bilimagga S
Journal: Journal of Clinical Oncology (2012)

e11536 Background: Majority of the breast cancer patients require adjuvant radiotherapy and chemotherapy for better locoregional and distant control. However the sequencing of these is still debatable . Hence concurrent chemo radiation may avoid the delay in either of the adjuvant therapies. Anthracyclines are not used concurrently with radiation because of severe toxicity. Hence the current study was taken to assess the feasibility of concurrent weekly paclitaxel and radiotherapy in adjuvant treatment of ca breast. Methods: A prospective study was conducted on 22 breast cancer patients, post modified radical mastectomy or breast conservative surgery from November 2008 to April 2010. Chest wall or whole breast radiotherapy was given on Tele Cobalt or Linac for a dose of 50 – 50.4Gy in conventional fractionation. Boost of 16 Gy was given to tumor cavity with photons or electrons for those undergone breast conservative surgery. All patients received Inj.paclitaxel 60 mg/m 2 once a week for 5 weeks. After completion of RT, paclitaxel dose was increased to 80mg/m 2 for remaining 7 cycles. This was followed by anthracycline based treatment sequentially as per standard adjuvant guidelines. Patients assessed weekly and toxicities graded based on CTC version 03. The minimum follow up was 2 months after completion of chemoradiation. Chi-Square test and Fisher exact test were used to interpret the results with literature. Results: See table below. Skin reaction was more frequent and severe of all toxicities (p=0.003).With available literatures on adjuvant radiation alone the grade III and higher skin reactions are 3% but in our study it is 28% because of which 5/22 (22%) patients had interruption of both chemotherapy and radiation. Conclusions: Concurrent chemoradiation with weekly paclitaxel in adjuvant treatment of ca breast is associated with more skin reactions which may result in significant treatment interruptions. It should be practiced cautiously which requires further randomized control studies to assess the toxicities in detail. [Table: see text]
68Ga DOTA-Exendin PET/CT for Detection of Insulinoma in a Patient With Persistent Hyperinsulinemic Hypoglycemia
Authors: Ashwin Singh Parihar, Shelvin Kumar Vadi, Rajender Kumar, Bhagwant Rai Mittal, Harmandeep Singh, Amanjit Bal, Rama Walia, Jaya Shukla, Saroj Kumar Sinha
Journal: Clinical Nuclear Medicine (2018)

Abstract Insulinomas are the most common functioning pancreatic neuroendocrine tumors and the leading cause of persistent hypoglycemia with hyperinsulinemia in adults. Glucagon-like-peptide-1 (GLP) receptor analogs are the latest agents being used in the detection of insulinomas, with initial reports suggesting high sensitivity due to universal GLP1 receptor expression on these tumors. PET/CT imaging in this patient using 68 Ga DOTA-Exendin, a GLP receptor analog, proved useful for accurate localization of the culprit lesion, aiding in the definitive management of the patient.
Endogenous Sex Hormones and Incident Cardiovascular Disease in Post-Menopausal Women
Authors: Di Zhao, Eliseo Guallar, Pamela Ouyang, Vinita Subramanya, Dhananjay Vaidya, Chiadi E. Ndumele, Joao A. Lima, Matthew A. Allison, Sanjiv J. Shah, Alain G. Bertoni, Matthew J. Budoff, Wendy S. Post, Erin D. Michos
Journal: Journal of the American College of Cardiology (2018)
Increased risk of depression in patients with cutaneous lupus erythematosus and systemic lupus erythematosus: a Danish nationwide cohort study
Authors: J.H. Hesselvig, A. Egeberg, K. Kofoed, G. Gislason, L. Dreyer
Journal: British Journal of Dermatology (2018)

There is a wide range in the reported prevalences of depression in patients with systemic lupus erythematosus (SLE), while the prevalence of depression in patients with cutaneous lupus erythematosus (CLE) remains severely understudied. To examine whether patients with SLE or CLE have an increased risk of depression. In this nationwide observational cohort study, we included patients aged ≥ 18 years with a first‐time diagnosis of SLE or CLE between 2000 and 2015 identified in the Danish National Patient Register, which were matched with the general population in a ratio of 1 : 10. After linkage to national Danish health registers of primary and secondary care, analyses of risk for depression and antidepressant use were performed using Cox regression models adjusted for age, sex, socioeconomic status, smoking, alcohol abuse, prior depression and prior antidepressant use. A total of 3489 patients with lupus erythematosus were followed for 23 373 person‐years. Compared with the general population, the adjusted hazard ratios (HRs) of depression were 2·07 [95% confidence interval (CI) 1·55–2·75] and 2·22 (95% CI 1·77–2·77) for patients with CLE and SLE, respectively; for hospitalization owing to depression at a department of psychiatry HRs were 2·63 (95% CI 0·80–8·67) and 3·52 (95% CI 1·53–8·11) for patients with CLE and SLE, respectively. The adjusted HRs for antidepressant use were 1·47 (95% CI 1·34–1·63) and 1·70 (95% CI 1·58–1·83) for patients with CLE and SLE, respectively. The risk of depression was significantly increased in patients with SLE and CLE. Awareness of an increased risk of depression in patients with SLE and CLE might be warranted.
Piloting a supportive oncology screener with adult survivors of childhood cancers.
Authors: Sofia F. Garcia, Sheetal Mehta Kircher, Katy Wortman, Karen Kinahan, Allison Fisher, Megan Slocum, Christine B. Weldon, Aarati Didwania, Frank J. Penedo
Journal: Journal of Clinical Oncology (2018)

9 Background: Adult survivors of childhood cancers experience a host of late effects. Our Survivors Taking Action and Responsibility (STAR) clinic treats those needs. Methods: We piloted the Coleman Supportive Oncology Tool (CSOT, which includes a concerns checklist &amp; the 4-item Patient Health Questionnaire [PHQ-4]) that patients completed before STAR visits. We used chi-square, T-tests, and logistic regression to identify differences in CSOT scores associated with patient characteristics. Results: Patients (n = 115) completed the CSOT: 54% women; 81% White; 34% leukemias, 30% lymphomas, 10% brain tumors, 8% sarcomas, and 18% other cancers. Mean years: current age = 33.48 (SD = 7.71) and age at diagnosis = 9.8 (SD = 5.84). The majority had chemotherapy (95%) and radiation (74%). A minority underwent surgery (38%) and transplant (22%); experienced a cancer recurrence or second malignancy (each 20%). We assessed 21 potential late effects; the mean number per patient was 1.92 (range = 0-9); most frequent were cardiologic (23%), endocrine (17%), musculoskeletal (17%) and infertility (16%). Controlling for current age, each 13 years (a) since diagnosis was associated with roughly 1 more long term effect (β = 1.02, p &lt; 0.01) and (b) at age of diagnosis was associated with 1 less (β = -1.02, p &lt; 0.01). Receiving &gt; = 300 mg anthracycline was associated with a nearly 8-fold increase in cardiologic late effects (OR = 7.94, p &lt; .01). Recurrence, second malignancy, and age &lt; 10 years at diagnosis were associated with significantly more late effects (p = &lt; .001, 01, &lt; .01, and .02 respectively); those variables were not associated with greater CSOT concerns. We assessed 32 CSOT supportive care concerns; the mean number per patient was 3.23 (range = 0-18); the most frequent were difficulties with body weight (34%), sleep (19%), work / school (18%), concentration and health insurance (each 17%). On an item assessing fear of recurrence (FoR) frequency, most (74%) endorsed “not at all” but any FoR was associated with endorsing a greater number of CSOT concerns (p &lt; .0001). Conclusions: Using a brief screener was feasible in a clinic providing follow-up care to adult survivors of childhood cancers to identify patients’ current medical and supportive care needs.
Over 600 general practices will be lost by 2020 without more funding, BMA warns
Authors: Abi Rimmer
Journal: BMJ (2018)

Between 618 and 777 practices in England will be lost between now and 2022 if funding for general practice is not increased, the BMA has warned.

If the projections, which are based on data from NHS Digital, play out then millions of patients will need to find a new practice, it said. The data show that there were 166 fewer practices in 2017 (7361) than in 2016 (7527), while the total number of practices had fallen by 963 since 2010, when England had 8324.1

Although the fall in …
Abstract 18435: ETCO2 Alone is Inadequate to Verify CPR Quality
Authors: Chengcheng Hu, Dan Spaite, Tyler Vadeboncoeur, Cameron Hypes, Ryan A Murphy, Annemarie Silver, Bentley Bobrow
Journal: Circulation (2015)

Background: Previous studies have described modest correlation between end-tidal CO 2 (ETCO 2 ) and CPR quality during resuscitation of cardiac arrest patients, but it is unclear whether ETCO 2 alone can indicate CPR quality. The present study investigated whether ETCO 2 adequately identifies the quality of CPR provided during out-of-hospital cardiac resuscitation. Methods: ETCO 2 was monitored with side-stream CO 2 (Philips/Respironics) and CPR quality measured with an accelerometer-based system (E Series, ZOLL Medical) during the treatment of consecutive adult OHCA patients with presumed cardiac etiology by 2 EMS agencies in the Arizona SHARE QI Program between 10/08-06/13. Minute-by-minute ETCO 2 and CPR quality were extracted. ETCO 2 values were log transformation to achieve approximate normality. Linear mixed effect models were fitted to use (transformed) ETCO 2 level to predict four CPR variables: chest compression (CC) depth, CC rate, CC release velocity (CCRV), and ventilation rate (VR). A random intercept for each case was included and a spatial power covariance structure assumed for measurements over time. Results: 230 subjects (median age 69 yrs, 69% male) with 1581 minutes of data were studied. Transformed ETCO 2 was significant for CC depth (p&lt; 0.0001), CCRV (p=0.003) and VR (p&lt;0.0001), but only explained 3.7%, 2.7%, and 10.0% of the total variance for these variables, respectively. Transformed ETCO 2 was not a significant predictor for CC rate (p=0.89). The Figure illustrates the overlap in CC depth over quartiles of ETCO 2 , demonstrating that any specific ETCO 2 level could be found over a wide range of CC depths. Conclusion: In this secondary analysis, ETCO 2 was not an independent indicator of CC rate but was a weak predictor for CC depth, CCRV and VR. These findings suggest that ETCO 2 may be not be an adequate substitute for CPR quality monitoring. Future studies should investigate how ETCO 2 and CPR quality monitoring can be used in conjunction to optimize CPR.
Effectiveness of targeted enhanced terminal room disinfection on hospital-wide acquisition and infection with multidrug-resistant organisms and Clostridium difficile: a secondary analysis of a multicentre cluster randomised controlled trial with crossover design (BETR Disinfection)
Authors: Deverick J Anderson, Rebekah W Moehring, David J Weber, Sarah S Lewis, Luke F Chen, J Conrad Schwab, Paul Becherer, Michael Blocker, Patricia F Triplett, Lauren P Knelson, Yuliya Lokhnygina, William A Rutala, Daniel J Sexton
Journal: The Lancet Infectious Diseases (2018)