tbuckley/cabot-search huggingface dataset:
Anti-leukemia activity of histone deacetylase (HDAC) inhibitor LBH589 involves depletion of EZH2 and DNA methyltransferase (DNMT) 1 through disruption of their chaperone association with heat shock protein (hsp) 90
Authors: K. N. Bhalla, W. Fiskus, B. Herger, R. Rao, C. Ustun, A. Jillella, P. Atadja
Journal: Journal of Clinical Oncology (2007)

10501 Background: LBH589 is a hydroxamate pan-HDAC inhibitor (HA-HDI) that also inhibits HDAC6, which induces acetylation of hsp90 and hsp70. This inhibits the ATP binding and chaperone function of hsp90. We recently reported that treatment with LBH589 depletes the levels of the polycomb repressive complex (PRC) 2 proteins EZH (enhancer of zeste homolog) 2, Suz12 and EED in AML cells. Since EZH2 has been shown to interact with and modulate the DNA methyltransferase activity of DNMT1, which affects its binding to the EZH2-targeted gene promoters, we determined the effects of LBH589 on the levels and interaction between EZH2 and DNMT1 in the CML blast crisis (CML-BC) K562 and LAMA-84 cells as well as in primary AML samples. Methods: Following exposure to 20 to 100 nM of LBH589 for 8 and 24 hours. immunoprecipitation and/or immunoblot analyses were performed to determine hsp90 binding and levels of DNMT1 and EZH2, as well as induction of JunB and loss of clonogenic survival of leukemia cells. Results: Treatment with LBH589 disrupted the chaperone association of DNMT1 and EZH2 with hsp90, resulting in polyubiquitylation and proteasomal degradation of DNMT1. Similar findings were also noted following treatment of leukemia cells with the hsp90 inhibitor, 17-DMAG. DNMT1 depletion by LBH589 was associated with induction of JunB in cultured and primary leukemia cells, which was further enhanced by co-treatment with decitabine. Consistent with this, methylation specific PCR analysis demonstrated increased demethylation of the JunB promoter. Co-treatment with decitabine and LBH589 or DMAG inhibited colony growth of the leukemia cells significantly more than treatment with either agent alone (p&lt;0.05). Conclusions: These findings indicate that in addition to mediating histone acetylation and demethylation, LBH589 treatment induces epigenetic DNA demethylation by targeted depletion of EZH2 and DNMT1 in human leukemia cells. These results support the rationale for testing novel anti- leukemia combinations for epigenetic targeting that include LBH589, decitabine and/or histone methyltransferase inhibitors. No significant financial relationships to disclose.
Short-term outcomes of immediate breast reconstruction using implant or tissue expander after mastectomy in breast cancer patients.
Authors: Haekyung Lee, Se Won Kim, Tae Ho Kang, Chan Seok Yoon, Seung Sang Ko, Min Hee Hur, Sung Soo Kang, Chul Hwan Seul
Journal: Journal of Clinical Oncology (2012)

176 Background: Mastectomy is a life-saving management but can cause significant adverse reactions. So, breast reconstruction is a concern in recovery after mastectomy. We report our experience with immediate breast reconstruction using implant or tissue expander, which confirmed the oncologic safety and high patients’ satisfaction. Methods: This study is a retrospective review of all patients who underwent reconstruction with implant or tissue expander immediately after mastectomy. Seventy-seven patients underwent breast reconstruction at a general hospital breast cancer center from January of 2008 to December of 2010 and 14 patients were excluded because of follow-up loss. Therefore 63 patients were included. To access patient’s satisfaction, questionnaire was sent to all patients. Results: Mean age of the patients is 44.1 years. ( range: 29-64) After median follow-up periods of 22.4 months, there was 1 case of locoregional recurrence, 1 case of distant metastasis and overall breast cancer specific survival was 100%. Overall major complication rate was 11.1% (7 patients), such as nipple areolar complex (NAC) necrosis and implant removal. Among 10 patients who had NAC necrosis, 6 patients improved after observation, and 4 patients performed NAC excision. Three patients were removed their implant due to severe infection, leakage or dissatisfaction. There were 32 cases of total mastectomy, 12 cases of skin sparing mastectomy (SSM), 19 cases of NAC sparing mastectomy (NSM). According to the result of questionnaire, 84.1% was satisfied with generalized operational result, 77.8% with cosmetic result. Among 19 patients who had performed NSM, 89.5% was satisfied with general result, 84.2% with cosmetic result. Conclusions: Immediate breast reconstruction using implant after mastectomy is technically feasible and oncologically safe as well as relatively good patient’s satisfaction. But we need more long-term experience.
The Effect of Cigarette Smoking on Lung Function in Young Adults with Asthma
Authors: Robert J. Hancox, Andrew R. Gray, Richie Poulton, Malcolm R. Sears
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

Rationale: Life-course persistent asthma and tobacco smoking are risk factors for irreversible airflow obstruction. It is often assumed that smoking and asthma have additive or multiplicative effects on the risk for airflow obstruction, but this has not been demonstrated in prospective studies of children with persistent asthma.Objectives: To investigate the effects of smoking and asthma on the development of airflow obstruction in a population-based birth cohort followed to age 38 years.Methods: Reports of childhood asthma from ages 9, 11, and 13 and self-reports of adult asthma at ages 32 and 38 years were used to define childhood-onset persistent asthma (n = 91), late-onset asthma (n = 93), asthma in remission (n = 85), and nonasthmatic (n = 572) phenotypes. Cumulative tobacco smoking histories and spirometry were obtained at ages 18, 21, 26, 32, and 38 years. Analyses were by generalized estimating equations adjusting for childhood spirometry, body mass index, age, and sex.Measurements and Main Results: Smoking history and childhood-onset persistent asthma were both associated with lower FEV1/FVC ratios. Associations between smoking and FEV1/FVC ratios were different between asthma phenotypes (interaction P < 0.001). Smoking was associated with lower prebronchodilator and post-bronchodilator FEV1/FVC ratios among subjects without asthma and those with late-onset or remittent asthma, but smoking was not associated with lower FEV1/FVC ratios among those with childhood-onset persistent asthma.Conclusions: Childhood-onset persistent asthma is associated with airflow obstruction by mid-adult life, but this does not seem to be made worse by tobacco smoking. We found no evidence that smoking and childhood-persistent asthma have additive or multiplicative effects on airflow obstruction.
Margaret McCartney: Pity the NHS—Jeremy Hunt has chosen the nuclear option
Authors: Margaret McCartney
Journal: BMJ (2016)

Why are junior doctors low in morale? Asking this while imposing the junior doctors’ contract is akin to wondering who started the fire as Jeremy Hunt holds a box of matches, an empty can of petrol, and a sign saying, “I did it.” Sorry, not a fire: it’s “the nuclear option.” Why would junior doctors—post-MTAS, in debt, on rotten shifts, and with the Antipodes calling—possibly feel demoralised?

The moral contract between healthcare professionals and patients is the one that matters more. The reason why we have …
Increased Nasal Plasmacytoid Dendritic Cells Are Associated with Recurrent Wheezing Following Severe RSV Bronchiolitis
Authors: Maleewan Kitcharoensakkul, Leonard B. Bacharier, Huiqing Yin-Declue, Toni Schweiger, Charles W. Goss, Jonathan S. Boomer, Geneline Sajol, Kenneth Schectman, Mario Castro
Journal: Journal of Allergy and Clinical Immunology (2016)
Circulating tumor cells as prognostic and predictive markers in neuroendocrine tumors.
Authors: Mohid Shakil Khan, Theodora Tsigani, Jorge Garcia-Hernandez, John Anthony Hartley, Martyn E Caplin, Tim Meyer
Journal: Journal of Clinical Oncology (2012)

4123 Background: Neuroendocrine tumors (NETs) are a heterogeneous group of tumors with variable survival. While Ki67 in tumour tissue is prognostic, there have been no prospectively validated circulating prognostic or predictive markers. Here we present results from a large prospective study of circulating tumor cells (CTCs) in patients with NETs. Methods: Patients about to commence therapy had a 7.5 ml blood sample taken at baseline with additional samples taken at 3-5 weeks after commencing treatment. CTCs were enumerated using the CellSearch system and counted independently by two observers. Radiological response was classified according to RECIST 1.1. PFS and OS were measured from start date of therapy, to date of progression and date of death, respectively. In order to define a prognostic cut off value for CTCs, 90 patients were enrolled in a training set and 85 patients in a validation set. The optimal cut-off level validated was CTC≥1. Prognostic factors including Ki67 were evaluated using Cox regression. Changes in CTCs after treatment were divided into tertiles. Results: 138 patients with metastatic NET (31 pancreatic, 81 midgut, 12 bronchopulmonary, 11 unknown primary, 3 hindgut) were recruited who were about to undergo treatment with somatostatin analogues(34), chemotherapy(28), PRRT(40), TAE(18), RFA(3), Sunitinib(4), interferon(4) and surgery(7). Median follow-up was 9.7 months (range 5-29). Patients with baseline CTC≥1 had significantly worse PFS (HR 4.3 95%CI 1.8-10.3), and OS (HR 6.1 95%CI 1.8-20.3) than those without CTCs. In multivariate analysis CTC presence was associated with worse PFS (HR 3.7 95%CI 1.5-8.9) and OS (HR 5.1 95%CI1.5-7.3). Changes in CTCs predicted response to therapy (Fisher’s exact p&lt;0.001) and those with increase in CTCs by ≥33% post-therapy had significantly worse PFS (HR 23.1 95%CI 5.37-99.0) and OS (HR18.9 95%CI 2.4-146) than a fall or &lt;33% increase. Conclusions: In metastatic NETs, CTCs are a promising prognostic marker and may be an early marker of response to therapy. Further evaluation of CTCs in the context of therapeutic trials is required.
Comparison of red blood cell transfusion rates of epoetin alfa and darbepoetin alfa in an inpatient oncology setting
Authors: F. Vekeman, R. S. McKenzie, S. Watson, S. Mody, P. Lefebvre, C. T. Piech, M. S. Duh
Journal: Journal of Clinical Oncology (2006)

16002 Background: Epoetin alfa (EPO) and darbepoetin alfa (DARB) are used to treat cancer-related anemia and to reduce the requirements for blood transfusions. To date, limited information on the relative effectiveness of these agents in the inpatient setting is available. This analysis evaluated red blood cell (RBC) transfusion rates in cancer patients receiving EPO or DARB during hospitalization. Methods: An analysis of electronic inpatient hospital records from the Premier Perspective Comparative Hospital Database was conducted to compare RBC transfusion rates in cancer patients receiving EPO or DARB therapy. Study subjects were identified through hospitalizations recorded between 07/2002 and 03/2005 from over 500 hospitals nationwide. Patients were required to be ≥18 years old, have a primary admitting diagnosis of cancer and be treated with EPO or DARB during hospitalization. Patients who had received renal dialysis were excluded. To minimize effects of outliers, 5% of patients with extreme doses in each group were excluded from the dosing analysis. In addition to descriptive statistics on transfusion requirements, a multivariate logistic model was employed to isolate the effect of an individual erythropoietic agent on the risk of RBC transfusion after controlling for patient demographics, comorbidities, admission characteristics, use of IV or oral iron and hospitalization severity markers. Results: Among the 24,814 EPO and 2,990 DARB study patients, mean age and gender distribution at admission were similar (age: EPO 65.3 years, DARB 64.5 years; %women: EPO 53%, DARB 55%). Mean cumulative dose per inpatient stay was EPO 61,656 ± 50,274 Units and DARB 259 ± 340 mcg. RBC transfusions occurred in 37.9% of EPO patients compared to 39.8% of DARB patients (p=0.0404). Transfused EPO patients received a mean of 2.24 units versus 2.20 units for DARB patients (p=0.2111). After adjusting for covariates, the multivariate model confirmed that DARB treatment was associated with a higher risk of transfusion compared to EPO (odds ratio: 1.2, 95% CI: 1.1–1.3, p=0.0007). Conclusions: This analysis of inpatients with cancer indicates DARB treatment is associated with a higher risk of receiving RBC transfusion compared to treatment with EPO. [Table: see text]
Determination of lung capillary blood volume and membrane diffusing capacity in patients with COLD using the NO-CO method
Authors: J Moinard, H Guenard
Journal: European Respiratory Journal (1990)

Lung capillary blood volume (Qc) and the membrane diffusing capacity (Dm) can both be determined from the combined measurement of nitric oxide (NO) and carbon monoxide (CO) transfers using the single-breath method. In ten healthy subjects, no differences was observed between the values of transfer factor of the lungs for carbon monoxide (TLCO) recovered after a 3 s or 9 s breath-holding time (tBH). The NO-CO method could thus be used with a short tBH and a low fraction of inspired nitric oxide (FINO) (8 ppm). However, in ten patients with chronic obstructive lung disease (COLD), the values of both transfer factor of the lungs for nitric oxide (TLNO) and TLCO were underestimated by around 20% at a short tBH (3 s). In COLD patients, the NO-CO method therefore requires a longer tBH and a higher inspired fraction of NO (30 ppm) than in healthy subjects. Similar values of Dm and Qc were obtained using the NO-CO method and the two-step conventional method, at two levels of the oxygenation. The former method gave less scatter. Furthermore, TLNO is independent of the fraction of inspired oxygen (FIO2) and directly proportional to carbon monoxide membrane diffusing capacity (DmCO).
Pressure supported nasal inhalation improving penetration of particles into the human lung
Authors: Keywan Sohrabi, Damiano Librizzi, Abass Sohrabi, Michael Scholtes, Helmut Hoeffken, Ulrich Koehler, Volker Gross
Journal: European Respiratory Journal (2012)

We here report on a new method to facilitate the pressure supported nasal long-term inhalation. The method is developed and technically realized by company NLI GmbH, Germany.  We examined the efficacy of the method by screening the deposition in nasal and thoracic airways. We used 99mTc-nanocoll to identify the activity scintigraphically in various respiratory sections.  This study included 10 patients (f = 5, m = 5), age range 49 to 75 years, presenting several COPD stages (GOLD I-III). The NLI system generated particle sizes from 1-2 µm. The pressure support was adjusted to 10 mbar.  We could show that deposition in the lung periphery by using the pressure supported transnasal application will increase significantly compared with conventional methods. The usual method produced an average nasal deposition of 5.9 MBq and a periphery deposition of 9.6 MBq, whereas NLI method results in an average nasal deposition of 4.2 MBq and a periphery deposition of 12.9 MBq, respectively.  Our study showed that it was possible to penetrate even in periphery pulmonary tissue in COPD patients by using the NLI system. In additon, we achieved an enhancement of the thoracic deposition of 99mTc-nanocoll, when recorded a reduction of activity in the nasopharyngeal zone. Further clinical trials with drug applications will be necessary to confirm the clinical relevance.
Renal functional reserve in kidney and heart transplant recipients.
Authors: J L Ader, I Tack, D Durand, T Tran-Van, L Rostaing, J M Suc
Journal: Journal of the American Society of Nephrology (1996)

Renal functional impairment paradoxically often seems less severe in kidney than in heart-transplant recipients (KTR and HTR, respectively) when both are submitted to cyclosporine therapy. Renal functional reserve (RFR), elicited by a 3-h intravenous amino acid infusion, was examined in 12 KTR and 13 HTR at 7 to 8 months, appropriately compared with either eight one-kidney or 12 two-kidney healthy control subjects (1K.C and 2K.C, respectively). Baseline GFR was 54 +/- 4 mL/min in KTR and 71 +/- 4 mL/min in HTR (P < 0.05). During amino acid infusion, the maximum increase in GFR (which represented RFR) was 17 +/- 3 mL/min in both KTR and HTR (P < 0.001). RFR in KTR was 96 +/- 18% of that in 1K.C, whereas RFR in HTR was only 59 +/- 9% of that in 2K.C. Effective RPF increased (41 +/- 8 mL/min, P < 0.001), and renal vascular resistances decreased (48 +/- 17 mm Hg/L per min, P < 0.05) in KTR but not in HTR. These results demonstrate that both KTR and HTR possess a renal reserve but that the single renal graft in KTR retains a proportionally higher baseline GFR and a better ability to exhibit a RFR than the two native kidneys in HTR. This dissimilar impairment could result from slightly higher cyclosporine dosage, activation of the intact renal sympathetic innervation accentuated by cardiac denervation, renal consequences of former heart failure and potential alterations in the cardiac graft function, and/or higher prevalence of hypertension and additive therapies in HTR.
Influence of Adiposity, Physical Activity, Fitness, and Screen Time on Insulin Dynamics Over 2 Years in Children
Authors: Mélanie Henderson, Andrea Benedetti, Tracie A. Barnett, Marie-Eve Mathieu, Johnny Deladoëy, Katherine Gray-Donald
Journal: JAMA Pediatrics (2016)

Despite extensive evidence showing that lifestyle habits play a critical role in preventing or delaying the onset of type 2 diabetes in adults, little is known regarding the impact of lifestyle habits on type 2 diabetes risk in childhood.To assess whether adiposity, fitness, moderate-to-vigorous physical activity, and screen time predict insulin sensitivity or insulin secretion during a 2-year period in children with a family history of obesity.This is a prospective longitudinal cohort study of 630 children, having at least 1 obese parent, recruited from schools in Quebec, Canada, between July 2005 and December 2008 in the Quebec Adipose and Lifestyle Investigation in Youth (QUALITY) cohort. Children were assessed at baseline (ages 8-10 years) and 2 years later. Fitness was measured by peak oxygen consumption, percentage of body fat (adiposity) by dual-energy x-ray absorptiometry, moderate-to-vigorous physical activity using accelerometry, and screen time by average daily hours of self-reported television, video game, or computer use. Regression models were adjusted for age, sex, season, and pubertal stage. The current analysis was completed in October 2015.Insulin sensitivity was measured by the homeostatic model assessment of insulin resistance and an oral glucose tolerance test-based index (Matsuda insulin sensitivity index). Insulin secretion was measured using the area under the curve of insulin to glucose during the first 30 minutes of the oral glucose tolerance test and using the area under the curve of insulin to glucose over 2 hours.Of 630 children evaluated at baseline (mean [SD] age, 9.6 [0.9] years; 54.4% male; 56.2% normal weight, 19.2% overweight, and 22.7% obese), 564 were evaluated at 2-year follow-up. Adiposity and changes in adiposity were the central predictors of insulin dynamics over time. Every additional 1% of body fat at ages 8 to 10 years decreased insulin sensitivity by 2.9% (95% CI, -3.3% to -2.5%; P < .001) and led to a 0.5% (95% CI, 0.09% to 0.8%; P = .02) increased requirement in the area under the curve of insulin to glucose during the first 30 minutes of the oral glucose tolerance test 2 years later. Higher levels of moderate-to-vigorous physical activity and lower screen time appear to be beneficial to insulin sensitivity in part through their effect on adiposity levels.Adiposity plays a determining role in cardiometabolic health at a young age. Public health strategies that promote healthy body weight, notably physical activity, need to target school-aged and possibly younger children.
Lack of coordination during Ebola outbreak was a “lost opportunity” to test therapies
Authors: Anne Gulland
Journal: BMJ (2015)

<h3>Objective:</h3> Numb chin syndrome (NCS) describes mental neuropathy manifesting as numbness or paresthesia of the chin and lower lip. Although commonly associated with dental or traumatic causes, NCS may be a sign of occult malignancy reported to portend an unfavorable prognosis1. <h3>Background:</h3> We present the case of a 59-year-old gentleman with history of hypertension, dyslipidemia, and ankylosing spondylitis who presented with a 3-week history of left chin numbness. The sole significant physical exam finding was numbness in left V3 region that extended 2.5 cm laterally from midline of chin. Additional review of systems was negative. The patient was taking adalimumab for ankylosing spondylitis and medication was discontinued. MRI with and without contrast revealed lesions of the diploic space and an enhancing scalp lesion in the parietal region. Initial scalp biopsy showed atypical lymphocytic infiltrate. Full-body CT/PET scan showed nodal, skin, and marrow-based hypermetabolism. On the day of the marrow biopsy, no abnormal circulating populations were seen on peripheral smear and pathology showed normocellular bone marrow with large atypical lymphoid cells. The diagnosis of T-cell-rich diffuse large B-cell lymphoma was made 53 days following presentation. Just prior to initiating chemotherapy, patient developed generalized fatigue. The mental neuropathy has persisted following multiple cycles of chemotherapy. <h3>Design/Methods:</h3> NA <h3>Results:</h3> NA <h3>Conclusions:</h3> NCS has been reported to herald underlying malignancy1. In addition, ankylosing spondylitis has been associated with increased incidence of lymphomas2. The concern for malignancy should be further heightened in patients with mental neuropathy and ankylosing spondylitis thus requiring a complete and expeditious evaluation. <b>Disclosure:</b> Dr. Majors has nothing to disclose. Dr. Fletcher has nothing to disclose. Dr. Sowell has nothing to disclose.