tbuckley/cabot-search huggingface dataset:
Sleep apnoea and the hypothalamic–pituitary–adrenal axis in men and women: effects of continuous positive airway pressure
Authors: Ilia Kritikou, Maria Basta, Alexandros N. Vgontzas, Slobodanka Pejovic, Julio Fernandez-Mendoza, Duanping Liao, Edward O. Bixler, Jordan Gaines, George P. Chrousos
Journal: European Respiratory Journal (2015)

Previous findings on the association of obstructive sleep apnoea (OSA) and the hypothalamic–pituitary–adrenal (HPA) axis are inconsistent, partly due to the confounding effect of obesity and infrequent sampling. Our goal was to examine whether in a relatively nonobese population, OSA is associated with elevated cortisol levels and to assess the effects of a 2-month placebo-controlled continuous positive airway pressure (sham-CPAP) use. 72 subjects (35 middle-aged males and post-menopausal females with OSA, and 37 male and female controls) were studied in the sleep laboratory for four nights. 24-h blood sampling was performed every hour on the fourth day and night in the sleep laboratory at baseline, after sham-CPAP and after CPAP treatment. In both apnoeic men and women, OSA was associated with significantly higher 24-h cortisol levels compared with controls, whereas CPAP lowered cortisol levels significantly, close to those of controls. These results suggest that OSA in nonobese men and slightly obese women is associated with HPA axis activation, similar albeit stronger compared with obese individuals with sleep apnoea. Short-term CPAP use decreased cortisol levels significantly compared with baseline, indicating that CPAP may have a protective effect against comorbidities frequently associated with chronic activation of the HPA axis, e.g. hypertension.
Prediction of prognosis in hepatocellular carcinoma based on a gene signature from highly tumorigenic liver cancer cells.
Authors: X. Yang, J. Fan, Y. Xu, J. Zhou, B. Yu
Journal: Journal of Clinical Oncology (2010)

4148 Background: Hepatocellular carcinoma (HCC) contains a minority population of cancer cells with higher tumorigenic capacity and stem cells proprieties which was called side-population (SP) cells, characterized by the ability to efflux Hoechst 33342. In this study, the clinical significance of SP cells was explored through analysis of transcript level profiles. Methods: We compared the gene expression profile of SP cells with that of non-SP cells in HCC cell lines. Differentially expressed genes were used to generate a 124-gene recurrence gene signature (RGS), which was evaluated for its association with the microarray database of 268 HCC patients according to the prognosis analysis. Based on the RGS, a refined signature containing five genes was developed and revalidated by real-time reverse-transcriptase polymerase chain reaction in an independent cohort containing 100 HCC patients. Results: The RGS was confirmed as a significant predictor of recurrence and survival for HCC patients, especially for those in early stages, with well-differentiated tumor and normal serum alpha-fetoprotein. A five-gene signature containing NEDD9, EPAS1, EPC2, JMJD1C and USP36 was an independent predictor for recurrence and survival of HCC patients in training, testing sets, and the validation cohort (p < 0.05 for all analyses). Further validation in protein level and gene function based on small-interfering RNA showed that NEDD9 expression related with tumor cell migration, invasiveness, proliferation, clonogenic abilities and recurrence of HCC. Conclusions: Gene signature from highly tumorigenic HCC cells is associated with poor prognosis of HCC. The five-gene signature can be a useful tool for clinicians to stratify HCC patients with high recurrent risk. No significant financial relationships to disclose.
Comparison between two inspiratory muscle-training programs in frail elderly: A randomized controlled trial
Authors: Maria dels Àngels Cebrià i Iranzo, Diego Sevilla Martínez, Celedonia Igual Camacho, Laura López Bueno, Mª Ángeles Tortosa Chuliá, José Manuel Tomás
Journal: European Respiratory Journal (2014)

Introduction: The oldest old with comorbidity and activity limitation, most of them institutionalized, present a respiratory muscle (RM) strength decline. Since RM training has been shown to be an effective method to improve RM functioning, the Threshold Inspiratory Muscle Trainer (IMT) device could be an efficient method to this purpose.

Aim: To compare the effects of two IMT programs in frail elderly. We hypothesized that a longer training protocol would obtain higher improvement in RM function.

Methods: Seventy institutionalized frail elderly, who were unable to participate in whole body exercise training, were randomly allocated to a control group (CG, n=24) or one of the two training groups (6-weeks group [6TG, n=23], and 8-weeks group [8TG, n=23]). Both supervised training programs were performed by means of the Threshold IMT device and consisted of 7 cycles of 2-minute work and 1-minute rest. The 6TG trained 5 days/week and the 8TG trained 3 days/week. Maximum inspiratory pressure (PImax), maximum expiratory pressure (PEmax) and maximum voluntary ventilation (MVV) were assessed and the differential effects of these two training programs on them as well as a comparison with the CG were tested.

Results: Baseline characteristics of the three groups did not show significant differences. The statistical analyses revealed significant improvements in PImax and PEmax for the 8TG after the training program. The 6TG showed a positive trend for the three variables, but these improvements were not statistically significant.

Conclusion: The longest training protocol showed a larger improvement in RM functioning, independently of session's number (30 vs. 24).
A Chronic Obstructive Pulmonary Disease Susceptibility Gene, <i>FAM13A</i>, Regulates Protein Stability of β-Catenin
Authors: Zhiqiang Jiang, Taotao Lao, Weiliang Qiu, Francesca Polverino, Kushagra Gupta, Feng Guo, John D. Mancini, Zun Zar Chi Naing, Michael H. Cho, Peter J. Castaldi, Yang Sun, Jane Yu, Maria E. Laucho-Contreras, Lester Kobzik, Benjamin A. Raby, Augustine M. K. Choi, Mark A. Perrella, Caroline A. Owen, Edwin K. Silverman, Xiaobo Zhou
Journal: American Journal of Respiratory and Critical Care Medicine (2016)

A genetic locus within the FAM13A gene has been consistently associated with chronic obstructive pulmonary disease (COPD) in genome-wide association studies. However, the mechanisms by which FAM13A contributes to COPD susceptibility are unknown.To determine the biologic function of FAM13A in human COPD and murine COPD models and discover the molecular mechanism by which FAM13A influences COPD susceptibility.Fam13a null mice (Fam13a(-/-)) were generated and exposed to cigarette smoke. The lung inflammatory response and airspace size were assessed in Fam13a(-/-) and Fam13a(+/+) littermate control mice. Cellular localization of FAM13A protein and mRNA levels of FAM13A in COPD lungs were assessed using immunofluorescence, Western blotting, and reverse transcriptase-polymerase chain reaction, respectively. Immunoprecipitation followed by mass spectrometry identified cellular proteins that interact with FAM13A to reveal insights on FAM13A's function.In murine and human lungs, FAM13A is expressed in airway and alveolar type II epithelial cells and macrophages. Fam13a null mice (Fam13a(-/-)) were resistant to chronic cigarette smoke-induced emphysema compared with Fam13a(+/+) mice. In vitro, FAM13A interacts with protein phosphatase 2A and recruits protein phosphatase 2A with glycogen synthase kinase 3β and β-catenin, inducing β-catenin degradation. Fam13a(-/-) mice were also resistant to elastase-induced emphysema, and this resistance was reversed by coadministration of a β-catenin inhibitor, suggesting that FAM13A could increase the susceptibility of mice to emphysema development by inhibiting β-catenin signaling. Moreover, human COPD lungs had decreased protein levels of β-catenin and increased protein levels of FAM13A.We show that FAM13A may influence COPD susceptibility by promoting β-catenin degradation.
Phase I trial evaluating the epidermal growth factor receptor inhibitor erlotinib in combination with the SRC kinase inhibitor dasatinib for patients with recurrent non-small cell lung cancer (NSCLC)
Authors: A. A. Chiappori, T. Tanvetyanon, C. A. Williams, S. Antonia, S. Litschauer, A. Neuger, R. Lush, E. B. Haura
Journal: Journal of Clinical Oncology (2008)

14605 Background: Erlotinib (E), an inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase (TK), can prolong survival in patients with advanced NSCLC. SRC TK proteins can cooperate with EGFR and can affect tumor growth, survival, invasion and angiogenesis. For these reasons, we performed a phase I trial investigating E and dasatinib (D), an oral SRC/multi-target TK inhibitor in patients with advanced NSCLC. Methods: Key eligibility criteria included Stage IIIB/IV NSCLC, >1 previous systemic therapies, RECIST measurable disease, ECOG PS 0–1, no prior exposure to EGFR targeting agents. Schema: E PO qD starting day 1, E pharmacokinetics (PK) analysis day 8/9, D PO BID starting day 9, E and D PK analysis day 15. Toxicity evaluation occurred every 7 days for weeks 1–4 (cycle 1) and response evaluation occurred on day 50 ±7. Dose limiting toxicities were recorded during cycle 1. Cohort 1: E 100 D50; Cohort 2: E150 D50; Cohort 3: E150 D70. Results: To date 9 patients (2 M, 7 F) have been enrolled (3, 3, 3) across cohorts 1–3. The average duration of treatment is 62 days. The main adverse events include skin rash (6 grade 1/2, 0 grade 3/4), diarrhea (3 grade 1/2, 0 grade 3/4), and pleural effusions (6 grade 1/2, 0 grade 3/4). Of 8 patients eligible for efficacy, there were no CR/PR, 5 SD, and 3 PD. The administration of escalating doses of D appears to have no affect on the pharmacokinetics of E. Conclusions: The combination of E 150 mg PO qD and D 70 mg PO BID appears to be tolerable with side effects consistent with the two agents (rash and pleural effusions). Additional patients are being examined on this schedule for tolerability and a second cohort of E 150 mg PO qD and D 140 mg PO qD will be explored in an attempt to minimize pleural effusions. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Genentech™ BioOncology Genentech™ BioOncology Bristol-Myers Squibb
Pegfilgrastim can be effectively administered the same day as chemotherapy to prevent neutropenia-related complications
Authors: N. K. Gupta, S. Thorpe, P. Vanderhoff, S. Gomez, M. Stiltner, D. Alvares, D. Lee, T. Chandler, S. Connelly, A. Clark, R. Bohnen
Journal: Journal of Clinical Oncology (2007)

19571 Background: Pegfilgrastim has been proven to reduce neutropenia-related complications of chemotherapy. However, the administration of pegfilgrastim 24 hours after chemotherapy treatment often poses an inconvenience for the patients and care givers. Methods: A retrospective chart review of the patients who received pegfilgrastim the same day as chemotherapy was done at a rural oncology practice, where some patients travel more than 100 miles each way for treatment. Incidence of febrile neutropenia (FN), defined as ANC = 500 and temperature =101° F; hospitalization for FN; dose-delay; dose-reduction (= 15% reduction in the planned dose); ANC recovery (ANC=1,500 on the day of next treatment), Grade III/IV neutropenia one week after chemotherapy and empiric use of prophylactic antibiotics was recorded. Results: Between 11/05 and 11/06, 243 doses of pegfilgrastim were given the same day as chemotherapy to 48 patients. M/F=14/34; Age(median): 61.2 yrs (range: 27–88 yrs).The diagnoses were NSCLC=13 (Stage II, III, IV: 2, 2 and 9, respectively); Breast Ca=11 (stage II, III, IV: 4, 6 and 1, respectively); Diffuse large B-cell lymphoma (DLBCL)= 6 (stage III, IV: 4, 2); Follicular lymphoma=3 (stage IV: 3); SCLC=3 (stage IV: 3); Ovarian Ca=2 (stage III, IV: 1, 1); and others=10. Twenty five different chemotherapy regimens were administered (Q3 wk. regimens: 19, Q2 wk. regimens: 4 and others=2). No patient had FN or hospitalization for FN. ANC recovery was sub- optimal twice (ANC of 880 and 1,010 on the day of next treatment). Dose was delayed only once due to neutropenia (ANC=880), patient with ANC of 1,010 received treatment as scheduled. Three patients needed dose-reduction of more than 15% (all had DLBCL). Grade III/IV neutropenia after one week of treatment (CBC was available after 235 treatments) was observed in 52 (0.2%) patients, 23 patients had had AC and 25 patients had had CHOP. Empiric prophylactic antibiotics were not given to any patient. Conclusions: Pegfilgrastim can be effectively given the same day as chemotherapy to ameliorate neutropenia-related complications. Same-day administration of pegfilgrastim could improve the quality of life of patients and may reduce the health care costs. Large prospective trials should be done to address this issue. No significant financial relationships to disclose.
In oesophageal squamous cells, nitric oxide causes S-nitrosylation of Akt and blocks SOX2 (sex determining region Y-box 2) expression
Authors: Kiyotaka Asanuma, Xiaofang Huo, Agoston Agoston, Xi Zhang, Chunhua Yu, Edaire Cheng, Qiuyang Zhang, Kerry B Dunbar, Thai H Pham, David H Wang, Katsunori Iijima, Tooru Shimosegawa, Robert D Odze, Stuart J Spechler, Rhonda F Souza
Journal: Gut (2015)

<h3>Objective</h3> Barrett9s metaplasia might develop if GORD causes oesophageal squamous cells to convert into columnar cells. Acid and bile exposures upregulate columnar differentiation genes like CDX2 in oesophageal squamous cells, but it is not known if such exposures downregulate squamous differentiation genes like SOX2. In addition to acid and bile, patients with GORD also have high oesophageal concentrations of nitric oxide (NO). This study aims to determine how acid, bile salts and NO affect genes that influence oesophageal cell phenotype. <h3>Design</h3> Oesophageal squamous cells from patients with Barrett9s oesophagus were exposed to acidic bile salts or NOC-9 (an NO donor). SOX2, p63 (squamous transcription factor) and CDX2 mRNAs were measured by quantitative RT-PCR. SOX2 and its regulatory Akt pathway proteins were evaluated by western blotting. S-nitrosylation by NO was blocked by dithiothreitol. Immunohistochemistry for SOX2 was performed on the oesophagus of rats with surgically induced GORD which were fed diets with and without nitrite supplementation. <h3>Results</h3> In oesophageal squamous cells, NO profoundly decreased SOX2 protein and caused a significantly greater decrease in SOX2 mRNA than did acidic bile salts. NO also decreased p63 and increased CDX2 expression. NO caused S-nitrosylation of Akt, blocking its phosphorylation. Akt pathway inhibition by LY294002 or Akt siRNA reduced SOX2 mRNA. Rats fed with nitrite-supplemented diets exhibited weaker SOX2 oesophageal staining than rats fed with normal diets. <h3>Conclusions</h3> In oesophageal squamous cells, NO blocks SOX2 expression through Akt S-nitrosylation. NO also increases CDX2 and decreases p63 expression. By triggering molecular events preventing squamous differentiation while promoting intestinal differentiation, NO might contribute to Barrett9s pathogenesis.
Induction chemotherapy followed by concomitant chemoradiotherapy for advanced head and neck cancer: impact on the natural history of the disease.
Authors: E E Vokes, M Kies, D J Haraf, R Mick, W J Moran, M Kozloff, B Mittal, H Pelzer, B Wenig, W Panje
Journal: Journal of Clinical Oncology (1995)

PURPOSE To determine survival rates and the pattern of failure in head and neck cancer patients treated with induction chemotherapy, limited surgery and concomitant chemoradiotherapy. PATIENTS AND METHODS Three cycles of induction chemotherapy with cisplatin, fluorouracil (5-FU), leucovorin, and interferon alfa-2b (PFL-IFN) were followed by optional surgery, and seven or eight cycles of 5-FU, hydroxyurea, and concurrent radiation for 5 days (FHX) for a total radiation dose of 65 to 75 Gy. Surgical resection was performed with the intent to spare organ function. RESULTS Seventy-one patients were treated at three institutions. Sixty-five patients (91%) had stage IV disease with N2/3 in 46. Thirty-three patients (51%; 95% confidence interval, 39% to 63%) achieved a clinical complete response (CR) to PFL-IFN. Local therapy consisted of surgery in 37 and/or FHX in 55 patients. With a median follow-up duration of 37 months, there have been 20 recurrences (15 local, four distant, and one both local and distant), and 29 deaths, 15 in patients with disease progression and 14 not directly related to the primary tumor. Four patients have developed second malignancies. At 3 years, 69% (+/- 6%) are progression-free and the overall survival rate is 60% (+/- 6%). Toxicity of PFL-IFN included severe or life-threatening mucositis (54%) and myelosuppression (60%). Five patients died of toxicity. During FHX, 70% of patients had grade 3 or 4 mucositis. CONCLUSION PFL-IFN is highly active, producing clinical CRs in 51% of patients, and, when followed by FHX, resulting in high local and distant control and overall survival rates. Second malignancies and intercurrent medical disease emerge as major risks to long-term survival. In view of the high toxicity and long treatment duration, further modifications of this approach are required.
Abstract P273: Leisure-Time Physical Activity and Mortality in the Northern Manhattan Study
Authors: Joshua Z Willey, Yeseon P Moon, Ayesha Sherzai, Palma Gervasi-Franklin, Ken Cheung, Ralph L Sacco, Mitchell S Elkind
Journal: Circulation (2015)

Introduction:  Leisure-time physical activity (LTPA) provides multiple health benefits, including a reduction in mortality. Fewer studies however have examined whether the health benefits of LTPA are modified by other risk factors for mortality, such as obesity.   Methods:  We collected baseline socio-demographics and cardiovascular risk factor data in a population-based, tri-ethnic prospective cohort (Northern Manhattan Study) using self-report and objective measures for vital signs and anthropometrics. The primary exposure was self-reported leisure-time physical activity and the outcomes of this analysis were total, vascular, and non-vascular deaths. Leisure-time physical activity was defined categorically as any activity versus none, and by quartiles of the Metabolic equivalents (MET)-score (weighted by total activity and intensity).We calculated the association of LTPA with the risk of mortality using multi-variable Cox-proportional hazards models, and examined interactions between leisure-time physical activity and body mass index (BMI)    Results:  A total of 3298 participants were enrolled (mean age 69, 52% Hispanic, 63% women) and followed over a mean of 11.8 years with 1589 total deaths (641 vascular, 819 non-vascular). In multi-variable models, compared to no LTPA, any activity (adjusted HR 0.84, 95%CI 0.75-0.94) and the upper quartile of the MET-score (adjusted HR 0.79, 95%CI 0.69-0.91) were associated with lower risk of all-cause mortality. There were similarly significant findings for non-vascular deaths, but the results for vascular death did not reach statistical significance (any activity versus none HR 0.90, 95%CI 0.76-1.08; upper quartile of the MET-score HR 0.89, 95%CI 0.71-1.10). We found that the effects of LTPA for risk of all-cause and vascular mortality were modified by obesity (all p for interactions   Discussion: We found that the survival benefit of LTPA depends on BMI, with no definite evidence of a benefit among the obese. The health benefits of exercise should be considered in the context of the ameliorating other cardiovascular disease risk factors.
Jules Stein, MD
Authors: Bradley R. Straatsma, David F. Weeks
Journal: Ophthalmology (2016)

PurposeTo report the lifetime activities and accomplishments of Jules Stein, MD.DesignRetrospective review.MethodsAssessment of published and unpublished biographical material.ResultsJules Stein combined his love of music and medicine with organizational skills to achieve successive careers as a musician, an ophthalmologist, an entertainment magnate, and an advocate for vision. To preserve vision, he founded Research to Prevent Blindness, founded the Jules Stein Eye Institute at the University of California, Los Angeles, and led a multiyear campaign to establish the National Eye Institute.ConclusionsWith successive careers and extraordinary achievements, Jules Stein created an enduring legacy of benefits to ophthalmology, vision research, and the prevention of blindness. To report the lifetime activities and accomplishments of Jules Stein, MD. Retrospective review. Assessment of published and unpublished biographical material. Jules Stein combined his love of music and medicine with organizational skills to achieve successive careers as a musician, an ophthalmologist, an entertainment magnate, and an advocate for vision. To preserve vision, he founded Research to Prevent Blindness, founded the Jules Stein Eye Institute at the University of California, Los Angeles, and led a multiyear campaign to establish the National Eye Institute. With successive careers and extraordinary achievements, Jules Stein created an enduring legacy of benefits to ophthalmology, vision research, and the prevention of blindness.
Haplo-insufficiency of both BubR1 and SGO1 accelerates cellular senescence
Authors: Sung-Hyun Park, Steve Xie, Chinthalapally V. Rao, Wei Dai
Journal: Journal of Hematology & Oncology (2016)

Spindle assembly checkpoint components BubR1 and Sgo1 play a key role in the maintenance of chromosomal instability during cell division. These proteins function to block the anaphase entry until all condensed chromosomes have been attached by the microtubules emanating from both spindle poles. Haplo-insufficiency of either BubR1 or SGO1 results in enhanced chromosomal instability and tumor development in the intestine. Recent studies show that spindle checkpoint proteins also have a role in slowing down the ageing process. Therefore, we want to study whether haplo-insufficiency of both BubR1 and SGO1 accelerates cellular senescence in mice. We took advantage of the availability of BubR1 and SGO1 knockout mice and generated primary murine embryonic fibroblasts (MEFs) with mutations in either BubR1, SGO1, or both and analyzed cellular senescence of the MEFs of various genetic backgrounds. We observed that BubR1 +/− SGO +/− MEFs had an accelerated cellular senescence characterized by morphological changes and expressed senescence-associated β-galactosidase. In addition, compared with wild-type MEFs or MEFs with a single gene deficiency, BubR1 +/− SGO1 +/− MEFs expressed enhanced levels of p21 but not p16. Taken together, our observations suggest that combined deficiency of BubR1 and Sgo1 accelerates cellular senescence.