tbuckley/cabot-search huggingface dataset:
S19 Molecular fingerprinting and metagenomic analysis reveals a polymicrobial element in patients with chronic obstructive pulmonary disease
Authors: P. J. Purcell, A. Nelson, A. Fisher, J. D. Perry, A. De-Soyza, S. P. Cummings
Journal: Thorax (2011)

<h3>Introduction and objectives</h3> Chronic obstructive pulmonary disease (COPD) patients commonly exhibit a multi-factorial pathology with neutrophilic inflammation and chronic obstructive bronchiolitis. COPD patients suffer episodes of pulmonary exacerbations. The role of bacteria in exacerbations has been investigated in COPD using culture-dependent techniques. Unlike cystic fibrosis (CF), there are few molecular studies describing the possibility of a microbial community in the COPD lung contributing to the pathogenesis of COPD. <h3>Methods</h3> Nine clinically stable COPD patients attending the Freeman Hospital had a bronchoalveolar lavage fluid (BALF) taken. DNA extraction from these samples was performed using an Ultraclean<sup>®</sup> Microbial DNA Isolation Kit. DNA obtained from these samples was then used as template for conventional PCR. Both primer sets used targeted the universal bacterial and fungal V3 variable regions of the 16S rRNA gene and 28S rRNA gene respectively with attachment of a GC-clamp. Amplicons were then run out for analysis by denaturing gradient gel electrophoresis (DGGE) performed on a DCode System (BIO-RAD). Microbial DNA extracted from all nine BAL samples was then sent for 454 pyrosequencing to perform metagenomic analysis. <h3>Results</h3> Molecular fingerprinting of BAL analysis by DGGE produced a distinct number of bands in each sample strongly indicating the presence of a diverse microbial community in the COPD infected lung. This was also seen in culture negative patients. Migration of bands present at the top of the denaturing gradient suggests that the lungs of COPD patients are heavily colonised with bacteria that have a low GC content such as <i>Haemophilus influenzae</i>, <i>Streptoccocus pneumoniae</i>, and <i>Moraxella catarrhalis</i>. Metagenomic analysis of the nine BAL samples by 454 pyrosequencing supports this hypothesis by detecting numerous other bacterial taxa present. <h3>Conclusions</h3> This preliminary study shows that the lungs of COPD sufferers are colonised with multiple species of bacteria and demonstrates that a complex microbial community is present. Metagenomic analysis performed demonstrates the key bacterial taxa which may be responsible for inducing the damaging inflammatory response and the differences in bacterial diversity shown in the nine patients studied. Thus a complex microbiota may elicit ongoing inflammation leading to lung function loss and destruction of the lung architecture.
Actively Engaging Patients in Treatment Decision Making and Monitoring as a Strategy to Improve Hypertension Outcomes in Diabetes Mellitus
Authors: Michele Heisler
Journal: Circulation (2008)

G ood blood pressure (BP) control is a central outcome of high-quality diabetes care. 1 In the landmark UK Prospective Diabetes Study (UKPDS), intensive BP control led to an absolute risk reduction of 11.2% in diabetes end points over 10 years, an effect 3.5 times greater than intensive blood glucose control. 2 Moreover, although intensive glycemic or cholesterol control has an incremental cost-effectiveness of $40 000 to $50 000 per quality-adjusted life-year, intensive BP control actually saves almost $2000 per quality-adjusted life-year. 3For these reasons, the American Diabetes Association and the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High BP (JNC 7) recommend a BP goal of Ͻ130/80 mm Hg in persons with diabetes mellitus. 4Yet, from 47% to 70% of patients with diabetes do not achieve that goal. 5,
Cellular detection of sst2A receptors in human gastrointestinal tissue
Authors: M Gugger
Journal: Gut (2004)

<b>Background and aim:</b> Many neuroendocrine gastrointestinal tumours express receptors for the regulatory peptide somatostatin. Among the five existing somatostatin receptor (sst) subtypes, sst2A is the most frequently expressed in these tumours. However, little information is available about the cellular location of sst2A in corresponding non-neoplastic epithelial tissues. <b>Methods:</b> We searched for sst2A immunoreactive cells in non-neoplastic gastrointestinal tissues, and evaluated their number and immunohistochemical characteristics with neuroendocrine markers. <b>Results:</b> The gastric antrum showed numerous sst2A cells, situated in the epithelium, corresponding to gastrin containing neuroendocrine cells, while the gastric corpus was largely devoid of sst2A cells, including enterochromaffin-like cells. The remaining foregut, namely the duodenum and proximal jejunum, also contained a large number of sst2A cells, all being neuroendocrine cells and many of them characterised as gastrin cells. Sst2A cells were also detected in the midgut, in low numbers in the epithelium of the distal jejunum and ileum, but not in the appendix vermiformis, the caecum, or the hindgut, despite the large number of neuroendocrine cells present in this area. In addition, sst2A cells were found in the whole gastrointestinal tract in the myenteric and submucosal plexus. <b>Conclusions:</b> While sst2A receptors on antral gastrin cells presumably mediate somatostatin inhibition of gastrin secretion, the effects of somatostatin on motility and ion transport in the lower gastrointestinal tract may be mediated by sst2A receptors in the neural plexus. These data provide a molecular basis for the physiological actions of somatostatin in human gastrointestinal tissue.
Mesoporous Calcium Carbonate as a Phase Stabilizer of Amorphous Celecoxib – An Approach to Increase the Bioavailability of Poorly Soluble Pharmaceutical Substances
Authors: Johan Forsgren, Mattias Andersson, Peter Nilsson, Albert Mihranyan
Journal: Advanced Healthcare Materials (2013)

Abstract The bioavailability of crystalline pharmaceutical substances is often limited by their poor aqueous solubility but it can be improved by formulating the active substance in the amorphous state that is featured with a higher apparent solubility. Although the possibility of stabilizing amorphous drugs inside nano‐sized pores of carbon nanotubes and ordered mesoporous silica has been shown, no conventional pharmaceutical excipients have so far been shown to possess this property. This study demonstrates the potential of using CaCO 3 , a widely used excipient in oral drug formulations, to stabilize the amorphous state of active pharmaceutical ingredients, in particular celecoxib. After incorporation of celecoxib in the vaterite particles, a five to sixfold enhancement in apparent solubility of celecoxib is achieved due to pore‐induced amorphization. To eliminate the possibility of uncontrolled phase transitions, the vaterite particles are stored in an inert atmosphere at 5 °C throughout the study. Also, to demonstrate that the amorphization effect is indeed associated with vaterite mesopores, accelerated stress conditions of 100% relative humidity are employed to impose transition from mesoporous vaterite to an essentially non‐porous aragonite phase of CaCO 3 , which shows only limited amorphization ability. Further, an improvement in solubility is also confirmed for ketoconazole when formulated with the mesoporous vaterite. Synthesis of the carrier particles and the incorporation of the active substances are carried out simultaneously in a one‐step procedure, enabling easy fabrication. These results represent a promising approach to achieve enhanced bioavailability in new formulations of Type II BCS drugs.
Endocrine Studies in Anencephaly
Authors: Alberto Hayek, Shirley G. Driscoll, Joseph B. Warshaw
Journal: Journal of Clinical Investigation (1973)

Endocrine function has been investigated in four anencephalic neonates to determine the influence of absence of cortical and hypothalamic tissue and of hypoplasia of the pituitary. Intravenous glucose administration resulted in higher peak values for blood sugar and more rapid glucose disposal rates than reported in normals. Intravenous insulin tolerance tests on two of the infants failed to evoke elevations in plasma growth hormone, and the infants showed a remarkable resistance to the hypoglycemic effect of insulin. Administration of lysine-vasopressin caused an active growth hormone release. Similarly, there was a large increase in serum thyrotropin after administration of synthetic thyrotropin-releasing hormone. Basal levels of both thyrotropin and growth hormone were low as compared with values reported for normal newborns. Prolactin values obtained on three of the infants were in the normal range. The results strongly suggest that anterior pituitary function mediated by the hypothalamus and its releasing factors is deficient in anencephaly. However, the anterior pituitary can release growth hormone and thyrotropin when stimulated directly and, in the case of thyrotropin release, may function autonomously. The normal prolactin values presumably reflect the absence of the hypothalamic prolactin inhibitory factor.
Thermogenesis and Thyroid Function
Authors: Hedley C. Freake, Jack H. Oppenheimer
Journal: Annual Review of Nutrition (1995)

The past 10 years have seen tremendous progress in the definition of the nuclear mechanism of action of thyroid hormones. Although the way in which these nuclear mechanisms underlie the 3,5,3'-triiodo-L-thyronine (T3)-dependent stimulation of metabolic rate remains to be clarified, evidence favoring non-nuclear pathways is limited. Clearly, T3 stimulates both the production and consumption of energy within cells. It also exerts a number of parallel effects that result in increased oxygen consumption, e.g. on mitochondrial structure and composition; on the metabolism of lipids, carbohydrates, and proteins, and on cardiac function. Additionally, T3 may increase the proton permeability of the inner mitochondrial membrane, which implies that it may decrease the efficiency of energy production. These metabolic effects of T3 appear to be restricted to homeothermic-animals, representing a coordinated response to the challenge of maintaining body temperature.
Short term salbutamol ingestion and supramaximal exercise in healthy women
Authors: B Le Panse, A Arlettaz, H Portier, A-M Lecoq, J De Ceaurriz, K Collomp
Journal: British Journal of Sports Medicine (2006)

Objective: To test the hypothesis that chronic salbutamol intake improves performance during supramaximal exercise and to estimate the effects of this treatment on body composition, bone mass, and metabolic indices in healthy women. Methods: Fourteen female volunteers (seven sedentary and seven recreationally trained) performed a 30 second Wingate test with and without salbutamol ingestion (12 mg/day for four weeks) in a random, double blind, crossover design. Blood samples were collected at rest, at the end of the test, and during passive recovery for lactate measurement. Body composition and bone mass were determined by dual energy x ray absorptiometry. Results: Peak power appeared significantly earlier and was significantly (p&lt;0.05) increased after salbutamol intake in all subjects. There was no difference in total work performed and fatigue indices with salbutamol compared with placebo. No significant alterations in lean or fat body mass and bone variables were observed with salbutamol treatment in either trained or untrained subjects during the trial. In contrast, blood lactate was significantly (p&lt;0.05) increased during the recovery period after salbutamol ingestion compared with placebo. Conclusion: As in men, chronic administration of therapeutic concentrations of salbutamol did not induce an anabolic effect in women but increased maximal anaerobic power. Further studies are necessary to clarify the mechanisms involved.
A functional comparison of the cortical collecting tubule and the distal convoluted tubule.
Authors: J B Gross, M Imai, J P Kokko
Journal: Journal of Clinical Investigation (1975)

Electrical and permeability features of the distal convoluted tubule (DCT) and the cortical collecting tubule (CCT) were examined using the technique in which isolated segments of rabbit tubules were perfused in vitro. When rabbits were given a regular diet and tubules were perfused and bathed in artificial solutions simulating plasma ultrafiltrate, the potential difference (PD) was +3.7 plus or minus 1.9 mV in the CCT and -40.4 plus or minus 2.8 mV in the DCT. When rabbits were given a low sodium, high potassium diet plus i.m. deoxycorticosterone acetate (DOCA) (1 mg/kg per day), the PD in both the CCT (-30.8 plus or minus 3.9 mV) and the DCT (-33.8 plus or minus 5.5 mV) was negative. The PD in the CCT was quantitatively similar to that of diet plus DOCA when animals were given DOCA alone. The PD in both segments was inhibited by ouabain (10-minus 5 M) in the bath or by amiloride (10-minus 5 M) in the perfusate. Addition of vasopressin (200 muU/ml) to the bath caused a gradual decline of PD to zero in the CCT but failed to produce a potential response in the DCT. Osmotic water permeability was essentially zero in both segments in the absence of vasopressin. After addition of the vasopressin to the bath, osmotic water permeability in the DCT remained zero but increased to 71.9 plus or minus 25.5 X 10-minus 7 cm/s per atm in the CCT. We conclude that both segments are similar in that each possesses an electrogenic transport process but that these segments differ in that: (a) the CCT requires either exogenous or endogenous mineralocorticoid to maintain a maximal negative PD, whereas the PD in the DCT appears to be independent of mineralocorticoid effect; and (b) the CCT responds to vasopressin with a marked rise in water permeability, whereas the DCT is impermeable to water before and after addition of vasopressin.
P161 Combined 18F-FDG PET/CT as part of a surveillance programme of patients with newly diagnosed pre-invasive endobronchial lesions detects synchronous lung cancers
Authors: L. J. E. Smith, I. Kayani, J. Bomanji, A. M. Groves, B. Carroll, N. Navani, J. P. George, S. M. Janes
Journal: Thorax (2011)

<h3>Background</h3> Patients with bronchial pre-invasive lesions represent a significant management challenge due to the risk of lung cancer both at the site of known dysplasia and at remote sites within their lungs. The role of combined positron emission tomography/CT (PET/CT) in those patients is unknown. <h3>Aims</h3> To evaluate the diagnostic and clinical utility of 18F-FDG PET/CT in a surveillance programme for patients with pre-invasive endobronchial lesions. This was defined as the ability of abnormal 18F-FDG uptake to detect invasive bronchial carcinomas adjacent to known pre-invasive lesions or at remote sites in the lung. The prognostic value of 18F-FDG uptake at dysplasia sites was also assessed with surveillance. Can 18F-FDG uptake predict progression of pre-invasive lesions or cancer elsewhere? <h3>Methods</h3> 39 patients with pre-invasive endobronchial lesions underwent 18F-FDG PET/CT examination prior to autofluorescence bronchoscopy. Pre-invasive lesions were classified as either high-grade (carcinoma in situ or severe dysplasia) or low grade (mild to moderate dysplasia). The degree of uptake of 18F-FDG was analysed without knowledge of the bronchoscopic or other clinical findings. <h3>Results</h3> 8/39 patients (all with high grade dysplasia) had increased 18F-FDG uptake at known dysplasia sites. Of these 8 patients 1 had surgical resection of invasive carcinoma and two patients were diagnosed and treated as invasive cancer based on imaging and follow-up. Eight patients had 18F-FDG uptake at sites remote from known dysplasia; 2/8 patients had synchronous invasive lung carcinoma (pT1N0M0), 2/8 recurrent cancer in hilar and mediastinal nodes, and 4/8 patients had inflammatory uptake in lung, mediastinal or hilar nodes. During surveillance of up to 3 years, 3/5 patients with positive 18F-FDG uptake developed biopsy proven invasive cancer at site of dysplasia. 3/31 patients with negative 18F-FDG uptake developed invasive cancer at high grade dysplasia sites during surveillance. No low grade lesion showed 18F-FDG uptake or progressed to invasive cancer during surveillance. <h3>Conclusions</h3> PET/CT was able to detect early synchronous cancers in patients with pre-invasive endobronchial lesions. PET/CT was also able to detect 18F-FDG uptake in a proportion of patients at known dysplasia sites suggesting adjacent or underlying occult invasive carcinoma.
Imatinib after induction for treatment of children and adolescents with Philadelphia-chromosome-positive acute lymphoblastic leukaemia (EsPhALL): a randomised, open-label, intergroup study
Authors: Andrea Biondi, Martin Schrappe, Paola De Lorenzo, Anders Castor, Giovanna Lucchini, Virginie Gandemer, Rob Pieters, Jan Stary, Gabriele Escherich, Myriam Campbell, Chi-Kong Li, Ajay Vora, Maurizio Aricò, Silja Röttgers, Vaskar Saha, Maria Grazia Valsecchi
Journal: The Lancet Oncology (2012)

Trials of imatinib have provided evidence of activity in adults with Philadelphia-chromosome-positive acute lymphoblastic leukaemia (ALL), but the drug's role when given with multidrug chemotherapy to children is unknown. This study assesses the safety and efficacy of oral imatinib in association with a Berlin-Frankfurt-Munster intensive chemotherapy regimen and allogeneic stem-cell transplantation for paediatric patients with Philadelphia-chromosome-positive ALL.
Phase I Dose-Escalation Study of the Multikinase Inhibitor Lenvatinib in Patients with Advanced Solid Tumors and in an Expanded Cohort of Patients with Melanoma
Authors: David S. Hong, Razelle Kurzrock, Jennifer J. Wheler, Aung Naing, Gerald S. Falchook, Siqing Fu, Kevin B. Kim, Michael A. Davies, Ly M. Nguyen, Goldy C. George, Lucy Xu, Robert Shumaker, Min Ren, Jennifer Mink, Cynthia Bedell, Corina Andresen, Pallavi Sachdev, James P. O'Brien, John Nemunaitis
Journal: Clinical Cancer Research (2015)

This "3+3" phase I study evaluated the safety, biologic, and clinical activity of lenvatinib, an oral multikinase inhibitor, in patients with solid tumors.Ascending doses of lenvatinib were administered per os twice daily in 28-day cycles. Safety and response were assessed for all patients. Angiogenic and apoptotic factors were tested as possible biomarkers in an expanded melanoma cohort.Seventy-seven patients were treated in 3 cohorts: 18 with intermittent twice-daily dosing (7 days on, 7 days off) of 0.1-3.2 mg; 33 with twice-daily dosing of 3.2-12 mg; and 26 with twice-daily dosing of 10 mg (expanded melanoma cohort). Maximum tolerated dose was established at 10 mg per os twice daily. Prominent drug-related toxicities included hypertension (43%), fatigue (42%), proteinuria (39%), and nausea (25%); dose-limiting toxicities included hypertension, fatigue, and proteinuria. Twelve patients (15.6%) achieved partial response (PR, n = 9) or unconfirmed PR (uPR, n = 3), and 19 (24.7%) achieved stable disease (SD) ≥23 weeks. Total PR/uPR/SD ≥23 weeks was 40.3% (n = 31). Responses (PR/uPR) by disease were as follows: melanoma, 5 of 29 patients (includes 1 patient with NRAS mutation); thyroid, 3 of 6 patients; pancreatic, 1 of 2 patients; lung, 1 of 1 patients; renal, 1 of 1 patients; endometrial, 1 of 4 patients; and ovarian, 1 of 5 patients. AUC(0-24) and C(max) increased dose proportionally. In multivariate Cox proportional hazard model analyses, increased baseline systolic blood pressure and decreased angiopoietin-1 ratio (2 hours:baseline) were associated with longer progression-free survival (PFS) in the expanded melanoma cohort (P = 0.041 and P = 0.03, respectively).The toxicity profile, pharmacokinetics, and antitumor activity of lenvatinib are encouraging. Decreases in the angiopoietin-1 ratio correlated with longer PFS in melanoma patients.
Response to Neoadjuvant Systemic Therapy for Breast Cancer in <i>BRCA</i> Mutation Carriers and Noncarriers: A Single-Institution Experience
Authors: Banu Arun, Soley Bayraktar, Diane D. Liu, Angelica M. Gutierrez Barrera, Deann Atchley, Lajos Pusztai, Jennifer Keating Litton, Vicente Valero, Funda Meric-Bernstam, Gabriel N. Hortobagyi, Constance Albarracin
Journal: Journal of Clinical Oncology (2011)

To compare the pathologic complete response (pCR) rate and relapse-free survival (RFS) and overall survival (OS) after neoadjuvant systemic chemotherapy (NST) in patients with breast cancer with and without deleterious BRCA1 and BRCA2 mutations.A total of 317 women who underwent BRCA genetic testing and were treated with NST for breast cancer between 1997 and 2009 were included in the study. The Kaplan-Meier product-limit method was used to estimate RFS and OS rates. Logistic regression models were fit to determine the associations between BRCA status, pCR, and survival.Fifty-seven (18%) and 23 (7%) patients had BRCA1 and BRCA2 mutations, respectively. Twenty-six (46%) of 57 BRCA1 carriers achieved a pCR, compared with three (13%) of 23 BRCA2 carriers and 53 (22%) of 237 BRCA noncarriers (P < .001). In the multivariate logistic model, BRCA1 status (odds ratio [OR] = 3.16; 95% CI, 1.55 to 6.42; P = .002), estrogen receptor (ER) negativity (OR = 1.96; 95% CI:1.05 to 3.65; P = .03) and concurrent trastuzumab use (OR = 4.18; 95% CI, 2.04 to 8.57; P < .001) remained as independent significant predictors for a pCR. At a median follow-up of 3.2 years, 69 patients (22%) experienced a disease recurrence or death. No significant differences were noted in survival outcomes with respect to BRCA status and type of NST received. However, among BRCA1 carriers, patients who achieved a pCR had better 5-year RFS (P = .001) and OS (P = .01) rates than patients who did not.BRCA1 status and ER negativity are independently associated with higher pCR rates in patients with breast cancer. Overall prognosis of breast cancer in BRCA carriers is similar to sporadic breast cancers.
Explaining, Predicting, and Treating HIV-Associated CD4 Cell Loss
Authors: W. Keith Henry, Pablo Tebas, H. Clifford Lane
Journal: JAMA (2006)

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