tbuckley/cabot-search huggingface dataset:
Biweekly gemcitabine and oxaliplatin (GEMOX) in first-line metastatic or recurrent nasopharyngeal carcinoma (NPC)—An early report
Authors: A. T. Chan, B. Ma, S. Tung, E. P. Hui, K. K. Yuen, A. King, S. F. Leung, I. Chan, M. Chan, B. Zee
Journal: Journal of Clinical Oncology (2007)

6071 Background: This multicenter phase II study evaluated the activity &amp; safety of oxaliplatin (Ox), a 3 rd generation platinum, in combination with gemcitabine (GEM) for the first time in the palliative setting for patients (pts) with undifferentiated/ poorly differentiated NPC. Methods: Pts with untreated metastatic (M1) or locoregionally recurrent (LR) NPC were treated with a biweekly ‘GEMOX’ regimen (D1: GEM, 1,000 mg/m 2 at 10 mg/m 2 /min; D2: Ox, 100 mg/m 2 over 2 hrs) for a max. of 12 cycles. Intrapatient dose escalation of GEM to 1,250 mg/m 2 was allowed from cycle 2 onwards if no significant toxicity occurred in cycle 1. Response was assessed every 4 cycles (RECIST criteria). Results: 23 pts accrued before 31 st July 06 were evaluated for toxicity &amp; response; cut-off date for data analysis was 15 th Oct 06. The median age was 53 yrs (range 38–72); 19 were men, all had ECOG status of 0–1. At enrolment, 7 pts (29%) had M1 disease only, 3 (12%) pts had LR only, &amp; the rest both M1 &amp; LR. All 7 pts with only LR received radical radiotherapy (RT) at initial diagnosis. A median of 11 cycles (range 3–13) were administered. Best overall response rate was 52%, with 12 partial responses &amp; 11 stable diseases. The median duration of response was 7 months (range 0.8–15). Grade (gr) 3–4 hematological toxicities (CTCAE ver 3) included neutropenia in 7 pts (30%, only 1 pt had fever), thrombocytopenia in 5 pts (26%, 1 gr 4 case with mild gum bleeding). Gr 3–4 non-hematological toxicities included gr 3 diarrhoea in 2 pts, gr 4 Ox-related hypersensitivity reaction in 1 pt, gr 3 epistaxis in 2 pts. The commonest non-hematological toxicities were gr 1–2 Ox-related sensory neuropathy (22pts). There were no treatment-related deaths &amp; only 1 pt withdrew from study due to drug-related toxicity. Conclusions: GEMOX is a promising regimen among pts with metastatic &amp; recurrent NPC. Accrual is ongoing with a planned total sample of 40 pts. No significant financial relationships to disclose.
Countries must prepare for more frequent food shortages, says task force
Authors: Matthew Limb
Journal: BMJ (2015)

Extreme weather linked to global warming will trigger more frequent food production “shocks” this century, worsening poverty and nutrition security, experts predict.

Substantial falls in crop yields and spikes in food prices would occur far more often and be widely destabilising in an increasingly interconnected world, they said.

People in sub-Saharan Africa, where most food is imported, would be among those hit the hardest, and other countries in the Middle East and north Africa that depended heavily on imports could see more social unrest, concluded a new report from the Taskforce on Extreme Weather and Global Food System Resilience.1 

The United Kingdom, United States, and Europe would be less directly affected but would be vulnerable to “indirect” risks, …
Mechanism of action of a novel series of inhibitors of the Hsp90 molecular chaperone
Authors: Swee Sharp, Alison Maloney, Paul A. Clarke, Wynne Aherne, Suzanne Eccles, Kathy Boxall, Martin Rowlands, Florence Raynaud, Bernard Nutley, Nicola Smith, Angela Hayes, Anthea Hardcastle, Laurence Pearl, Christomos Prodromou, Karen E. Ball, Jack Cheung, Thomas P. Matthews, Edward MacDonald, Martin Drysdale, Paul Workman
Journal: Cancer Research (2004)

3994   Inhibition of the molecular chaperone Hsp90 is a highly attractive anticancer strategy because of its potential to provide combinatorial blockade of multiple oncogenic pathways and simultaneous antagonism of all of the malignant hallmarks of cancer. Although the geldanamycin analogue 17AAG shows promise in early clinical trials, the natural product inhibitors have liabilities that would best be overcome by identifying synthetic small molecule agents. We previously described the discovery by high throughput screening of an early lead compound designated CCT018159 (Aherne et al Proc. AACR 44 Abstract #4002). We now report the biological properties of a series of closely related analogues of this diarylpyrazole lead structure. Improved activity and potency has been observed against the yeast and human recombinant Hsp90 ATPase activity using a malachite green colorimetric assay for inorganic phosphate. Anticancer activity in cell culture has been demonstrated in a range of tumour types, including HCT116 colon carcinoma as well as various melanoma cell lines. The molecular signature of Hsp90 inhibition, defined in details by proteomic and gene expression microarray analysis, has been confirmed using western blotting and ELISA for elevation of Hsp70 and Aha1 and depletion of C-Raf-1, ErbB2 and phospho-ERK1/2, together with other client proteins and co-chaperones. Cell-line dependent G1 and G2M arrest has been demonstrated by dual-stain Hoechst-propidium iodide flow cytometry and apoptosis has been confirmed by sub-G1 peak, morphology, PARP and caspage cleavage. Activity is retained in a P-glycoprotein positive cell line made resistant to doxorubicin and also in cells made resistant to platinum agents. Pharmacokinetic properties are promising, with glucuromide conjugation of the resorcinol ring being a major clearance mechanism. In summary, this series of compounds shows significant promise for development as Hsp90 inhibitors with potential for broad spectrum anticancer activity.  Supported by Cancer Research UK, the Wellcome Trust and Vernalis .
Pulmonary lymphoid neogenesis in idiopathic pulmonary arterial hypertension
Authors: Frederic Perros, Peter Dorfmuller, David Montani, Hamida Hammad, Wim Waelput, Barbara Girerd, Nicolas Raymond, Olaf Mercier, Sacha Mussot, Sylvia Cohen-Kaminsky, Marc Humbert, Bart N. Lambrecht
Journal: European Respiratory Journal (2012)

Background: Idiopathic pulmonary arterial hypertension (IPAH) patients present circulating autoantibodies against vascular wall components. Pathogenic antibodies may be generated in tertiary (i.e. ectopic) lymphoid tissues (tLTs).  Aims and objectives: To assess how frequent are tLTs in IPAH lungs as compared to controls and flow-induced PAH (Eisenmenger syndrome -ES-) and to identify local mechanisms responsible for their formation, perpetuation and function.  Methods: tLTs composition and structure were studied by multiple immunostainings. Cytokines/chemokines and growth factor expression was quantified by real-time PCR and localized by immunofluoresence. The systemic mark of pulmonary lymphoid neogenesis was investigated by flow cytometry analyses of circulating lymphocytes.  Results: As opposed to controls and ES, IPAH lungs contained perivascular tLTs, comprising B and T cell areas with high endothelial venules and dendritic cells. Lymphocyte survival factors, such as IL-7 and PDGF-A, were expressed in tLTs as well as the lymphorganogenic cytokine/chemokines, lymphotoxin-α/-β, CCL19, CCL20, CCL21 and CXCL13, which might explain depletion of circulating CCR6+ and CXCR5+ lymphocytes. The presence of germinal center centroblasts, follicular DCs, activation-induced cytidine deaminase and IL21+PD1+ T follicular helper cells in tLTs together with CD138+ plasma cells accumulation around remodeled vessels in areas of Ig deposition argued for local immunoglobulin (Ig) class switching and ongoing Ig production.  Conclusions: We highlight the main features of lymphoid neogenesis specifically in the lungs of patients with IPAH providing new evidence of immunological mechanisms in the evolution of this fatal condition.
Proinflammatory cytokines in induced sputum and COPD phenotype
Authors: Joanna Domagala-Kulawik, Julita Stepien, Grazyna Hoser, Ryszarda Chazan
Journal: European Respiratory Journal (2011)

Chronic obstructive lung disease (COPD) does not have a uniform clinical and morphological nature. Airflow limitation is caused by inflammation and parenchymal destruction, there are patients with predominance of emphysema and those with predominance of chronic bronchitis. The aim of the study was to characterize the inflammatory process in two distinct forms of COPD.  35 COPD patients were investigated. They were divided into two groups: emphysema (E, n=25) and chronic bronchitis pts (CB, n=10); the presence of emphysema in HRCT and hyperinflation in pletysmography were the distinguishing criteria. The concentration of cytokines (IL-8, IL-1β, IL-6, IL-10, TNFα and IL-12) in induced sputum (IS) was measured using flow cytometry with Cytometric Bead Array method.  The median concentration of proinflammatory cytokines (IL-8, IL-6, IL1β and TNFα) did not differ between two groups. The concentration of IL-10 and IL-12 was slightly, but not significantly, higher in the E when compared with CB group (median: 57 vs 41 pg/mL, 1553 vs 1122 pg/mL, respectively). There was a significant correlation between the concentrations of IL-8, IL-6, IL1β and TNFα in the CB group.  When we analysed the relation of cytokine concentration with the clinical parameters, we observed a difference between the E and CB group. There was a significant correlation of IL-10, TNFα and IL-12 concentration with the degree of emphysema (RV, TLC, Raw) and FEV1 only in the E group. A significant correlation of IL-6 concentration with pack/years, TLC and with the inflammatory cell total count was observed only in the CB group.  The differences in cytokine profile and correlations indicate a possible different character of inflammation in two COPD phenotypes.
Antituberculosis chemotherapy toxicity reduction
Authors: Svetlana Naryshkina, Sergey Medvedev, Elena Pushkareva
Journal: European Respiratory Journal (2012)

Increasing number of TB patients with co-morbidities (including hepatitis) affects the tolerance to treatment and - as a consequence - the efficiency of the treatment.

Purpose: To reduce the toxicity of TB treatment.

Method: a prospective study of 92 patients with pulmonary tuberculosis with drug-sensitive MBT. Study Design: Case control. TB Patients were treated by standard chemotherapy regimens, including those in the study group (46 patients) - anti-TB medications lecithin-based ultra-emulsion.

Results: the application of anti-TB drugs in form of lecithin-based ultra-emulsion does not reduce the effectiveness of treatment in comparison with the conventional method, while significantly improves patient tolerance to chemotherapy. The analysis of tolerance demonstrated that adverse events were occurring with standard chemotherapy in 19 (41.3%), the application of the proposed method - only in 3 patients (6.5%, p <0,001, χ2). We found that of development hepatotoxic reactions is 9.4 (p = 0,008, χ2) in patients with the standard chemotherapy of pulmonary tuberculosis with chronic viral hepatitis. Hepatotoxic reactions were not registered in group with application of anti-TB medications lecithin-based ultra-emulsion.

Conclusion: The proposed method for the treatment of pulmonary tuberculosis prevents development of hepatotoxic complications. The patent of the Russian Federation has been obtained.
Antibody blocking of MHC II on human activated regulatory T cells abrogates their suppressive potential
Authors: M. Peiser, A. Becht, R. Wanner
Journal: Allergy (2007)

Natural regulatory CD4(+)CD25(+)Foxp3(+) T cells control peripheral immune responses. Freshly isolated regulatory T-cell populations are regarded as being unable to suppress the proliferation of strongly stimulated effector T cells. We now provide evidence that it is not the strength of the proliferative signal to effector T cells but activation and accessibility of regulatory T cells that determine whether suppression may occur. Human regulatory T cells were initially cocultured with allogeneic monocyte-derived dendritic cells for a short time and were then rendered accessible for effector T cells by removal of the dendritic cells. That way activated regulatory T cells effectively suppressed the proliferation of autologous effector T cells which was strongly driven by cell-sized Dynabeads coated with CD3/CD28 antibodies. Although regulatory T cells are known to display MHC II molecules and to upregulate their expression along with activation, a role of MHC II molecules in forming the contact to effector T cells was not yet envisaged. However, blocking of MHC II on activated regulatory T cells abrogated their suppressive potential. It should not be excluded that self-MHC molecules on physically accessible activated regulatory T cells arrange the contact to effector T cells.
Particulate air pollution on systemic inflammatory response: Roles of monocytes and neutrophils
Authors: Qinghua Sun, Silis Jiang, Xiaohua Xu
Journal: European Respiratory Journal (2012)

Research has increasingly demonstrated the detrimental effects of air pollution on systemic human diseases. However, there has been little examination of the pattern and scope how neutrophils and monocytes respond to the inhalatants. We exposed C57BL/6 mice to ambient fine particulate matter (PM2.5) in a timely manner to investigate the roles of neutrophils and monocytes. C57BL/6 mice were exposed to PM2.5 or filtered air 6 hours a day, 5 days a week for up to 3 weeks in Columbus, OH in a versatile aerosol concentration enrichment system. The measurements were conducted at days 5, 14, and 21 for circulating inflammatory biomarkers via magnetic beads, leukocytes rolling and adhesion in mesentery via intravital microscopy, inflammatory responses in the lung and visceral adipose tissues via flow cytometry and immunohistochemical staining (IHS), and inflammatory chemotaxic responses via Boyden chamber. We found that both rolling and adhesion leukocytes were increased in mesentery, especially at days 14 and 21. Circulating MCP-1, IL-6, and TNFα were elevated, especially at day 5. There were increases in Ly6G+ (neutrophil) and F4/80+ (monocyte) expression from lung bronchoaveolar lavage by flow cytometry and lung and visceral adipose tissues by IHS, especially F4/80 expression throughout the time course. Boyden chamber assay also indicated that lung and visceral adipose tissues were “inflamed”, especially monocytes/macrophages after PM2.5 exposure. We concluded that, in this murine model of inhalational exposure to ambient PM2.5, the murine monocytes respond rapidly to chemokines locally (in the lung) and systemically (in visceral adipose tissue), which may not be accompanied by neutrophils.
Media: Opening eyes to child abuse
Authors: H. Marcovitch
Journal: BMJ (1999)

Charities must be going through a hard time as they battle to hold their own against the all consuming UK national lottery. One answer must be to take the risk of pumping cash into a major publicity campaign to divert the fickle public purse in the desired direction. The charity most paediatricians put at the top of their Christmas list, the National Society for the Prevention of Cruelty to Children, has done just that with its FULL STOP campaign. Its aim is to raise £250m ($400m)—the biggest ever appeal by a UK charity.

The first the UK public learned of FULL STOP was a series of uncompromising TV commercials. The message was that we hide from child abuse because facing up to it is too painful. No children are seen but there is constant repetition of the image of covered eyes: the teddy bear wallpaper which we see while a mother threatens to smash her crying baby's face against the cot, shows the animal's paws across its face; as a man creepily invites an unseen child—perhaps his son—to “sit over here,” we see a poster …
Venous thromboembolic events in tuberculosis
Authors: Hans Dabó, Manuel Vaz, Nelson Teixeira, Isabel Gomes
Journal: European Respiratory Journal (2013)

Introduction: Respiratory infections are known to increase the risk of venous thromboembolic events (VTE), which are considered rare in TB patients, and linked to rifampicin treatment.  Objectives: To assess the frequency of VTE in patients hospitalized for TB, its demographic and clinical characteristics, therapy and mortality.  Methods: Adult patients hospitalized for TB in a tertiary hospital without HIV infection between 2007 and 2011 were evaluated. VTE were diagnosed by chest angioTC (pulmonary embolism - PE) or Ecodoppler (deep vein thrombosis - DVT). Prior TB treatment institution, prophylactic therapy of VTE and VTE treatment were evaluated.  Results: Of the 208 TB patients (mean age 54 years, male: 76%) 15 (7.2%) were diagnosed with VTE (mean age 56 years, male: 67%): pulmonary TB: 12 cases, disseminated TB: 2, lymph node TB: 1. Five patients had PE, 7 limb DVT, 2 cervical vessels DVT, and 1 had PE, cervical vessel DVT and right atrium thrombus. VTE occurred less than 1 month after starting antibacillary drugs, except in 1 patient (3 months). All were treated with rifampicin. Most patients (73%) didn’t receive thromboprophylaxis; 73% were treated with low molecular weight heparin. Two patients died (13%), with the remaining being discharged, most (85%) with oral anticoagulants.  Conclusions: The frequency of VTE in this study was higher than in previous studies regarding hospitalized patients with TB (up to 3.4%). The authors conclude that VTE is an important complication in this population, mainly in the initial phase of antituberculous treatment, justifying the use of thromboprophylaxis in patients with known risk factors for VTE. Rifampicin and other uncharted factors may influence prevalence of VTE in TB patients.
Carboplatin in the treatment of advanced breast cancer: a phase II study using a pharmacokinetically guided dose schedule.
Authors: M E O'Brien, D C Talbot, I E Smith
Journal: Journal of Clinical Oncology (1993)

PURPOSE We performed a phase II study of single-agent carboplatin against metastatic/locally advanced breast cancer using a pharmacokinetically guided dose schedule, to define further the potential role for this agent in combination and high-dose therapy. PATIENTS AND METHODS Forty patients with metastatic/locally advanced breast cancer were treated with carboplatin based on glomerular filtration rate (GFR) to achieve an area under the concentration-versus-time curve (AUC) of 7 mg/mL.min, with each course repeated at 4-week intervals. The median age was 57 years (range, 37 to 71). RESULTS Ten patients achieved a partial response (PR), for an overall response rate of 25% (95% confidence interval, 13% to 41%). One of 13 (8%) previously treated patients responded compared with nine of 27 (33%) patients who had not received previous chemotherapy. Median response duration was 18 weeks (range, 10 to 68). World Health Organization (WHO) grade 2 or greater toxicity was as follows: anemia, 42%; leukopenia, 20%; thrombocytopenia, 35%; nausea/vomiting, 39%; and infection, 9%. CONCLUSION This study confirms other reports indicating that carboplatin has moderate activity in previously untreated patients, but not in previously treated patients. In our view, carboplatin is a more appropriate agent than cisplatin for inclusion in high-dose chemotherapy schedules with autologous bone marrow rescue, and our results support the concept of calculating dose escalation on the basis of the area under the dose-response curve using the Calvert formula, rather than on surface area.
Relationship between Acute Suppurative Otitis Media and Chronic Secretory Otitis Media: Role of Antibiotics
Authors: Robert Mills, Ann Uttley, Michelle McIntyre
Journal: Journal of the Royal Society of Medicine (1984)

A total of 204 chronic middle ear effusions from 122 children have been studied. Bacteria were isolated from 30 effusions. The commonest species found were Strep. pneumoniae and H. influenzae. These are also the commonest organisms causing acute otitis media (AOM). A similar pattern of serotypes was also demonstrated. In vitro sensitivity testing showed that most of the organisms isolated were sensitive to most commonly-used antibiotics. The main exception was resistance to penicillin amongst strains of H. influenzae and Staph. aureus. It is suggested that some cases of chronic secretory otitis media (SOM) may arise as a result of incomplete resolution of AOM and that the use of penicillin to treat AOM may be one factor in this process.
Dietary vitamin E supplementation ameliorates renal injury in chronic puromycin aminonucleoside nephropathy.
Authors: H Trachtman, N Schwob, J Maesaka, E Valderrama
Journal: Journal of the American Society of Nephrology (1995)

Chronic puromycin aminonucleoside nephropathy (PAN) is an experimental analog of focal segmental glomerulosclerosis. Progressive renal damage in this model is partly mediated by excessive production of oxidant species. Whether dietary supplementation with vitamin E, an endogenous lipophilic antioxidant, ameliorates the severity of chronic PAN was tested. PAN was induced by seven serial injections of the glomerular epithelial cell toxin puromycin aminonucleoside, 2 mg/100 g body wt per dose, over a 12-wk period. Experimental animals (N = 8) received vitamin E-enriched chow (100 IU/kg), whereas control PAN rats (N = 10) were fed standard rodent diet containing vitamin E (30 IU/kg of chow). The administration of vitamin E had no effect on somatic growth or blood pressure; however, rats with PAN fed the vitamin E-enriched diet had an increased hematocrit. In addition, the experimental diet resulted in a 50% reduction in urinary total protein and albumin excretion and stabilization of the serum albumin, cholesterol, and triglyceride concentrations (P < 0.01). The inulin clearance was 69% higher in the vitamin E-supplemented animals (P < 0.001). Tubular function, namely, phosphate reabsorption and beta 2-microglobulin excretion, was improved in rats with chronic PAN treated with the vitamin E-enriched diet. There was a significant decrease in glomerulosclerosis and glomerular planar area, and tubulointerstitial scarring was diminished in vitamin E-treated animals with chronic PAN (P < 0.01). These beneficial effects on renal structure and function were associated with reduced malondialdehyde content in the kidney and liver.(ABSTRACT TRUNCATED AT 250 WORDS)
Serum aminotransferase levels in patients with severe obstructive sleep apnea
Authors: Parisa Adimi, Froogh Soltani, Nazanin Kiapour, Zohreh Mohammad Taheri, Nader Fayazi
Journal: European Respiratory Journal (2012)

Background  Obstructive sleep apnea (OSA) is one of the most common sleep disorders with a plethora of consequences. Currently the impact of hypoxia due to OSA on liver function is targeted growing attention. This study evaluated the association between serum aminotransferase levels as accepted predictive factor for liver injury and factors connected with OSA severity (apnea hypopnea index (AHI), lowest oxygen saturation level, oxygen desaturation index (DI), percent of time below 90% saturation [T  Materials and Methods  66 patients with BMI≥30, who their OSA was confirmed by PSG, were divided equally into two groups based on AHI. 33 patients in control group with 5  Result  Mean DI was (56.33 ± 26.97) (14.00 ± 10.46) in case and control group respectively (P-value   Conclusions  This study showed there is no significant correlation between serum aminotransferase levels and OSA severity.