tbuckley/cabot-search huggingface dataset:
Hydralazine and Breast Cancer&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: David W. Kaufman, Judith P. Kelly, Lynn Rosenberg, Paul D. Stolley, David Schottenfeld, Samuel Shapiro
Journal: JNCI Journal of the National Cancer Institute (1987)

Hydralazine (CAS: 86-54-4; 1-hydrazinonaphthalazine) is a well-established antihypertensive agent. There are no conclusive data on the drug as a human carcinogen, but one of its metabolites, hydrazine (CAS: 302-01-2), has been shown to be carcinogenic in rats and mice. To assess the relationship of hydralazine to human breast cancer, 3,419 women with breast cancer and 3,219 hospital control subjects were studied. Data were obtained by interview in hospitals in the United States and Canada. A total of 1.4% of the cases and 1.2% of the controls had used hydralazine. Compared with never use, the relative risk (RR) estimate for hydralazine that was first used at least 18 months before admission was 0.9 [95% confidence interval (CI), 0.5-1.7] after risk factors for breast cancer and the use of other antihypertensive drugs and diuretics were taken into account by multivariate analysis. The RR estimate for hydralazine use lasting at least 1 year was 0.9 (95% CI, 0.5-1.7). RR estimates for longer durations of use (up to 5 or more yr), and for use within strata of risk factors for breast cancer, were close to 1.0. The results suggest that hydralazine does not increase the risk of breast cancer in humans in the short term. Whether the risk is increased after latent intervals of many years could not be evaluated.
Alveolar macrophages activate STAT3 in epithelial cells via gp130 dependant steroid insensitive mechanism
Authors: Jonathan Plumb, Arjun Ravi, George Booth, Dave Singh
Journal: European Respiratory Journal (2013)

Rationale  Increased production of the IL-6 cytokine family is a hallmark of many human chronic inflammatory diseases including COPD. Elevated IL-6 levels are associated with increased mortality, faster rate of decline in lung function and increased exacerbation frequency in COPD. IL-6 ligation to the IL-6 receptor complex induces the JAK-STAT signalling cascade resulting in the activation of the transcription factor STAT3. Aims: to determine whether STAT3 is activated within the small airways of COPD patients.  Methods  STAT3 phosphorylation (STAT3p) was analysed by immunohistochemistry in small airway samples from 44 patients (COPD n = 24, smoking controls (S) n = 10 and non-smoking controls (NS) n = 10) undergoing surgical resection. BEAS-2B cells were cultured in conditioned media from alveolar macrophages (AM) +/- LPS as well as induced sputum supernatants; STAT3p was analysed by Western blot.  Results  Increased levels of STAT3p were detected within the small airways of COPD patients compared to S and NS controls. There were also increased numbers of STAT3p+ cells within the sub-epithelium of COPD small airways (mean 820 cells/mm2) compared to S (mean 403 cells/mm2) and NS (mean 348 cells/mm2) (ANOVA p  Conclusion  We propose that IL-6 released by AM activates STAT3 in the small airways of COPD patients in a corticosteroid resistant manner. Selective targeting of the IL-6-STAT3-gp130 signalling axis may provide a useful novel therapy in COPD.
Pharmacodynamics of fluorouracil-based induction chemotherapy in advanced head and neck cancer.
Authors: E E Vokes, R Mick, M S Kies, M E Dolan, D Malone, I Athanasiadis, D J Haraf, M Kozloff, R R Weichselbaum, M J Ratain
Journal: Journal of Clinical Oncology (1996)

PURPOSE AND METHODS To optimize the biochemical modulation of fluorouracil (5-FU), we administered the pure I-stereoisomer of leucovorin (LV) as a 132-hour continuous intravenous infusion (CIV) with cisplatin 100 mg/m2, 5-FU 640 mg/m2/d as a 120-hour CIV, and interferon alfa-2b (IFN) at 2 MU/m2/d for 6 days for three cycles (I-PFL-IFN). Pharmacologic parameters included morning (AM) and afternoon (PM) plasma concentrations of 5-FU, LV and its active metabolite 5-methyl tetrahydrofolate (MTHF), and dihydropyrimidine dehydrogenase (DPD) activity in peripheral mononuclear cells. RESULTS Eighty-nine patients were treated (86 stage IV). Neutropenia and mucositis were the most common toxicities. Sixty-six percent achieved a complete remission (CR). There was a trend for higher PM versus AM 5-FU concentrations (median, 1.64 v 1.51 mumoles/L; P = .08), but not for LV plus MTHF (P = .66). The mean +/- SD DPD activity was 0.21 +/- 0.14 nmol/min/mg and did not correlate with plasma concentrations of 5-FU or LV plus MTHF or clinical toxicities. Higher PM 5-FU concentrations correlated with worse leukopenia (P = .04) and severity of mucositis (P = .04). PM 5-FU concentration was higher in women than in men (P = .07), with no apparent difference in severity of toxicities. The maximum 5-FU concentration was higher in CR than non-CR patients (median, 2.01 v 1.54 mumoles/L; P = .02) and higher in women than men who achieved a CR (median, 2.77 v 1.91 mumoles/L; P = .03). No correlation of CR with dose-intensity was found. CONCLUSION L-PFL-IFN is active in stage IV head and neck cancer. 5-FU concentration is a significant predictor of toxicity. In women, optimization of response outcome requires a higher 5-FU concentration. Individualized 5-FU dosing to obtain higher 5-FU plasma concentrations may be indicated.
Prognostic factors for children with recurrent Wilms' tumor: results from the Second and Third National Wilms' Tumor Study.
Authors: P Grundy, N Breslow, D M Green, K Sharples, A Evans, G J D'Angio
Journal: Journal of Clinical Oncology (1989)

The characteristics of 367 stage I-IV National Wilms' Tumor Study (NWTS) children who relapsed after initial treatment for unilateral disease in the second and third NWTS trials (NWTS-2 and -3) were analyzed to identify features predictive of survival. Although modifications in initial therapy resulted in a lower rate of first relapse in these two studies compared with NWTS-1, all previously identified prognostic factors after relapse remained statistically significant predictors of survival. Tumor histology, length of initial remission, initial therapy with two v three drugs, and site of relapse each were independently predictive of postrelapse survival. The 3-year postrelapse survival for all 367 patients was 30% +/- 3%; however, subgroups classified by these prognostic factors were identified that had 3-year postrelapse survival rates of greater than 40%. These subgroups included patients who had tumors of favorable histology (FH) that recurred (1) only in the lungs, (2) in the abdomen when radiotherapy (RT) was not initially given, or (3) that were originally stage I, (4) that were originally treated with only two drugs, or (5) that recurred 12 months or more after diagnosis. These results were achieved with the use of standard treatments, ie, surgery, RT, and chemotherapy using dactinomycin (AMD), vincristine (VCR), and Adriamycin [( ADR] doxorubicin; Adria Laboratories, Columbus, OH). It is suggested that patients in these groups might be managed with aggressive use of conventional therapies until newer chemotherapeutic agents and drug combinations are shown to be more effective. Patients with adverse prognostic features at relapse have a poor survival expectancy with standard measures. Salvage attempts for these patients are better based on experimental approaches.
The effect of surgery on thoraco abdominal volumes in congenital diaphragmatic hernia (CDH) patients
Authors: Marianna Laviola, Clara Ceruti, Andrea Zanini, Andrea Aliverti
Journal: European Respiratory Journal (2013)

CDH consists of an incomplete formation of the diaphragm and the subsequent erniation of abdominal bowels. Two kinds of reconstructive surgery are usually applied in CDH: when enough diaphragmatic tissue is present, primary suture of flaps is performed; in case of a large defect of the diaphragm, a diaphragmatic patch is used to avoid a straight hemidiaphragm. Functional evaluation is a problem, since the patients are babies and often uncooperative.  The aim of the study was to assess thoraco-abdominal volume in CDH patients by opto-electronic plethysmography, which obviates the problem of patient cooperation.  Fourteen CDH patients (7M/7F, age 5±2yrs) and 9 healthy control subjects (9M, age 7±3yrs) were studied during 3 minutes of quiet breathing in supine position. Patients were divided in 2 groups based on the kind of surgery: 5 patients with suture (group S) and 9 patients with diaphragmatic patch (group P).  In overall CDH, the abdomen was the main contributor to tidal volume (V T ), but it was significantly lower than controls, whereas the upper and lower rib cage had a higher contribution to V T . In patients belonging to group P abdominal volume variations were lower than group S (see fig.).  In conclusion, in CDH the mobility of the diaphragm is reduced compared to controls and inspiratory rib cage muscle must be used to compensate this reduced mobility. Diaphragmatic patch further reduces diaphragm mobility.
Inadequacy of Antidepressant Treatment for Patients With Major Depression Who Are at Risk for Suicidal Behavior
Authors: Maria A. Oquendo, Kevin M. Malone, Steven P. Ellis, Harold A. Sackeim, J. John Mann
Journal: American Journal of Psychiatry (1999)

The authors' goal was to determine whether suicide attempters with major depression received more intensive antidepressant treatment than depressed patients who had not attempted suicide.One hundred eighty inpatients who met DSM-III-R criteria for a major depressive episode according to the Structured Clinical Interview for DSM-III-R were enrolled in the study. All patients were assessed for lifetime history of suicide attempts. Depressive symptoms at the index hospitalization were assessed with the Hamilton Depression Rating Scale and the Beck Depression Inventory. Strength of antidepressant treatment over the 90 days preceding the hospitalization was scored by using the Antidepressant Treatment History Form.A large majority of the depressed patients with a history of suicide attempts, who were at higher risk for future suicide and suicide attempts, received inadequate treatment. Similarly, most of the depressed patients at lower risk for suicide attempts also received inadequate treatment.Major depression is undertreated pharmacologically, regardless of history of suicide attempt. Some suicide attempts may be preventable if the problem of underdiagnosis and undertreatment of depression can be overcome by psychoeducation for health professionals and the public.
Prospective participant selection and ranking to maximize actionable pharmacogenetic variants and discovery in the eMERGE Network
Authors: David R Crosslin, Peggy D Robertson, David S Carrell, Adam S Gordon, David S Hanna, Amber Burt, Stephanie M Fullerton, Aaron Scrol, James Ralston, Kathleen Leppig, Andrea Hartzler, Eric Baldwin, Mariza de Andrade, Iftikhar J Kullo, Gerard Tromp, Kimberly F Doheny, Marylyn D Ritchie, Paul K Crane, Deborah A Nickerson, Eric B Larson, Gail P Jarvik
Journal: Genome Medicine (2015)

In an effort to return actionable results from variant data to electronic health records (EHRs), participants in the Electronic Medical Records and Genomics (eMERGE) Network are being sequenced with the targeted Pharmacogenomics Research Network sequence platform (PGRNseq). This cost-effective, highly-scalable, and highly-accurate platform was created to explore rare variation in 84 key pharmacogenetic genes with strong drug phenotype associations.To return Clinical Laboratory Improvement Amendments (CLIA) results to our participants at the Group Health Cooperative, we sequenced the DNA of 900 participants (61 % female) with non-CLIA biobanked samples. We then selected 450 of those to be re-consented, to redraw blood, and ultimately to validate CLIA variants in anticipation of returning the results to the participant and EHR. These 450 were selected using an algorithm we designed to harness data from self-reported race, diagnosis and procedure codes, medical notes, laboratory results, and variant-level bioinformatics to ensure selection of an informative sample. We annotated the multi-sample variant call format by a combination of SeattleSeq and SnpEff tools, with additional custom variables including evidence from ClinVar, OMIM, HGMD, and prior clinical associations.We focused our analyses on 27 actionable genes, largely driven by the Clinical Pharmacogenetics Implementation Consortium. We derived a ranking system based on the total number of coding variants per participant (75.2±14.7), and the number of coding variants with high or moderate impact (11.5±3.9). Notably, we identified 11 stop-gained (1 %) and 519 missense (20 %) variants out of a total of 1785 in these 27 genes. Finally, we prioritized variants to be returned to the EHR with prior clinical evidence of pathogenicity or annotated as stop-gain for the following genes: CACNA1S and RYR1 (malignant hyperthermia); SCN5A, KCNH2, and RYR2 (arrhythmia); and LDLR (high cholesterol).The incorporation of genetics into the EHR for clinical decision support is a complex undertaking for many reasons including lack of prior consent for return of results, lack of biospecimens collected in a CLIA environment, and EHR integration. Our study design accounts for these hurdles and is an example of a pilot system that can be utilized before expanding to an entire health system.
The value of spirometry to diagnose a restrictive pattern
Authors: Liliana Raposo, António Bugalho
Journal: European Respiratory Journal (2013)

Background: The assessment of total lung capacity (TLC) is the gold standard to detect a restrictive pattern. However, in some cases, patients are subjected only to spirometry and a low forced vital capacity (FVC) with a normal FEV1/FVC ratio is classified as restriction.  Objectives: Determine the value of FVC measured by spirometry to diagnose a restrictive abnormality and identify FVC cut-off values that may predict a restrictive pattern.  Methods: Spirometry and plethysmography results from 1.937 adult patients who undertook both tests in the same appointment were evaluated in a retrospective study. All patients with a normal or low FVC ( 70%) and a normal or low TLC (  Results: A total of 374 patients (19.3%) had a restrictive pattern, mean age was 57.8 years and 189 were females (50.5%). FVC determined by spirometry had a 48.5% sensibility, 95.6% specificity, 80% positive predictive value (PPV) and 83.3% negative predictive value (NPV) to detect restriction. The best cut-off values to determine a restrictive impairment were FVC  Conclusion: Spirometry is able to correctly diagnose a restrictive pattern in specific subgroups of patients according to FVC severity. These results may help clinicians, especially in primary care, to decide which patients need to perform additional lung measurements.
Safety, tolerability and pharmacokinetics (PK) of single and repeat nebulised doses of a novel phosphoinositide 3-kinase δ inhibitor (PI3Kδ), GSK2269557, administered to healthy male subjects in a phase I study
Authors: Robert Wilson, Anthony Cahn, Amanda Deans, Iain McSherry, Curtis Rambaran, Ana Sousa, Darren Wilbraham
Journal: European Respiratory Journal (2013)

Introduction:  GSK2269557 was investigated in a single centre, double blind, placebo controlled trial in healthy male subjects and smokers. Safety, tolerability and PK data were collected following single (25-6400 µg) and repeat dose (3200 µg b.i.d. for 7 days) in healthy and biomarker cohorts (400 and 6400 µg single doses) in smokers (ERS abstract ref 850263). Plasma PK and lung PK data (from bronchoalveolar lavage) were calculated. Lung PK are expressed as the concentrations in epithelial lining fluid (ELF) using [urea] as a marker of lavage dilution.   Results:  Adverse Events (AE’s) were few and mostly of mild to moderate intensity. 5 withdrawals occurred with 1 deemed study drug related (an inability to tolerate administration of 6400 µg).  After single dosing plasma C max  (T max  at approx 5 min) dropped rapidly ( 1/2  was 19-42h. Dose proportionality was observed and plasma PK was unaffected by smoking status. Mean plasma C max  and AUC (0-24h)  values were 0.06 to 4.3 ng/mL (50 to 6400 µg) and 0.38 to 34 ng.h/mL (200 to 6400 µg) respectively.  Twice daily dosing for 7 days showed accumulation in plasma with peak and trough levels increased by 2.4-fold and 6-fold respectively.  Derived mean ELF concentration at 3h was 598 ng/mL (lung:plasma ratio 440:1).   Conclusions:  GSK2269557 was well tolerated in healthy male subjects. There was a low incidence of AE’s and plasma PK was well defined with ELF data confirming high levels of drug within the lung compared to plasma.
Randomized phase II clinical trial of comparison of epirubicin (E) plus cyclophosphamide (C) and weekly paclitaxel (P) as primary systemic therapy (PST) in patients (pts) with stages II and III breast cancer (BC)
Authors: M. Miyashita, N. Kohno, S. Takao, K. Wakita, M. Konishi, I. Kokufu, H. Yoshimura, Y. Kasahara, S. Kohno, Y. Minari
Journal: Journal of Clinical Oncology (2008)

568 Background: Response and survival rates achieved by anthracycline and P (q 3 weeks [W]) pts with metastatic BC are comparable (ECOG1193). Weekly P is expected to produce higher response rates and lower hematologic toxicity than tri-weekly P for PST (MDACC2002). This study evaluated the activity and toxicity of weekly P therapy compared with EC therapy for stage II and III BC treated by PST. The primary endpoint was the pathologic complete response(pCR) rate. Methods: Pts with histologically confirmed BC, stage II or III, performance status 0–2, and absence of prior chemotherapy were randomized to either Arm A (EC: E 75mg/m2 and C 600 mg/m2 every 3 W for 4 cycles) or Arm B (weekly P: P 80 mg/m2 weekly for 12 W). Pts received PST for 12 W, then underwent surgery. All pts received a cross-over regimen as adjuvant chemotherapy after surgery. Results: Between November 2003 and May 2006, 171 pts were recruited. One hundred fifty-six pts (Arm A: n=80, Arm B: n=76) were evaluable. The clinicopathologic characteristics of pts (age, tumor size, stage, nodal status, hormone receptor and HER2 status) were well balanced in the two arms. Pathologic effect on the primary lesion in 156 pts showed that the pCR rates were 12.5% in Arm A and 18.5% in Arm B (p=0.22). Clinical overall response (OR) rate was 65.0% in Arm A and 64.5% in Arm B. Disease-free survival rate of 43 month was 83.6% in Arm A and 81.4% in Arm B (p=0.96). OR rate in HER2-positive pts (67.7% vs. 65.6%) and the breast conservation rate (50% vs. 55.3%) were equal in both arms. The incidence of grade 3/4 neutropenia (26.3% vs. 5.3%, p=0.0004) was lower in the Arm B than in Arm A, while that of vomiting (18.8% vs. 5.3%, p=0.01) was higher in Arm A. Nausea and mucositis were more frequently seen in Arm A than in Arm B, but there was no significant difference. The incidence of neuropathy (3.8% vs. 39.5%, p<0.001) was higher in Arm B. Conclusions: OR rate and pCR rate were equal in both arms. Weekly P was associated with less toxicity than EC therapy, but more frequently induced neuropathy. Therefore, induction of PST by weekly P therapy seems to be promising. No significant financial relationships to disclose.
Whole body PET(CT) with FDG for treatment monitoring of patients with bone metastatic breast cancer
Authors: V. Huyge, P. Flamen, P. Bergmann, L. Ameye, B. Vanderlinden, C. Garcia, J. Alexiou, M. Lemort, A. Awada, J. Body
Journal: Journal of Clinical Oncology (2008)

1088 Background: The therapeutic response of bone metastases (mets) is notoriously difficult to ascertain. Whole body PET(CT) allows the simultaneous metabolic assessment of bone and visceral metastatic breast cancer mets in a single imaging session. It can be repeated during systemic treatment to assess the metabolic response on a lesion-by-lesion basis. The aim of this study was to examine the distribution and heterogeneity of the therapy-induced PET changes and to correlate the overall PET(CT) response with the clinical time to progression (TTP). Methods: Only PET(CT)-response evaluations where PET(CT) was performed before and during a new treatment were retrospectively selected for analysis. The EORTC criteria were used to define PET response (i.e. all baseline PET lesions should have a more than 25% reduction of their FDG uptake). Results: 46 PET(CT)-response evaluations (cases) in 25 patients were selected for analysis: 26 (56%) of them had bone-only mets. The overall median clinical TTP was 7 months. PET(CT) showed a response in 9 (20%), stable disease in 16 (35%) and progressive disease in 21 (46%) cases. The TTP was significantly longer in cases with a PET(CT) response (median TTP: 11 months) compared to a non-response (median TTP: 6 months; p < 0.01). In cases with bone-only mets (n=26) the TTP was, similarly, 11 months versus 6 months, respectively (p<0.01). PET(CT) indicated a discordant response between bone and visceral sites in 6/20 (30%) cases. Considering only the bone mets, PET(CT) showed a mixed response including responsive and non responsive lesions in the same patient in 16/46 (35%) cases. Conclusions: The PET(CT) response in bone-metastatic breast cancer is related to treatment outcome. Whole-body PET(CT) represents an improvement in the monitoring of these patients because it accounts for the heterogeneity in tumor response among metastases. No significant financial relationships to disclose.
Nuclear disasters and health: lessons learned, challenges, and proposals
Authors: Akira Ohtsuru, Koichi Tanigawa, Atsushi Kumagai, Ohtsura Niwa, Noboru Takamura, Sanae Midorikawa, Kenneth Nollet, Shunichi Yamashita, Hitoshi Ohto, Rethy K Chhem, Mike Clarke
Journal: The Lancet (2015)
Biology and pathogenesis of cytomegalovirus in periodontal disease
Authors: Adolfo Contreras, Javier Enrique Botero, Jørgen Slots
Journal: Periodontology 2000 (2013)

Abstract Human periodontitis is associated with a wide range of bacteria and viruses and with complex innate and adaptive immune responses. Porphyromonas gingivalis , Tannerella forsythia , Aggregatibacter actinomycetemcomitans , Treponema denticola , cytomegalovirus and other herpesviruses are major suspected pathogens of periodontitis, and a combined herpesvirus–bacterial periodontal infection can potentially explain major clinical features of the disease. Cytomegalovirus infects periodontal macrophages and T‐cells and elicits a release of interleukin‐1β and tumor necrosis factor‐α. These proinflammatory cytokines play an important role in the host defense against the virus, but they also have the potential to induce alveolar bone resorption and loss of periodontal ligament. Gingival fibroblasts infected with cytomegalovirus also exhibit diminished collagen production and release of an increased level of matrix metalloproteinases. This article reviews innate and adaptive immunity to cytomegalovirus and suggests that immune responses towards cytomegalovirus can play roles in controlling, as well as in exacerbating, destructive periodontal disease.