tbuckley/cabot-search huggingface dataset:
Abstract 2618: Bone Morphogenic Protein-9 Stimulates Endothelin-1 Synthesis by Human Pulmonary Microvascular Endothelial Cells: A Possible Contributor to the Pathogenesis of Pulmonary Arterial Hypertension
Authors: Greg P Star, Michele Giovinazzo, David Langleben
Journal: Circulation (2008)

Pulmonary arterial hypertension (PAH) is thought to be related to progressive obliteration of the pulmonary microvasculature. Endothelial proliferation and dysfunction is a central process, and increased levels of the potent endothelial-derived vasoconstrictor and mitogen, endothelin-1 (ET-1) have been described. It is not known what triggers these increased ET-1 levels. With the description of mutations in receptors for bone morphogenic proteins (BMP) and other members of the TGF-beta family of proteins as causative events in hereditary forms of PAH, we hypothesized that BMPs might modulate ET-1 synthesis. Recently, BMP-9, which acts via the type-1 TGF-beta receptor activin-like kinase 1 (ALK-1), has been identified as a potent regulator of endothelial proliferation and migration. We therefore studied the effects of BMP-9 on ET-1 in-vitro production by human lung microvascular endothelial cells (HLMVEC), the cell implicated in the pathogenesis of PAH. HLMVEC were cultured to confluence in EGM-2MV medium and then BMP-9 (0 –100 ng/ml) was added to the medium for 24 and 48 hours. All concentrations increased ET-1 production at both time points, with 10 ng/ml resulting in a 99% increase versus controls at 24 hours and 104% at 48 hours (all p&lt;0.001). Addition of SB-431542 (10 uM) a specific inhibitor of the kinase activity of ALK-5 significantly reduced the 48 hour ET-1 synthesis provoked by BMP-9, with a 41% decrease for 1 ng/ml BMP-9 but only a 9% reduction for 10 and 100ng/ml BMP-9. In conclusion, this is the first identification of BMP-9 as a potent stimulator of ET-1 production by HLMVEC. Although the actions of BMP-9 are thought to be through ALK-1, there may be a component of interaction with ALK-5, or ALK-5 may have cross-talk with ALK-1. ALK-5 inhibitors such as SB-431542 can reduce BMP-9 mediated ET-1 production and might ultimately have therapeutic benefit for PAH.
Gender differences in right-ventricular arterial coupling in idiopathic pulmonary arterial hypertension
Authors: Pia Trip, Frances S. de Man, Harm J. Bogaard, Nico Westerhof, Anton Vonk-Noordegraaf
Journal: European Respiratory Journal (2013)

Introduction Male sex is an independent predictor of prognosis in idiopathic pulmonary hypertension (IPAH). We aimed to: 1) assess baseline gender differences in load-independent right ventricular (RV) systolic function and RV-arterial coupling, 2) assess the influence of baseline RV-arterial coupling on the gender-specific survival difference.

Methods In 86 treatment naive IPAH patients we determined RV end-systolic elastance (Ees), arterial elastance (Ea), RV-arterial coupling (Ees/Ea) and survival. Right heart catheterization was used to measure mean pulmonary artery pressure (mPAP) and stroke volume (SV). Maximal isovolumic pressure (Piso) was estimated from RV pressure curves with the single-beat method. Ees=(Piso-mPAP)/SV and Ea=mPAP/SV.

Results Baseline hemodynamics are shown in table 1. Figure 1 shows Ees, Ea, and Ees/Ea. Male (N=29) and female patients (N=57) showed similar Ees- (p=0.08) and Ea–values (p=0.66). However, Ees/Ea was lower in males (p<0.05). A total of 20 patients died during follow-up. Kaplan-Meier analysis showed a worse survival for male patients independent of Ees/Ea (log-rank p<0.01).

Conclusions Male IPAH patients present with a lower RV-arterial coupling ratio compared to females, despite a similar afterload level. The lower baseline coupling ratio does not explain the observed survival difference between males and females.

![Figure][1]  [1]: pending:yes
High-Dose Therapy and Autologous Stem-Cell Transplantation Versus Conventional-Dose Consolidation/Maintenance Therapy as Postremission Therapy for Adult Patients With Lymphoblastic Lymphoma: Results of a Randomized Trial of the European Group for Blood and Marrow Transplantation and the United Kingdom Lymphoma Group
Authors: John W. Sweetenham, Gino Santini, Wendi Qian, Monica Guelfi, Norbert Schmitz, Sarah Simnett, Arnon Nagler, Harald Holte, Stein Kvaloy, Paulo Bruzzi, Anthony H. Goldstone
Journal: Journal of Clinical Oncology (2001)

PURPOSE: To determine whether a combination of high-dose therapy and autologous stem-cell transplantation (ASCT) is superior to conventional-dose consolidation and maintenance chemotherapy as postremission therapy in adults with lymphoblastic lymphoma. PATIENTS AND METHODS: One hundred nineteen patients were entered onto this prospective randomized trial from 37 centers. Patients received standard remission induction therapy, and responding patients were randomized either to continue with a conventional consolidation/maintenance protocol (CC) or to receive high-dose therapy and ASCT. In some centers, patients with HLA-identical sibling donors were registered on the trial but proceeded to allogeneic bone marrow transplantation (BMT) without randomization. RESULTS: Of the 119 patients entered, 111 were assessable for response to induction therapy. The overall response rate was 82% (56% complete response, 26% partial response). Of the 98 patients eligible for randomization, 65 were randomized, 31 to ASCT and 34 to CC. Reasons for failure to randomize included patient refusal (12 patients), early progression or death on induction therapy (eight patients), excessive toxicity of induction regimen (six patients), and elective allogeneic BMT (12 patients). With a median follow-up of 37 months, the actuarial 3-year relapse-free survival rate is 24% for the CC arm and 55% for the ASCT arm (hazards ratio = 0.55 in favor of the ASCT arm; 95% confidence interval [CI], 0.29 to 1.04; P = .065). The corresponding figures for overall survival are 45% and 56%, respectively (hazards ratio = 0.87 in favor of the ASCT arm; 95% CI, 0.42 to 1.81; P = .71). CONCLUSION: The use of ASCT in adults with lymphoblastic lymphoma in first remission produced a trend for improved relapse-free survival but did not improve overall survival compared with conventional-dose therapy in this small randomized trial.
Cetuximab plus 5-FU/FA/oxaliplatin (FOLFOX-4) versus FOLFOX-4 in the first-line treatment of metastatic colorectal cancer (mCRC): OPUS, a randomized phase II study
Authors: C. Bokemeyer, I. Bondarenko, A. Makhson, J. T. Hartmann, J. Aparicio, M. Zampino, S. Donea, H. Ludwig, A. Zubel, P. Koralewski
Journal: Journal of Clinical Oncology (2007)

4035 Background: FOLFOX-4 is a standard first-line treatment for patients (pts) with mCRC. The IgG1 monoclonal antibody cetuximab has proven activity in combination with cytotoxic chemotherapy. Excellent response rates (RRs) have been reported with first-line cetuximab and FOLFOX-4. This randomized, controlled study was conducted to compare RRs of FOLFOX-4 + cetuximab vs FOLFOX-4. Methods: Pts with previously untreated epidermal growth factor receptor (EGFR)-expressing mCRC not resectable with curative intent were eligible. They were randomized 1:1, stratified by ECOG performance status (PS) (0–1 vs 2), to either Group A (cetuximab 400 mg/m 2 initial dose then 250 mg/m 2 /week plus FOLFOX-4 every 2 weeks [oxaliplatin 85 mg/m 2 day (d) 1; FA 200 mg/m 2 d1, 2; 5-FU 400 mg/m 2 bolus + 600 mg/m 2 infusion over 22 h, d1, 2]) or Group B (FOLFOX-4 only). The primary objective was the best confirmed RR assessed by independent review; secondary objectives were progression- free survival (PFS), overall survival (OS), the R 0 resection rate after metastatic surgery of curative intent and safety. Results: Between July 2005 and March 2006, 337 pts were randomized and treated in more than 70 centers in Europe. 181 (53.7%) pts were male; the median age of all pts was 61.0 years [24–82]; 305 (90.5%) pts had an ECOG PS of 0 or 1, and 32 (9.5%) of 2. The best overall confirmed RR was 45.6% in A and 35.7% in B. For pts with ECOG PS 0–1, RR was 49.0% in A and 36.8% in B (Odds Ratio 1.648, 95%CI [1.043- 2.604]). PFS and OS results are not yet available. The most common grade 3/4 adverse events were neutropenia (27.6% in A; 31.5% in B), diarrhea (7.1 and 6.0%), leucopenia (7.1 and 5.4%) and rash (9.4%, in A only). Conclusions: The addition of cetuximab increased the RR of FOLFOX-4 in first-line treatment of mCRC. Grade 3/4 adverse events, with the exception of skin rash, were not significantly more frequent in the cetuximab arm. No significant financial relationships to disclose.
Diabetic ketoacidosis in adults
Authors: Shivani Misra, Nick S Oliver
Journal: BMJ (2015)

What is DKA?Diabetic ketoacidosis (DKA) is an extreme metabolic state caused by insulin deficiency.The breakdown of fatty acids (lipolysis) produces ketone bodies (ketogenesis), which are acidic.Acidosis occurs when ketone levels exceed the body's buffering capacity (figure⇓). 1 2 How common is DKA?Data from the UK National Diabetes audit shows a crude one year incidence of 3.6% among people with type 1 diabetes. 3In the UK nearly 4% of people with type 1 diabetes experience DKA each year, 3 the number of DKA episodes per 100 patient years is 4.8, 4 about 6% of cases of DKA occur in adults newly presenting with type 1 diabetes, 5 and about 8% of episodes occur in hospital patients who did not primarily present with DKA. 6 How does DKA present?DKA usually develops quickly, within 24 hours.Typically, patients develop polyuria and polydipsia along with vomiting, dehydration, and, if severe, an altered mental state, including coma (box 1).Signs of the underlying cause may also be present-for example, infection. 7Abdominal pain is a common feature of DKA and may be part of the acute episode or, less often, represent an underlying cause.DKA should be considered in any unwell patient with diabetes (type 1 or type 2). How is DKA diagnosed?DKA is usually diagnosed in the presence of hyperglycaemia, acidosis, and ketosis.However, hyperglycaemia may not be present (euglycaemic ketoacidosis), and low levels of blood ketones (<3 mmol/L) may not always exclude a diagnosis.Clinical judgment therefore remains crucial.Guidelines differ on the exact biochemical thresholds for diagnosis (table 1⇓).
Survivin-specific CD4+ T cells are decreased in patients with survivin-positive myeloma
Authors: Frederick L Locke, Meghan Menges, Anandharaman Veerapathran, Domenico Coppola, Dmitry Gabrilovich, Claudio Anasetti
Journal: Journal for ImmunoTherapy of Cancer (2015)

Survivin is a small protein inhibitor of apoptosis and a tumor associated antigen. Survivin expression in multiple myeloma is associated with poor prognosis, disease progression, and drug resistance. The CD4+ response against survivin remains uncharacterized.In order to better understand the anti-tumor immune response to survivin, and optimize vaccination strategies, we characterized the spontaneous CD4+CD25- T cell response against survivin in healthy donors and myeloma patients using survivin derived peptide pools.Healthy donors and myeloma patients' CD4+CD25- T cells exhibited a proliferative and IFN-gamma response against survivin peptides loaded onto autologous dendritic cells. We employed limiting dilution analysis to quantify the precursor frequency of survivin reactive CD4+CD25- T cells. Multiple myeloma patients (range 0% to 2.2x10(-3)%, n=12) had fewer survivin reactive CD4+CD25- T cells than healthy blood donors (range 1.1x10(-3) to 8.4x10(-3)%, n=10), p = 0.021. The survivin reactive CD4+CD25- T cell precursor frequency was inversely associated with tumor survivin mRNA expression (p = 0.0028, r = -1.0, n = 6), and survivin tumor protein expression by IHC (p = 0.0295, r = -0.67, n = 10). A full length mutant survivin protein-pulsed dendritic cell vaccine expanded survivin reactive CD4+CD25- T cells after 12 days of in vitro culture (range 0-540x,median = 42x), and expansion was achieved even in patients with low baseline survivin reactive CD4+ precursors.We have, for the first time, quantified the circulating CD4+CD25- precursor frequency against survivin and demonstrated this is lower in myeloma patients than healthy donors. The number of survivin reactive CD4+CD25- T cells is inversely associated with tumor survivin expression suggesting suppression of survivin responsive CD4+CD25- T cells. Further exploration of a full length mutant survivin protein vaccine which expands survivin reactive CD4+ cells independent of the survivin reactive precursor frequency is warranted.
Safety and Efficacy of Bisphosphonates Beyond 24 Months in Cancer Patients
Authors: S. M. Ali, F. J. Esteva, G. Hortobagyi, H. Harvey, J. Seaman, R. Knight, L. Costa, A. Lipton
Journal: Journal of Clinical Oncology (2001)

PURPOSE: Bisphosphonate therapy has decreased the risk of skeletal complications associated with osteolytic bone lesions in patients with breast cancer and multiple myeloma. The large prospective studies have used 21 to 24 months of treatment. We studied the safety and efficacy of bisphosphonates in a subset of patients who received therapy for more than 24 months. PATIENTS AND METHODS: Patients who received bisphosphonates (pamidronate or zoledronic acid) were identified. Data on skeletal events and laboratory parameters were gathered by chart review. RESULTS: We studied 22 patients who received intravenous pamidronate or zoledronic acid for a duration of 3.6 years (range, 2.2 to 6.0 years). Prolonged therapy was well tolerated. No significant calcium, phosphorus, electrolyte, or WBC count abnormalities were encountered. There was a clinically insignificant decrease in hemoglobin and platelet count and an increase in creatinine in these patients. The fracture rate beyond 2 years was no greater than during the first 2 years of treatment. There were no stress fractures of long bones with prolonged therapy. CONCLUSION: Prolonged treatment with the potent bisphosphonates pamidronate and zoledronic acid seems to be well tolerated and should be studied in prospective, randomized studies to document prolonged skeletal efficacy.
A novel IL-17 signaling pathway controlling keratinocyte proliferation and tumorigenesis via the TRAF4–ERK5 axis
Authors: Ling Wu, Xing Chen, Junjie Zhao, Bradley Martin, Jarod A. Zepp, Jennifer S. Ko, Chunfang Gu, Gang Cai, Wenjun Ouyang, Ganes Sen, George R. Stark, Bing Su, Charlotte M. Vines, Cathy Tournier, Thomas A. Hamilton, Allison Vidimos, Brian Gastman, Caini Liu, Xiaoxia Li
Journal: The Journal of Experimental Medicine (2015)

Although IL-17 is emerging as an important cytokine in cancer promotion and progression, the underlining molecular mechanism remains unclear. Previous studies suggest that IL-17 (IL-17A) sustains a chronic inflammatory microenvironment that favors tumor formation. Here we report a novel IL-17–mediated cascade via the IL-17R–Act1–TRAF4–MEKK3–ERK5 positive circuit that directly stimulates keratinocyte proliferation and tumor formation. Although this axis dictates the expression of target genes Steap4 (a metalloreductase for cell metabolism and proliferation) and p63 (a transcription factor for epidermal stem cell proliferation), Steap4 is required for the IL-17–induced sustained expansion of p63+ basal cells in the epidermis. P63 (a positive transcription factor for the Traf4 promoter) induces TRAF4 expression in keratinocytes. Thus, IL-17–induced Steap4-p63 expression forms a positive feedback loop through p63-mediated TRAF4 expression, driving IL-17–dependent sustained activation of the TRAF4–ERK5 axis for keratinocyte proliferation and tumor formation.
Across-shift decrease in fractional exhaled nitric oxide among Tanzanian cement production workers
Authors: Alexander Tungu, Magne Bråtveit, Simon Mamuya, Bente Moen
Journal: European Respiratory Journal (2012)

Background 

There is limited information on fractional exhaled nitric oxide (FENO), a marker of respiratory inflammation, among cement production workers.

Aim 

To explore possible across-shift changes in FENO over an 8h shift among dust exposed cement production workers in Tanzania.

Methods 

We examined 48 cement production workers (exposed) and 27 workers from a mineral water factory (controls), all non-smokers. Pre-shift and post shift FENO measurements (parts per billion, ppb) were performed using a NIOX MINO machine, for 2 day shifts among controls and 3 day shifts among exposed. Full shift personal total dust samples were collected in participants' breathing zone.

Results 

Baseline geometric mean (GM) of FENO for the respective days of examination were 20.4 ppb, 20 ppb and 19.1 ppb among exposed, and 16.3 ppb and 16.2 ppb among controls. There was a significant across shift decrease in FENO for the three days of examination among the exposed (2.9 ppb, 2.4 ppb and 3.4 ppb, respectively, paired t-test, p<0.05), while the decrease was not significant among controls (1.4 ppb and (0.2 ppb). The change in across shift FENO was not significantly different between exposed and controls. The GM for total dust exposure among exposed was 9.4 mg/m3 and 0.28 mg/m3 among controls. There was no correlation between the across shift FENO change and total dust exposure.

Conclusion 

The across-shift FENO decrease in cement production workers was not significantly associated with occupational dust exposure, and the reason for this change should be determined in future studies.
Immune responses to SS-A 52-kDa and 60-kDa proteins and to SS-B 50-kDa protein in mothers of infants with neonatal lupus erythematosus
Authors: N. Yukiko
Journal: British Journal of Dermatology (2000)

Mothers who have anti-SS-A/Ro and anti-SS-B/La antibodies have a greater risk of bearing infants with neonatal lupus erythematosus (NLE). However, most mothers with anti-SS-A/Ro and anti-SS-B/La antibodies give birth to infants with no evidence of NLE. We studied mothers who had the combination of clinical evidence of connective tissue disorder, positive antinuclear antibody and positive anti-SS-A/Ro and/or anti-SS-B/La antibodies. We analysed SS-A/Ro and SS-B/La antibody responses to recombinant 60-, 52- and 50-kDa proteins in eight mothers of NLE infants and 19 mothers whose children did not have NLE. Molecular analysis of the anti-SS-A/Ro and anti-SS-B/La antibodies was carried out by enzyme-linked immunosorbent assay using recombinant 60-, 52- and 50-kDa proteins. The mothers of children with cutaneous NLE were all positive for a high titre of 50-kDa protein. Mothers of children with NLE with complete heart block (CHB) were positive for 52- and 60-kDa proteins. We conjecture that anti-SS-B/La antibody influences the development of cutaneous NLE, and that anti-SS-A/Ro antibody influences the development of NLE with CHB.
Mefloquine as a potential drug against multidrug-resistant tuberculosis
Authors: David Krieger, Silvan Vesenbeckh, Nicolas Schönfeld, Gudrun Bettermann, Torsten Thomas Bauer, Holger Rüssmann, Harald Mauch
Journal: European Respiratory Journal (2015)

In the article by Alsaad et al. [1] in a recent issue of the European Respiratory Journal the authors reviewed six drugs with antimicrobial activity against Mycobacterium tuberculosis (phenothiazine, metronidazole, doxycycline, disulfiram, tigecycline and co-trimoxazole) which are not listed in the World Health Organization guidelines on multidrug-resistant tuberculosis (MDR-TB) treatment, but could be potential candidates for this use. Despite of the release of new drugs (delamanid, bedaquiline), treatment alternatives are still warranted, last but not least because of treatment costs. We would like to extend this list by evaluating the anti-malaria drug mefloquine. Mefloquine has in vitro activity against MDR- and non-MDR-TB and should be evaluated in clinical studies <http://ow.ly/OYKEv>
Bile duct paucity is part of the neonatal ichthyosis-sclerosing cholangitis phenotype
Authors: I.F. Nagtzaam, M. Van Geel, A. Driessen, P.M. Steijlen, M.A.M. Van Steensel
Journal: British Journal of Dermatology (2010)

Neonatal ichthyosis-sclerosing cholangitis (NISCh) syndrome is a rare autosomal recessive disorder associated with scalp hypotrichosis, scarring alopecia, ichthyosis and sclerosing cholangitis. It is caused by homozygous mutations in the CLDN1 gene coding for the tight junction component claudin-1. Only five patients have been reported so far: four patients from two inbred Moroccan families, all carrying a dinucleotide deletion c.200_201delTT in the CLDN1 gene and a Swiss patient with a 1-bp deletion (c.358delG) in exon 2. Here, we report on three Moroccan brothers born of consanguineous parents (first cousins) presenting with ichthyosis, hypotrichosis and congenital paucity of bile ducts. In our patients, we found the same dinucleotide deletion (c.200_201delTT) in the CLDN1 gene that had been reported previously. In our view, this is suggestive of a founder effect. Interestingly, our patients presented not with sclerosing cholangitis but with congenital paucity of bile ducts. Although the two conditions cannot always be easily distinguished, we would suggest that paucity of bile ducts could be a manifestation of NISCh.
Abstract 15961: Clinical Outcomes of Mitraclip Therapy for Functional Mitral Regurgitation in High-Risk Patients: A Comparison With a Large Surgical Series
Authors: Maurizio Taramasso, Paolo Denti, Micaela Cioni, Andrea Guidotti, Antonio Colombo, Ottavio Alfieri, Francesco Maisano
Journal: Circulation (2011)

OBJECTIVES:  Mitraclip is an emerging option for selected high risk patients with functional mitral regurgitation (FMR). The aim of this study is to compare the outcomes of patients who underwent surgical mitral repair and Mitraclip therapy for FMR in our experience.   METHODS:  From March 2000, 143 patients with FMR were treated in our Institution: 91 patients (63.6%) underwent surgical mitral repair (49% ischemic; 51% dilatative) and 52 patients (36.4%) underwent Mitraclip implantation (71% ischemic; 29% dilatative). Associate procedures in surgical group were myocardial revascularization in 35%, tricuspid repair in 25% and atrial fibrillation ablation in 26%. Follow-up was 100% complete (29.2±30.1 months for surgery and 9.6±7.7 months for Mitraclip).   RESULTS:  Mitraclip patients were older (p=0.04), had higher Log-EuroScore (p   CONCLUSIONS:  Mitraclip therapy is a safe therapeutic option in selected high-risk patients with FMR and it is associated with lower hospital mortality and shorter length-of-stay compared to surgery, in spite of worse preoperative conditions. However, residual MR is higher with Mitraclip and further studies are needed to determine the long-term clinical impact.
Childhood type 1 diabetes may increase the risk of atopic dermatitis
Authors: C.‐H. Lin, C.‐C. Wei, C.‐L. Lin, W.‐C. Lin, C.‐H. Kao
Journal: British Journal of Dermatology (2015)

Epidemiological investigations have examined the association between type 1 diabetes mellitus (T1DM) and atopic disease, but have obtained conflicting results.To analyse the association between T1DM and atopic dermatitis (AD) in a population-based, retrospective cohort study that investigated the hypothesis that childhood T1DM is a risk factor for subsequent AD.From claims data of the National Health Insurance programme of Taiwan, we identified 3386 patients with T1DM newly diagnosed from 1998 to 2011 and 12 725 randomly selected controls without T1DM. These were frequency matched by age, sex and year of diagnosis. Both cohorts were followed up until the end of 2011 to evaluate the AD risk. We used Cox proportional hazards regression models to analyse the risk of AD.The overall incidence rate of AD was 1·40-fold (significantly) higher in the T1DM cohort than in the non-T1DM cohort (3·31 vs. 2·35 per 1000 person years). After adjustment for potential risk factors, the overall risk of AD remained higher in the T1DM cohort [adjusted hazard ratio (HR) 1·76, 95% confidence interval (CI) 1·29-2·39] than in those without T1DM. Compared with the non-T1DM cohort, the patients with T1DM with more emergency room visits (adjusted HR 30·1, 95% CI 18·7-48·5) or hospitalizations (adjusted HR 70·3, 95% CI 45·6-114·5) had a higher risk of subsequent AD.This nationwide, retrospective cohort study demonstrates that childhood T1DM may increase the risk of AD.