tbuckley/cabot-search huggingface dataset:
Seasonal variation of viral lower respiratory tract infections in immunocompromised patients undergoing diagnostic bronchoscopy
Authors: Kathleen Jahn, Lilian Junker, Jörg Halter, Daiana Stolz, Michael Tamm
Journal: European Respiratory Journal (2012)

Pulmonary infectious and non-infectious complications are frequent in immunocompromised patients. Multiplex PCR allows to make a better differentiation of viral infections in immunocompromised patients suffering from respiratory symptoms. We analysed the types of viral infection in a large cohort of patients undergoing diagnostic bronchoscopy for symptoms of LRT infection. Multiplex PCR for respiratory viral infection consisted of 13 viruses. 670 patients underwent a bronchoscopy with BAL from October 2009 to January 2012. 351 of the patients suffered from haematologic disorders, 157 underwent solid organ transplantation (including 137 lung transplantation, 10 kidney transplantation, 5 heart transplantation and 5 liver transplantation) and 174 were immunocompromised for other reasons (HIV, rheumatological diseases, interstitial lung disease). Overall respiratory viral infection could be documented in 212 cases (31.6%). The most frequent viruses were rhinovirus in 109 samples. A single viral infection was found in 196 cases (29.3%) whereas at least two viruses were detected in 16 patients (2.4%). Rhinovirus was found throughout the whole year whereas coronavirus, parainfluenza, RSV and hMPV were documented from November to April. There were only nine cases of adenovirus and eigth cases of influenza respectively. H1N1 was only present in the winter of 2009.

Summary and conclusion : Multiplex PCR in BAL allows to diagnose rapidly viral infection in a high percentage of immunocompromised patients suffering from respiratory tract infection. Except for rhinovirus most viruses show seasonal pattern. However the “winter” period lasts for at least 6 months.
Home administration of bortezomib in multiple myeloma is cost-effective and is preferred by patients compared with hospital administration: results of a prospective single-center study
Authors: A. Lassalle, P. Thomaré, C. Fronteau, B. Mahé, C. Jubé, N. Blin, M. Voldoire, V. Dubruille, B. Tessoulin, C. Touzeau, C. Chauvin, M. Loirat, A. Lok, J. Bourcier, E. Lestang, R. Mocquet, V. Barbarot, P. Moreau
Journal: Annals of Oncology (2015)
LBA-08 Results of a phase 1b study of the selective BRAF V600 inhibitor encorafenib in combination with cetuximab alone or cetuximab + alpelisib for treatment of patients with advanced BRAF-mutant metastatic colorectal cancer
Authors: E. Elez, J. Schellens, R. van Geel, J. Bendell, A. Spreafico, M. Schuler, T. Yoshino, J-P. Delord, Y. Yamada, M. Lolkema, J.E. Faris, F. Eskens, S. Sharma, R. Yaeger, H-J. Lenz, Z. Wainberg, E. Avsar, A. Chatterjee, S. Jaeger, T. Demuth, J. Tabernero
Journal: Annals of Oncology (2015)
Correlation of receptor activator of nuclear factor kappa b (RANK) expression in breast cancer (BC) at the time of diagnosis with recurrence-free survival (RFS) and risk of bone-dominant metastases (BDM) in the I-SPY 1 trial (CALGB 150007/150012; ACRIN 6657).
Authors: Jiali Li, Christina Yau, Michael Campbell, Laura Esserman, John W. Park, Hope S. Rugo
Journal: Journal of Clinical Oncology (2012)

2 Background: RANK is a tumor necrosis factor receptor family protein that is critical to bone turnover. The ligand to RANK (RANKL) can induce metastases from RANK-expressing tumor cells, and treatment with a RANKL inhibitor can reduce BC metastases (mets) in pre-clinical models and there is an FDA approved drug that targets RANKL. Osteoprotegerin (OPG) is a RANKL decoy receptor that blocks the interaction of RANK/RANKL. I-SPY 1 was a multicenter neoadjuvant trial with well annotated gene expression data and detailed clinical outcomes; we studied the impact of RANK expression on both RFS and BDM. Methods: OPG/RANK/RANKL pathway expression in core biopsies was evaluated at diagnosis in patients (pts) on I-SPY 1, then correlated with ER, intrinsic subtype, stage, response to chemotherapy, site of mets and RFS using the student t-test. Results: Gene arrays were performed on pretreatment tumor from 221 pts; 149 pts have available data with n being ER+. At a median follow-up of 3.5 yrs, 36 pts developed recurrence; 13 pts had BDM, 15 had non-bone mets (NBDM), and 8 pts were not evaluable. RANK, but not OPG or RANKL, was more highly expressed in ER- vs ER+ tumors (p=0.04) and in basal vs luminal A/B subtypes (p= 0.04), but no difference in expression based on tumor grade, node status or response to chemotherapy. Higher (&gt;50%) RANK and lower (&lt;50%) OPG expression correlated with worse RFS (p=0.03). Pts who developed BDM had higher expression of RANK, but not RANKL or OPG compared those with NBDM (p=0.05). After adjusting for ER and intrinsic subtypes, RANK expression was even more significantly correlated with risk for BDM (p=0.004). Conclusions: Higher RANK and lower OPG expression in primary tumor tissue correlates with poor RFS, and high RANK expression is associated with increased risk for BDM. These data suggests that targeting the OPG/RANK/RANKL pathway could be a promising strategy in preventing BDM in pts with high risk BC.
Adjuvant 5-FU/cisplatin (FP) chemotherapy in curatively resected stage IIIA-IV M0 gastric cancer
Authors: T. M. Kim, J. S. Kim, S.-A. Im, T. Y. Kim, H. K. Yang, W. H. Kim, D. S. Heo, Y. J. Bang, K. U. Lee, N. K. Kim
Journal: Journal of Clinical Oncology (2005)

4214 Background: After a curative resection for gastric cancer, loco-regional and systemic relapse were more frequently observed with advanced stage. To date, no definitive conclusions concerning the efficacy of adjuvant chemotherapy for gastric cancer have been reached. FP chemotherapy is one of the most widely used regimen for treating patients with advanced gastric cancer. The aim of this phase II study is to evaluate the efficacy of adjuvant FP in terms of relapse rate and survival and to assess prognostic factors affecting relapse and survival. Methods: From November 1995 to November 2003, 80 patients with AJCC stage III-IV (M0) were given adjuvant FP chemotherapy after curative gastric resection with D2 dissection. Cisplatin (60mg/m2 as 15min i.v infusion) followed by 5-FU (1,200mg/m2 as 12 hours continuous i.v infusion for 4days) was given in cycles of 21days. Results: Among 80 patients who were treated as above, a total of 79 patients were available for the analysis. The male to female ratio was 2.2:1 (54:25) and median age was 51.7 (range 29–71). 46 patients were given total gastrectomy and 33 patients were given subtotal gastrectomy. Pathologic stages were as follows: IIIA 30(38%), IIIB 19(24.1%), and IV 30(38%). 68 patients (79.1%) finished 6 cycles of chemotherapy. During median follow-up of 25.3 months (4.3–108.3 months), a total of 41 patients (51.9%) relapsed. (locoregional 29.3% vs. systemic 70.7%) Advanced stage and nodal status were significant risk factor for relapse (hazard ratio for IV (M0): 2.60 and N3: 7.44). Relapse rates according to stage were as follows: IIIA 40.0%, IIIB 42.1%, and IV 70.0%. 3-year disease free survival rate and overall survival rate were 33.6% and 57.3%, respectively. Grade 3–4 leucopenia (15.1%) and neutropenia (62.9%) were most common toxicities, and 2 patients died of febrile neutropenia. Conclusions: In patients with stage III-IV (M0) gastric cancer, adjuvant FP chemotherapy was tolerable. N status was the most powerful predictor of relapse. Adjuvant FP apparently did not confer survival advantage in curatively resected stage III-IV gastric cancer. Clinical trial using more active chemotherapeutic agents is mandatory. No significant financial relationships to disclose.
Renal toxicity associated with zoledronic acid and pamidronate in multiple myeloma patients: A retrospective study
Authors: T. L. Nickolas, L. Chen, G. Markowitz, J. Green, N. Wintfeld, M. Neary, M. Duh
Journal: Journal of Clinical Oncology (2006)

17515 Background: Patients (pts) with multiple myeloma (MM) are at an increased risk of renal impairment as part of disease progression. Herein we compared rates of renal toxicity in MM pts treated with zoledronic acid (ZO), pamidronate (PA), and no bisphosphonate (BP) treatment (NT). Methods: Medical and pharmacy claims and laboratory data were reviewed from &gt;35 managed care plans between 01/2000 and 12/2004. Inclusion criteria were ≥2 claims for MM, no gap in health coverage, and serum creatinine readings before and after first ZO or PA infusion. MM pts who received NT served as a separate reference group. Observation periods extended from initial BP infusion to health plan disenrollment (BP monotherapy) or BP switch. Renal impairment was defined as a ≥25% decrease in glomerular filtration rate (GFR,abbreviated MDRD formula) from baseline. Andersen-Gill model, adjusted for demographics and baseline comorbidities, was used to analyze multiple events in a given pt, as physician practice patterns indicate that administration of both BPs continues even after the development of a first renal event. Results: The study population comprised 122 ZO-treated pts, 90 PA-treated pts, and 213 NT pts. Baseline characteristics of ZO and PA groups were similar except the ZO group had a significantly better baseline GFR and higher previous nephrotoxic drug use (both p &lt; 0.01). After treatment, ZO and PA groups had similar renal impairment rates that were significantly higher than the NT group and increased with treatment duration (ZO 21.7%, PA 22.9%, NT 17.0% in pts treated for &lt;6 months; increasing to ZO 53.8%, PA 50.0%, NT 33.7% in pts treated for ≥18 months). Mean renal impairment events per person-year were significantly higher for ZO than PA (1.83 vs 0.78, p &lt; 0.001). Multiple-event analysis found a 2.6 times risk of renal impairment for ZO than PA (p &lt; 0.0001). Compared with PA, ZO-treated pts had a steeper decrease in mean GFR from baseline by 8.5% (p = 0.03). Conclusions: This retrospective observational study suggests that in MM patients, both ZO and PA are associated with a similar higher risk of renal impairment than NT, but ZO-treated pts are significantly more likely to experience multiple impairment events upon repeated administrations. [Table: see text]
hTERT promotes the invasion of gastric cancer cells by enhancing FOXO3a ubiquitination and subsequent ITGB1 upregulation
Authors: Changjiang Hu, Zhenghong Ni, Bo-sheng Li, Xin Yong, Xin Yang, Jian-wei Zhang, Dan Zhang, Yong Qin, Meng-meng Jie, Hui Dong, Song Li, Fengtian He, Shi-ming Yang
Journal: Gut (2015)

<h3>Background and aims</h3> Human telomerase reverse transcriptase (hTERT) plays an important role in cancer invasion, but the relevant mechanism is not well known. This study aims to investigate the role and mechanism of hTERT in gastric cancer metastasis. <h3>Design</h3> Proteomics analysis, qPCR and western blotting were used to screen for hTERT-regulated candidate molecules in gastric cancer invasion. Chromatin immunoprecipitation (ChIP) qPCR was performed to identify the binding sites of hTERT at the regulatory region of the integrin β1 (<i>ITGB1</i>) gene. ChIP assays were further applied to elucidate the transcription factors that bound to the regulatory region. The interactions between hTERT and the transcription factors were tested by co-immunoprecipitation (Co-IP) and glutathione S-transferase (GST) pull-down experiments. Moreover, the revealed pathway was verified in tumour-bearing nude mice and human gastric cancer tissues. <h3>Results</h3> <i>ITGB1</i> was identified as a downstream gene of hTERT, and there were two hTERT-binding regions within this gene. hTERT alleviated the binding of forkhead box O3 (FOXO3a) to FOXO3a binding element (+9972∼+9978), but it enhanced the binding of forkhead box M1 (FOXM1) to FOXM1 binding element (−1104∼−1109) in <i>ITGB1</i> gene. Importantly, FOXO3a played a major role in hTERT-induced ITGB1 expression, and the hTERT/murine double minute 2 (MDM2) complex promoted the ubiquitin-mediated degradation of FOXO3a. Moreover, hTERT increased ITGB1 expression in xenograft gastric cancer, and the level of hTERT was positively correlated with that of ITGB1 in human gastric cancer tissues. <h3>Conclusions</h3> The hTERT/MDM2–FOXO3a–ITGB1 pathway markedly contributes to hTERT-promoted gastric cancer invasion, suggesting that this pathway might be a novel target for the prevention and treatment of gastric cancer metastasis.
Global refugee total reached almost 60 million in 2014, highest since WWII
Authors: Anne Gulland
Journal: BMJ (2015)

The sexual and reproductive health needs of women and girls are often neglected in the response to humanitarian disasters and conflict, a United Nations report has warned.1

The report highlighted that, of the 100 million people around the world currently in need of humanitarian assistance, about a quarter—26 million—are women and adolescent girls of childbearing age. It warned, however, that sexual and reproductive health services are most scarce when they are most needed.

In 2014 the global total of refugees reached 59.5 million, …
Studies on the Immunochemical Basis for Antigenic Variation Among Polyoma Virus Strains&lt;xref ref-type="fn" rid="FN2"&gt;2&lt;/xref&gt;
Authors: J. Donald Hare, M.D., James C. Chan, Ph.D.
Journal: JNCI Journal of the National Cancer Institute (1970)

An immunochemical analysis of 2 serologically distinct, plaque-size variants of polyoma virus, 3049 and 210, demonstrated a major antigenic determinant, “S,” in the small plaque 210 that was not detectable in the large plaque 3049 particle. Hyperimmune anti-3049 rabbit serum, however, contained antibody to S, suggesting that this antigenic determinant is present in 3049 virus preparations but in reduced quantities or sterically hidden. The S antigen of 210 virus did not cross-react with an antigen in the small plaque variant of Toronto polyoma virus. Shared antigens were detectable in the 3049 and 210 and in the large and small plaque variants of the Toronto strain. Immunochemically, the 2 large plaque strains were more similar than the 2 small plaque strains, a finding which correlates well with previous serological comparisons. Immunoelectrophoretically distinct patterns were found for the 4 strains.
A phase I trial combining motexafin gadolinium (MGd) with docetaxel in the treatment of advanced solid tumors
Authors: K. J. Pandya, S. Phan
Journal: Journal of Clinical Oncology (2006)

13115 Background: MGd is a novel therapeutic agent that concentrates in tumors and generates reactive oxygen species. Pre-clinical models show that MGd enhances in tumors the cytotoxic activity of selected chemotherapies, including taxanes. This phase I trial studied the combination of MGd and docetaxel. Methods: Patients (pts) with advanced solid tumors, adequate bone marrow, hepatic and renal function were eligible. Cohorts of 3 pts were treated with MGd starting at 2.5 mg/kg followed 30 minutes later by docetaxel 75 mg/m 2 . Treatments were repeated q3wks. The primary objective was to determine the maximum tolerated dose (MTD) of MGd in combination with docetaxel on this schedule and to determine the dose limiting toxicities (DLT). The secondary objective was to evaluate the response rate. MGd dose was escalated in successive cohorts while docetaxel dose remained fixed. Results: Sixteen pts were entered (9 males, 7 females) at MGd dose of 2.5 to 10 mg/kg. The median age was 60.5 yrs (range 35 -75). ECOG PS0 (4), 1 (14). Diagnoses included prostate (1); ovarian (2); breast (2) and non-small cell lung (NSCLC) (11). Median number of prior chemotherapy regimens: 2 (range 1–14), 7 pts had previously received a taxane: paclitaxel 5, docetaxel 2. Reported toxicities (all grades) include urine discoloration from excretion of MGd (68%), fatigue (87%), diarrhea (81%) and nausea (56%), Grade 3 neutropenia (37.5%) febrile neutropenia (6%), neuropathy (foot drop) was seen in 1 patient, therefore additional pts were entered (4 registered, but 1 never treated) at 10 mg/kg dose. Recurrence of prior radiation esophagitis was seen in 1 pt therefore it was felt that DLT was reached and study was closed. Responses are as follows: PR by CT in 1 breast and 4 NSCLC, and by PSA in 1 prostate; SD by CT in 1 breast and 2 NSCLC. Conclusion: MGd 10 mg/kg in combination with docetaxel 75 mg/m 2 is feasible and did not increase docetaxel toxicity while showing promising responses. Phase II study of this combination is underway in NSCLC. [Table: see text]
Associations of Oral α-, β-, and γ-Human Papillomavirus Types With Risk of Incident Head and Neck Cancer
Authors: Ilir Agalliu, Susan Gapstur, Zigui Chen, Tao Wang, Rebecca L. Anderson, Lauren Teras, Aimée R. Kreimer, Richard B. Hayes, Neal D. Freedman, Robert D. Burk
Journal: JAMA Oncology (2016)

Prospective studies are needed to examine the temporal relationship between oral human papillomavirus (HPV) detection and risk of head and neck squamous cell carcinoma (HNSCC). Moreover, the oral cavity contains a wide spectrum of α-, β-, and γ-HPV types, but their association with risk of HNSCC is unknown.To prospectively examine associations between α-, β-, and γ-HPV detection in the oral cavity and incident HNSCC.A nested case-control study was carried out among 96 650 participants, cancer free at baseline, with available mouthwash samples in 2 prospective cohort studies: (1) the American Cancer Society Cancer Prevention Study II Nutrition Cohort and (2) the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Incident cases of HNSCC (n = 132) were identified during an average 3.9 years of follow-up in both cohorts. Three controls per case (n = 396) were selected through incidence density sampling and matched on age, sex, race/ethnicity, and time since mouthwash collection.Through a next-generation sequencing assay, DNA from α-, β-, and γ-HPV types were detected. Conditional logistic regression models were used to estimate odds ratios (ORs) and 95% CIs, adjusting for smoking history, alcohol consumption, and detection of HPV-16 for β- and γ-HPVs.Incident HNSCC, which includes cancers of the oropharynx, oral cavity, and larynx.A total of 132 participants developed HNSCC during the follow-up period (103 men and 29 women; average age at baseline, 66.5 years). Oral HPV-16 detection was associated with incident HNSCC (OR, 7.1; 95% CI, 2.2-22.6), with positive association for oropharyngeal SCC (OR, 22.4; 95% CI, 1.8-276.7), but not for oral cavity (OR, 4.5; 95% CI, 0.6-34.7) or laryngeal SCCs (OR, 0.11; 95% CI, 0.01-834.80). Detection of β1-HPV-5 and β2-HPV-38 types, as well as γ-11 and γ-12 species, had ORs for HNSCC that ranged from 2.64 to 5.45 (P < .01 for all comparisons). Detection of β1-HPV-5 type was associated with oropharyngeal (OR, 7.42; 95% CI, 0.98-56.82; P = .054), oral cavity (OR, 5.34; 95% CI, 1.51-18.80; P = .01), and laryngeal SCCs (OR, 2.71; 95% CI, 1.00-7.43; P = .05), whereas γ11- and γ12-HPV species were associated with both oral cavity (OR, 7.47; 95% CI, 1.21-46.17; P = .03; and OR, 6.71; 95% CI, 1.47-30.75; P = .01, respectively) and laryngeal SCCs (OR, 7.49; 95% CI, 1.10-51.04; P = .04 and OR, 5.31; 95% CI, 1.13-24.95; P = .03, respectively).This study demonstrates that HPV-16 detection precedes the incidence of oropharyngeal SCC. Associations of other HPVs, including γ11- and γ12-HPV species and β1-HPV-5 type suggest a broader role for HPVs in HNSCC etiology.
Clinical and pharmacologic study of multidrug resistance reversal with vinblastine and bepridil.
Authors: S C Linn, C K van Kalken, O van Tellingen, P van der Valk, C J van Groeningen, C M Kuiper, H M Pinedo, G Giaccone
Journal: Journal of Clinical Oncology (1994)

PURPOSE To achieve an adequate plasma concentration of bepridil, a calcium channel blocker, which reverts multidrug resistance (MDR) in vitro, when administered in combination with vinblastine in patients with advanced colorectal cancer, a tumor characterized by high MDR1 gene expression. To study the pharmacokinetics of both drugs, tolerability and antitumor activity in relation to the MDR1 expression in tumor tissue. PATIENTS AND METHODS Sixteen colorectal cancer patients entered the study. Bepridil was administered by central venous catheter as 5-mg/kg bolus over 30 minutes, followed by 12 mg/kg for 12 hours and 5 mg/kg for 24 hours. Vinblastine 5 mg/m2 was administered as an intravenous (i.v.) bolus 24.5 hours after the start of bepridil. MDR1/P-glycoprotein (Pgp) expression was assessed in 14 tumor samples by immunohistochemistry and RNase protection assay. RESULTS The bepridil plasma level was greater than 2 mumol/L at the time of vinblastine administration in all patients investigated. At the dose used in the study, bepridil produced a QTc-prolongation more than 50 ms, which prevented further dose escalation. However, cardiac toxicity was asymptomatic in all treated patients, and other side effects were mild. MDR1/Pgp expression was positive in nine of 14 cases. Of fifteen patients assessable for response, one complete remission of 8 months' duration and 14 progressions were observed. The responding patient attained complete remission again when re-treated on progression with vinblastine alone. CONCLUSION Bepridil plasma concentrations needed in vitro to modulate MDR could be achieved in this study with tolerable toxicity; however, despite most tumors being MDR1/Pgp-positive, no response was obtained that could be attributed to the drug combination. Mechanisms of drug resistance other than MDR are probably implicated in drug resistance of colorectal cancer.
LSC 2014 abstract - Inhibition of the HIF/leptin/ObR axis prevents experimental pulmonary hypertension and attenuates treg impairment
Authors: Alice Huertas, Ly Tu, Morane Le Hiress, Nicolas Ricard, Raphaël Thuillet, Carole Phan, Marc Humbert, Christophe Guignabert
Journal: European Respiratory Journal (2014)

Impaired regulatory T lymphocytes (Treg) in pulmonary arterial hypertension (PAH) could be influenced by excessive pulmonary endothelial (P-EC)-derived leptin, a HIF-1α-dependent gene (Huertas, A.  et al . Eur Respir J 2012; 40:895-904). However, the significance of the HIF/leptin/leptin receptor (ObR) axis for PAH susceptibility and/or progression remains unexplored.  Hence, we hypothesized that modulating this axis could reduce the susceptibility/progression of pulmonary hypertension (PH) and protect against Treg impairment.  Herein, we used two in vivo strategies in a rat hypoxic PH model: a curative treatment with dichloroacetate (DCA; a HIF-1α inhibitor) and ObR-deficient rats (ZDF). DCA-treated and ZDF rats developed less severe PH, with lower hemodynamics at right heart catheterization, decreased percentage of pulmonary muscularized arteries and in situ inflammation, compared to untreated and wild type rats, respectively. Moreover, Treg function from DCA-treated and ZDF rats was less impaired in hypoxia, as measured by their leptin signaling pathway activation state (pSTAT3) and by their secretion levels of IL-10 and TGF-β. Importantly, we showed a time-dependent leptin-induced Treg impairment and its reversibility using a soluble leptin neutralizer. Finally, cultured human P-ECs incubated with DCA secreted less leptin, suggesting DCA efficacy in Treg protection.  We are demonstrating for the first time that the HIF/leptin/ObR axis contributes to PH susceptibility/progression, possibly through Treg impairment, highlighting the crucial role of P-EC dysfunction and autoimmunity crosstalk in PAH. This crosstalk may represent a new therapeutical target.