tbuckley/cabot-search huggingface dataset:
Corticosteroids significantly delay the onset of docetaxel-induced fluid retention: final results of a randomized study of the European Organization for Research and Treatment of Cancer Investigational Drug Branch for Breast Cancer.
Authors: M J Piccart, J Klijn, R Paridaens, M Nooij, L Mauriac, R Coleman, M Bontenbal, A Awada, J Selleslags, A Van Vreckem, M Van Glabbeke
Journal: Journal of Clinical Oncology (1997)

PURPOSE To confirm the efficacy of docetaxel in patients with breast cancer previously treated with one chemotherapy regimen for advanced or metastatic disease and to compare the incidence of fluid retention (FR) and skin toxicity when docetaxel is administered with and without prophylactic corticosteroids. PATIENTS AND METHODS Eighty-three patients, pretreated with one chemotherapy regimen for metastatic breast cancer (MBC) with bidimensionally measurable and progressive disease, were eligible for this randomized trial. Docetaxel with prophylactic oral antihistamine was administered at a dose of 50 mg/m2 as a 1-hour infusion on days 1 and 8 every 21 days and patients were randomized to receive methylprednisolone (40 mg days -1, 0, 1, 7, 8, and 9 of each cycle) (arm A) or no methylprednisolone (arm B). RESULTS Twenty-eight patients (34%, 95% confidence interval [CI], 23% to 45%) achieved on objective response. The median time to disease progression and median overall survival time were 5 and 13.5 months, respectively. In total, 415 cycles of docetaxel were administered (arm A: N = 219, median = six; arm B: N = 196, median = five). The most common toxicity observed was grade 3 or 4 neutropenia, which occurred in 79% of patients. Clinically significant nonhematologic side effects included skin reactions and asthenia. In an intent-to-treat analysis, patients who received methylprednisolone premedication had a delayed onset of FR (median time to onset of FR: arm A, 84 days; arm B, 62 days; P = .01) and received a higher median cumulative dose of docetaxel before the onset of FR (arm A, 333 mg/m2; arm B, 215 mg/m2; P = .001). There was no statistically significant difference in the incidence of skin toxicity between the two arms. CONCLUSION Docetaxel, at this dose and schedule, has definite antitumor activity in pretreated MBC patients. Moreover, this is the first randomized trial to show that corticosteroids have a favorable impact on docetaxel-induced FR.
UK law on consent: the need for longer consultations
Authors: P. A. Ballard
Journal: BMJ (2015)

Edozien’s editorial describes the evolution of medical negligence, particularly consent case law up till now.1 Although I agree with Edozien’s description of our current formulaic practice in obtaining consent, and the need to impress on the profession the change in the law, I think one of the greatest hurdles will be creating time …
Iron deficiency may lead to false diagnosis of diabetes
Authors: J. Wise
Journal: BMJ (2015)

Anaemia can lead to a false diagnosis of diabetes by distorting readings of glycated haemoglobin (HbA1c) concentrations, concludes a systematic review of the evidence published in Diabetologia .1

The World Health Organization and the American Diabetes Association both recommend using HbA1c levels to diagnose type 2 diabetes, at a value of 6.5% (48 mmol/mol). This same cut-off level is also used in the United Kingdom and most of Europe.

Emma English from the University of …
TCDD-mediated induction of altered gene expression and oxidative DNA damage in human MCF-7 breast cancer cells exposed to 17β-estradiol
Authors: Po-Hsiung Lin, Kuo-Lung Hou, Ju-Ping Fang, Chia-Hua Lin
Journal: Cancer Research (2004)

Proc Amer Assoc Cancer Res, Volume 45, 2004

1549 

DNA damage induced by 2,3,7,8-tetrachlorodibenzo- p -dioxin (TCDD) and 17β-estradiol (E2) was investigated in human MCF-7 breast cancer cells. The abasic sites resulting from the spontaneous depurination/depyrimidination of the modified bases and the aldehydic base and sugar lesions resulting from the oxidative damage to deoxyribose moiety on the DNA molecules were measured by an aldehyde reactive probe. To investigate the dioxin-mediated modulation of the disposition of E2 to quinones and the subsequent induction of DNA damage, MCF-7 cells were exposed to E2 with or without the pretreatment with TCDD and Ro 41-0960, a catechol-O-methyltransferase (COMT) inhibitor. Results indicated that a 2-fold increase in the number of aldehydic DNA lesions (ADL) was detected in MCF-7 cells exposed to E2 (30 μM) pretreated with TCDD and COMT inhibitor when compared to the corresponding control (p<0.05). Further characterization confirmed that the ADL induced by E2 in MCF-7 cells was predominantly(95%)putrescine-excisable ADL. This evidence indicated that TCDD was capable of modulating the disposition of estrogen to the reactive quinones and the subsequent induction of promutagenic DNA lesions. To examine the TCDD-induced altered gene expression, in one set of experiments, MCF-7 cells were incubated separately with TCDD (10 nM). Specific gene expression, including cytochrome P450 1A1 ( Cyp1A1 ), P450 1B1 ( Cyp1B1 ), 8-oxo-guanine DNA glycosylase 1 ( hOGG1 ), human AP endonuclease ( hAPE ), glutathione reductase ( GR ), glutathione peroxide ( GPx ), Mn-containing superoxide dismutase ( MnSOD ) and Cu- and Zn-containing superoxide dismutase ( Cu/ZnSOD ) genes was determined by semi-quantitative reverse-transcription polymerase chain reaction (RT-PCR) analysis. Results from the RT-PCR analyses indicated that TCDD was able to induce significant increases (2 –3 folds) in the expression of genes including CYP 1A1 and CYP 1B1 and suppress the expression of genes including hOGG1 and hAPE (∼2 folds). mRNA levels of GR , GPx , MnSOD , and Cu/ZnSOD genes were not significantly altered by TCDD exposure. Overall, our investigation confirmed that TCDD can potentiate the formation of quinonoid derivatives of E2 and the subsequent induction of oxidative DNA lesions in MCF-7 cells via induction of imbalances in the expression of genes involving the bioactivation of E2 (CYP 1A1 and CYP 1B1 ) and DNA repair ( hOGG1 and hAPE) . (This work was supported by the National Science Council, Taiwan, through grant NSC 91-2320-B-005-005 and NSC 91-3112-B-005-002).
Long-term remission durability and functional status of patients treated for diffuse histiocytic lymphoma with the CHOP regimen.
Authors: J O Armitage, M A Fyfe, J Lewis
Journal: Journal of Clinical Oncology (1984)

Thirty-eight (51%) of 75 patients treated with CHOP for diffuse histiocytic lymphoma achieved complete remission. Twenty-three of the complete responders are currently alive in complete remission 24-78 months (median, 38 months) after discontinuing therapy. Eleven patients died from recurrent lymphoma and four patients died in complete remission from other causes. Evaluation of the 23 patients alive in complete remission found them mostly well and without serious sequelae to therapy. Comparison with 20 patients who were in the same age range, were disease free after surgery, and had no other therapy for colon cancer revealed only an increased frequency of sexual dysfunction in the chemotherapy-treated lymphoma patients. Sixty-one percent of patients who achieved complete remission with the CHOP regimen are long-term disease-free survivors and are generally well except for an apparently high frequency of sexual dysfunction.
Abstract 381: Characterizing the role of heterochromatin protein 1 gamma in normal intestinal homeostasis and tumorigenesis
Authors: Ka Ian Lio, Alan Clarke, Karen Reed
Journal: Cancer Research (2014)

Abstract Background: Epigenetic modifications are being increasingly recognized to contribute to colorectal cancer formation. Heterochromatin Protein 1 gamma (HP1gamma) has an important role in carcinogenesis and tumorigenesis by regulating several mechanisms, such as heterochromatin formation, gene silencing and DNA replication and repair. The aim of this study was to characterize the role of HP1gamma in normal intestinal homeostasis, tumorigenesis and cancer progression. Methods: The Cbx3 gene (encoding the HP1gamma protein) was conditionally deleted in the murine small intestinal epithelium under normal intestinal homeostasis and in the context of aberrant Wnt signaling using transgenic mouse models. Furthermore, the effect of CBX3 depletion on Wnt activation was investigated using an in vitro system. Results: The level of Cbx3 was significantly up-regulated in small intestinal cancer tissues of mouse models, consistent with our preliminary observations that CBX3 was highly expressed in tumor samples of colorectal cancer patients compared to matched normal tissues. We found a dramatic increase in the lifespan of our colorectal cancer mouse model following the loss of Cbx3. Both in vivo and in vitro studies demonstrated that depletion of Cbx3 leads to decreased transcription of a subset of Wnt target genes and Wnt signaling activity, respectively. Furthermore, marked epigenetic alternations were observed in association patterns of HP1gamma and the heterochromatin markers (H3K9me2, H3K9me3 and H4K20me3) in wild-type and mouse model of colorectal cancer. Conclusions: HP1gamma may play direct or indirect roles in regulating Wnt target gene expression by binding H3K9me3 or H4K20me3 and altering heterochromatin formation. These data provide stepping stones for further investigation of the mechanistic role of HP1gamma in normal intestinal homeostasis, tumor initiation and progression. Citation Format: Ka Ian Lio, Alan Clarke, Karen Reed. Characterizing the role of heterochromatin protein 1 gamma in normal intestinal homeostasis and tumorigenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 381. doi:10.1158/1538-7445.AM2014-381
Alpha 1-protease inhibitor moderates human neutrophil elastase-induced emphysema and secretory cell metaplasia in hamsters
Authors: P J Stone, E C Lucey, G D Virca, T G Christensen, R Breuer, G L Snider
Journal: European Respiratory Journal (1990)

A study was undertaken to determine whether emphysema and airway secretory cell metaplasia, induced in hamsters by intratracheal treatment with human neutrophil elastase (HNE), could be moderated by pretreatment with human alpha 1-protease inhibitor (API). API (4.9 mg) was given intratracheally to hamsters 1 h before 0.3 mg HNE. Eight weeks later, lung volumes and pressure-volume relationships were measured in the anaesthetized animals. Mean linear intercepts and secretory cell indices were measured in lung sections. API given 1 h before HNE moderated the development of bronchial secretory cell metaplasia. The severity of emphysema was reduced by 75%. Clearance studies indicated that 80% of the functional activity of instilled API could be lavaged from the lungs after 1 h, indicating a 4 h half-life in the lavageable compartment of the lungs. We calculate that for 50% protection from emphysema the molar ratio of lavageable API to HNE at the time of HNE instillation was 4.8 as compared with 0.78 for 50% inhibition of elastolytic activity in vitro, indicating that API is only 16% as efficient in vivo as compared with its in vitro HNE inhibitory effectiveness. Nevertheless, we conclude that human API given intratracheally is efficacious against HNE-induced emphysema and secretory cell metaplasia.
MOPP/ABV hybrid chemotherapy for advanced Hodgkin's disease significantly improves failure-free and overall survival: the 8-year results of the intergroup trial.
Authors: J H Glick, M L Young, D Harrington, R L Schilsky, T Beck, R Neiman, R I Fisher, B A Peterson, M M Oken
Journal: Journal of Clinical Oncology (1998)

PURPOSE To compare the efficacy of sequential mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) followed by doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) versus the MOPP/ABV hybrid regimen in advanced-stage Hodgkin's disease. PATIENTS AND METHODS A total of 737 patients with previously untreated stages III2A, IIIB, IVA, or IVB Hodgkin's disease and patients in first relapse after radiotherapy were prospectively randomized to sequential MOPP-ABV or MOPP/ABV hybrid. Of 691 eligible patients, 344 received the sequential regimen and 347 received the hybrid. RESULTS The overall response rate was 95%, with complete responses (CRs) in 79%: 83% on the MOPP/ABV hybrid and 75% on the sequential MOPP-ABVD arm (P = .02). With a median follow-up time of 7.3 years, the 8-year failure-free survival (FFS) rates were 64% for MOPP/ABV hybrid and 54% far sequential MOPP-ABVD (P = .01; 0.69 relative risk of failure, comparing MOPP/ABV hybrid v MOPP-ABVD). The 8-year overall survival rate was significantly better for the MOPP/ABV hybrid (79%) as compared with sequential MOPP-ABVD (71%) (P = .02; relative risk, 0.65). MOPP/ABV hybrid had significantly more life-threatening or fatal neutropenia and pulmonary toxicity than the sequential MOPP-ABVD arm, which was associated with significantly greater thrombocytopenia. Nine cases of acute myelogenous leukemia or myelodysplasia were reported on the sequential regimen as compared with only one on the hybrid (P = .01). CONCLUSION MOPP/ABV hybrid chemotherapy was significantly more effective than sequential MOPP-ABVD. FFS and overall survival were significantly improved on the hybrid arm, which was also associated with a lower incidence of acute leukemia or myelodysplasia.
Abstract 5937: Cardiovascular Phenotypic Characterization of a Missense Adenylyl Cyclase 6 Genetic Variant in Humans
Authors: Gary J Hodges, Robert Gros, Stan Van Uum, Robert A Hegele, J. K Shoemaker, Ross D Feldman
Journal: Circulation (2009)

Adenylyl cyclase (ADCY) is a critical regulator of metabolic and cardiovascular function. The phenotypic effect of a recently discovered hyper-functional ADCY6 S674 variant is unclear. The hypothes...
Modification of empirical antibiotic therapy in community acquired pneumonia
Authors: Daniel Coutinho, Daniel Vaz, Maria Brito, Teresa Shiang
Journal: European Respiratory Journal (2014)

Purpose:  To assess the frequency and identify the factors involved in changing empiric antibiotics during the treatment of community acquired pneumonia (CAP).   Methods:  Retrospective study including all patients admitted to a pulmonology ward of a Portuguese tertiary hospital with primary diagnosis of CAP from January to October 2013. Socio-demographic variables, smoking status and pack-years of smoking, comorbidities, CURB65, laboratory and radiologic findings on admission, microbiologic findings and length of hospital stay were recorded. All p-values    Results:  One hundred and twenty patients were included (mean age 62.4±14.6 years, 82 male, 38 female). The empirical treatment adopted in 96.7% of patients was consistent with international guidelines. Modification of empirical antibiotic treatment occurred in 35 (29.2%) cases, conditioned by lack of clinical response in 30 (85.7%) cases and isolation of a microorganism not covered by treatment in 3 (8.6%). Overall mortality rate was 0.8%. Length of stay was associated with modification of antibiotic therapy (p   Conclusion:  Attending to the low rates of etiological diagnosis in CAP patients, an adequate empirical therapy is crucial for a good outcome in these patients. In our study, almost 30% of patients needed a modification of empirical therapy, due mainly to clinical reasons. The individual factors involved in this change process remained uncertain in our population.
FOLFOXIRI/bevacizumab (bev) versus FOLFIRI/bev as first-line treatment in unresectable metastatic colorectal cancer (mCRC) patients (pts): Results of the phase III TRIBE trial by GONO group.
Authors: Alfredo Falcone, Chiara Cremolini, Gianluca Masi, Sara Lonardi, Vittorina Zagonel, Lisa Salvatore, Patrizia Trenta, Gianluca Tomasello, Monica Ronzoni, Libero Ciuffreda, Alberto Zaniboni, Giuseppe Tonini, Angela Buonadonna, Chiara Valsuani, Silvana Chiara, Chiara Carlomagno, Corrado Boni, Lorenzo Marcucci, Luca Boni, Fotios Loupakis
Journal: Journal of Clinical Oncology (2013)

3505 Background: Doublets plus bev are a standard option for the first-line treatment of mCRC. First-line FOLFOXIRI demonstrated superior RR, PFS and OS compared to FOLFIRI. A phase II study of FOLFOXIRI/bev showed promising activity and manageable toxicities. The objective of the TRIBE trial was to confirm the superiority of FOLFOXIRI vs FOLFIRI when bev is added to chemotherapy (CT). Methods: Eligibility criteria included: measurable and unresectable mCRC, age 18-75 years, no prior CT for advanced disease. Pts were randomized to either FOLFIRI/bev (arm A) or FOLFOXIRI/bev (arm B). Both treatments were administered for a maximum of 12 cycles followed by 5FU/bev until progression. Primary endpoint was PFS. Results: Between July 2008 and May 2011 508 pts were randomized. Pts characteristics were (arm A/arm B): median age 60/61, ECOG PS 1-2 11%/10%, synchronous metastases 81%/79%, multiple sites of disease 74%/70%, liver-only disease 18%/23%, prior adjuvant (adj) 12%/12%. At a median follow-up of 26.6 mos 424 pts progressed and 244 died. Median PFS and OS in the intention to treat (ITT) population were 10.9 and 30.9 mos. FOLFOXIRI/bev significantly increased PFS (median 9.7 vs 12.2 mos, HR 0.73 [0.60-0.88] p=0.0012). Subgroup analyses based on stratification factors (PS, prior adj) and baseline characteristics (site of primary, liver only disease, resection of primary, Kohne score) did not evidence significant interactions between treatment and analyzed factors. A trend toward a more consistent effect of FOLFOXIRI/bev was reported in no prior adj (HR 0.68 [0.55-0.83]) compared to prior adj group (HR 1.18 [0.67-2.08], p for interaction=0.071). Response rate (RECIST) was also significantly improved (53% vs 65% p=0.006). FOLFOXIRI/bev did not increase the R0 secondary resection rate in the ITT population (12% vs 15%, p=0.327), or in the liver-only subgroup (28% vs 32%, p=0.823). Conclusions: FOLFOXIRI/bev compared to FOLFIRI/bev, significantly increases PFS and response rate. Subgroup analysis suggests a possible interaction between prior adj CT and PFS benefit. Secondary resection rate does not differ between treatment arms. Clinical trial information: NCT00719797.
Positive selection is a general phenomenon in the evolution of abalone sperm lysin.
Authors: Y H Lee, T Ota, V D Vacquier
Journal: Molecular Biology and Evolution (1995)

Lysin is a 16kDa acrosomal protein used by abalone sperm to create a hole in the egg vitelline envelope (VE). The interaction of lysin with the VE is species-selective and is one step in the multistep fertilization process that restricts heterospecific (cross-species) fertilization. For this reason, the evolution of lysin could play a role in establishing prezygotic reproductive isolation between species. Previously, we sequenced sperm lysin cDNAs from seven California abalone species and showed that positive Darwinian selection promotes their divergence. In this paper an additional 13 lysin sequences are presented representing species from Japan, Taiwan, Australia, New Zealand, South Africa, and Europe. The total of 20 sequences represents the most extensive analysis of a fertilization protein to date. The phylogenetic analysis divides the sequences into two major clades, one composed of species from the northern Pacific (California and Japan) and the other composed of species from other parts of the world. Analysis of nucleotide substitution demonstrates that positive selection is a general process in the evolution of this fertilization protein. Analysis of nucleotide and codon usage bias shows that neither parameter can account for the robust data supporting positive selection. The selection pressure responsible for the positive selection on lysin remains unknown.
Low Serum Dopamine β-Hydroxylase Activity
Authors: Lawrence D. Horwitz, Victoria L. Travis
Journal: Journal of Clinical Investigation (1978)

To gain information about the nature of disturbances in sympathetic nervous system control in congestive heart failure, serum dopamine beta-hydroxylase (DBH) activity was measured in 30 patients with heart failure of diverse etiologies and 29 healthy normotensive controls. The heart failure patients had been symptomatic for at least 6 wk and had elevated filling pressures, low cardiac indices, low ejection fractions, and wide arteriovenous oxygen differences. DBH activity was 47.1+/-4.7 (mean+/-SE) for the controls and 14.4+/-2.7 IU for the heart failure patients (P < 0.001). Sera from some patients with heart failure had potent inhibitory effects on DBH activity of normal sera. The inhibitor was heat stable and dialyzable and could be demonstrated despite presence of N-ethylmaleimide or Cu(++) in the reaction mixture. However, some inhibitory activity was also present in sera of normal patients; this inhibitory property was not demonstrable in unheated normal serum, but was unmasked when DBH was heat inactivated. It is proposed that although the inhibitor may have been a factor in low serum DBH activity in some patients with heart failure, the major cause of the low activity in the heart failure group was a reduced rate of synthesis or release of the enzyme by sympathetic nerves. This may reflect a dissociation between rates of neural release of norepinephrine and release of DBH in chronic, severe heart failure. The observation of low serum DBH levels in patients with heart failure suggests that measurement of DBH levels may serve as a useful indicator of cardiac dysfunction.
Abstract 1595: Decreased LCAT Protein and Increased Activated Complement Fragments in the Dysfunctional HDL of Individuals With Diabetes and the Hp 2-2 Genotype
Authors: Dan Farbstein, Shiri Kalet-Litman, Mordechai Pollak, Shany Blum, Roy Asaf, Avery Schwartz, Rabea Asleh, Neta Perry, Ido Barkay, Andrew Levy
Journal: Circulation (2009)
Viral Infection of Tumors Overcomes Resistance to PD-1-immunotherapy by Broadening Neoantigenome-directed T-cell Responses
Authors: Norman Woller, Engin Gürlevik, Bettina Fleischmann-Mundt, Anja Schumacher, Sarah Knocke, Arnold M Kloos, Michael Saborowski, Robert Geffers, Michael P Manns, Thomas C Wirth, Stefan Kubicka, Florian Kühnel
Journal: Molecular Therapy (2015)

There is evidence that viral oncolysis is synergistic with immune checkpoint inhibition in cancer therapy but the underlying mechanisms are unclear. Here, we investigated whether local viral infection of malignant tumors is capable of overcoming systemic resistance to PD-1-immunotherapy by modulating the spectrum of tumor-directed CD8 T-cells. To focus on neoantigen-specific CD8 T-cell responses, we performed transcriptomic sequencing of PD-1-resistant CMT64 lung adenocarcinoma cells followed by algorithm-based neoepitope prediction. Investigations on neoepitope-specific T-cell responses in tumor-bearing mice demonstrated that PD-1 immunotherapy was insufficient whereas viral oncolysis elicited cytotoxic T-cell responses to a conserved panel of neoepitopes. After combined treatment, we observed that PD-1-blockade did not affect the magnitude of oncolysis-mediated antitumoral immune responses but a broader spectrum of T-cell responses including additional neoepitopes was observed. Oncolysis of the primary tumor significantly abrogated systemic resistance to PD-1-immunotherapy leading to improved elimination of disseminated lung tumors. Our observations were confirmed in a transgenic murine model of liver cancer where viral oncolysis strongly induced PD-L1 expression in primary liver tumors and lung metastasis. Furthermore, we demonstrated that combined treatment completely inhibited dissemination in a CD8 T-cell-dependent manner. Therefore, our results strongly recommend further evaluation of virotherapy and concomitant PD-1 immunotherapy in clinical studies.