tbuckley/cabot-search huggingface dataset:
Phase II Study of Neoadjuvant Androgen Deprivation Followed by External-Beam Radiotherapy With 9 Months of Androgen Deprivation for Intermediate- to High-Risk Localized Prostate Cancer
Authors: Jonas J. Heymann, Mitchell C. Benson, Kathleen M. O'Toole, Bozena Malyszko, Rachel Brody, Darleen Vecchio, Peter B. Schiff, Mahesh M. Mansukhani, Ronald D. Ennis
Journal: Journal of Clinical Oncology (2006)

Purpose To evaluate the toxicity and efficacy of individualized neoadjuvant androgen deprivation (AD) to maximal response followed by external beam radiotherapy (RT) with continued AD for a total of 9 months in a prospective phase II trial. Patients and Methods One hundred twenty-three patients received a total of 9 months of flutamide and luprolide combined with RT. RT initiation was individualized to begin after maximum response to AD as assessed by monthly digital rectal examination and prostate-specific antigen (PSA). The neoadjuvant phase was restricted to no more than 6 months. Results Median time to initiation of RT was 4.7 months. Indications to begin RT (and their rates) were undetectable PSA (28%), PSA unchanged from one month to the next (46%), PSA rising from one month to the next (10%), 6 months of AD (14%), and other (2%). Five-year outcomes were biochemical disease-free survival, (DFS) 63% ± 7%; clinical DFS, 75% ± 5%; cancer-specific survival, 99% ± 1%; and overall survival, 89% ± 3%. Patients initiating RT after 6 months of AD had significantly lower biochemical and clinical DFS. Those patients whose testosterone recovered to normal after completion of AD had a significantly superior survival rate. Of those patients potent before treatment, 65% remained so at last follow-up. Conclusion The combination of 9 months of AD and RT, with initiation of RT individualized on the basis of maximum response to AD, achieves disease control rates comparable with past studies, while preserving potency in many patients. Further studies are warranted to determine the optimal combination of AD and RT in this patient population.
Antiapoptotic Function of Apoptosis Inhibitor 2-MALT1 Fusion Protein Involved in t(11;18)(q21;q21) Mucosa-Associated Lymphoid Tissue Lymphoma
Authors: Yoshitaka Hosokawa, Hiroko Suzuki, Yasuyuki Suzuki, Ryosuke Takahashi, Masao Seto
Journal: Cancer Research (2004)

Abstract t(11;18)(q21;q21) is a characteristic chromosomal translocation in mucosa-associated lymphoid tissue (MALT) type lymphoma, and this translocation results in fusion transcript of apoptosis inhibitor 2 (API2), also known as c-IAP2, and MALT translocation gene 1 (MALT1). Although the API2-MALT1 fusion protein has been shown to enforce activation of nuclear factor κB signaling, its precise role in the apoptotic signaling pathway remains to be established. To identify proteins that bind the API2-MALT1 protein, we used coimmunoprecipitation and SDS-PAGE, followed by liquid chromatography-electrospray ionization tandem mass spectrometry. As a result, three important regulators of apoptosis, Smac, HtrA2, and TRAF2, and three other proteins were identified as potential API2-MALT1-binding proteins. Immunoprecipitation analyses verified that API2-MALT1 indeed binds to both exogeneous and endogeneous Smac proteins. It is especially noteworthy that stably transfected API2-MALT1 significantly suppressed both UV- and etoposide-induced apoptosis in HeLa cells, thus demonstrating for the first time that API2-MALT1 indeed possesses antiapoptotic function. Furthermore, API2-MALT1 significantly suppressed Smac-promoted apoptosis in UV-irradiated HeLa cells. Thus, our results provide direct experimental evidence that API2-MALT1 can confer resistance to apoptosis, at least in part, by neutralizing apoptosis promoted by Smac.
Maturation Stage of T-cell Acute Lymphoblastic Leukemia Determines BCL-2 versus BCL-XL Dependence and Sensitivity to ABT-199
Authors: Triona Ni Chonghaile, Justine E. Roderick, Cian Glenfield, Jeremy Ryan, Stephen E. Sallan, Lewis B. Silverman, Mignon L. Loh, Stephen P. Hunger, Brent Wood, Daniel J. DeAngelo, Richard Stone, Marian Harris, Alejandro Gutierrez, Michelle A. Kelliher, Anthony Letai
Journal: Cancer Discovery (2014)

Abstract Acute lymphoblastic leukemia (ALL) is a hematopoietic malignancy derived from immature B-lymphoid and T-lymphoid cells (T-ALL). In T-ALL, there is an early T-cell progenitor (ETP) subgroup that has a very high risk for relapse. In this study, we used mitochondrial BH3 profiling to determine antiapoptotic protein dependencies in T-ALL. We found that T-ALL cell lines and primary patient samples are dependent upon BCL-XL, except when the cancer bears an ETP phenotype, in which case it is BCL-2 dependent. These distinctions directly relate to differential sensitivity to the BH3 mimetics ABT-263 and ABT-199, both in vitro and in vivo. We thus describe for the first time a change of antiapoptotic protein dependence that is related to the differentiation stage of the leukemic clone. Our findings demonstrate that BCL-2 is a clinically relevant target for therapeutic intervention with ABT-199 in ETP-ALL. Significance: ETP T-ALL is a treatment-resistant subtype of T-ALL for which novel targeted therapies are urgently needed. We have discovered, through BH3 profiling, that ETP-ALL is BCL-2 dependent and is very sensitive to in vitro and in vivo treatment with ABT-199, a drug well tolerated in clinical trials. Cancer Discov; 4(9); 1074–87. ©2014 AACR. This article is highlighted in the In This Issue feature, p. 973
Eosinophils in atopic dermatitis
Authors: KRISTIN M. LEIFERMAN
Journal: Allergy (1989)

The eosinophilic granulocyte is commonly associated with allergic inflammation. Although blood eosinophilia frequently accompanies atopic dermatitis, accumulation of tissue eosinophils is not prominent. Recent studies have elucidated the structure, content, and activities of the eosinophil. In addition, immunofluorescence localization of eosinophil granulate proteins has shown that eosinophils disrupt in tissue depositing toxic granule proteins in several diseases. Here, evidence for eosinophil degranulation in atopic dermatitis is presented and mechanisms whereby eosinophil degranulation may mediate pathophysiologic effects in atopic dermatitis and related conditions are discussed.
The impact of residential proximity to ophiolitic units in the development of asbestos related diseases
Authors: Mehmet Bayram, Isa Döngel, Nur Dilek Bakan, Huseyin Yalcin
Journal: European Respiratory Journal (2011)

Aim:  To determine the relation between risk of asbest related diseases (ARD) and the proximity of birthplaces to ophiolitic units (OU) which contains serpentin in province of Sivas, Turkey.   Method:  Records between 2000 and 2010 of mesothelioma, pleural plaque (PP), prostate cancer and breast cancer patients from cancer registry were reviewed. Samples were obtained from indoor plasters and source of plasters. Birthplaces of patients were marked on a map with OU modified from geological map (mesothelioma: red square, PP: black star and OU: green areas).  The distance between residental area of birthplace of the patients and OU were measured.   Result:  Birthplaces of 100 mesothelioma, 133 PP, 161 prostate cancer and 139 breast cancer patients were included. Samples of plasters and soil were identified as 95% serpentine. Mean distance to OU of patients with ARD and control cases were 5.9 and 15.5 kilometers.  Logistic regression analysis after age adjustment between groups showed that risk for ARD increased with decrease of distance to OU (Odds ratio: 1.72 for every 5 km decrease).   Conclusion:  The proximity of birthplace to OU increases the risk of ARD.
Novel concepts in HDL pharmacology
Authors: A. T. Remaley, G. D. Norata, A. L. Catapano
Journal: Cardiovascular Research (2014)

High-density lipoproteins (HDL) are a target for drug development because of their proposed anti-atherogenic properties. In this review, we will briefly discuss the currently established drugs for increasing HDL-C, namely niacin and fibrates, and some of their limitations. Next, we will focus on novel alternative therapies that are currently being developed for raising HDL-C, such as CETP inhibitors. Finally, we will conclude with a review of novel drugs that are being developed for modulating the function of HDL based on HDL mimetics. Gaps in our knowledge and the challenges that will have to be overcome for these new HDL based therapies will also be discussed.
The potential role of hepatitis C virus in the pathogenesis of the neurological syndrome in chronic hepatitis C
Authors: C Caudai, D Maimone, P Almi, P Annunziata, I Bastianoni, C A Boggiano, G C Guazzi, M Padula, P E Valensin
Journal: Gut (1997)

A 72 year old man developed chronic sensory neuropathy (CSN) during chronic hepatitis C (HCV) infection. Neurological symptoms began one year after acute HCV hepatitis and slowly worsened over three years. No conventional cause for CSN was found. Circulating antinervous tissue antibodies (including anti-Hu) and inflammatory infiltrates in sural nerve biopsy specimens were absent. However, the presence of anti-HCV antibody and HCV-RNA in cerebrospinal fluid indicated that HCV had reached the intrathecal compartment, suggesting the direct viral involvement in the pathogenesis of CSN.
p53-Defective Tumors With a Functional Apoptosome-Mediated Pathway: A New Therapeutic Target
Authors: Tetsuo Mashima, Tomoko Oh-hara, Shigeo Sato, Mikiko Mochizuki, Yoshikazu Sugimoto, Kanami Yamazaki, Jun-ichi Hamada, Mitsuhiro Tada, Tetsuya Moriuchi, Yuichi Ishikawa, Yo Kato, Hiroshi Tomoda, Takao Yamori, Takashi Tsuruo
Journal: JNCI Journal of the National Cancer Institute (2005)

Background: Although cancer cells appear to maintain the machinery for intrinsic apoptosis, defects in the pathway develop during malignant transformation, preventing apoptosis from occurring. How to specifically induce apoptosis in cancer cells remains unclear. Methods: We determined the apoptosome activity and p53 status of normal human cells and of lung, colon, stomach, brain, and breast cancer cells by measuring cytochrome c–dependent caspase activation and by DNA sequencing, respectively, and we used COMPARE analysis to identify apoptosome-specific agonists. We compared cell death, cytochrome c release, and caspase activation in NCI-H23 (lung cancer), HCT-15 (colon cancer), and SF268 (brain cancer) cells treated with Triacsin c, an inhibitor of acyl-CoA synthetase (ACS), or with vehicle. The cells were mock, transiently, or stably transfected with genes for Triacsin c–resistant ACSL5, dominant negative caspase-9, or apoptotic protease activating factor-1 knockdown. We measured ACS activity and levels of cardiolipin, a mitochondrial phospholipid, in mock and ACSL5-transduced SF268 cells. Nude mice carrying NCI-H23 xenograft tumors (n = 10) were treated with Triacsin c or vehicle, and xenograft tumor growth was assessed. Groups were compared using two-sided Student t tests. Results: Of 21 p53-defective tumor cell lines analyzed, 17 had higher apoptosome activity than did normal cells. Triacsin c selectively induced apoptosome-mediated death in tumor cells (caspase activity of Triacsin c–treated versus untreated SF268 cells; means = 1020% and 100%, respectively; difference = 920%, 95% CI = 900% to 940%; P <.001). Expression of ACSL5 suppressed Triacsin c–induced cytochrome c release and subsequent cell death (cell survival of Triacsin c–treated mock- versus ACSL5-transduced SF268 cells; means = 40% and 83%, respectively; difference = 43%, 95% CI = 39% to 47%; P <.001). ACS was also essential to the maintenance of cardiolipin levels. Finally, Triacsin c suppressed growth of xenograft tumors (relative tumor volume on day 21 of Triacsin c–treated versus untreated mice; means = 4.6 and 9.6, respectively; difference = 5.0, 95% CI = 2.1 to 7.9; P = .006). Conclusions: Many p53-defective tumors retain activity of the apoptosome, which is therefore a potential target for cancer chemotherapy. Inhibition of ACS may be a novel strategy to induce the death of p53-defective tumor cells.
Tamoxifen Therapy for Primary Breast Cancer and Risk of Contralateral Breast Cancer
Authors: C. I. Li, K. E. Malone, N. S. Weiss, J. R. Daling
Journal: JNCI Journal of the National Cancer Institute (2001)

Background: Women diagnosed with breast cancer have a twofold to sixfold greater risk of developing contralateral breast cancer than women in the general population have of developing a first breast cancer. Tamoxifen therapy reduces this risk, but it is unclear if this benefit exists for both estrogen receptor (ER)-positive and ER-negative contralateral tumors. Methods: Using data from a population-based tumor registry that collects information on the ER status of breast tumors, we followed 8981 women residing in western Washington State who were diagnosed with a primary unilateral invasive breast cancer during the period from 1990 through 1998 to identify cases of contralateral breast cancer. We restricted our analyses to women who were at least 50 years old and whose first breast cancer had a localized or regional stage; women who received adjuvant hormonal therapy but not chemotherapy (n = 4654) were classified as tamoxifen users, while those who received neither adjuvant hormonal therapy nor chemotherapy (n = 4327) were classified as nonusers of tamoxifen. By reviewing selected patient abstracts, we estimated that 94% of the subjects were classified correctly with respect to tamoxifen use. The risk of contralateral breast cancer associated with tamoxifen use was estimated with the use of Cox regression. All statistical tests were two-sided. Results: Of the 89 tamoxifen users and 100 nonusers of tamoxifen diagnosed with contralateral breast cancer, 112 had ER-positive tumors, 20 had ER-negative tumors, and 57 had tumors with an ER status that was unknown or had not been determined by an immunohistochemical assay. The risk of developing an ER-positive and an ER-negative contralateral tumor among tamoxifen users was 0.8 (95% confidence interval [CI] = 0.5 to 1.1) and 4.9 (95% CI = 1.4 to 17.4), respectively, times that of nonusers of tamoxifen. This difference in risk by ER status was statistically significant (P<.0001). Conclusions: Tamoxifen use appears to decrease the risk of ER-positive contralateral breast tumors, but it appears to increase the risk of ER-negative contralateral tumors.
Abbreviated Breast Magnetic Resonance Imaging (MRI): First Postcontrast Subtracted Images and Maximum-Intensity Projection—A Novel Approach to Breast Cancer Screening With MRI
Authors: Christiane K. Kuhl, Simone Schrading, Kevin Strobel, Hans H. Schild, Ralf-Dieter Hilgers, Heribert B. Bieling
Journal: Journal of Clinical Oncology (2014)

We investigated whether an abbreviated protocol (AP), consisting of only one pre- and one postcontrast acquisition and their derived images (first postcontrast subtracted [FAST] and maximum-intensity projection [MIP] images), was suitable for breast magnetic resonance imaging (MRI) screening.We conducted a prospective observational reader study in 443 women at mildly to moderately increased risk who underwent 606 screening MRIs. Eligible women had normal or benign digital mammograms and, for those with heterogeneously dense or extremely dense breasts (n = 427), normal or benign ultrasounds. Expert radiologists reviewed the MIP image first to search for significant enhancement and then reviewed the complete AP (consisting of MIP and FAST images and optionally their nonsubtracted source images) to characterize enhancement and establish a diagnosis. Only thereafter was the regular full diagnostic protocol (FDP) analyzed.MRI acquisition time for FDP was 17 minutes, versus 3 minutes for the AP. Average time to read the single MIP and complete AP was 2.8 and 28 seconds, respectively. Eleven breast cancers (four ductal carcinomas in situ and seven invasive cancers; all T1N0 intermediate or high grade) were diagnosed, for an additional cancer yield of 18.2 per 1,000. MIP readings were positive in 10 (90.9%) of 11 cancers and allowed establishment of the absence of breast cancer, with a negative predictive value (NPV) of 99.8% (418 of 419). Interpretation of the complete AP, as with the FDP, allowed diagnosis of all cancers (11 [100%] of 11). Specificity and positive predictive value (PPV) of AP versus FDP were equivalent (94.3% v 93.9% and 24.4% v 23.4%, respectively).An MRI acquisition time of 3 minutes and an expert radiologist MIP image reading time of 3 seconds are sufficient to establish the absence of breast cancer, with an NPV of 99.8%. With a reading time < 30 seconds for the complete AP, diagnostic accuracy was equivalent to that of the FDP and resulted in an additional cancer yield of 18.2 per 1,000.
S10 Are We Overlooking Persistent Small Airways Dysfunction in Community-Managed Asthma?: Abstract S10 Table 1
Authors: WJ Anderson, E Zajda, BJ Lipworth
Journal: Thorax (2012)

<h3>Background</h3> It is unknown if small airways dysfunction persists in asthmatics receiving standard community treatment. Impulse oscillometry (IOS) is a sensitive measure of small airways function. We wished to assess the degree of small airways dysfunction in a cross-section of community-managed asthmatics. <h3>Methods</h3> We analysed primary care referral data from persistent asthmatics (n=378) receiving standard community therapy, screened using spirometry and IOS. We compared patients by British Thoracic Society asthma treatment step (2–4). <h3>Results</h3> Step 2 were not different from step 3 patients receiving long-acting beta-agonist (LABA). Step 4 patients differed from step 2 by: higher inhaled corticosteroid (ICS) dose (p&lt;0.0001); lower forced expiratory volume in 1s (FEV1%, p=0.02) and forced mid-expiratory flow (FEF25–75%, p=0.001); higher frequency of resonance (Fres, p=0.02) and peripheral airway resistance (R5-R20, p=0.006); while for steps 3 vs. 4, there were differences in Fres (p&lt;0.05) and R5-R20 (p=0.006). There were high proportions of abnormality for R5-R20 (&gt;0.03kPa/L/s) at steps 2, 3 &amp; 4 respectively: 64.6%, 63.5% and 69.9%. Step 2 patients receiving extra-fine particle ICS demonstrated lower total airway resistance at 5Hz (R5) versus patients receiving standard ICS (124.1% vs. 138.3%, p&lt;0.05), with no difference in FEV1 (Table 1). At step 4, R5 remained elevated at 141.3% despite concomitant LABA, with only 2.4% using extra-fine ICS. <h3>Conclusion</h3> There is persistent small airways dysfunction despite treatment at steps 2–4 of current asthma guidelines. Extra-fine ICS may reduce airway resistance at step 2. Prospective studies with extra-fine ICS±LABA at steps 2–4 are required to discern whether improving small airways function might result in long-term improved control.
Nitric Oxide Synthase Inhibition Enhances the Tumor Vascular-Damaging Effects of Combretastatin A-4 3-<i>O</i>-Phosphate at Clinically Relevant Doses
Authors: Gillian M. Tozer, Vivien E. Prise, Gemma Lewis, Shaoping Xie, Ian Wilson, Sally A. Hill
Journal: Clinical Cancer Research (2009)

The therapeutic potential of combining the prototype tumor vascular-disrupting agent combretastatin A-4 3-O-phosphate (CA-4-P) with systemic nitric oxide synthase (NOS) inhibition was investigated preclinically.Vascular response (uptake of (125)I-labeled iodoantipyrine; laser Doppler flowmetry) and tumor response (histologic necrosis; cytotoxicity and growth delay) were determined.Inducible NOS selective inhibitors had no effect on blood flow in the P22 rat sarcoma. In contrast, the non-isoform-specific NOS inhibitor N(omega)-nitro- l-arginine (l-NNA; 1 and 10 mg/kg i.v. or chronic 0.1 or 0.3 mg/mL in drinking water) decreased the P22 blood flow rate selectively down to 36% of control at 1 hour but did not induce tumor necrosis at 24 hours. CA-4-P, at clinically relevant doses, decreased the P22 blood flow rate down to 6% of control at 1 hour for 3 mg/kg but with no necrosis induction. However, l-NNA administration enhanced both CA-4-P-induced tumor vascular resistance at 1 hour (chronic l-NNA administration) and necrosis at 24 hours, with 45% or 80% necrosis for 3 and 10 mg/kg CA-4-P, respectively. Bolus l-NNA given 3 hours after CA-4-P was the most effective cytotoxic schedule in the CaNT mouse mammary carcinoma, implicating a particular enhancement by l-NNA of the downstream consequences of CA-4-P treatment. Repeated dosing of l-NNA with CA-4-P produced enhanced growth delay over either treatment alone in P22, CaNT, and spontaneous T138 mouse mammary tumors, which represented a true therapeutic enhancement.The combination of NOS inhibition with CA-4-P is a promising approach for targeting tumor vasculature, with relevance for similar vascular-disrupting agents in development.
Predicting VO2max in elderly: Could equations established in younger subjects be used?
Authors: Cristina Pistea, Evelyne Lonsdorfer, Stéphane Doutreleau, Irina Enache, Thomas Vogel, Anne Charloux
Journal: European Respiratory Journal (2012)

Background: Equations recommended by the ERS/ATS for estimating maximal oxygen consumption (VO2max or peak) have been established in population samples with few subjects > 70 years. As a result, predicted values (pred) for elderly are largely extrapolated from linear models.

We aimed to determine if VO2max values measured in people aged >70 years diverged from pred using recommended equations.

Methods: We measured VO2peak in 184 subjects (40% women and 60% men) aged 69-89 years and used Hansen's equations for estimating VO2max.

Results: There were 49 non-diseased (ND) males and 62 with at least one disease (D) (COPD, cancer, coronary disease). In females, 34 were ND, and 39 had at least one D. VO2peak was 1.82 (0.44) L/min, 106% of pred, in ND males and 1.34 (0.45) L/min, 82% of pred, in D males. In ND females, VO2peak was 1.17 (0.29) L/min, 111% of pred, and was 1.07 (0.26) L/min, 102% of pred, in D females (NS).

![Figure][1] 



4% of ND males and 3% of ND females had VO2peak < 70% of pred. The mean difference between pred VO2max and measured VO2peak was -0.09 L/min in ND males and -0.11 L/min in ND females. 90% of (predicted-measured VO2max) differences ranged between -0.77 and +0.58 L/min in ND males, and -0.57 and +0.36 L/min in ND females. Subjects with higher level of activity/week had higher VO2max (p<0.001.

Conclusions : These results support the use of Hansen's equations in elderly in populations comparable to ours.

 [1]: pending:yes