tbuckley/cabot-search huggingface dataset:
Abstract #2937: A purine scaffold heat shock protein 90 (Hsp90) inhibitor destabilizes BCL6 and has specific anti-tumor activity in BCL6 dependent lymphomas in vitro and in vivo
Authors: Leandro Cerchietti, Eloisi Lopes, Shao Ning Yang, Katerina Hatzi, Rita Shaknovich, Ana Robles, Jennifer Walling, Kapil Bhalla, Gabriela Chiosis, Ari Melnick
Journal: Cancer Research (2009)

Although Hsp90 is a rational therapeutic target in cancer, the clinical use of the available quinone Hsp90 inhibitors has been challenged by their liver toxicity. We developed a non-quinone Hsp90 inhibitor named PU-H71. Relatively little is known about the efficacy of Hsp90 inhibitors in diffuse large B-cell lymphomas (DLBCL). The BCL6 transcriptional repressor is the main oncoprotein in DLBCL. The continued presence of the BCL6 is required for survival of DLBCL. Considering that Hsp90 is overexpressed in DLBCLs, we hypothesized that sustained BCL6 expression in DLBCL could be regulated by Hsp90 chaperone activity. In that case, Hsp90 inhibition would affect the maintenance of the malignant phenotype by BCL6. When screened against 12 DLBCL cell lines, PU-H71 selectively killed DLBCLs that are biologically dependent on the BCL6 activity. Cell uptake and Hsp90 inhibition were similar among the cell lines. Treatment of DLBCL cells with PU-H71 resulted in apoptosis and destabilization and subsequent degradation of BCL6. The destabilization of BCL6 occurred at the mRNA and protein levels. The BCL6 protein half-life decreased 5 times in the treated cells. PU-H71-induced downregulation of BCL6 was partially blocked by treatment with a proteasome inhibitor. By co-IP we showed that BCL6 and Hsp90 interact at the nuclear level. Moreover, ChIP assays revealed the presence of both proteins at the critical BCL6 target genes ATR and TP53. In addition, PU-H71 increased the BCL6 mRNA decay rate by 32%. PU-H71 was also active in 19 out of 21 primary DLBCL cells obtained from patient biopsies. To evaluate the in vivo effect, PU-H71 75mg/kg/day or vehicle were administered to Farage, Ly7 and SUDHL4 xenografts (n=5 per treatment and per cell line). By day 10, a 76%, 95% and 95% inhibition of tumor growth was observed in Farage, Ly7 and SUDHL4 mice respectively (p=0.002, p  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 2937.
Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: a systematic review and meta-analysis of cardiovascular outcome trials
Authors: Søren L Kristensen, Rasmus Rørth, Pardeep S Jhund, Kieran F Docherty, Naveed Sattar, David Preiss, Lars Køber, Mark C Petrie, John J V McMurray
Journal: The Lancet Diabetes & Endocrinology (2019)
Cetuximab, capecitabine, oxaliplatin, and radiotherapy as preoperative triple treatment for rectal cancer (CET-CAPOX-RT-Phase-I/II Study): Influence on long-term survival and relevance of biomarkers.
Authors: Torsten Liersch, Lena-Christin Conradi, Thilo Sprenger, Peter Middel, Heiko Sülberg, Franz Rödel, Josef Rüschoff, Tim Beissbarth, Dirk Arnold, Claus Rödel
Journal: Journal of Clinical Oncology (2012)

e14162 Background: Preoperative application of cetuximab and radiochemotherapy combined with 5-FU+oxaliplatin (CET-CAPOX-RT-phase-I/II-study) failed to increase the complete remission rate (pCR, primary endpoint) in rectal cancers. Here, we report longterm survival in respect of biomarkers. Methods: In 45 of 53 patients (85%) total mesorectal excision (TME) was performed with curative intention. Disease-/progression-free survival (DFS/PFS) and overall cancer specific survival (CSS) were correlated with clinicopathological findings (e.g. tumor regression grading (TRG), KRAS-, HER-2-, Ki67-, EGFR-, IGF1R-, Src-, PTEN-, Survivin-, XIAP- and thymidylatesynthase(TS)-status). Results: After triple RCT, ypUICC stages were 0 (4x), I (17x), II (10x), III (14x) and IV (7x); RCT-induced T-level- (49%) and UICC-downcategorizing (53%) correlated with major (38% TRG 3-4) versus minor response (62.3% TRG 0-2) (p=0.005 and p=0.02, respectively). During follow-up (63 months) 7/53 patients with M1-status at surgery died. In 45 patients with M0-status no locoregional failure but in 5 patients metastatic recurrences were detected. DFS at 1, 3 and 5 years was 90.7% (CI: 82.5-99.8), 88.3% (CI: 79.2-98.5) and 88.3% (CI: 79.2-98.5); the CSS was 97.6% (CI: 93.1-100), 95.2% (CI: 89-100), and 90.3% (CI: 82-99.8), respectively. Patients with ypN0-status demonstrated better DFS (p=0.027), PFS (p=0.024) and CSS (p=0.016). KRAS mutations (33%) had no prognostic influence but a positive HER-2-status (18%) seemed to be associated with better CSS (p=0.11). High Ki-67-expression (p=0.09) as well as the loss of RCT-induced Survivin-downregulation (p=0.05) correlated with reduced CSS. No prognostic influence was found for EGFR-, IGF1R-, Src-, PTEN-, XIAP- and TS-expression. Conclusions: The disappointing pCR rate of the CET-CAPOX-RT-phase-I/II-study did not translate to poor longterm survival.
Abstract #1492: Role of microRNA-101 in regulating histone methyltransferase EZH2 in cancer
Authors: Qi Cao, Sooryanarayana Varambally, Ram-Shankar Mani, Sunita Shankar, Xiaosong Wang, Bushra Ateeq, Bharathi Laxman, Xuhong Cao, Kalpana Ramnarayanan, Xiaojun Jing, J. Chad Brenner, Jindan Yu, Jung kim, Bo Han, Patrick Tan, Chandan Kumar-Sinha, Robert Lonigro, Nallasivam Palanisamy, Christopher Maher, Arul Chinnaiyan
Journal: Cancer Research (2009)

Background: Prostate and breast cancer are major causes of cancer-related deaths. Prostate and breast cancer are genetic diseases that develop as a result of dysregulated gene function and environmental factors. Like other cancers, many complex molecular events initiate breast cancer development. Currently, there is no clear understanding of the genetic events that govern the ability of breast cancer cells to migrate and colonize at distant sites. Importantly, however, understanding the molecular mechanisms leading to cancer metastasis may lead to the identification of novel targets for individualized therapeutic intervention. Recent studies indicate that selected miRNAs may play a role in human cancer pathogenesis. MicroRNAs are endogenous non-coding RNAs that regulate gene expression through translational repression by binding to a target mRNA. Our previous studies showed that EZH2 has properties consistent with those of an oncogene, as overexpression promotes cell proliferation, colony formation, and increased invasion of benign cells in vitro and in vivo. Methods and Results: We transfected miR-101 precursor in prostate and breast carcinoma cells and found histone methyltransferase EZH2 was decreased at both transcript and protein levels by qPCR and immunoblots. miR-101 overexpression could also inhibit EZH2-mediated cell proliferation, invasion, and anchorage-independent growth. Re-introduction of EZH2 can rescue its function repressed by miR-101. At the epigenome, introduction of microRNA-101 resulted in reduced histone H3-lysine 27 trimethylation and reactivation of EZH2 repressed tumor suppressors such as ADRB2 and E-cadherin. Furthermore, we have demonstrated that microRNA-101 expression is anti-correlated with EZH2 expression in tumor tissues. Importantly, the genomic loci of microRNA-101 are lost in prostate and breast cancer as well as other aggressive tumors overexpressing EZH2. Conclusion: Our study suggests a mechanism by which genomic loss of miR-101 in cancer leads to overexpression of EZH2 and concomitant dysregulation of epigenetic pathways resulting in cancer progression and metastasis. Approaches to re-introduce microRNA-101 into tumors may have therapeutic benefit by reverting the epigenetic program of tumor cells to a more normal state.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 1492.
Warm Autoimmune Hemolytic Anemia
Authors: Robert A. Brodsky
Journal: New England Journal of Medicine (2019)

Warm autoimmune hemolytic anemia is a chronic, relapsing disease characterized by anemia, reticulocytosis, other evidence of hemolysis, and a positive direct antiglobulin test. First-line therapy (after prompt transfusion of ABO- and RhD-matched blood in patients with severe anemia) involves glucocorticoids and rituximab.
Paternal military service and risk of leukemia among children with Down syndrome: A children’s oncology group (COG) study
Authors: Amy Linabery, Franklin Smith, Leslie Robison, Nyla Heerema, Andrew Olshan, Julie Ross
Journal: Cancer Research (2008)

1068  Active military service may be a surrogate measure for hazardous exposures, such as defoliant agents (e.g., Agent Orange) used widely in the Vietnam War. Such exposures are cause for ongoing health concern among current and former military employees and their families. A prior COG epidemiologic study reported that paternal military service in Vietnam or Cambodia was associated with a modestly increased risk of acute myeloid leukemia (AML) in children; however, the Institute of Medicine concluded in 2004 that there is inadequate information to determine whether or not an association exists between parental military service and cancer in offspring. Children with Down syndrome (DS) have a 10-to-20-fold increased risk of developing acute leukemia compared to children without DS and are therefore a valuable population for the study of leukemia etiology. The purpose of this case-control study analysis was to examine the possible association between paternal military service and acute leukemia in children with DS. Children with DS (controls) were frequency matched by age to children with DS and leukemia (cases) diagnosed in 1997-2002 at ages 0-19 years at participating COG institutions in North America. Fathers (n=275), and mothers serving as surrogates (n=40), of 152 cases (n=93 acute lymphoblastic leukemia (ALL) and n=59 AML) and 163 controls were asked to complete a one-hour telephone interview, including items regarding paternal military service. Unconditional logistic regression was employed to evaluate the association, resulting in odds ratios (ORs) and 95% confidence intervals (CIs). Reference age, paternal age at the time of the index child’s birth, paternal race, and paternal alcohol use were included in the final multivariate models. There was little evidence to support an association between any paternal military service (OR=1.12, 95% CI: 0.95-1.31), service in Vietnam or Cambodia (OR= 2.26, 95% CI: 0.41-12.49), or service in other countries (OR=0.91, 95% CI: 0.40-2.11) and leukemia in the offspring. Similar results were observed among ALL and AML cases analyzed separately. These null results are generally consistent with those from the previous COG study, which found that paternal military service was not associated with leukemia in offspring (not restricted to children with DS); however, our results failed to replicate the former finding that service in Vietnam or Cambodia was modestly associated with AML. Service in Vietnam or Cambodia is a poor surrogate for Agent Orange exposure and is a limitation of the current study; future research should utilize more sophisticated exposure assessment methods. Overall, we found little evidence in support of a causal association between paternal military service and leukemia in children with DS.  Research supported by NIH Grants R01 CA75169 and T32 CA099936 and the Children’s Cancer Research Fund, Minneapolis, MN.
Clonal Evolution of FLT3 -ITD Positive AML in Patients Treated with Midostaurin in Combination with Chemotherapy within the Ratify (CALGB 10603) and AMLSG 16-10 Trials
Authors: Laura K. Schmalbrock, Sibylle Cocciardi, Anna Dolnik, Mridul Agrawal, Frauke Theis, Nikolaus Jahn, Tamara J. Blätte, Verena I. Gaidzik, Peter Paschka, Ekaterina Panina, Walter Fiedler, Helmut R. Salih, Gerald Wulf, Ulrich Germing, Michael Lübbert, Felicitas Thol, Michael Heuser, Richard A. Larson, Arnold Ganser, Richard F. Schlenk, Richard M. Stone, Hartmut Döhner, Konstanze Döhner, Lars Bullinger
Journal: Blood (2017)
Using Google Trends to investigate global COPD awareness
Authors: Anna Boehm, Alex Pizzini, Thomas Sonnweber, Judith Loeffler-Ragg, Claudia Lamina, Guenter Weiss, Ivan Tancevski
Journal: European Respiratory Journal (2019)

<b>Google Trends provides many features that might help to identify geographic regions with low disease awareness and could contribute to a better understanding of the current needs of COPD patients</b>http://bit.ly/2YXfGHz
Phase 2 trial of talabostat and cisplatin in patients with stage IV melanoma
Authors: C. Cunningham, A. C. Pavlick, K. D. Khan, G. Frenette, S. O’Day, J. Stephenson, R. Gonzalez, Z. Yang, V. Vrhovac, M. J. Uprichard
Journal: Journal of Clinical Oncology (2006)

8040 Background: Talabostat (TAL) is an oral inhibitor of dipeptidyl peptidases such as fibroblast activation protein found on the stroma of tumors, draining lymph nodes, and in melanomas. TAL up-regulates cytokines and chemokines, leading to specific T-cell immunity and T-cell independent activity. TAL significantly enhances the activity of cisplatin (C) in mice, and reduces tumor size &gt;60% in melanoma xenografts (A375, A2058). This trial evaluated the activity of TAL and C in patients with Stage IV melanoma. Methods: Open-label, single-arm, Phase 2 study of 4 x 3-week cycles of C-75mg/m 2 (Day 1) and TAL-300mcg BID orally on Days 2–15 with dose-escalation to TAL-400mcg BID depending on tolerability. Single-agent TAL could be continued beyond 4 cycles until disease progression or unacceptable toxicity. Eligibility criteria included: ≤1 prior bio- or chemotherapy regimen, ECOG 0–2, measureable disease per RECIST, no symptomatic CNS metastases, LDH, ALT, and AST &lt;3X ULN. Primary endpoint was disease response; secondary endpoints included PFS, duration of response, and survival. Results: 74 patients (50 men, 24 women) entered the study; median age was 58 years (range 27 to 79); 94.6% were caucasian. Most patients (71.4%) were M1c, and the majority (64.3%) had received at least 1 prior regimen; 72.9% of these had received prior cytokine treatment. A PR was reported in 5/42 evaluable patients (11.9%), and SD for at least 4 cycles in an additional 21/42 (50%). Median PFS and survival are currently estimated at 2.6 months (95% CI 2.1, 3.4) and 8.5 months (95% CI 5.4, infinity), respectively in the ITT population. Most frequent AEs were nausea (46%), fatigue (35%), and vomiting (34%); the high unevaluability rate patients was due to non-compliance related to C-associated N/V (thus the dose of C was reduced mid-study from 100 to 75mg/m 2 ). Grade 3 toxicities were neutropenia, fatigue, and dehydration, all at 3.4%. Grade 4 toxicities were organ failure, renal failure, and PD (1 patient each). 4 patients died due to PD, and 1 each due to renal and organ failure. Conclusions: The combination of TAL and C is active in patients with Stage IV melanoma. Most AEs were related to C-associated nausea and vomiting, limiting the oral delivery of TAL. Additional studies of TAL in melanoma with other drug combinations are warranted. [Table: see text]
Genomic and transcriptomic association studies identify 16 novel susceptibility loci for venous thromboembolism
Authors: Sara Lindström, Lu Wang, Erin N. Smith, William Gordon, Astrid van Hylckama Vlieg, Mariza de Andrade, Jennifer A. Brody, Jack W. Pattee, Jeffrey Haessler, Ben M. Brumpton, Daniel I. Chasman, Pierre Suchon, Ming-Huei Chen, Constance Turman, Marine Germain, Kerri L. Wiggins, James MacDonald, Sigrid K. Braekkan, Sebastian M. Armasu, Nathan Pankratz, Rebecca D. Jackson, Jonas B. Nielsen, Franco Giulianini, Marja K. Puurunen, Manal Ibrahim, Susan R. Heckbert, Scott M. Damrauer, Pradeep Natarajan, Derek Klarin, Paul S. de Vries, Maria Sabater-Lleal, Jennifer E. Huffman, Theo K. Bammler, Kelly A. Frazer, Bryan M. McCauley, Kent Taylor, James S. Pankow, Alexander P. Reiner, Maiken E. Gabrielsen, Jean-François Deleuze, Chris J. O'Donnell, Jihye Kim, Barbara McKnight, Peter Kraft, John-Bjarne Hansen, Frits R. Rosendaal, John A. Heit, Bruce M. Psaty, Weihong Tang, Charles Kooperberg, Kristian Hveem, Paul M. Ridker, Pierre-Emmanuel Morange, Andrew D. Johnson, Christopher Kabrhel, David-Alexandre Trégouët, Nicholas L. Smith
Journal: Blood (2019)
Nanomaterials multifunctional behavior for enlightened cancer therapeutics
Authors: Ganji Seeta Rama Raju, Begum Dariya, Sathish Kumar Mungamuri, Gayathri Chalikonda, Sung-Min Kang, Ishaq N. Khan, Pinninti Santosh Sushma, Ganji Purnachandra Nagaraju, Eluri Pavitra, Young-Kyu Han
Journal: Seminars in Cancer Biology (2019)
Testing the reflexes
Authors: A J Lees, Brian Hurwitz
Journal: BMJ (2019)

### What you need to know

Eliciting the deep tendon reflexes is a vital component of medical assessments in general practice (where 9% of medical problems are believed to be neurological in origin1) and in hospital (where 10-20% of admissions have a primary neurological problem2). Reflex testing contributes to accurate bedside diagnosis in many cases of neuromuscular disease, providing localising diagnostic information that cannot be obtained by any other method (including clinical neurophysiological and neuroradiological investigations). It can be helpful in deciding if neurological, neurosurgical, or orthopaedic referral is required.

This article briefly describes the clinical and pathological rationales for reflex testing and gives practical tips on when and how to elicit the deep tendon reflexes.

When a tendon is tapped briskly its muscle contracts as a consequence of a synchronous volley of afferent impulses from the primary sensory endings of the muscle spindles in the stretched muscle. This involves a two neurone reflex in the spinal or brain stem segment that innervates the muscle (fig 1). At the same time, neurones modulated by descending corticospinal fibres are stimulated which activate opposing muscle groups around the joint dampening the resulting jerk.



Fig 1 
The reflex arc



Patients presenting with motor or sensory symptoms in the limbs should have their reflexes tested to help distinguish between a lower motor neurone lesion (due to damage in the final common pathway that connects the anterior horn cells of the spinal cord with muscles via the nerve roots, plexuses, peripheral nerves, and neuromuscular junction) and …
Loss of heterozygosity at the BRCA2 locus is a common finding in prostate cancer in men with a germline BRCA2 mutation
Authors: S. Dawson, A. Willems, H. Thorne, H. Samaratunga, Y. C. Antill
Journal: Journal of Clinical Oncology (2007)

10539 Background: The prevalence of prostate cancer (PC) is higher in men with a germline mutation in BRCA2 and to a lesser extent BRCA1. It is unclear as to whether a causal relationship exists between these mutations and PC tumorigenesis. The primary aim of this pilot study was to examine for loss of heterozygosity (LOH) in PC samples from men with a known BRCA1/2 mutation. Secondary aims included assessment of the clinical and pathological features of PC in these individuals. Methods: Subjects were male carriers of a germline BRCA1/2 mutation enrolled in kConFab with a diagnosis of PC. LOH analysis was performed using multiplex ligation-dependent probe amplification and confirmed using PCR and sequencing. Clinical data was obtained on all individuals together with histopathology review. Results: In total, 134 pedigrees from BRCA1/2 mutation positive families known to include = 1men with PC were reviewed; 192 men were identified as having PC, however, only 26 were found to carry a pathogenic family specific mutation. Of these, 14 were ineligible as prostate tissue was unavailable. LOH was therefore assessed in 12 subjects (3 BRCA1 and 9 BRCA2). LOH at the BRCA2 locus was seen in 8/9 (89%) subjects with a BRCA2 mutation whilst the ninth showed no LOH. None of the samples from BRCA1 carriers were found to have LOH at the BRCA1 locus. For samples showing LOH, sequencing confirmed loss of the wild-type allele. No unique clinical or histopathological subtype was identified. Conclusions: LOH appears to occur very frequently at the BRCA2 locus in PC arising in men known to carry a germline BRCA2 mutation with LOH heavily biased towards loss of the wild-type allele. Whilst the cohort studied is small, these two results strongly indicate that BRCA2 is a tumour suppressor of PC and is the first gene shown to have this property. In contrast, failure to identify LOH in the BRCA1 samples suggests that BRCA1 is unlikely to be integral in the development of PC. These results should be confirmed in a larger cohort and further research into the mechanisms of BRCA2 induced prostate tumorigenesis is warranted. No significant financial relationships to disclose.
Structure- and NMR-based design of novel Bcl-xL antagonists.
Authors: Michele Rega, Jun Wei, Hongbin Yuan, Shinichi Kitada, John Reed, Maurizio Pellecchia
Journal: Cancer Research (2008)

1278  Pro- and anti-apoptotic members of the Bcl-2 (B-cell lymphocyte/leukemia-2) family of proteins are central regulators of the apoptotic machinery. Over-expression of anti-apoptotic Bcl-2-family proteins, such as Bcl-2, Bcl-xL, Mcl-1, Bfl-1, Bcl-W and Bcl-B, occurs during the pathogenesis or progression of most cancers and leukemias, rendering these proteins potential drug targets. A hydrophobic groove on the surface of the anti-apoptotic Bcl-2 proteins is responsible for sequestering respective pro-apoptotic counterparts that bind via a conserved hetero-dimerization α-helical region, also known as the BH3 domain. We describe a variety of structure and NMR-guided fragment-based approaches to derive novel BH3 mimetics. Preliminary ADME properties as well as cell-based and subsequent in vivo efficacy evaluations of the most potent compounds will be reported.
A Phase 1 accelerated titration dose escalation study of the vascular disrupting agent NPI-2358 utilizing DCE-MRI.
Authors: Patricia LoRusso, Kyri Papadopoulos, Anthony Tolcher, Chia-Chi Lin, Kenneth Lloyd, Elizabeth Morgan, Edward Ashton, Gillian Cropp, Matthew Spear
Journal: Cancer Research (2007)

3987  NPI-2358 is a novel tumor vascular disrupting agent acting on β-tubulin that destabilizes tumor vascular endothelial cells with an additional direct cytotoxic activity. NPI-2358 selectively induces tumor vascular collapse and tumor regression in multiple murine tumor models. NPI-2358 is particularly effective as a single agent in models for breast tumors and sarcomas and in combinations with irinotecan (colorectal model), paclitaxel (breast model) and docetaxel (NSCLC model). A Phase 1 study of NPI-2358 is being conducted in patients with solid tumors and lymphomas. In addition to standard safety monitoring studies and pharmacokinetics, DCE-MRI is being utilized as a pharmacodynamic measure of tumor blood flow. An improved two-compartment model is utilized which incorporates motion correction and an automated arterial input function. This is expected to improve the accuracy and reproducibility in the estimation of the volume transfer constant (Ktrans) by eliminating variability associated with subject motion, contrast injection, and cardiac output. Patients in this study were treated with NPI-2358 administered as a weekly IV infusion. The dose of NPI-2358 is escalated in cohorts of 1-6 patients dependent on observed adverse events. In addition to weekly safety monitoring (including ECGs and blood pressure), echocardiography and pharmacokinetics were performed on Days 1 and 15 (D1 & D15), and a DCE-MRI obtained 4 hours after the first dose was compared to baseline. The dose has been escalated from 2 mg/m2 to 9 mg/m2 without evidence of dose-limiting toxicity or other significant toxicities including cardiovascular or neurotoxicity. D15 Cmax and AUClast have increased linearly from 16.2 ng/ml to 33.6 ng/ml, and from 54.3 ng/ml*hr to 95.4 ng/ml*hr respectively, without evidence of accumulation. The average T1/2 is 4.5 hours. Intrapatient values for Ktrans appear highly reproducible.