tbuckley/cabot-search huggingface dataset:
Mutational Signatures in Breast Cancer: The Problem at the DNA Level
Authors: Serena Nik-Zainal, Sandro Morganella
Journal: Clinical Cancer Research (2017)

Abstract A breast cancer genome is a record of the historic mutagenic activity that has occurred throughout the development of the tumor. Indeed, every mutation may be informative. Although driver mutations were the main focus of cancer research for a long time, passenger mutational signatures, the imprints of DNA damage and DNA repair processes that have been operative during tumorigenesis, are also biologically illuminating. This review is a chronicle of how the concept of mutational signatures arose and brings the reader up-to-date on this field, particularly in breast cancer. Mutational signatures have now been advanced to include mutational processes that involve rearrangements, and novel cancer biological insights have been gained through studying these in great detail. Furthermore, there are efforts to take this field into the clinical sphere. If validated, mutational signatures could thus form an additional weapon in the arsenal of cancer precision diagnostics and therapeutic stratification in the modern war against cancer. Clin Cancer Res; 23(11); 2617–29. ©2017 AACR. See all articles in this CCR Focus section, “Breast Cancer Research: From Base Pairs to Populations.”
Cell-Cycle Therapeutics Come of Age
Authors: Matthew Ingham, Gary K. Schwartz
Journal: Journal of Clinical Oncology (2017)

The ability to sustain unscheduled proliferation is a hallmark of cancer. The normal process of cell division occurs via the cell cycle, a series of highly regulated steps that are orchestrated at the molecular level by specific cyclins that act in association with cyclin-dependent kinases (CDKs). Cyclin D and CDK4/6 play a key role in cell-cycle progression by phosphorylating and inactivating the retinoblastoma protein, a tumor suppressor that restrains G1- to S-phase progression. The first-generation CDK inhibitors demonstrated broad activity upon several CDKs, which likely explains their considerable toxicities and limited efficacy. Palbociclib, ribociclib, and abemaciclib represent a new class of highly specific ATP-competitive CDK4/6 inhibitors that induce reversible G1-phase cell-cycle arrest in retinoblastoma-positive tumor models. Both palbociclib and ribociclib have been approved in combination with hormone-based therapy for the treatment of naïve hormone receptor-positive advanced breast cancer on the basis of an improvement in progression-free survival. In general, CDK4/6 inhibitors are cytostatic as monotherapy but demonstrate favorable tolerability, which has prompted interest in combination approaches. Combinations with phosphatidylinositol 3-kinase and mammalian target of rapamycin inhibitors in breast cancer, and inhibitors of the RAS/RAF/mitogen-activated protein kinase pathway in RAS-mutant cancers are particularly promising approaches that are currently being evaluated. Although the subject of intense preclinical study, predictive biomarkers for response and resistance to these drugs remain largely undefined. CDK4/6 inhibitors have emerged as the most promising of the cell-cycle therapeutics and intense efforts are now underway to expand the reach of this paradigm.
THE INFLUENCE OF THE TIME SCALE USED IN TIME-TO-EVENT ANALYSES ON THE IDENTIFICATION OF TRAINING-RELATED RISK FACTORS IN RUNNING
Authors: Camma Damsted, Rasmus Oestergaard Nielsen, Laurent Malisoux
Journal: British Journal of Sports Medicine (2017)

Background Training errors are considered as one of the main causes of running-related injuries, although few of them have been identified. Time-to-event analysis is a useful tool for researchers within sports injury prevention. In running, the time scale is commonly defined as kilometres or hours of practice. However, using calendar days as time scale could also be relevant. Objective To determine the influence of the time scale on the association between cumulated running distance and injury risk. Design Observational study with a 6-month follow-up. Setting Leisure-time runners. Participants Study participants (n=553) were required to report any running activity and injury using a dedicated internet platform. Assessment of Risk Factors The main exposure was cumulated running distance over the week prior to a given session (time-dependent exposure) and was categorised as &lt;20 km (reference group), between 20 and 30 km, and ≥30 km. Cox regression analyses were used to compare injury rates between exposure states, using either kilometres or calendar days as time scale. Main Outcome Measurements First running-related injury based on a 1-day time loss definition. Results A total of 93 of the runners reported at least one injury. When the time scale was kilometres at risk, the results revealed injury rate to be lower when the participants cumulated a higher running distance. Hazard ratios (HR) were respectively 0.52 (95% confidence intervals −95% CI=0.30–0.89) and 0.40 (95% CI=0.23–0.70) in the 20–30 km and ≥30 km exposure states compared with the reference. When the time scale was calendar days, these HR were respectively 1.38 (95% CI=0.80–2.38) and 1.83 (95% CI=1.12–3.00) for the same exposure states, which suggests that injury risk was higher when more kilometres were cumulated. Conclusions The choice of time scale revealed highly contrasting results, and has to be carefully considered in studies examining risk factors for running-related injuries.
Variation in the EGFR gene is associated with lung cancer
Authors: Weiping Zhang, Marjorie Romkes, Laura P. Stabile, Jill M. Siegfried
Journal: Cancer Research (2005)

3629  The epidermal growth factor receptor (EGFR) plays a critical role in cell growth and differentiation through the EGFR signaling pathway and is believed to be related to development and progression of lung cancer. The EGFR signaling pathway encompasses several steps including ligand binding to the cell surface receptor, receptor dimerization, tyrosine kinase (TK) activation, nuclear translation and transcriptional regulation. Recently, studies have revealed that never smoking lung cancer patients who have somatic mutations in the TK domain of EGFR have a dramatic response to gefitinib, an inhibitor of the EGFR-TK. To elucidate how common EGFR-TK domain mutations are in never smoking lung cancer patients compared to smoking patients, we sequenced the EGFR gene in exons 18-21 (the EGFR-TK domain) from lung tumor tissues of smokers and never smokers. A point mutation in the TK domain of EGFR was found in five of 35 never smokers (frequency of 14.2%), but no mutation was detected in 18 smokers. Mutations found in never smokers included: three heterozygous point mutations at T2573G (L858R) in exon 21, one point mutation at G2320A (V774M) in exon 20, and another point mutation at T2497G (L833V) in exon 21. By sequencing 16 lung cancer cell lines derived from smokers available in our laboratory, one mutant cell line (273T) harboring a EGFR-TK mutation has been identified: A2180G (Y727C) in exon 18, in cells derived from a squamous cell tumor of a female smoker. The in vitro sensitivity to gefitinib by MTT assay of the 273T cell line was slightly lower (IC50 of 17μM) compared to wildtype (WT) cell lines (IC50 of 30μM). This cell line also shows a higher (6-fold) EGFR expression by immunoblot compared to WT cell lines cultured in normal growth medium. During sequencing of the TK domain in blood samples, lung fibroblasts and tumor specimens, a polymorphism in EGFR, G2361A in exon 20, was identified and found to occur at a significantly higher frequency in lung cancer cases (n = 96) than in controls ( n = 32)[OR: 2.86, 95% CI: 1.02 -8.06, P = 0.04], but no difference in the polymorphism frequency was found between smoking (n = 21) and never smoking (n =35) lung cancer cases (OR: 1.78, 95% CI: 0.32 -9.79, P = 0.503). This may suggest that individuals who carry at least one copy of the A allele at nucleotide 2361 in the EGFR-TK domain are more susceptible to lung cancer, independent of smoking status. In addition, homozygote for the A allele at nucleotide 2361 was also most common in lung cancer cases (frequency of 53.7%) vs. controls (frequency of 21.9%). This study confirms the more frequent rate of EGFR-TK domain mutation in never smokers with lung cancer than in smokers, but suggests that EGFR mutation may sometimes occur in smokers, and suggests a novel polymorphism in the EGFR-TK domain may be related to lung cancer risk. Supported by 5R25 CA89507 and P50 CA090440, SPORE in Lung Cancer.
<i>Amanita phalloides</i> Mushroom Poisonings — Northern California, December 2016
Authors: Kathy T. Vo, Martha E. Montgomery, S. Todd Mitchell, Pieter H. Scheerlinck, Daniel K. Colby, Kathryn H. Meier, Susan Kim-Katz, Ilene B. Anderson, Steven R. Offerman, Kent R. Olson, Craig G. Smollin
Journal: MMWR Morbidity and Mortality Weekly Report (2017)

Amanita phalloides, colloquially known as the "death cap," belongs to the Phalloideae section of the Amanita family of mushrooms and is responsible for most deaths following ingestion of foraged mushrooms worldwide (1). On November 28, 2016, members of the Bay Area Mycological Society notified personnel at the California Poison Control System (CPCS) of an unusually large A. phalloides bloom in the greater San Francisco Bay Area, coincident with the abundant rainfall and recent warm weather. Five days later, CPCS received notification of the first human A. phalloides poisoning of the season. Over the following 2 weeks, CPCS was notified of an additional 13 cases of hepatotoxicity resulting from A. phalloides ingestion. In the past few years before this outbreak, CPCS received reports of only a few mushroom poisoning cases per year. A summary of 14 reported cases is presented here. Data extracted from patient medical charts revealed a pattern of delayed gastrointestinal manifestations of intoxication leading to dehydration and hepatotoxicity. Three patients received liver transplants and all but one recovered completely. The morbidity and potential lethality associated with A. phalloides ingestion are serious public health concerns and warrant medical provider education and dissemination of information cautioning against consuming foraged wild mushrooms.
Vitamin D status and skeletal health in black men starting androgen deprivation therapy for prostate cancer.
Authors: Orvar Gunnarsson, Shehzad Basaria, Gretchen Gignac
Journal: Journal of Clinical Oncology (2012)

e15139 Background: Androgen deprivation therapy (ADT) for prostate cancer (PCa) is associated with increased incidence of osteoporosis and fractures. However, much of this information is in Caucasian men. Our aim was to evaluate the prevalence low 25-hydroxyvitamin-D levels and low bone mass in black men starting ADT. Methods: A chart-based retrospective review was conducted on all patients diagnosed with PCa and were deemed appropriate to start ADT in a tertiary care center between September 2007 and July 2010. Baseline data were collected on vitamin-D status and bone mineral density (BMD). Vitamin-D sufficiency was defined as levels ≥30 ng/ml, insufficiency as &lt;30ng/ml and deficiency as ≤20ng/ml. Osteopenia was defined when T scores were between -1 to -2.5 and osteoporosis when T scores ≤ -2.5. Results: A total of 113 black men had evaluable data (mean age 68.9±9.0; range 45-92). At baseline, mean vitamin-D levels were 20.8±9.0 ng/ml (range 4.0-43.0), lumbar Spine T-score was -0.37±1.46 (range -4.20-3.34;) and femoral neck T-score was -0.94±1.04 (range -3.00-1.50). A total of 49.4% of our patients were vitamin-D deficient (13.5±4.6), 33.7% had insufficiency (24.5±3.1) and 16.9% had sufficient vitamin-D levels ( 34.7±4.3). 59.3% of patients had normal BMD, 31.5% had osteopenia and 9.3% had osteoporosis. Conclusions: A significant proportion of black men starting ADT have low Vitamin-D levels and low bone mass. These observations should be taken into account when starting ADT in black men.
Preclinical activity of the Hsp90 inhibitor, ganetespib, in ALK- and ROS1-driven cancers.
Authors: David A Proia, Jaime Acquaviva, Qin Jiang, Liquan Xue, Donald Smith, Julie C Friedland, Suqin He, Jim Sang, Stephan Morris, Yumiko Wada
Journal: Journal of Clinical Oncology (2012)

3090 Background: Ganetespib is a potent inhibitor of heat shock protein 90 (Hsp90) currently being studied in a broad range of clinical trials. Phase II results with ganetespib demonstrated an encouraging objective response rate of 50% in non-small cell lung carcinoma (NSCLC) patients whose tumors contained ALK translocations and had progressed on previous treatments. To further understand the clinical potential of ganetespib in ALK-driven cancers, we evaluated its activity in (1) crizotinib-sensitive and -resistant cancer cells harboring ALK fusions; (2) cells expressing amplified ALK or ROS1 translocations (a kinase structurally similar to ALK); and (3) in combination with crizotinib. Methods: H3122 NSCLC cells, which express EML4-ALK, were treated with ganetespib, crizotinib or the combination, and cell viability and signaling cascades were assessed. Similar experiments were done in cells with amplified, constitutively active ALK (NB-39-nu) or ROS1 kinase fusions (HCC-78, U118MG). To generate a model of crizotinib resistance, NPM-ALK-expressing BaF3 cells were exposed to various crizotinib concentrations. Fifteen different ALK kinase domain substitutions were identified; clonal NPM-ALK/BaF3 cells were made for each resistance mutation and assayed for sensitivity to ganetespib. Results: Ganetespib was 50-fold more potent than crizotinib in killing H3122 cells, and when combined together at sub-lethal doses, displayed strong synergistic anticancer activity. Ganetespib showed similar potency in other cells driven by constitutively active ALK or ROS1 kinase fusions, due to abrogation of their oncogenic kinase activity. All 15 of the crizotinib-resistant NPM-ALK/BaF3 mutant clones were highly sensitive to ganetespib (IC50 values ranging from 14-23 nM), including the 7 mutations reported to date in patients with ALK-driven tumors. Conclusions: Ganetespib effectively inhibits the activity of ALK and ROS1, kinases associated with several tumor types, resulting in marked single agent anticancer activity in cells driven by them. Importantly, ganetespib retains its potency irrespective of the mutational status of ALK. The strong synergy observed between ganetespib and crizotinib warrants further study.
Abstract 316: A Potential Mechanism Involving mTOR For The Expression Of CTGF In Agonist-stimulated Adult Cardiomyocytes
Authors: Kamala P Sundararaj, Sundaravadivel Balasubramanian, Dorea Pleasant, Dhandapani Kuppuswamy
Journal: Circulation Research (2013)

Cardiac hypertrophy ensues as a response to multiple stimuli, such as mechanical stress, neurohumoral activation, growth factors and cytokines. Connective Tissue Growth Factor (CTGF), a potent fibrogenic cytokine, regulates a wide range of biological functions including ECM deposition, wound repair, angiogenesis, migration, differentiation, survival and proliferation. While CTGF overexpression in fibroblasts has been shown to be responsible for fibrosis in various organs, controversy exists about the source of CTGF. Since interstitial fibrosis contributes to ventricular wall stiffness and impairs diastolic function, understating how key factors such as CTGF are expressed and released for the genesis of fibrosis in the hypertrophying heart is important to develop new treatment options. To this end, we explored the signaling pathway(s) involved in the phenylephrine (PE), a hypertrophic agonist, induced expression of CTGF by cardiomyocytes (CMs). Since mammalian target of rapamycin (mTOR) is reported to regulate PE-induced hypertrophic signaling, we hypothesize that mTOR plays a role in PE induced CTGF expression in CMs. To test if CMs produce CTGF, we treated adult feline CMs with phenylephrine. PE stimulated CTGF mRNA expression in a dose and time dependent manner. mTOR forms two distinct complexes, mTORC1 and mTORC2. Whereas both complexes are sensitive to a pharmacological inhibitor Torin1, only mTORC1 is sensitive to Rapamycin inhibition. Our results indicate that PE stimulated CTGF expression could be substantially enhanced by torin1 pretreatment of CMs. Moreover, shRNA mediated silencing of Rictor in CMs, one of the components of mTORC2, significantly augmented the PE induced CTGF mRNA expression. But mTORC1 inhibition using Rapamycin or activation of its downstream target S6K1 using Rapamycin resistant S6K1 adenovirus had no impact in PE -stimulated CTGF expression. The same trend was also observed in the level of secreted CTGF. In conclusion, these results strongly indicate that mTORC2 plays a repressive role in CTGF mRNA expression in adult CMs, and that the loss of such repression in PO myocardium might be a potential mechanism for the onset of cardiac fibrosis in hypertrophying myocardium.
Reply to Rodolfo Montironi, Silvia Gasparrini, Antonio Lopez-Beltran, et al's Letter to the Editor re: Umberto Leone Roberti Maggiore, Simone Ferrero, Massimo Candiani, et al. Bladder Endometriosis: A Systematic Review of Pathogenesis, Diagnosis, Treatment, Impact on Fertility, and Risk of Malignant Transformation. Eur Urol 2017;71:790–807. Benign Müllerian Lesions in the Urinary Bladder: Endometriosis, Endocervicosis, Endosalpingiosis, and Müllerianosis
Authors: Umberto Leone Roberti Maggiore, Simone Ferrero, Massimo Candiani, Edgardo Somigliana, Paola Viganò, Paolo Vercellini
Journal: European Urology (2017)
A randomized controlled trial (RCT) to improve enrollment to cancer clinical trials.
Authors: Catriona Parker, Jeremy Laurence Millar, David M. Dilts, Michael Jefford, Rory Wolfe, Raymond D. Snyder
Journal: Journal of Clinical Oncology (2015)

6514 Background: The proportion of adults with cancer recruited to clinical trials is low. Cancer Council Victoria awards funding to clinical trial sites through its Clinical Trials Management Scheme (CTMS). With this state-wide scheme, there appeared to be a temporal relationship between growth or stability in funding and the number of patients recruited. We undertook a RCT to evaluate the hypothesis that additional funding would improve trial recruitment. Methods: Participating sites (n = 34) were stratified into four strata based on 2011 recruitment numbers. Control sites (n = 18) received usual CTMS funds only while intervention sites (n = 16) received usual funds plus additional funds, proportional to the number of patients recruited in 2011. Additional funding was a median increase of 300% (IQR: 112.5%, 459%) relative to usual CTMS funds and was an average 11.8% (IQR: 8%, 12.3%) increase in a site’s budget. Additional funds were provided in early 2013. Sites were to use funds with the aim of increasing recruitment. The primary study endpoint was the number of new participants recruited to clinical trials in 2013 relative to recruitment in 2012. Negative binomial regression analysis was used to model the endpoint in intention-to-treat analysis adjusting for any imbalance in randomized groups’ features and historical recruitment. An online survey was used to assess strategies employed to increase recruitment. Results: The median number of new trial recruits in 2013 was 21 (IQR: 5, 39) in the control arm and 12.5 (IQR: 3.5, 44.5) in the intervention arm. The ratio of the annual recruitment rate of new trial recruits at the intervention sites compared to control sites in 2013 adjusting for 2012 numbers and institution type was 0.99 (95%CI: 0.69, 1.43, p = 0.96). We found no evidence of a differential intervention effect across strata of higher pre-trial recruitment (χ23 = 2.27, p = 0.5). The survey revealed most intervention sites utilized funds for increased staffing. Conclusions: Additional funding at a site level did not lead to a contemporaneous increase in trial recruitment. A lag-effect may become apparent. In our setting, simply providing more funding without targeting and managing its use does not immediately increase trial accrual.
Panitumumab after progression on cetuximab in patients with KRAS wild-TYPE (WT) metastatic colorectal cancer (MCRC): A single institution experience.
Authors: Antonella Marino, Chiara Caliolo, Francesco Sponziello, Angelo Nacci, Annamaria Quaranta, Enrica Mazzoni, Federica Federico, Pietro Rizzo, Nicola Calvani, Laura Orlando, Paola Schiavone, Palma Fedele, Maria D' Amico, Maria Concetta Chetrì, Margherita Cinefra, Pasqualinda Ferrara, Saverio Cinieri
Journal: Journal of Clinical Oncology (2013)

e14605 Background: Cetuximab and panitumumab are monoclonal antibodies that target EGFR, approved for the treatment of KRAS WT MCRC. Few data describe the activity of panitumumabafter cetuximab-irinotecan based regimen failure. Methods: The aim of this study is to assess if panitumumab has some activity in pts with KRAS WT MCRC that has progressed on prior cetuximab. Results: We retrospectively analysed 25 pts with KRAS WT MCRC who received from 07/2009 to 01/2013 panitumumab after progression on cetuximab. Median age: 63 yrs (40-78), primary site tumor: colon 64%, rectum 36%; synchronous metastases 36%, metachronous 64%. Sites of metastases: liver 44%, liver and lung 8%, other sites 48%. All pts had previously received cetuximab associated with irinotecan (20 pts) or oxaliplatin (5 pts) and subsequently received panitumumab. We withdrew cetuximab because of intolerance in 4 pts (16%), while 21 pts (84%) with ECOG PS 0-1 who had previously responded to cetuximab (ORR plus SD lasting more than 5 months) received panitumumab “off-label” after progression on cetuximab because strongly motivated to continue treatment. Median cycles of panitumumab were 7 (1-54). Only eighteen pts were evaluable for ORR (4 pts received 1-2 cycles and then died, 3 pts too early). We observed one PR (5%); five pts (28%) had SD, median duration 9 months. Median PFS was 5 months (3-28) and median OS 8 months (5-41). All pts were evaluable for toxicity. No pts developed anemia, nor neutropenia. One patient (4%) developed grade 2 CTCAE version 4.03 thrombocytopenia. Eight pts (32%) developed grade 2-3 CTCAE version 4.03 dry skin or rash, 2 pts (8%) grade 2 CTCAE version 4.03 nausea-vomiting. Conclusions: Panitumumab has minimal benefit in pts with KRAS WT MCRC who have progressed on prior cetuximab andthis approach up to date should not be adopted in the clinical practice. Our data anyway show a longer PFS and OS as compared to other few series in the same setting. Further confirmatory prospective studies with larger series of pts would be necessary.