tbuckley/cabot-search huggingface dataset:
Personalized <i>In Vitro</i> and <i>In Vivo</i> Cancer Models to Guide Precision Medicine
Authors: Chantal Pauli, Benjamin D. Hopkins, Davide Prandi, Reid Shaw, Tarcisio Fedrizzi, Andrea Sboner, Verena Sailer, Michael Augello, Loredana Puca, Rachele Rosati, Terra J. McNary, Yelena Churakova, Cynthia Cheung, Joanna Triscott, David Pisapia, Rema Rao, Juan Miguel Mosquera, Brian Robinson, Bishoy M. Faltas, Brooke E. Emerling, Vijayakrishna K. Gadi, Brady Bernard, Olivier Elemento, Himisha Beltran, Francesca Demichelis, Christopher J. Kemp, Carla Grandori, Lewis C. Cantley, Mark A. Rubin
Journal: Cancer Discovery (2017)

Abstract Precision medicine is an approach that takes into account the influence of individuals' genes, environment, and lifestyle exposures to tailor interventions. Here, we describe the development of a robust precision cancer care platform that integrates whole-exome sequencing with a living biobank that enables high-throughput drug screens on patient-derived tumor organoids. To date, 56 tumor-derived organoid cultures and 19 patient-derived xenograft (PDX) models have been established from the 769 patients enrolled in an Institutional Review Board–approved clinical trial. Because genomics alone was insufficient to identify therapeutic options for the majority of patients with advanced disease, we used high-throughput drug screening to discover effective treatment strategies. Analysis of tumor-derived cells from four cases, two uterine malignancies and two colon cancers, identified effective drugs and drug combinations that were subsequently validated using 3-D cultures and PDX models. This platform thereby promotes the discovery of novel therapeutic approaches that can be assessed in clinical trials and provides personalized therapeutic options for individual patients where standard clinical options have been exhausted. Significance: Integration of genomic data with drug screening from personalized in vitro and in vivo cancer models guides precision cancer care and fuels next-generation research. Cancer Discov; 7(5); 462–77. ©2017 AACR. See related commentary by Picco and Garnett, p. 456. This article is highlighted in the In This Issue feature, p. 443
Final Results of the IELSG-19 Randomized Trial of Mucosa-Associated Lymphoid Tissue Lymphoma: Improved Event-Free and Progression-Free Survival With Rituximab Plus Chlorambucil Versus Either Chlorambucil or Rituximab Monotherapy
Authors: Emanuele Zucca, Annarita Conconi, Giovanni Martinelli, Reda Bouabdallah, Alessandra Tucci, Umberto Vitolo, Maurizio Martelli, Ruth Pettengell, Gilles Salles, Catherine Sebban, Armando Lopez Guillermo, Graziella Pinotti, Liliana Devizzi, Franck Morschhauser, Hervé Tilly, Valter Torri, Stefan Hohaus, Andrés J.M. Ferreri, Pierre Zachée, André Bosly, Corinne Haioun, Caterina Stelitano, Monica Bellei, Maurilio Ponzoni, Anne Moreau, Andrew Jack, Elias Campo, Luca Mazzucchelli, Franco Cavalli, Peter Johnson, Catherine Thieblemont
Journal: Journal of Clinical Oncology (2017)

Purpose There is no consensus on the optimal systemic treatment of patients with extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue. The IELSG-19 phase III study, to our knowledge, was the first such study to address the question of first-line treatment in a randomized trial. Patients and Methods Eligible patients were initially randomly assigned (1:1 ratio) to receive either chlorambucil monotherapy (6 mg/m
Single-nucleotide polymorphisms (SNPs) associated with outcomes in patients with localized and metastatic renal cell carcinoma (RCC).
Authors: Carmen Garrigos, Marta Espinosa, Ignacio Osman, Rainiero Ávila, Rafael Medina, Ricardo Melendez, Ana Salinas, Begona Perez Valderrama, Ignacio Duran
Journal: Journal of Clinical Oncology (2017)

437 Background: Despite major advances in the knowledge of the molecular basis of RCC, prognosis is still defined using clinical and pathological parameters. Moreover, no valid predictive biomarkers exist to help us selecting the best treatment for each patient. The aim of this work is analyzing the expression and determining the prognostic and predictive value of 64 key SNPs in 18 genes related with angiogenesis or metabolism of antiangiogenics in patients (pts) with both localized and advanced RCC treated at Hospital Universitario Virgen del Rocío. Methods: DNA from formalin fixed paraffin embedded tumor and non-tumor samples from 99 pts with RCC (26 advanced/ 73 localized) was extracted with QiAGEN Kit and amplified with a specific primers pool for every SNP as determined by the manufacturer (Lifetech). 64 SNPs were chosen based on their Minor Allele Frequency by HapMap, linkage disequilibrium by Haploview, and information from SNP data base (dSNP) and were studied by TaqMan OpenArray (Lifetech). The presence of the selected SNPs was correlated with clinical features, disease free survival (DFS), overall survival (OS), and response to treatment (RR). SPSS v16 was utilized for statistical analyses. Results: In pts with localized RCC, 6 SNPs in 3 genes involved in angiogenesis predicted for worse DFS (VEGFR2: rs10013228, rs2071559; PDGFRA: rs2228230) and shorter OS (VEGFR2: rs10013228; VEGFR3: rs6877011, rs307826) (p&lt;0.05). In the advanced setting, 7 SNPs in genes related to both angiogenesis and metabolism of antiangiogenics determined inferior OS (IL8: rs2227543, NR1l2: rs3814055, NR1l3: rs2307424, PDGFA: rs9800958, PDGFRB: rs2302273) and worse RR (VEGFA: rs699947, rs3025010 p&lt;0.01)). Additionally 3 SNPs in PDGFR-B and VEGF isoforms predicted for better RR (PDGFRB: rs17708574 (p=0.08), VEGFB: rs594942 (p=0.03), VEGFC: rs2016110 (p=0.07). Conclusions: Genetic analysis of RCC patients might provide valuable prognostic/predictive information. A set of SNPs in genes critical to angiogenesis and metabolism of antiangiogenics seem to determine post-surgical outcomes and treatment response in our series. These results are promising. Validation of the results is ongoing.
Never Stop Caring
Authors: Pamela A. Lipsett
Journal: JAMA Surgery (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Surgery HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Surgery journal
A phase I dose-escalation study of TKM-080301, a RNAi therapeutic directed against polo-like kinase 1 (PLK1), in patients with advanced solid tumors: Expansion cohort evaluation of biopsy samples for evidence of pharmacodynamic effects of PLK1 inhibition.
Authors: Donald W. Northfelt, Solomon I. Hamburg, Mitesh J. Borad, Mahesh Seetharam, Kelly Kevelin Curtis, Peter Lee, Brynne Crowell, Linda Vocila, Paul Fredlund, Mark J. Gilbert, Catherine Patricia Mast, Sean C. Semple, Adam D. Judge, Ian MacLachlan, Ramesh K. Ramanathan
Journal: Journal of Clinical Oncology (2013)

TPS2621 Background: TKM-080301 is a lipid nanoparticle formulation of a small interfering RNA (siRNA) directed against PLK1, a serine/threonine kinase that regulates multiple critical aspects of cell cycle progression and mitosis. Anti-tumor activity, RNA interference and pharmacodynamic effects of PLK1 inhibition have been conclusively demonstrated in preclinical models. Demonstration of pharmacodynamic effects of PLK1 inhibition in patient biopsy samples is an exploratory objective of this first-in-human study. Methods: TKME080301 is being evaluated in an open-label, non-randomized, dose-escalation study in patients with advanced solid tumors or lymphoma. Sequential cohorts of 3 to 6 patients receive TKME080301 as a 30-minute intravenous infusion on Days 1, 8 and 15 of a 28-day cycle. Treatment can continue until disease progression, based on overall clinical benefit. Tumor response is determined according to RECIST criteria. Primary study objectives include determination of safety, maximum tolerated dose and dose limiting toxicities. Secondary objectives include characterization of pharmacokinetics and the preliminary assessment of anti-tumor activity. Five cohorts have been enrolled and a tentative Phase 2 dose has been identified. An expansion cohort of 10 patients began enrolling in February, 2013. The focus of the expansion cohort will be to collect additional safety and pharmacokinetic data at the tentative Phase 2 dose, as well as pharmacodynamic data from mandatory biopsy samples. Pre- and post-dose biopsy samples will be evaluated for potential evidence of PLK1 inhibition using 5’ RACE (rapid amplification of cDNA ends) polymerase chain reaction (to identify the predicted PLK1 mRNA cleavage product), histology (to assess for the presence of aberrant mitotic figures) and immunohistochemistry. An update on enrollment and pharmacodynamic evaluations will be presented. Clinical trial information: NCT01262235.
Outcome of adjuvant therapy for biliary tract cancers.
Authors: Anne Horgan, Thomas Walter, Mairead McNamara, Elizabeth McKeever, Trisha Min, Elaine Margaret Wallace, David W Hedley, Monika K. Krzyzanowska, Malcolm J. Moore, Sean P Cleary, Steven Gallinger, Paul David Greig, Stefano Serra, Laura A. Dawson, Jennifer J. Knox
Journal: Journal of Clinical Oncology (2012)

e14592 Background: There are high rates of recurrence following definitive surgery in patients (pts) with biliary tract cancers (BTCs). Our aim was to review patterns of use and effectiveness of adjuvant therapy (AT) (chemotherapy (CT) +/- radiotherapy (RT)) in pts who underwent definitive surgery for BTC at a tertiary referral centre (Princess Margaret Hospital, Toronto). Methods: The clinical/pathological characteristics, treatment details and survival data of all pts with a diagnosis of BTC who had definitive surgery from Jan 1987 to Sept 2011 were reviewed. Results: The cohort includes 297 pts of which 42% were male, with a median age of 63 yrs, performance status 0-1 in 88%. 56 (19%) had well differentiated, 144 (48%) moderately and 60 (2%) poorly differentiated tumors, 37 (12%) data not available (NA). 125 (42%) and 41 (14%) had R0/R1 resection respectively, 131 (44%) NA. 122 (41%) were node positive, 72 (24%) NA. AT was given in 78 (27%) pts, 49 receiving adjuvant CT and 29 concurrent CT/RT; 34% receiving AT in distal bile duct, 14% in gallbladder, 12% in intrahepatic and 27% in klatskin. 179 (60%) pts recurred; 56/78 (72%) in the AT group (grp) and 123/179 (68%) in non-AT grp, 40 (13%) NA. In the AT and non-AT grps, local recurrence was seen in 7/56 (13%) and 26/123 (21%), distant in 32/56 (57%) and 73/123 (59%), and both in 176/56 (30%) and 24/123 (20%) respectively. In multivariate analysis, node positivity, HR 0.54, 95% CI 0.37 – 0.77, (p=0.001) was the only prognostic factor of DFS after definitive surgery. In node positive population (n=48 with AT, 50 without AT), median DFS was greater in AT grp; 13.8mo vs. 10.4mo (p=0.068). DFS and overall survival (OS) for entire cohort is detailed in Table. Conclusions: Given the limits of this retrospective cohort analysis and potential bias to treat higher risk pts, it does appear that pts receiving adjuvant therapy with node positive disease derived DFS advantage following definitive surgery, though not significant, and is probably an effective option for node positive, curative resected, BTC. However, larger prospective trials are paramount. [Table: see text]
Future considerations for clinical dermatology in the setting of 21st century American policy reform: The Medicare Access and Children's Health Insurance Program Reauthorization Act and the Merit-based Incentive Payment System
Authors: John S. Barbieri, Jeffrey J. Miller, Harrison P. Nguyen, Howard P. Forman, Jean L. Bolognia, Marta J. VanBeek
Journal: Journal of the American Academy of Dermatology (2017)
Rates of HER2 overexpression and trastuzumab response in Caribbean women with breast cancer.
Authors: Qi Feng, Donald Elmore Dietz, Gurinder Singh Sidhu, Constantine A Axiotis, Albert S. Braverman
Journal: Journal of Clinical Oncology (2014)

e17558 Background: In eight studies of 2,764 American (BC) patients, HER2+ prevalence ranged from 17 to 32%; median 23% and mean 24%. The results of 26 world studies were similar. Two USA reports comparing Afro-American to Caucasian patients revealed similar HER2+ prevalence in both groups: 29 v. 32% and 21 v. 23%. Four USA studies including 1,517 patients reported Her2+ prevalence’s amongst stage I and II patients; results ranged from 13 to 26%. Methods: The charts of 382 of stage I, II and III BC patients at Kings County Hospital were retrospectively reviewed. The patients were primarily Afro-Caribbean, with some Afro-Americans and others. Patients were considered HER2+ if they were 3+ by IHC, or 2+, with FISH confirmation of gene amplification. Results: Overall, 169 of 382 patients were HER2+ (44.2%). Of the 162 stage I and II patients, 69 (42.6%) were Her2+; 26/68 (38.2%) stage I, and 43/94 (45.7%) stage II. Of the 148 stage I and II patients whose tumor grade was known, 75 (50.1%) were grade 3. Of 220 stage IIIA-C patients, 100 (46%) were HER2+. Of the 208 whose grades were known, 137 (66%) were grade 3. The prevalence of grade 3 tumors for HER2+ and HER2- stage I and II patients was equal (49%); for stage III tumors, 67% of HER2+ and 59% of HER2- were grade 3. Of 52 HER+ stage I-III patients treated with trastuzumab, only 4 (7.7%) recurred, suggesting that HER2 over-expression was clinically significant. Conclusions: Our patients’ grade 3 prevalence was similar to that of other reported BC populations. But HER2+ prevalence was higher in stage I and II Caribbean patients than among the 1,517 reported African-American or Caucasian patients (p=0.0001). The reason for this difference is not clear; confirmation from additional studies of Caribbean patients is needed.
In silico identification of potential inhibitors targeting Streptococcus mutans sortase A
Authors: Hao Luo, Dan-Feng Liang, Min-Yue Bao, Rong Sun, Yuan-Yuan Li, Jian-Zong Li, Xin Wang, Kai-Min Lu, Jin-Ku Bao
Journal: International Journal of Oral Science (2017)

Dental caries is one of the most common chronic diseases and is caused by acid fermentation of bacteria adhered to the teeth. Streptococcus mutans (S. mutans) utilizes sortase A (SrtA) to anchor surface proteins to the cell wall and forms a biofilm to facilitate its adhesion to the tooth surface. Some plant natural products, especially several flavonoids, are effective inhibitors of SrtA. However, given the limited number of inhibitors and the development of drug resistance, the discovery of new inhibitors is urgent. Here, the high-throughput virtual screening approach was performed to identify new potential inhibitors of S. mutans SrtA. Two libraries were used for screening, and nine compounds that had the lowest scores were chosen for further molecular dynamics simulation, binding free energy analysis and absorption, distribution, metabolism, excretion and toxicity (ADMET) properties analysis. The results revealed that several similar compounds composed of benzofuran, thiadiazole and pyrrole, which exhibited good affinities and appropriate pharmacokinetic parameters, were potential inhibitors to impede the catalysis of SrtA. In addition, the carbonyl of these compounds can have a key role in the inhibition mechanism. These findings can provide a new strategy for microbial infection disease therapy. A team of researchers has demonstrated a potential new method of designing treatments for dental caries via computer modeling. Jin-Ku Bao and collaborators from Sichuan University, China, used computer-aided drug design techniques to search libraries of compounds for inhibitors of Streptococcus mutans sortase A. This enzyme allows the bacteria to adhere to teeth and facilitate decay. After narrowing the search to nine candidates, Bao's team modeled the compounds' toxicity and pharmacological properties: how the compounds were likely to be absorbed, distributed, metabolized and excreted by hosts. The team found several potent inhibitors, offering a potential new path for designing treatments for diseases associated with bacterial adhesion. The findings are particularly significant considering the status of S. mutans as the principal cause of dental caries.
Monotherapy with Subcutaneous (SC) Injections of Low Doses of Humanized Anti-CD20 Veltuzumab Is Active in Chronic Lymphocytic Leukemia (CLL)
Authors: Matt Kalaycio, O George Negrea, Rebecca Elstrom, Charles Farber, Heather Horne, William A Wegener, David M Goldenberg
Journal: Blood (2012)
Is cancer information exchanged on social media scientifically accurate?
Authors: Molli Warunek, Elizabeth Gage-Bouchard
Journal: Journal of Clinical Oncology (2017)

186 Background: Cancer patients and their caregivers are increasingly using social media as a platform to share cancer experiences, connect with support, and exchange cancer-related information. Yet, little is known about the nature and scientific accuracy of cancer-related information exchanged on social media. Methods: We conducted a content analysis of 12 months of data from 18 publically available Facebook pages hosted by parents of children with Acute Lymphoblastic Leukemia (n = 15,852 posts), and extracted all exchanges of medically-oriented cancer information. We systematically coded for themes in the nature of cancer-related information exchanged on personal Facebook pages, and two oncology experts independently evaluated the scientific accuracy of each post. Results: Of the 15,852 total posts, 171 posts contained medically-oriented cancer information. The most frequent type of cancer information exchanged was information related to treatment protocols and health services use (35%) followed by information related to side effects and late effects (26%), medication (16%), medical care-giving strategies (13%), alternative and complementary therapies (8%), and other (2%). Overall, 67% of all cancer information exchanged was deemed medically/scientifically accurate, 19% was not medically/scientifically accurate, and 14% described unproven treatment modalities. Conclusions: These findings highlight the potential utility of social media as a cancer-related resource, but also indicate that providers should focus on recommending reliable, evidence-based sources to patients and caregivers.
Factors associated with neurokinin-1 receptor antagonist use among commercially insured cancer patients receiving highly emetogenic chemotherapy.
Authors: Maika Onishi, Sowmya Vasan, Melissa Kate Accordino, Grace Hillyer, Alfred I. Neugut, Jason Dennis Wright, Dawn L. Hershman
Journal: Journal of Clinical Oncology (2017)

24 Background: Neurokinin-1 receptor antagonists (NK1RA) reduce chemotherapy-induced nausea/vomiting (CINV) among patients undergoing highly emetogenic chemotherapy (HEC). We evaluated factors associated with the use of NK1RA in patients treated with HEC. Methods: We performed a retrospective cohort study using Truven Health Marketscan to identify subjects who initiated HEC (doxorubicin or cisplatin) between 2009 and 2013, and concurrently received a NK1RA. Multivariable logistic regression was used, to determine the association of clinical and demographic factors and NK1RA use. Results: Of 32,004 subjects with cancer who were treated with either doxorubicin or cisplatin-containing regimens, 11,325 (33.3%) did not receive an NK1RA. From 2009 to 2013, NK1RA use increased from 53.2% to 73.5% (p &lt; 0.0001). Compared to non-users, NK1RA users were more frequently treated with cisplatin-based regimens (67.9% vs. 32.1%, p &lt; 0.0001), had in-network claims (66.7% vs. 33.3%, p &lt; 0.0001), were younger, and without other comorbidities. Multivariate analysis demonstrated that NK1RA use was more likely with cisplatin compared to doxorubicin (OR = 1.71, 95% CI 1.62-1.81) and with female compared to male patients (OR = 1.75, 95% CI 1.65-1.84). In-network claims (OR 1.26, 95% CI 1.16-1.36) and comprehensive benefit plans (OR = 1.14, 95% CI 1.04-1.25) were associated with increased NK1RA use, compared to out-of network claims and preferred provider organizations (PPO), respectively. Age ≥ 65 years (OR = 0.64, 95% CI 0.5-0.69) and increased comorbidities (comorbidity score of 1: OR 0.88, 95% CI 0.83-0.94; score of 2- OR 0.61, 95% CI 0.56-0.67) versus a score of 0 were associated with decreased NK1RA use. Conclusions: A substantial proportion of patients receiving HEC do not receive NK1RA, and type of insurance coverage was associated with receipt.
Mutant α2-chimaerin signals via bidirectional ephrin pathways in Duane retraction syndrome
Authors: Alicia A. Nugent, Jong G. Park, Yan Wei, Alan P. Tenney, Nicole M. Gilette, Michelle M. DeLisle, Wai-Man Chan, Long Cheng, Elizabeth C. Engle
Journal: Journal of Clinical Investigation (2017)

Duane retraction syndrome (DRS) is the most common form of congenital paralytic strabismus in humans and can result from α2-chimaerin (CHN1) missense mutations. We report a knockin α2-chimaerin mouse (Chn1KI/KI) that models DRS. Whole embryo imaging of Chn1KI/KI mice revealed stalled abducens nerve growth and selective trochlear and first cervical spinal nerve guidance abnormalities. Stalled abducens nerve bundles did not reach the orbit, resulting in secondary aberrant misinnervation of the lateral rectus muscle by the oculomotor nerve. By contrast, Chn1KO/KO mice did not have DRS, and embryos displayed abducens nerve wandering distinct from the Chn1KI/KI phenotype. Murine embryos lacking EPH receptor A4 (Epha4KO/KO), which is upstream of α2-chimaerin in corticospinal neurons, exhibited similar abducens wandering that paralleled previously reported gait alterations in Chn1KO/KO and Epha4KO/KO adult mice. Findings from Chn1KI/KI Epha4KO/KO mice demonstrated that mutant α2-chimaerin and EphA4 have different genetic interactions in distinct motor neuron pools: abducens neurons use bidirectional ephrin signaling via mutant α2-chimaerin to direct growth, while cervical spinal neurons use only ephrin forward signaling, and trochlear neurons do not use ephrin signaling. These findings reveal a role for ephrin bidirectional signaling upstream of mutant α2-chimaerin in DRS, which may contribute to the selective vulnerability of abducens motor neurons in this disorder.