tbuckley/cabot-search huggingface dataset:
Evaluation of flap endonuclease-1 (FEN1) as a prognostic, predictive, and therapeutic target in breast (BC) and ovarian cancer (OVC).
Authors: Tarek M. A. Abdel-Fatah, Roslin Russell, David J. Maloney, Vivek Mohan, Dorjbal Dorjsuren, Oscar Rueda, Ipek Gorguc, Abhik Mukherjee, Ajit Jadhav, Anton Simeonov, David M. Wison III, Devika Ravindra Agarwal, Graham Ball, Stephen Chan, Carlos Caldas, Ian O. Ellis, Srinivasan Madhusudan
Journal: Journal of Clinical Oncology (2013)

1016 Background: FEN1 is a multifunctional protein with essential roles in long patch base excision repair (LP-BER), Okazaki fragment maturation during replication, resolution of tri-nucleotide repeat sequence-derived secondary structures, rescue of stalled replication forks, maintenance of telomere stability and apoptotic fragmentation of DNA. In the current study we have evaluated FEN1 as a prognostic, predictive and therapeutic target in BC and OVC. Methods: Clinico-pathological significance of FEN1 mRNA expression was evaluated in a BC training cohort [n=128], test cohort (n=249) and validated in a large cohort of 1,980 BC (METABRIC). Neural network analysis (NNA) was conducted to identify FEN1 interaction genes. FEN1 protein expression was investigated in three consecutive series of BC and OVC: 568 ER negative (ER- BC), 894 ER positive (ER+ BC) and 195 OVC cohorts. Pre-clinically, FEN1 deficient and proficient HeLa cell lines were investigated for chemotherapy sensitization. A high throughput screening (HTS) strategy was developed to identify FEN1inhibitors for therapeutic application. Results: FEN1mRNA overexpression is associated with adverse clinicopathological features such as high grade, high mitotic index, and triple negative (ps&lt;0.0001). High FEN1 mRNA expression was highly significantly associated with PAM50 Her2, PAM50 Basal and PAM50 LumB (ps&lt;0.0001) BC. FEN1 mRNA overexpression is associated with resistance to chemotherapy (p=0.019), endocrine therapy (p&lt;0.0001) and independently with poor survival (p&lt;0.0001). NNA revealed novel interaction genes with predominant roles in proliferation, cell growth, DNA repair, differentiation, invasion, migration, metabolism and apoptosis. FEN1 protein overexpression is significantly associated with aggressive clinico-pathological features and independently with poor survivals in ER+ BC, ER- BC and in OVC (ps&lt;0.001). HTS assay has identified novel FEN1 inhibitors for therapeutic development. Conclusions: This is the first study to investigate FEN1 in BC and OVC. We provide confirmatory evidence that FEN1 is a promising biomarker as well as a therapeutic anti-cancer drug target for clinical application.
Epigenetic alterations of primary tumor and metastatic site of colorectal carcinoma (mCRC)
Authors: S. Tommasi, N. Silvestris, D. Petriella, R. Pinto, B. Pilato, R. Lacalamita, A. Gernone, A. Paradiso, F. A. Zito, G. Colucci
Journal: Journal of Clinical Oncology (2009)

4128 Background: K-ras gene mutation detection is essential to set a therapy with anti-EGFR antibodies (cetuximab, panitumumab) in mCRC and NCCN guidelines for treatment with cetuximab foresees that only lack of mutations permits the treatment. However, recent studies demonstrated that the presence of BRAF mutations could also indicate an ineffective anti-EGFR therapy. Furthermore, k-ras and BRAF mutations resulted to be mutually exclusive. Aberrant DNA promoter methylation frequently occurs as early event in carcinogenesis as important mechanism of inactivation of tumor suppressor genes. Our hypothesis states a potential role of tumor suppressor methylation in inhibiting EGFR signaling cascade thus blocking anti-EGFR therapeutic effect. Our further aim was to evidence the role of epigenetic alterations in metastatic progression. Methods: Fifty consecutive patients affected by mCRC have been enrolled in this study. Primary tumor and liver metastatic tissues have been characterized for k-ras and BRAF mutations and for promoter methylation of p16, RASSF1A and RARbeta suppressor genes by Quantitative Methylation-Specific PCR (QMSP). Results: k-ras resulted mutated in 32% of cases while BRAF in 5%. The two genes conserved their characteristics in both site of disease: primary tumor and liver metastasis. RARbeta, RASSF1A and p16 genes resulted methylated in 50%, 60% and 30% of primary tumors, respectively. RARbeta promoter methylation mean content resulted significantly higher in k-ras mutated with respect to k-ras wt tumors (209.96 vs 0.44 respectively, p&lt;0.01). Interestingly, the percentage of RARbeta methylation in metastatic sites of k-ras wt tumors is significantly higher than that of the related primary tumors (20% vs 100% respectively, p&lt;0.05). RASSF1A and p16 genes resulted less methylated in k-ras wt patients and significantly higher methylated in metastatic than in primary site (p&lt;0.01). Conclusions: These results might suggest that genetic and epigenetic changes specifically interact to promote tumorigenesis of colon carcinoma and that epigenetic events have to be taken into account when setting biological therapy mainly in metastatic disease. No significant financial relationships to disclose.
Pleurodesis with systemic chemotherapy in cancer patients
Authors: H. A. Gonzalez
Journal: Journal of Clinical Oncology (2009)

e20688 Background: Pleural effusions are a common complication in cancer. All tumors, except CNS tumors, can produce pleural effusions. Pleural effusions are usually caused by direct tumor pleural involvement. Diagnosis is clinical and paraclinical. In cancer patients, in pneumonia absence, most of pleural effusions are malignant, regardless cytology results. Among different treatment modalities, chemical pleurodesis is the oftenest, but it is not etiologic nor physiologic. Chemotherapy in chemosensitive cancers is a good management approach. The objective of this study was measure systemic chemotherapy effectiveness in cancer pleural effusion after drainage and emphasize this method as treatment. Methods: Beginning 1/March/2001 and finalizing 30/July/2006, patients with chemosensitive cancers, malignant pleural effusions, no previous chemotherapy, KI &gt; 80, life expectancy &gt; 6 months, were included. Procedure: Chest X - ray, chest tube insertion for draining pleural effusion, systemic chemotherapy application, generally IV, tube remotion the day after ending chemotherapy, clinical and paraclinical follow up. No effusion reproduction minimum per six months. Effectiveness goal was 80% minimum. General statistic analysis was used. Results: 42 patients were studied, male: 38,09%, female: 61,91%. Median age: 59. Cancers: bronchogenic carcinoma: 42,8%, breast carcinoma: 28,5%, ovarian carcinoma: 14,2 %, carcinoma of unknown origin: 9,52%, others: 4,76%. Clinical stages: III B: 57,2%, most of them bronchogenic carcinoma, IV: 42,8%. Total effectiveness: 85,7%. Effectiveness in known origin cancers: 92,1%. Effectiveness in unknown origin cancers: 25%. Pleural effusion recurrence 14,3%. Drugs employed in appropriate drug regimens: cisplatin, carboplatin, etoposide, gemcitabine, vinorelbine, cyclophosphamide, doxorubicin, docetaxel, capecitabine. Conclusions: Systemic chemotherapy after draining effusions is a good approach for treating chemosensitive cancer pleural effusions, because can produce pleurodesis, is etiologic, has a high effectiveness and can improve survival. No significant financial relationships to disclose.
Rate of durable complete remission (CR) using two sequential, dose-dense regimens of cisplatin, gemcitabine, paclitaxel (CGP) followed by m-VAC in patients with metastatic urothelial cancer (mUC).
Authors: Matteo Brighenti, Stefano Panni, Bruno Perrucci, Mariangela Maltese, Wanda Liguigli, Gianluca Tomasello, Rossana Poli, Federica Negri, Margherita Ratti, Maddalena Donini, Laura Toppo, Carlo del Boca, Luigi Benecchi, Andrea Prati, Daniel Martens, Michele Potenzoni, Rodolfo Passalacqua
Journal: Journal of Clinical Oncology (2013)

e15502 Background: mUC is a chemotherapy sensitive tumor. Currently, CGP and MVAC are the most active regimens in this setting. According to Norton and Simon hypothesis, the administration of two sequential non cross-resistant, dose-dense chemotherapy regimens may target different cancer cells, avoid drug resistance, improve response rate and CR. Methods: Patients with histological diagnosis of mUC, PS 0–2 (ECOG), adequate organ function and no previous systemic regimens were treated with 4 cycles of CGP dose-dense (Gemcitabine 1000 mg/m2 d 1, Paclitaxel 140 mg/m2 d 1, Cisplatin 70 mg/m2 d 2 plus PegFilgrastim 6 mg on day 3, every 2 weeks) followed by 4 cycles of M-VAC (Methotrexate 30 mg/m2 d 1,Vinblastine 3 mg/m2 d 2, Doxorubicin 30 mg/m2 d 2, Cisplatin 70 mg/m2 d 2 plus Pegfilgrastim 6 mg on day 3 every 2 weeks). All were evaluated with CT scan at the baseline, after 4 cycles, at the end of chemotherapy and then every 3 months for two years and 6 months thereafter. Metastatic sites included retroperitoneal nodes, lung, liver and bone. Results: From January 2007, 35 consecutive pts followed in the same oncology institution were included. Male were 74%; median age 65 years; median PS ECOG was 1; Bajorin risk factors was 0 in 37%, 1 in 43%, 2 in 20%. All pts were hospitalized for three days and received chemotherapy with hydration and supportive therapy. After the first 4 cycles of CGP we observed 14.3% CR, 48.6% PR, 22.9% SD and 14.3% PD. After the 4 sequential cycles of M-VAC we observed a global 37.1% of CR, 25.7% of PR, 8.6% of SD and 28.6% of PD. Median TTP was 9.9 months ( 95 % CI, 7.53-14.83) and median OS was 24.27 months ( 95 % CI, 10.03-38.43). Main grade 3–4 toxicity included asthenia ( 27%), anemia (21%), neutropenia (12 %), febrile (9%), thrombocytopenia (9%) and peripheral neuropathy (6 %). After a median follow up of 33 months, 6 of 13 patients who obtained a complete response are free of disease. Conclusions: These data confirm that the sequential use of this two dose-dense regimens is very active and 17 % of patients maintained a CR status.
Accelerating the Science of SCD Therapies—Is a Cure Possible?
Authors: Edward J. Benz, Traci Heath Mondoro, Gary H. Gibbons
Journal: JAMA (2019)

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 HomeNew OnlineCurrent IssueFor Authors Podcasts Clinical Reviews Editors' Summary Medical News Author Interviews More 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 journal
A combination of humanised anti-CD19 and anti-BCMA CAR T cells in patients with relapsed or refractory multiple myeloma: a single-arm, phase 2 trial
Authors: Zhiling Yan, Jiang Cao, Hai Cheng, Jianlin Qiao, Huanxin Zhang, Ying Wang, Ming Shi, Jianping Lan, Xiaoming Fei, Lai Jin, Guangjun Jing, Wei Sang, Feng Zhu, Wei Chen, Qingyun Wu, Yao Yao, Gang Wang, Jing Zhao, Junnian Zheng, Zhenyu Li, Kailin Xu
Journal: The Lancet Haematology (2019)
AAV-PHP.B Administration Results in a Differential Pattern of CNS Biodistribution in Non-human Primates Compared with Mice
Authors: William A. Liguore, Jacqueline S. Domire, Dana Button, Yun Wang, Brett D. Dufour, Sathya Srinivasan, Jodi L. McBride
Journal: Molecular Therapy (2019)

The ability of recombinant adeno-associated virus (AAV) to deliver transgenes to the CNS has allowed for several advancements in the field of gene therapy to treat brain disorders. Although most AAVs do not readily cross the blood-brain barrier and transduce the CNS following peripheral administration, AAV-PHP.B has recently been shown to transduce brains of mice with higher efficiency compared with its parent serotype, AAV9, following injection into the retro-orbital sinus. Here, we extended this foundational work by comparing AAV-PHP.B transduction efficiency in wild-type C57BL/6J mice using four clinically applicable delivery strategies including two intravascular (intra-jugular vein and intra-carotid artery) and two intra-cerebral spinal fluid (CSF) routes (intra-cisterna magna and intra-lateral ventricle). We scaled up these comparisons in a larger-animal model and evaluated transduction efficiency of AAV-PHP.B in the rhesus macaque. We found widespread and largely equal CNS transduction in mice following all four injection strategies, whereas we observed a differential pattern of transduction in macaques with broad cortical and spinal cord transduction seen after intrathecal administration and only very low transduction following intravascular administration. Taken together, these results suggest that AAV-PHP.B may be a useful gene therapy vector for neurological disorders, particularly those stemming from broad cortical or spinal cord neuropathology.
Cryo-Electron Microscopy: Moving Beyond X-Ray Crystal Structures for Drug Receptors and Drug Development
Authors: Javier García-Nafría, Christopher G. Tate
Journal: The Annual Review of Pharmacology and Toxicology (2019)

Electron cryo-microscopy (cryo-EM) has revolutionized structure determination of membrane proteins and holds great potential for structure-based drug discovery. Here we discuss the potential of cryo-EM in the rational design of therapeutics for membrane proteins compared to X-ray crystallography. We also detail recent progress in the field of drug receptors, focusing on cryo-EM of two protein families with established therapeutic value, the γ-aminobutyric acid A receptors (GABAARs) and G protein-coupled receptors (GPCRs). GABAARs are pentameric ion channels, and cryo-EM structures of physiological heteromeric receptors in a lipid environment have uncovered the molecular basis of receptor modulation by drugs such as diazepam. The structures of ten GPCR-G protein complexes from three different classes of GPCRs have now been determined by cryo-EM. These structures give detailed insights into molecular interactions with drugs, GPCR-G protein selectivity, how accessory membrane proteins alter receptor-ligand pharmacology, and the mechanism by which HIV uses GPCRs to enter host cells.
Cancer management in the Pacific region: a report on innovation and good practice
Authors: Alec Ekeroma, Rachel Dyer, Neal Palafox, Kiki Maoate, Jane Skeen, Sunia Foliaki, Andrew J Vallely, James Fong, Merilyn Hibma, Glen Mola, Martina Reichhardt, Livinston Taulung, George Aho, Toakase Fakakovikaetau, David Watters, Pamela J Toliman, Lee Buenconsejo-Lum, Diana Sarfati
Journal: The Lancet Oncology (2019)
SAKK 24/09: Safety and tolerability of bevacizumab plus paclitaxel versus bevacizumab plus metronomic cyclophosphamide and capecitabine as first-line therapy in patients with HER2-negative advanced stage breast cancer—A multicenter, randomized phase III trial.
Authors: Christoph Rochlitz, Roger von Moos, Martin Bigler, Khalil Zaman, Sandro Anchisi, Marc Küng, Kyung Jae Na, Daniela Baertschi, Markus M. Borner, Tamara Rordorf, Daniel Rauch, Andreas Mueller, Thomas Ruhstaller, Marcus Vetter, Juerg Bernhard, Andreas Trojan, Ursula Hasler-Strub, Richard Cathomas, Ralph C. Winterhalder
Journal: Journal of Clinical Oncology (2014)

518 Background: Bevacizumab combined with chemotherapy has been shown to improve response rate and PFS in metastatic breast cancer. The aim of our study was to demonstrate decreased toxicity of metronomic chemotherapy/bevacizumab when compared to paclitaxel/bevacizumab. Methods: In this multicenter, randomized phase III trial, we compared bevacizumab (10 mg/kg i.v. q 2 weeks) with either paclitaxel (90 mg/m2) i.v. on days 1, 8, and 15 of a 4 week cycle (arm A) or daily oral capecitabine (3x500 mg) and cyclophosphamide (50 mg) (arm B) as first-line treatment in patients with HER2-negative advanced breast cancer. Primary endpoint was the incidence of grade 3–5 adverse events (AE): febrile neutropenia, infection, sensory and motor neuropathy, mucositis and hand-foot-syndrome. Secondary endpoints included: objective response (OR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS), other adverse events (AEs), and quality of life (QoL). Results: Between September 2010 and December 2012, 147 patients were included at 22 centers in Switzerland, 73 in arm A and 74 in arm B. The incidence rates of primary endpoint events were 25% (18/71; 95% CI 15–35%) for arm A and 24% (16/68; 95% CI 13–34%) for arm B (p=0.96). Objective response rates were 58% (42/73; 95% CI 0.46–0.69) and 50% (37/74; 95% CI 0.39–0.61) in arms A and B, respectively (p=0.45). Median PFS was 10.3 months (95% CI 8.7–11.3) in arm A and 8.5 months (95% CI 6.5–11.9) in arm B, p=0.90; other secondary efficacy endpoints (DCR, OS) were not significantly different between the two arms. Less hair loss in arm B was the only clinically and statistically significant difference in QOL. Conclusions: This trial failed to meet its primary endpoint of a reduced rate of prespecified grade 3–5 AEs of metronomic bevacizumab, cyclophosphamide and capecitabine but the combination could be an active, convenient treatment in HER-2-negative metastatic breast cancer. Clinical trial information: NCT01131195.
A Viewpoint on Viewpoints—Tips for Authors From <i>JAMA Dermatology</i>
Authors: Kenneth A. Katz
Journal: JAMA Dermatology (2019)

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 Dermatology 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 Dermatology journal
Decline in Left Ventricular Ejection Fraction Following Anthracyclines Predicts Trastuzumab Cardiotoxicity
Authors: Shom Goel, Jia Liu, Hao Guo, William Barry, Richard Bell, Bronwyn Murray, Jodi Lynch, Patricia Bastick, Lorraine Chantrill, Belinda E. Kiely, Ehtesham Abdi, Josie Rutovitz, Ray Asghari, Anne Sullivan, Michelle Harrison, Maija Kohonen-Corish, Jane Beith
Journal: JACC Heart Failure (2019)

The aim of CATS (Cardiotoxicity of Adjuvant Trastuzumab Study) was to prospectively assess clinical, biochemical, and genomic predictors of trastuzumab-related cardiotoxicity (TRC). Cardiac dysfunction is a common adverse effect of trastuzumab. Studies to identify predictive biomarkers for TRC have enrolled heterogeneous populations and yielded mixed results. A total of 222 patients with early-stage human epidermal growth factor receptor 2–positive breast cancer scheduled to receive adjuvant anthracyclines followed by 12 months of trastuzumab were prospectively recruited from 17 centers. Left ventricular ejection fraction (LVEF), troponin T, and N-terminal prohormone of brain natriuretic peptide were measured at baseline, post-anthracycline, and every 3 months during trastuzumab. Germline single-nucleotide polymorphisms in ERBB2, FCGR2A, and FCGR3A were analyzed. TRC was defined as symptomatic heart failure; cardiac death, arrhythmia, or infarction; a decrease in LVEF of >15% from baseline; or a decrease in LVEF of >10% to <50%. TRC occurred in 18 of 217 subjects (8.3%). Lower pre-anthracycline LVEF and greater interval decline in LVEF from pre- to post-anthracycline were each associated with TRC on multivariate analyses (odds ratio: 3.9 [p = 0.0001] and 7.9 [p < 0.0001] for a 5% absolute change in LVEF). Higher post-anthracycline N-terminal prohormone of brain natriuretic peptide level was associated with TRC on univariate but not multivariate analyses. There were no associations between troponin T or ERBB2/FGCR polymorphisms and TRC. Baseline LVEF and LVEF change post-anthracycline were used to generate a "low-risk TRC score" to identify patients with low TRC incidence. Low baseline LVEF and greater LVEF decline post-anthracycline were both independent predictors of TRC. The other biomarkers did not further improve the ability to predict TRC. (Cardiotoxicity of Adjuvant Trastuzumab [CATS]; NCT00858039)
Should age affect our treatment decisions for head and neck cancer?
Authors: Estrella M. Carballido, Jon N Burton, Miguel Ricardo Pelayo, Judith C McCaffrey, Tapan Padhya, Thomas V McCaffrey, Andy Trotti, Nikhil G Rao, Richard Reich, Tawee Tanvetyanon, Ronald C. De Conti, Julie Ann Kish
Journal: Journal of Clinical Oncology (2012)

5564 Background: Current opinion suggests elderly patients (pts) with head and neck cancer, those 65 or older, do not tolerate surgery, chemotherapy, or radiation as well as their younger counterparts. If this holds true, elderly pts may not be offered standard treatments to prevent assumed complications. Methods: A retrospective cohort study at our comprehensive cancer center was conducted of newly diagnosed pts with head and neck squamous cell carcinoma to explore differences in treatment-related complications between older and younger groups. We included data from the first 199 eligible pts (99 younger than 65 year old and 100 older than 65) evaluated between April 2009 and June 2010. Results: 79% of pts receiving treatment were male with a mean age of 54.9 and 71.6 years for the younger and older groups respectively. The older group had significantly more comorbidities (p &lt; 0.001). The majority of older pts presented with oral cavity tumors (46%) while the oropharynx was the predominant site in the younger group (45%). 55% of younger and 49% of older pts presented with stage 4 disease across all sites. A total of 51 pts were p16 positive with no statistical differences between the groups. Surgery was the initial treatment for 57% of older pts (p &lt; 0.008) while 46% of younger pts received concurrent chemotherapy and radiation as the primary treatment (p &lt; 0.008). There was no statistically significant difference in surgical or radiation complications between the groups. Although most pts receiving chemotherapy experienced complications, older pts had slightly more (93% vs. 78%; p&lt;0.031). The mean survival was 24.8 months with no statistical difference between groups. Significantly more pts in the older group, at last follow-up, were disease free (p &lt; 0.012). Conclusions: The treatment of elderly pts with head and neck squamous cell carcinoma in our experience was congruent with that of younger pts. Elderly pts did not suffer more complications with surgery or radiation, however chemotherapy produced somewhat more complications in the elderly pts. Elderly pts did display less evidence of disease on follow-up. Age is always a consideration when treating individuals, but should not preclude the curative standard.