tbuckley/cabot-search huggingface dataset:
Secalonic acid D induces cell apoptosis in both sensitive and ABCG2-overexpressing multidrug resistant cancer cells through upregulating c-Jun expression
Authors: Hong Zhang, Liyan Huang, Liyang Tao, Jianye Zhang, Fang Wang, Xu Zhang, Liwu Fu
Journal: Acta Pharmaceutica Sinica B (2018)

Secalonic acid D (SAD) could inhibit cell growth in not only sensitive cells but also multidrug resistant (MDR) cells. However, the molecular mechanisms need to be elucidated. Here, we identified that SAD possessed potent cytotoxicity in 3 pairs of MDR and their parental sensitive cells including S1-MI-80 and S1, H460/MX20 and H460, MCF-7/ADR and MCF-7 cells. Furthermore, SAD induced cell G2/M phase arrest via the downregulation of cyclin B1 and the increase of CDC2 phosphorylation. Importantly, JNK pathway upregulated the expression of c-Jun in protein level and increased c-Jun phosphorylation induced by SAD, which was linked to cell apoptosis via c-Jun/Src/STAT3 pathway. To investigate the mechanisms of upregulation of c-Jun protein by SAD, the mRNA expression level and degradation of c-Jun were examined. We found that SAD did not alter the mRNA level of c-Jun but inhibited its proteasome-dependent degradation. Taken together, these results implicate that SAD induces cancer cell death through c-Jun/Src/STAT3 signaling axis by inhibiting the proteasome-dependent degradation of c-Jun in both sensitive cells and ATP-binding cassette transporter sub-family G member 2 (ABCG2)-mediated MDR cells.
p62/SQSTM1 Fuels Melanoma Progression by Opposing mRNA Decay of a Selective Set of Pro-metastatic Factors
Authors: Panagiotis Karras, Erica Riveiro-Falkenbach, Estela Cañón, Cristina Tejedo, Tonantzin G. Calvo, Raúl Martínez-Herranz, Direna Alonso-Curbelo, Metehan Cifdaloz, Eva Perez-Guijarro, Gonzalo Gómez-López, Pilar Ximenez-Embun, Javier Muñoz, Diego Megias, David Olmeda, Jorge Moscat, Pablo L. Ortiz-Romero, Jose L. Rodríguez-Peralto, María S. Soengas
Journal: Cancer Cell (2018)
Abstract 12841: Mutations in the BMPR2 Gene Are Associated With Worse Survival in Patients With Pulmonary Arterial Hypertension
Authors: Jonathan D Evans, Barbara Girerd, David Montani, Zhi-Cheng Jing, Yi Yan, Xiao-Jian Wang, Nazzareno Galiè, Alessandra Manes, Massimiliano Palazzini, Eric D Austin, Lisa A Wheeler, Greg Elliott, Ikue Nakayama, Koichiro Asano, Ekkehard Grünig, Christina Eichstaedt, Katrin Hinderhofer, Matthias Wolf, Erika B Rosenzweig, Wendy K Chung, Florent Soubrier, Gerald Simonneau, Stefan Gräf, Stephen Kaptoge, Emanuele Di Angelantonio, Marc Humbert, Nicholas W Morrell
Journal: Circulation (2015)

Introduction: Mutations in the BMPR2 gene are the commonest genetic cause of pulmonary arterial hypertension (PAH), however the impact of BMPR2 mutations on clinical phenotype and outcomes remains uncertain. Methods: We collated individual participant-level data on 1550 patients with idiopathic, familial and anorexigen-associated PAH from 8 studies that had systematically tested for the presence of BMPR2 mutations. 1164 patients from 6 studies were included in the primary survival analysis. Associations of BMPR2 mutation status with risk of all cause death and death or transplant were assessed by calculating age and sex adjusted hazard ratios (95% CI) using Cox proportional-hazard regression models stratified by study. Results: Overall, 448 (28.9%) of 1550 patients had a BMPR2 mutation. BMPR2 mutation carriers were younger at diagnosis, (mean ±SD) 35 ±15 versus 42 ±18 years, p&lt;0.001), had a higher mean pulmonary artery pressure (61 ±14 versus 56 ±15 mmHg, p&lt;0.001) and pulmonary vascular resistance (17 ±8 versus 13 ±8 Wood units, p&lt;0.001) and lower cardiac index (2.1 ±0.7 versus 2.5 ±0.9 L/min/m2, p&lt;0.001) at diagnostic right heart catheterization. Patients with BMPR2 mutations were less likely to respond to acute vasodilator testing (2.7% versus 16.6%, p&lt;0.001). Hazard ratios for those carrying a BMPR2 mutation for all cause death and death or transplant are shown in the figure below. In a complete case analysis, the increased risk of all cause death (HR 1.50 (1.07-2.12), p=0.02) and death or transplant (HR 1.76 (1.31-2.38), p&lt;0.001) in those aged &lt;50 at diagnosis persisted after adjusting for right atrial pressure, pulmonary vascular resistance and NYHA functional class at diagnosis. Conclusions: Patients with PAH and BMPR2 mutations are younger at diagnosis and present with more severe disease. Patients with BMPR2 mutations (particularly those diagnosed at a younger age) are at increased risk of death or transplantation compared with BMPR2 negative patients.
Accuracy of a 3-Dimensionally Printed Navigational Template for Localizing Small Pulmonary Nodules
Authors: Lei Zhang, Long Wang, Xiermaimaiti Kadeer, Li Zeyao, Xiwen Sun, Weiyan Sun, Yunlang She, Dong Xie, Mu Li, Liling Zou, Gaetano Rocco, Ping Yang, Chang Chen, Chia-Chuan Liu, René H. Petersen, Calvin Sze Hang Ng, Scott Parrish, Yu Shrike Zhang, Raffaele Giordano, Luigi di Tommaso
Journal: JAMA Surgery (2018)

Localization of small lung nodules are challenging because of the difficulty of nodule recognition during video-assisted thoracoscopic surgery. Using 3-dimensional (3-D) printing technology, a navigational template was recently created to assist percutaneous lung nodule localization; however, the efficacy and safety of this template have not yet been evaluated. To assess the noninferiority of the efficacy and safety of a 3-D-printed navigational template guide for localizing small peripheral lung nodules. This noninferiority randomized clinical trial conducted between October 2016 and October 2017 at Shanghai Pulmonary Hospital, Shanghai, China, compared the safety and precision of lung nodule localization using a template-guided approach vs the conventional computed tomography (CT)-guided approach. In total, 213 surgical candidates with small peripheral lung nodules (<2 cm) were recruited to undergo either CT- or template-guided lung nodule localization. An intention-to-treat analysis was conducted. Percutaneous lung nodule localization. The primary outcome was the accuracy of lung nodule localization (localizer deviation), and secondary outcomes were procedural duration, radiation dosage, and complication rate. Of the 200 patients randomized at a ratio of 1:1 to the template- and CT-guided groups, most were women (147 vs 53), body mass index ranged from 15.4 to 37.3, the mean (SD) nodule size was 9.7 (2.9) mm, and the mean distance between the outer edge of target nodule and the pleura was 7.8 (range, 0.0-43.9) mm. In total, 190 patients underwent either CT- or template-guided lung nodule localization and subsequent surgery. Among these patients, localizer deviation did not significantly differ between the template- and CT-guided groups (mean [SD], 8.7 [6.9] vs 9.6 [5.8] mm; P = .36). The mean (SD) procedural durations were 7.4 (3.2) minutes for the template-guided group and 9.5 (3.6) minutes for the CT-guided group (P < .001). The mean (SD) radiation dose was 229 (65) mGy × cm in the template-guided group and 313 (84) mGy × cm in CT-guided group (P < .001). The use of the 3-D-printed navigational template for localization of small peripheral lung nodules showed efficacy and safety that were not substantially worse than those for the CT-guided approach while significantly simplifying the localization procedure and decreasing patient radiation exposure. ClinicalTrials.gov identifier: NCT02952261.
Abstract 16300: Initial Low-Density Lipoprotein Cholesterol and LDL Paradox in Statin-Naïve Patients Presenting With Acute Coronary Syndrome in China
Authors: Lan Shen, Yujun Sun, Linghong Shen Shen, Ben He
Journal: Circulation (2018)

Introduction: The prevalence of initial LDL level has not been well characterized in Chinese population, as well as the association between LDL level and in-hospital mortality. Hypothesis: Initial ...
Highlights of the 2nd International Symposium on Tribbles and Diseases: tribbles tremble in therapeutics for immunity, metabolism, fundamental cell biology and cancer
Authors: Bing Cui, Patrick Eyers, Leonard Dobens, Nguan Tan, Peter Mace, Wolfgang Link, Endre Kiss-Toth, Karen Keeshan, Takuro Nakamura, Warren Pear, Yodit Feseha, Jessica Johnston, Arkatiz Carracedo, Marcel Scheideler, Zabran Llyas, Robert Bauer, Jorge Erusalimsky Aa, Dominika Grzesik, Juan Salamanca-Viloria Ac, Jin Ae, Ke Li, Guillermo Velasco, Shuang Shang, Jose Lizcano Ah, Xiaowei Zhang, Jichao Zhou, Jiaojiao Yu, Fang Hua, Feng Wang, Shanshan Liu, Jinmei Yu, Zhuowei Hu
Journal: Acta Pharmaceutica Sinica B (2018)

The Tribbles (TRIB) family of pseudokinase proteins has been shown to play key roles in cell cycle, metabolic diseases, chronic inflammatory disease, and cancer development.A better understanding of the mechanisms of TRIB pseudokinases could provide new insights for disease development and help promote TRIB proteins as novel therapeutic targets for drug discovery.At the 2nd International Symposium on Tribbles and Diseases held on May 7-9, 2018 in Beijing, China, a group of leading Tribbles scientists reported their findings and ongoing studies about the effects of the different TRIB proteins in the areas of immunity, metabolism, fundamental cell biology and cancer.Here, we summarize important and insightful overviews from 4 keynote lectures, 13 plenary lectures and 8 short talks that took place during this meeting.These findings may offer new insights for the understanding of the roles of TRIB pseudokinases in the development of various diseases.
Breast cancer intrinsic subtypes by PAM50 in older women.
Authors: Emily Oldham Jenkins, Allison Mary Deal, Carey K. Anders, Aleix Prat, Charles M. Perou, Lisa A. Carey, Hyman Bernard Muss
Journal: Journal of Clinical Oncology (2012)

1524 Background: Breast cancer (BC) incidence dramatically increases with age and the number of older BC patients (pts) in the U.S. is rising. Although immunohistochemical (IHC) data confirm that the incidence of luminal BC increases with age while the incidence of triple negative (TN) BC decreases, age-specific data on the frequency of BC subtypes defined by gene expression is limited. We characterized the incidence of BC intrinsic subtypes using gene microarrays according to age. Methods: Data from 2,150 pts were pooled from publicly available microarray datasets to determine the incidence of PAM50 breast cancer intrinsic subtypes (Luminal A [LumA], Luminal B [LumB], HER2-enriched [Her2E], Basal-like [Basal] and Normal-like [Norm]) by age. Adjuvant treatment data (none, chemotherapy, endocrine therapy or both) were available for 1,741 samples. Relapse-free (RFS) and overall survival (OS) differences were determined using the Kaplan-Meier method. Results: PAM50 intrinsic subtypes by age are tabulated below. The incidence of luminal (A, B, A+B) tumors increased with age (p&lt;0.01, p&lt;0.0001, p&lt;0.0001, respectively), while the percentage of basal tumors decreased (p&lt;0.0001). Basal tumors represented 13% of pts aged &gt; 70 years (yrs); of the 70% with available IHC data, 74% were TNBC. Age as a continuous variable was not associated with RFS (p = 0.37). Subtype alone (n=2031), and after controlling for treatment (n=1645), was significantly associated with RFS (both p&lt;0.0001). The addition of age to a multivariate analysis added no prognostic information. Conclusions: Though more favorable subtypes increase with age, older BC pts still have a substantial percentage of high-risk subtypes. Age alone was not a significant factor in outcome. Tumor biology as defined by intrinsic subtype is an important clinical predictor. [Table: see text]
Clinical Efficacy of Anti-CD22 Chimeric Antigen Receptor T Cells for B-Cell Acute Lymphoblastic Leukemia Is Correlated with the Length of the Scfv Linker and Can be Predicted Using Xenograft Models
Authors: Marco Ruella, Shannon L Maude, Boris Engels, David M. Barrett, Noelle Frey, Katherine T Marcucci, Olga Shestova, Nathan Singh, Jessica Perazzelli, David A Christian, Dana Haagen, Simon F Lacey, J. Joseph Melenhorst, Jennifer Brogdon, Regina M Young, David L Porter, Carl H June, Stephan A Grupp, Saar I. Gill
Journal: Blood (2017)
Efficacy, safety and immunogenicity of live attenuated varicella vaccine in healthy children in China: double-blind, randomized, placebo-controlled clinical trial
Authors: B. Hao, Z. Chen, G. Zeng, L. Huang, C. Luan, Z. Xie, J. Chen, M. Bao, X. Tian, B. Xu, Y. Wang, J. Wu, S. Xia, L. Yuan, J. Huang
Journal: Clinical Microbiology and Infection (2019)
Depth of Response in Waldenstrom Macroglobulinemia
Authors: Jonas Paludo, Jithma Prasad Abeykoon, Morie A. Gertz, Prashant Kapoor, Aneel Paulus, Sikander Ailawadhi, Craig B. Reeder, Thomas E. Witzig, Thomas M. Habermann, Anne J Novak, Francis K. Buadi, Angela Dispenzieri, Yi Lin, Ronald S. Go, Martha Q. Lacy, Shaji K. Kumar, S. Vincent Rajkumar, Robert A. Kyle, Stephen M. Ansell
Journal: Blood (2018)
Presence of parasite DNA in clinically unaffected nasal mucosa during cutaneous leishmaniasis caused by Leishmania (Viannia) braziliensis
Authors: A. Canário, M. Queiroz, G. Cunha, T. Cavalcante, V. Riesz, R. Sharma, A. de Noronha, T. Correia, M. Barral-Netto, A. Barral, R. Khouri, V. Boaventura
Journal: Clinical Microbiology and Infection (2019)

ObjectivesWe aimed to detect Leishmania DNA carriage in nasal mucosa of individuals with cutaneous leishmaniasis (CL) caused by Leishmania (Viannia) braziliensis.MethodsA cross-sectional study was performed in all individuals with CL without nasal lesions (n = 153) attended within 2 years in an endemic area of L. (Viannia) braziliensis in Bahia (Brazil). An otorhinolaryngologist assessed the clinical status of the nasal mucosa by anterior rhinoscopy and endoscopic examinations. Swab samples were collected for parasite DNA detection by PCR from all individuals before standard treatment for leishmaniasis. A second evaluation 3 months after treatment was performed to assess clinical outcomes.ResultsParasite DNA was detected in 7.8% (12/153) of clinically healthy nasal mucosa of individuals with CL. Interestingly, DNA was more frequently identified in individuals with more skin lesions (median 1.5, interquartile range (IQR) 1–3.5 versus 1.0, IQR 1–1.5; p 0.044), or larger injuries (median 2.7, IQR 2–3.8 versus 1.6, IQR 1–2.5; p 0.013). Additionally, the disease of those individuals with positive PCR evolved more frequently to unusual forms of leishmaniasis (recidiva cutis and disseminated) (45.5% (5/11) versus 11.5% (14/122); p 0.009), and required more cycles of treatment to reach clinical cure (median 2, IQR 1–4 versus 1, IQR 1–2; p 0.05).ConclusionThese findings suggest an early parasite tropism to nasal mucosa in L. (Viannia) braziliensis infection and a clinical phenotype of CL cases associated with parasite DNA in nasal mucosa. Future studies should evaluate whether PCR of nasal swab samples could serve as a prognostic tool for individuals at risk of mucocutaneous leishmaniasis.
Combining carfilzomib and panobinostat to treat relapsed/refractory multiple myeloma: results of a Multiple Myeloma Research Consortium Phase I Study
Authors: Jonathan L. Kaufman, Roberto Mina, Andrzej J. Jakubowiak, Todd L. Zimmerman, Jeffrey J. Wolf, Colleen Lewis, Charise Gleason, Cathy Sharp, Thomas Martin, Leonard T. Heffner, Ajay K. Nooka, R. Donald Harvey, Sagar Lonial
Journal: Blood Cancer Journal (2019)

Abstract Proteasome (PIs) and hystone deacetylase inhibitors (HDACis) have previously shown synergistic activity in the treatment of relapesed/refractory multiple myeloma (RRMM) patients. In this phase 1 study, we combined carfilzomib, a second generation PI, with panobinostat, a HDACi, to determine the maximum tolerated dose (MTD) of the combination (CarPan) and assess safety and efficacy among RRMM patients. Thirty-two patients (median of 4 prior lines of therapy) were enrolled. The MTD was carfilzomib 36 mg/m 2 (on days 1, 2, 8, 9, 15, and 16) and panobinostat 20 mg (TIW, 3 weeks on/1 week off, every 28 days), administered until progression. At the MTD, the most common grade 3/4, treatment-related adverse events were thrombocytopenia (41%), fatigue (17%), and nausea/vomiting (12%). The objective response rate (ORR) and clinical benefit rate were 63% and 68%, respectively. Median progression-free survival (PFS) and overall survival (OS) for the entire population were 8 and 23 months, respectively. No differences in terms of ORR (55% vs. 57%), median PFS (months 8 vs. 7 months) and OS (24 vs. 22 months) were observed between bortezomib-sensitive and -refractory patients. CarPan proved to be a safe and effective steroid-sparing regimen in a heavily pre-treated population of MM patients. (Trial registered at ClinicalTrial.gov: NCT01549431)
Influence of Recombination and GC-biased Gene Conversion on the Adaptive and Nonadaptive Substitution Rate in Mammals versus Birds
Authors: Marjolaine Rousselle, Alexandre Laverré, Emeric Figuet, Benoit Nabholz, Nicolas Galtier
Journal: Molecular Biology and Evolution (2018)

Recombination is expected to affect functional sequence evolution in several ways. On the one hand, recombination is thought to improve the efficiency of multilocus selection by dissipating linkage disequilibrium. On the other hand, natural selection can be counteracted by recombination-associated transmission distorters such as GC-biased gene conversion (gBGC), which tends to promote G and C alleles irrespective of their fitness effect in high-recombining regions. It has been suggested that gBGC might impact coding sequence evolution in vertebrates, and particularly the ratio of nonsynonymous to synonymous substitution rates (dN/dS). However, distinctive gBGC patterns have been reported in mammals and birds, maybe reflecting the documented contrasts in evolutionary dynamics of recombination rate between these two taxa. Here, we explore how recombination and gBGC affect coding sequence evolution in mammals and birds by analyzing proteome-wide data in six species of Galloanserae (fowls) and six species of catarrhine primates. We estimated the dN/dS ratio and rates of adaptive and nonadaptive evolution in bins of genes of increasing recombination rate, separately analyzing AT → GC, GC → AT, and G ↔ C/A ↔ T mutations. We show that in both taxa, recombination and gBGC entail a decrease in dN/dS. Our analysis indicates that recombination enhances the efficiency of purifying selection by lowering Hill-Robertson effects, whereas gBGC leads to an overestimation of the adaptive rate of AT → GC mutations. Finally, we report a mutagenic effect of recombination, which is independent of gBGC.
Evaluating magnetic resonance imaging (MRI) as a positive predictive tool in locally advanced rectal cancer (RC): A retrospective 12-year experience.
Authors: Niamh Coleman, Anuradha Jayaram, Louise Catherine Connell, Fatimah Zahra Mohamad Rom, Niamh Keegan, Emily Harrold, Chalen Lee, Brian Mehigan, M. John Kennedy
Journal: Journal of Clinical Oncology (2014)

e14568 Background: MRI is increasingly used to stage RC and allow stratification of patients (pts) facilitating better targeting of preoperative therapy. Accurate preoperative staging is crucial to identify patients who will most benefit from neoadjuvant therapy (NAT) prior to curative surgical resection (Sx). We assessed our institution’s experience of NAT versus upfront Sx in stage I-III RC, assessing the utility of MRI as a predictive tool in evaluation of LN status. Methods: In a retrospective analysis, we assessed preoperative MRI staging & definitive histopathological confirmation of LN status collecting data from a prospectively maintained database for patients with a dx of stage I-III RC from Jan 2002-Jan 2014. Results: A total of 326 patients underwent curative Sx for RC. Of these, 151(46%) had upfront Sx (81 male, 70 female) with a median age 62 (range 33-91). LN staging by MRI was accurate in 51% cases(n=77). LN status could not be evaluated(Nx) in 15.89% (n=24). More advanced LN staging noted on histology (hx) in 21.85%(n=33) while LN stage deemed more aggressive by MRI in 11.26%(n=17). 39 patients received adjuvant 5FU-based chemotherapy. Relapsed disease was noted in 21 patients(6.44%), 20 systemic & 1 local recurrence. Of the 175 (64%) pts who proceeded to NAT, 117 were male, 58 female with a median age 56(range 26-86). In this cohort, 79% pts (n=138) had both a preoperative MRI & hx report available for comparison. MRI in this group matched hx in 51.4% cases (n=90). 23 pts (13.1%) had more advanced LN staging on hx while LN stage was deemed more aggressive by MRI in 14.28% (n=25). Relapsed disease in this cohort occurred in 42 pts (12.8%) with 3 local recurrences, 39 systemic. For the first 150 patients treated, MRI sensitivity was 44.8%, compared with the next 150 patients with MRI sensitivity of 51%. Overall in our study, MRI accurately predicted LN status in 58.95% (n=167). Conclusions: MRI is a valuable tool in stratifying pts who may benefit from NAT, but similar to previous data from our institution, its predictive value has limitations. In this larger cohort, improved overall accuracy was noted in MRI over time, illustrating a distinct learning curve in our institution.
Statistical Considerations for Planning Clinical Trials with Quantitative Imaging Biomarkers
Authors: Nancy A Obuchowski, P David Mozley, Dawn Matthews, Andrew Buckler, Jennifer Bullen, Edward Jackson
Journal: JNCI Journal of the National Cancer Institute (2018)

As imaging technologies and treatment options continue to advance, imaging outcome measures are becoming increasingly utilized as the basis of making major decisions in new drug development and clinical practice. Quantitative imaging biomarkers (QIBs) are now commonly used for subject selection, response assessment, and safety monitoring. Although quantitative measurements can have many advantages compared with subjective, qualitative endpoints, it is important to recognize that QIBs are measured with error. This study uses Monte Carlo simulation to examine the impact of measurement error on a variety of clinical trial designs as well as to test proposed adjustments for measurement error. The focus is on some of the QIBs currently being studied by the Quantitative Imaging Biomarkers Alliance. The results show that the ability of QIBs to discriminate between health states and predict patient outcome is attenuated by measurement error; however, the known technical performance characteristics of QIBs can be used to adjust study sample size, control the misinterpretation rate of imaging findings, and establish statistically valid decision thresholds. We conclude that estimates of the precision and bias of a QIB are important for properly designing clinical trials and establishing the level of imaging standardization required.