tbuckley/cabot-search huggingface dataset:
Clinical importance of including new and nontarget lesion assessment of disease progression (PD) to predict overall survival (OS): Implications for randomized phase II study design.
Authors: William Leonard Mietlowski, Weichao Bao, Patricia Ann Wood, Denise E Williams, Mona El-Hashimy, Celine Sarr, Andrew Marc Stein, Michael Shi, Dirk Weber, Dany Habr, Maria Grazia Porro
Journal: Journal of Clinical Oncology (2012)

2543 Background: Fridlyand (2011) retrospectively compared PFS vs. change in tumor burden as a primary endpoint in phase II non-small cell lung cancer (NSCLC) trials to inform phase III decision making and found the use of PFS was superior. Since the classic tumor burden model only uses measurements of target lesions, we investigated whether the model could be strengthened by incorporating new and non-target lesion progression. The ability to use a strong tumor burden model has the benefit of potentially earlier decision making and considerable timeline savings. Methods: We analyzed five phase III trials of combination chemotherapy ± targeted therapies with an OS primary endpoint: 1st, 2nd line NSCLC (ATTRACT-1, -2), 1st, 2nd line colorectal carcinoma (CONFIRM-1, -2), and 2nd line ovarian cancer (EPO906A2303). We applied Cox’s proportional hazards model to OS using the covariates of baseline tumor burden, 1st tumor assessment percentage change from baseline, new lesions, and non-target PD. Results: See table. Conclusions: We show that predictive models for OS should consider new and non-target lesions for PD, as well as target lesion tumor burden, findings independently corroborated by Suzuki (2011). We propose a longitudinal rank-based randomized phase II design, ranking a patient’s risk of death, differentially weighting PDs by type and time of PD, and percentage change in tumor burden. This may be more informative for phase II decision making for phase III trials based on OS, than PFS which only uses time of PD. Further studies with other tumor types and treatment modalities are warranted. [Table: see text]
Abstract 17697: Myocardial Response to Milrinone in Single Ventricle Heart Disease
Authors: Stephanie J Nakano, Penny Nelson, Carmen C Sucharov, Shelley D Miyamoto
Journal: Circulation (2015)

Background: Single ventricle heart disease (SV) is a subset of congenital heart defects characterized by a univentricular circulation. Despite surgical intervention, progressive heart failure (HF) is a common cause of death and indication for heart transplantation in children with SV. The exact mechanisms underlying SV HF are poorly understood, limiting the ability to identify effective therapies. Empiric treatment with milrinone, a phosphodiesterase 3 inhibitor (PDE3i), has become increasingly common in SV HF; however the response to milrinone has yet to be characterized in the pediatric SV population. The purpose of this study was to determine the myocardial response to PDE3i in children with SV. Methods and Results: Cyclic adenosine monophosphate (cAMP) levels, phosphodeisterase (PDE) activity, and phospholamban phosphorylation (pPLB) were determined in explanted human ventricular myocardium from non-failing pediatric donors (n=10) and pediatric patients transplanted secondary to SV HF (of right ventricular [RV] morphology). SV HF subjects were divided into those who received milrinone therapy (n=13) and those who did not (n=12). In comparison to non-failing RV myocardium, cAMP levels are lower in SV HF patients treated with milrinone (ANOVA, p=0.046). Chronic milrinone treatment does not alter total PDE or PDE3 activity in SV myocardium. Additionally, when compared with non-failing RV myocardium, SV myocardium (both with and without milrinone) demonstrates equivalent pPLB at the protein kinase A site (serine 16 residue). Conclusions: As evidenced by preserved pPLB, the molecular adaptation associated with SV HF differs significantly from that demonstrated in pediatric HF due to dilated cardiomyopathy. These alterations support a pathophysiologically distinct mechanism of HF in pediatric SV patients, which has direct implications regarding the putative response to PDE3i treatment in this population.
Single institution experience of brentuximab vedotin (SGN-35) impact on allogeneic transplant in patients with relapsed/refractory CD 30 positive lymphoma.
Authors: Benjamin Marshall Parsons, Patrick J. Stiff, Scott E. Smith
Journal: Journal of Clinical Oncology (2013)

e19511 Background: Case series to date (Chen and Gopal) have reported safety and efficacy of b. vedotin prior to allo-SCT. We report our experience using b. vedotin prior to allo-SCT. Methods: Patients were treated with b. vedotin through Seattle Genetics trials and identified retrospectively using a registry of b. vedotin use and subsequent allo-HCT. Patients were treated per study protocol and received 1.8 mg/kg b. vedotin administered every 3 weeks for up to 16 cycles. Patients were followed for response, survival/disease status and subsequent therapy. Results: 7 patients were identified with a median of 5.7 prior therapies. Of these patients 5 had HL histology and 2 had ALK+, ALCL histology. The median age was 37.0 years. The median time since initial diagnosis was 60.4 months. All 7 patients had previously received an autologous SCT. Patients with primary refractory disease accounted for 42% of patients. Patients received a median of 8.6 cycles of b. vedotin and 86% of patients achieved an objective response; best response was CR for 3 patients and PR for 3 patients. Median maximum tumor reduction was 43%. Median time from b. vedotin to transplant was 7.6 months. Three patients received additional chemotherapy post b.vedotin and prior to allo-SCT. The PFS and OS are 86% with 6 patients alive and without relapse in follow-up post allo-SCT. There was 1 transplant related death at induction which did not appear related to b. vedotin. The median follow up is 17.5 months. The median time to neutrophil engraftment was 12.3 days. The median time to platelet engraftment was 21.6 days. Their were no episodes of aGVHD and 33% of patients developed cGVHD all Grade I/II. No increase in infections was observed. Conclusions: Treatment with b.vedotin provided significant decrease in tumor volume in patients with relapsed CD30+ lymphoma, and allowed for allo-SCT. There was no evidence of a delay in engraftment, aGVHD, cGVHD, or post transplant infectious complications. Our results add to prior reports that b. vedotin is a safe and effective option for reducing tumor burden to facilitate a potentially curative allo-SCT and warrants further study.
Hepatitis B virus-induced modulation of liver macrophage function promotes hepatocyte infection
Authors: Suzanne Faure-Dupuy, Marion Delphin, Ludovic Aillot, Laura Dimier, Fanny Lebossé, Judith Fresquet, Romain Parent, Matthias Sebastian Matter, Michel Rivoire, Nathalie Bendriss-Vermare, Anna Salvetti, Danijela Heide, Lalo Flores, Klaus Klumpp, Angela Lam, Fabien Zoulim, Mathias Heikenwälder, David Durantel, Julie Lucifora
Journal: Journal of Hepatology (2019)
Speciation in Howea Palms Occurred in Sympatry, Was Preceded by Ancestral Admixture, and Was Associated with Edaphic and Phenological Adaptation
Authors: Owen G Osborne, Adam Ciezarek, Trevor Wilson, Darren Crayn, Ian Hutton, William J Baker, Colin G N Turnbull, Vincent Savolainen
Journal: Molecular Biology and Evolution (2019)

Howea palms are viewed as one of the most clear-cut cases of speciation in sympatry. The sister species Howea belmoreana and H. forsteriana are endemic to the oceanic Lord Howe Island, Australia, where they have overlapping distributions and are reproductively isolated mainly by flowering time differences. However, the potential role of introgression from Australian mainland relatives had not previously been investigated, a process that has recently put other examples of sympatric speciation into question. Furthermore, the drivers of flowering time-based reproductive isolation remain unclear. We sequenced an RNA-seq data set that comprehensively sampled Howea and their closest mainland relatives (Linospadix, Laccospadix), and collected detailed soil chemistry data on Lord Howe Island to evaluate whether secondary gene flow had taken place and to examine the role of soil preference in speciation. D-statistics analyses strongly support a scenario whereby ancestral Howea hybridized frequently with its mainland relatives, but this only occurred prior to speciation. Expression analysis, population genetic and phylogenetic tests of selection, identified several flowering time genes with evidence of adaptive divergence between the Howea species. We found expression plasticity in flowering time genes in response to soil chemistry as well as adaptive expression and sequence divergence in genes pleiotropically linked to soil adaptation and flowering time. Ancestral hybridization may have provided the genetic diversity that promoted their subsequent adaptive divergence and speciation, a process that may be common for rapid ecological speciation.
Demystifying fibrotic hypersensitivity pneumonitis diagnosis: it's all about shades of grey
Authors: Simon L.F. Walsh, Luca Richeldi
Journal: European Respiratory Journal (2019)

<b>The headcheese pattern which describes a form of mosaic attenuation which combines areas of ground-glass opacification, lobular areas of low attenuation and normal lung is highly specific for a diagnosis of fibrotic hypersensitivity pneumonitis</b>http://bit.ly/2WO2mn7
Sorafenib in the treatment of metastatic paraganglioma: A case report.
Authors: Meral Gunaldi, Ismail Oguz Kara, Cigdem Usul Afsar, Berna Bozkurt Duman
Journal: Journal of Clinical Oncology (2012)

e13523 Background: Paragangliomas (extra-adrenal pheochromocytomas) are rare chromaffin cell tumors that can often be cured by resection. Excess release of catecholamines is characteristic for paragangliomas. Paragangliomas are mostly benign if diagnosed and treated early. Overall 0–36% of paraganglioma patients develop metastatic disease, depending on the type of tumor. Methods: We present a case of a 43-year-old woman who admitted to our department with a history of episodic headaches, diaphoresis and weakness. Hypertension and tachycardia were diagnosed. She had elevated plasma catecholamine levels and a right paraaortic mass (9x9.5cm) was visualized on CT. The mass was excised and the diagnosis of paraganglioma was confirmed. In postoperative follow-up the patient's blood pressure and catecholamine levels were normalized. After twenty months follow up, local recurrence and metastases were detected in thorax, abdomen, and skeletal system. Plasma catecholamine levels were high. Results: Chemotherapy with CVD (adriamycine (7mg/m 2 ), dacarbazine (400mg/m 2 ), cyclophosphamide (500mg/m 2 ), vincristine (1.4mg/m 2 ) on day 1 and 2, repeated every 21 days; were administered and no improvement was observed in PET-CT following a treatment of three cycles. Sorafenib (800mg/m 2 /day) was applied for three-months. Finally the patient’s plasma catecholamine levels and metastatic lesions regressed. Conclusions: Treatment options of metastatic paragangliomas (MP) are removal by excision or ablation, chemotherapy, or targeted pharmaceuticals. Benefits of CVD chemotherapy for MP appears to be short-term and do not include an increase in patient survival. As targeted therapy, treatment of MP with everolimus or imatinib were attempted with no significant benefit, and thus are not recommended. However partial response was reported with Sunitinib some cases. We used sorafenib as another multiple TKI and detected complete response. So far, sorafenib has not been applied in the treatment of MP in literature. Sorafenib can be preferred in the treatment of MP. Therefore, more comprehensive clinical trials are needed.
Role of promoter methylation in the induction of ABCB1 gene expression in anthracycline-resistant and paclitaxel-resistant breast tumor cells
Authors: Kerry Reed, Stacey Hembruff, Jason Sprowl, Monique Laberge, Amadeo Parissenti
Journal: Cancer Research (2008)

4291  A major obstacle in the successful treatment of breast cancer is the acquisition of multidrug resistance (MDR), which in vitro often involves the elevated expression and activity of the ABCB1 drug transporter. While the exact mechanism responsible for increased ABCB1 expression in drug-resistant cancer cells remains unclear, it has been proposed that changes in the methylation status of a CpG island within the ABCB1 promoter may be involved.  A novel system to study the role of epigenetics in the acquisition of drug resistance within breast cancer cells has been developed within our laboratory. Three panels of drug-resistant MCF-7 cell lines were established by selection in increasing concentrations of various chemotherapy agents. Resistance to doxorubicin, epirubicin and paclitaxel was acquired at specific threshold doses (29.1 nM, 31.5 nM and 3.66 nM respectively) and resistance levels continued to increase with higher selection doses. Gene expression analysis of the drug-resistant cell lines in comparison to MCF-7 co-cultured control cells by quantitative-PCR (Q-PCR) revealed that ABCB1 expression was dramatically higher in epirubicin-resistant (MCF-7EPI) and paclitaxel-resistant (MCF-7TAX-2) cell lines at or above the threshold dose [X2(4)=11.067,p
Reply to K. Masuda et al
Authors: Dean A. Fennell, Paul Taylor, David Gilligan, Takashi Nakano, Arnaud Scherpereel, Nick Pavlakis, Jan P. van Meerbeeck, Joachim G.J.V. Aerts, Anna K. Nowak, Hedy Kindler, Paul Baas
Journal: Journal of Clinical Oncology (2019)
On how to not misuse hierarchical clustering on principal components to define clinically meaningful patient subgroups. Response to: ‘On using machine learning algorithms to define clinical meaningful patient subgroups’ by Pinal-Fernandez and Mammen
Authors: Alain Meyer, Lionel Spielmann, François Séverac
Journal: Annals of the Rheumatic Diseases (2019)

We thank Pinal-Fernandez and Mammen for their interesting methodological comment on our work in which we used hierarchical clustering on principal components to define clinically meaningful subgroups of patients with anti-Ku antibodies.1 2 

We fully agree with the conclusion of the authors: ‘machine learning methods may be fundamentally flawed if a cornerstone of the analysis depends upon the incorrect use of a complex biostatistical technique’.

In this regard, the example of hierarchical clustering on principal components they provide in their comment is an illustration on how this statistical tool can be misused and generate false discoveries:

1.  First, hierarchical clustering on principal components is a descriptive method that is fitted to describe heterogeneous datasets. Prior …
Particulate matter air pollution and national and county life expectancy loss in the USA: A spatiotemporal analysis
Authors: James E. Bennett, Helen Tamura-Wicks, Robbie M. Parks, Richard T. Burnett, C. Arden Pope, Matthew J. Bechle, Julian D. Marshall, Goodarz Danaei, Majid Ezzati
Journal: PLoS Medicine (2019)

Background Exposure to fine particulate matter pollution (PM2.5) is hazardous to health. Our aim was to directly estimate the health and longevity impacts of current PM2.5 concentrations and the benefits of reductions from 1999 to 2015, nationally and at county level, for the entire contemporary population of the contiguous United States. Methods and findings We used vital registration and population data with information on sex, age, cause of death, and county of residence. We used four Bayesian spatiotemporal models, with different adjustments for other determinants of mortality, to directly estimate mortality and life expectancy loss due to current PM2.5 pollution and the benefits of reductions since 1999, nationally and by county. The covariates included in the adjusted models were per capita income; percentage of population whose family income is below the poverty threshold, who are of Black or African American race, who have graduated from high school, who live in urban areas, and who are unemployed; cumulative smoking; and mean temperature and relative humidity. In the main model, which adjusted for these covariates and for unobserved county characteristics through the use of county-specific random intercepts, PM2.5 pollution in excess of the lowest observed concentration (2.8 μg/m3) was responsible for an estimated 15,612 deaths (95% credible interval 13,248–17,945) in females and 14,757 deaths (12,617–16,919) in males. These deaths would lower national life expectancy by an estimated 0.15 years (0.13–0.17) for women and 0.13 years (0.11–0.15) for men. The life expectancy loss due to PM2.5 was largest around Los Angeles and in some southern states such as Arkansas, Oklahoma, and Alabama. At any PM2.5 concentration, life expectancy loss was, on average, larger in counties with lower income and higher poverty rate than in wealthier counties. Reductions in PM2.5 since 1999 have lowered mortality in all but 14 counties where PM2.5 increased slightly. The main limitation of our study, similar to other observational studies, is that it is not guaranteed for the observed associations to be causal. We did not have annual county-level data on other important determinants of mortality, such as healthcare access and quality and diet, but these factors were adjusted for with use of county-specific random intercepts. Conclusions According to our estimates, recent reductions in particulate matter pollution in the USA have resulted in public health benefits. Nonetheless, we estimate that current concentrations are associated with mortality impacts and loss of life expectancy, with larger impacts in counties with lower income and higher poverty rate.
Endoscopic submucosal dissection of a large pedunculated gastric lesion: avoiding massive bleeding to achieve en bloc resection
Authors: Gonçalo Nunes, Diogo Libânio, Rui Castro, Inês Marques-de-Sá, Davide Gigliano, Mário Dinis-Ribeiro
Journal: Endoscopy (2019)

A 72-year-old woman with long-term dyspepsia underwent an outpatient upper gastrointestinal endoscopy, which showed a large pedunculated polypoid lesion of 30 mm on the lesser curvature of the gastric body ([Fig. 1 a]). As endoscopic biopsies showed tubulovillous adenoma with low grade dysplasia, the patient was referred to the hospital for endoscopic resection. Pre-procedural reassessment using virtual chromoendoscopy (narrow-band imaging [NBI]) revealed areas with an irregular glandular and vascular pattern in the pedicle and surrounding mucosa, with biopsies confirming low grade dysplasia in both sites.
Abstract 16692: MicroRNA 1825 Acts as a Master Regulator Inducing Proliferation of Adult Cardiomyocytes and Regenerates Ischemic Myocardium
Authors: Raghav Pandey, Shazia Durrani, Shujia Jiang, Umeirra Savani, Rafeeq P Ahmed
Journal: Circulation (2014)

Background: While cardiomyocytes (CMs) in zebrafish and neonatal mice are known to proliferate and regenerate the infarcted heart, this capacity is lost in adult mammals. From our unpublished RNA sequencing data using rat neonatal CMs (NCM) transfected with miR-1825 we identified miR-99a and miR-199a to be downstream effectors of miR-1825. In this study we aim to elucidate the mechanism and relative contribution of each of these miRs in inducing adult CM (ACM) proliferation. Methods and Results: CMs were isolated from 8-12 week old adult rat hearts and transfected with miR-cel-67 (control), miR-1825, miR-99a, and miR-199a. To label proliferating CMs EDU was added daily. On day 5 cells were fixed and stained for EDU, and Troponin I (TnI) (CM marker). MiR-1825 transfected CMs showed 50±5% increase in proliferation compared to control 11.2±3%, while miR-99a and miR-199a showed an increase of 14±3% and 16±2%, respectively. To identify the relative contribution of these downstream miRs additional experiments using respective miRNA inhibitors were carried out revealing proliferation of 40±4% with miR-1825+anti-miR-99a and 22±3% with miR-1825+anti-miR-199a, which were lower than miR-1825 alone. These results indicate that miR-1825 works both independently as well as through miR-99a and miR-199a. To elucidate a mechanism for miR-1825 mediated proliferation of ACM, we performed protein analysis and found a significant reduction in expression of p16, while cyclin-D1 was significantly increased in miR-1825 transfected ACMs. To further identify in-vivo proliferative potential, following LAD ligation we transduced 12 week old (C57BL/6) mice hearts with miR-1825 and miR-cel-67(control). EDU was administered IP up to day 12 post surgery. Four weeks after LAD ligation mice were euthanized and hearts were perfused and harvested for histochemical studies. A significant increase in proliferating ACMs was seen in heart receiving miR-1825 (11.4±3.6% ) vs miR-cel-67 control (1.35± 0.5%). Conclusion: We determine that miR-1825 acts as a master regulator of downstream miRs, and induces proliferation of ACMs through regulation of cyclin-D1 and p16. Overall, this project determines a hierarchical role of miR-1825 and elucidates a novel mechanism of ACM proliferation.
Molecular portraits and trastuzumab responsiveness of estrogen receptor-positive, progesterone receptor-positive, and HER2-positive breast cancer
Authors: Shen Zhao, Xi-Yu Liu, Xi Jin, Ding Ma, Yi Xiao, Zhi-Ming Shao, Yi-Zhou Jiang
Journal: Theranostics (2019)

Background: Estrogen receptor-positive, progesterone receptor-positive, and HER2-positive breast cancers (triple-positive breast cancers, TPBCs) account for 5% to 10% of all breast cancers.The clinical and molecular features of TPBCs remain elusive.In this study, we aim to analyze the multiomics landscape and responsiveness of TPBCs to trastuzumab.Methods: We employed five cohorts.The first cohort was from the Surveillance, Epidemiology, and End Results database (n=32,056) and was used to determine the clinical characteristics of TPBC.The second, third and fourth cohorts were from The Cancer Genome Atlas (n=162), GSE2603 (n=37) and GSE2109 (n=30) datasets, respectively, and were used to examine the genomic features and molecular classification of TPBC.The fifth cohort comprised TPBC patients treated at Fudan University Shanghai Cancer Center (FUSCC, n=171) and was used to investigate an immunohistochemistry-defined luminal A-like subgroup of TPBC.Results: Patients with TPBC had a significantly better prognosis than those with ER-PR-HER2+ breast cancer.Genomic analysis revealed that TPBCs showed a lower TP53 mutation rate (30% vs. 69%, P < 0.001) and lower levels of HER2 mRNA and protein expression than ER-PR-HER2+ breast cancers.More than 40% of TPBCs were classified as the luminal A intrinsic subtype, with an even lower HER2 expression level.Based on the immunohistochemical detection of CDCA8, BCL2 and STC2, we identified a luminal A-like subgroup of TPBCs in the FUSCC cohort (CDCA8-negative, BCL2-and/or STC2-positive).Patients with luminal A-like TPBC had a better prognosis and benefited less from trastuzumab than those with TPBC of other subtypes.Conclusions: TPBCs consist of clinically and genomically heterogeneous subgroups that may require different therapeutic strategies.The luminal A-like subgroup of TPBCs is associated with a better prognosis and reduced benefit from trastuzumab.