tbuckley/cabot-search huggingface dataset:
The Fc Domain of Immunoglobulin Is Sufficient to Bridge NK Cells with Virally Infected Cells
Authors: Hong-Sheng Dai, Nathaniel Griffin, Chelsea Bolyard, Hsiaoyin Charlene Mao, Jianying Zhang, Timothy P. Cripe, Tadahiro Suenaga, Hisashi Arase, Ichiro Nakano, E.A. Chiocca, Balveen Kaur, Jianhua Yu, Michael A. Caligiuri
Journal: Immunity (2017)
Population pharmacokinetics (popPK) and exposure-response (ER) analyses to confirm alectinib 600 mg BID dose selection in a crizotinib-progressed or intolerant population.
Authors: Joy C. Hsu, Ronan Carnac, Volkmar Henschel, Katrijn Bogman, Meret Martin-Facklam, Elena Guerini, Bogdana Balas, Ali Hassan Zeaiter, Alex Phipps, Peter N. Morcos, Nicolas Frey
Journal: Journal of Clinical Oncology (2016)

e20598 Background: Alectinib, a potent and selective CNS-active ALK inhibitor, which has received FDA accelerated approval for treatment of patients with ALK+ NSCLC who have progressed on, or are intolerant to, crizotinib. This analysis evaluated the popPK and ER relationships for alectinib efficacy and safety to confirm the recommended Phase 2 dose. Methods: A popPK model for alectinib and its major, similarly active metabolite, M4, was developed in NONMEM 7.2 software using plasma concentrations collected from patients receiving alectinib 300–900 mg BID. Covariates (demographics, laboratory values, disease status) were evaluated to determine their potential influence on the between-patient variability in the PK of alectinib and M4. Graphical analyses were explored for ER relationships for alectinib-associated antitumor activity across alectinib 300–900 mg BID dose escalation. Logistic regression and Cox proportional hazards analyses were conducted for evaluation of alectinib ER for BOR and PFS following alectinib 600 mg BID. Logistic regression analyses were conducted for ER relationships to key safety parameters. Results: Alectinib and M4 plasma concentration-time course were best described by a 1-compartment open model with first-order elimination and with a sequential zero and first-order absorption/formation. Body weight with allometric scaling exponents was the only statistically significant covariate influencing alectinib and M4 clearances and volumes. There was no effect of age, gender, race, mild-to-moderate renal impairment, or mild hepatic impairment on alectinib or M4 PK. Alectinib antitumor activity increased with ascending alectinib exposure across 300–900 mg BID, with a plateau observed at exposures corresponding to 600 mg BID. There was no significant ER relationship for alectinib efficacy or safety at 600 mg BID in the pivotal studies. Conclusions: These results demonstrate alectinib exposures in pivotal studies are at the plateau of ER for efficacy with best benefit/risk ratio, which confirms that the 600 mg BID dose is appropriate in a crizotinib-progressed or intolerant population. Clinical trial information: NCT01801111 and NCT01871805.
Coordinating Wnt/LRP6/Axin/Snail axis on multistep process of uterine cervical cancer
Authors: Hyun Sil Kim, Ju kyoung Ryu, So Young Cha, Nam Hee Kim, Sang Hwy Lee, Yoon Jung Choi, Jong In Yook
Journal: Clinical Cancer Research (2007)

A15   Wnt signaling is involved in the normal development and tumorigenesis via epithelial-mesenchymal transition (EMT), initiated by down-regulation of E-cadherin by the transcription factor Snail. Wnt signaling inhibits Snail phosphorylation through Axin2-dependent pathway that sustains nuclear accumulation of Snail by driving GSK3β nucleocytoplasmic export, then consequently increases Snail protein levels and induces an EMT. However, the roles of Wnt and Axin expression and their functional implication on Snail dependent EMT program are not clear during the multistep carcinogenic process. We examined that canonical Wnt signaling engaging multistep carcinogenic process of uterine cervical cancer through Wnt-Axin2-Snail axis. In normal cervical mucosa, Wnt1, Wnt3a, and Axin2 mRNA expression were localized in basal cell layer suggesting that canonical Wnt is required for maintenance of self-renewal program of cervical epithelial cells. With progression to cervical intraepithelial neoplasia (CIN) and carcinoma, Wnt1, Wnt3a, Axin2, and Snail expression were gradually increased in patient samples suggesting that canonical Wnt pathway is involved in early step of carcinogenesis in uterine cervix. LRP6 and Axin2 transfected cells showed the highly increased nuclear Snail resulted from decreased level of nuclear GSK3β, indicating that LRP6-Axin2 serves to stabilize Snail protein levels and sustains its nuclear accumulation by driving GSK3β. RNA interference of Axin2 and Snail on SiHa cells relieved E-cadherin proximal promoter activity and block the in vivo chorioalantoic membrane invasion. These results suggest the canonical Wnt signaling regulating Axin2-GSK3β compartmentalization may important for stabilization of E-cadherin repressor Snail during the multistep carcinogenic process of uterine cervix. It may lead to not only tracing the proper biomarker of cancer progression, but also the development of new targets for therapeutic intervention in cancer.
Abstract 139: Using Cyclic Strain to Improve Cardiac Progenitor Cell Cooperation
Authors: Kristin M French, Marcos J Fierro, Todd D Johnson, Karen L Christman, Michael E Davis
Journal: Circulation Research (2013)

Introduction: Cell therapies have grown in popularity for myocardial regeneration post-infarction, but still suffer from poor retention, maturation and integration of delivered cells. Mechanical strain has been shown to alter cell size, shape, adherence and gene expression in cardiac cells. As a more recently identified cell type, the effect of mechanical strain on cardiac progenitor cells (CPCs) is unknown. This work aims to elucidate the role mechanical strain plays in CPC phenotype and if this response is matrix protein specific. We hypothesize that mechanical strain will improve CPC alignment and potential for connectivity. Methods: To examine the role of mechanical strain on CPCs, CPCs were seeded on FlexCell plates in the presence of a naturally-derived cardiac extracellularmatrix (cECM), collagen I (COL) or no protein (TCP) and strained 0% (static) or 10% at 1 Hz for 24 hours in a BioFlex system. CPC elongation, alignment, and size were evaluated by rhodamine-phalloidin staining. Connexin-43 expression was measured by Western and normalized to GAPDH. Data were analyzed by two-way ANOVA and Bonferroni post-test. Results: CPC area, independent of culture conditions, was 1020 ± 40 um2, corresponding to neonatal cardiomyocyte area. The aspect ratio (major/minor axis) of CPCs showed a trend for increased elongation with strain at (e.x. 2.0±0.2 for unstrained cECM compared to 2.7±0.1 for strained cECM; n=4, p&gt;0.05). Static culture conditions, independent of matrix coating, showed 20±3% alignment of CPCs. Under strain, alignment increased to 30±2% on COL (n=4; p&gt;0.05 for strained COL verus static COL) and 48±8% on cECM (n=4; p&lt; 0.01 for strained cECM versus strained COL and p&lt;0.001 for strained cECM verus static cECM). A fold change &gt;2 for connexin-43 protein in strained versus static conditions, independent of matrix, was observed (n=2, p&gt;0.05) and confirmed by immunocytochemistry. Conclusion: This work suggests that mechanical strain alters CPC phenotype. Increased strain-induced alignment appears to be matrix dependent. In conclusion, these studies provide insight into the role of both mechanical forces and biochemical responses in the function of CPCs; which could lead to improved outcomes following cellular transplantation.
Cataract surgery is cost effective and should not be rationed, says NICE
Authors: Gareth Iacobucci
Journal: BMJ (2017)

New evidence that cataract surgery is cost effective will make it harder for service commissioners in England to ration treatment, experts have told The BMJ .

Draft guidelines1 from the National Institute for Health and Care Excellence for managing cataracts in adults contain new economic modelling that shows that cataract surgery for first or second eye is cost effective compared with no or delayed surgery.

The guidelines, which are out to consultation and will be published in October 2017, also make clear that restricting access to cataract surgery on the basis of visual acuity thresholds is inappropriate.

Experts said that the …
Diffuse Increased Sodium Fluoride Gastric Activity in a Patient With Hypercalcemia
Authors: Fuqiang Shao, Shumao Zhang, Chi Qi, Yu Wang, Yue Chen
Journal: Clinical Nuclear Medicine (2017)

Increased extraosseous uptake of sodium fluoride can be visualized because of many different etiologies. A 62-year-old man with a history of osteoporosis had an 18F–sodium fluoride PET/CT scan for accessing chest pain caused by an accident. The images showed multiple fractures. Unexpectedly, diffuse activity was noted in the gastric wall, which was suggestive of possible hypercalcemia. The serum calcium level confirmed the patient had hypercalcemia.
Human papillomavirus detection in head and neck squamous cell carcinoma in Turkey.
Authors: Yasemin Kemal, Ozgur Kemal, Mehmet Kefeli, Ayse Bel, Nilgun Sahin, Sinan Atmaca, Mehmet Koyuncu, Idris Yucel
Journal: Journal of Clinical Oncology (2017)

e17538 Background: Head and neck squamous cell carcinoma (HNSCC) is the sixth most common type of cancer worldwide. In Turkey, 5538 new cases and 2340 deaths from head and neck cancer are estimated to occur every year. Tobacco and alcohol are the most important etiological risk factors but in the past three decads tobacco usage is decreased and Human Papilloma Virus (HPV) has changed HNSCC epidemiology. Many new reports suggests that almost 25% of all cases of HNSCC are related to HPV. But its prevelans shows a wide variation among different populations.Today in Turkey HPV positivity in HNSCC is currently not known and this retrospective study aimed to to evaluate the HPV infection in our HNSCC patients. Methods: We included 125 HNSCC patients diagnosed and treated in our hospital beween January 2010 and December 2016. Oral cavity, oropharyngeal, laryngeal and hypopharyngeal cancers were included. Nasopharyngeal and salivary gland cancers were exculuded. Head and neck cancer tissue samples fixed using 10% Neutral Buffered Formalin and embedded blocks were used. From an initial evaluation of 125 patients records 77 of the paients blocks could be adequate for the HPV testing. Detection and genotyping of HPV genotypes were done using a polymerase chain reaction (PCR) protocol. Results: PCR amplification was succesful in 61 of 77 patients. Among the 61 HNSCC patients only 3 patients were HPV positive(4.9 %). HPV 16 subtype was detected in one patient who was 70 years old male, stage III laryngeal cancer with a smoking history. The subtypes detected in other two patients were different from 16 and 18. One of these patients was 42 years old nonsmoker female stage IVa hypopharyngeal cancer and the other one was 56 years old smoker male with stage II oropharyngeal cancer. Conclusions: In Turkey, this is the first study that evaluated HPV positivity in HNSCC. Our results suggest a low prevelance of HPV in Turkish HNSCC patients; large scale population based studies are needed to confirm our findings.
A Comprehensive Analysis of Transcript-Supported De Novo Genes in Saccharomyces sensu stricto Yeasts
Authors: Tzu-Chiao Lu, Jun-Yi Leu, Wen-Chang Lin
Journal: Molecular Biology and Evolution (2017)

Novel genes arising from random DNA sequences (de novo genes) have been suggested to be widespread in the genomes of different organisms. However, our knowledge about the origin and evolution of de novo genes is still limited. To systematically understand the general features of de novo genes, we established a robust pipeline to analyze >20,000 transcript-supported coding sequences (CDSs) from the budding yeast Saccharomyces cerevisiae. Our analysis pipeline combined phylogeny, synteny, and sequence alignment information to identify possible orthologs across 20 Saccharomycetaceae yeasts and discovered 4,340 S. cerevisiae-specific de novo genes and 8,871 S. sensu stricto-specific de novo genes. We further combine information on CDS positions and transcript structures to show that >65% of de novo genes arose from transcript isoforms of ancient genes, especially in the upstream and internal regions of ancient genes. Fourteen identified de novo genes with high transcript levels were chosen to verify their protein expressions. Ten of them, including eight transcript isoform-associated CDSs, showed translation signals and five proteins exhibited specific cytosolic localizations. Our results suggest that de novo genes frequently arise in the S. sensu stricto complex and have the potential to be quickly integrated into ancient cellular network.
Frequency, risk factors, and outcomes of central nervous system relapse in lymphoma patients treated with dose-adjusted EPOCH plus rituximab
Authors: Mary‐Kate Malecek, Adam M. Petrich, Shaina Rozell, Benjamin Chu, Steven Trifilio, Natalie Galanina, Matthew Maurer, Umar Farooq, Brian K. Link, Grzegorz S. Nowakowski, Chadi Nabhan, Ayed O. Ayed
Journal: American Journal of Hematology (2017)

Central nervous system (CNS) relapse in non-Hodgkin lymphoma (NHL) is a rare but serious complication that carries a poor prognosis. The use of infusional etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (EPOCH-R) for frontline treatment of diffuse large B cell lymphoma (DLBCL) is increasing, though little is known about incidence of and risk factors for CNS relapse with this regimen PATIENTS AND METHODS: We completed a chart review of patients with NHL who received EPOCH-R as front line therapy. Data obtained included baseline and treatment characteristics including if patients received CNS directed therapy. We measured overall survival (OS), progression free survival (PFS), and progression to CNS involvement.
Cost-effectiveness of High-performance Biomarker Tests vs Fecal Immunochemical Test for Noninvasive Colorectal Cancer Screening
Authors: Iris Lansdorp-Vogelaar, S. Lucas Goede, Linda J.W. Bosch, Veerle Melotte, Beatriz Carvalho, Manon van Engeland, Gerrit A. Meijer, Harry J. de Koning, Marjolein van Ballegooijen
Journal: Clinical Gastroenterology and Hepatology (2017)
Comments on “Increased risk of mortality by fibrosis stage in nonalcoholic fatty liver disease: Systematic review and meta‐analysis”
Authors: Saeid Safiri, Salman Khazaei, Kamyar Mansori, Erfan Ayubi
Journal: Hepatology (2017)

Potential conflict of interest: Nothing to report. TO THE EDITOR: We have read with great interest the article by Dulai et al. published in Hepatology.1 The systematic review aimed to evaluate risk of mortality by fibrosis stage in nonalcoholic fatty liver disease and to present the results through meta‐analysis.1. The authors provide interesting data on fibrosis stage–specific all‐cause and liver‐related mortality. However, we noticed that the results are still biased because of data sparsity, which have not been addressed by an efficient way. The authors reported in the article that mortality rate ratio (95% confidence intervals [CIs])) by stage 4 is 42.30 (95% CI, 3.51‐510.34).1 The huge effect‐size estimates and impossibly large confidence intervals is a marker of sparse data bias in the estimating of the effect size where there are inadequate data such as 0 number in the strata of Exposure‐Outcomes.2 The authors tried to reduce the bias in the risk estimation attributed to 0 mortality for any stages through adding 0.05 to each cell of number of deaths and person‐years of follow‐up. However, in the presence of data sparsity for tabulated data, conventional bias reduction method is the Firth bias adjustment as half will be added to each cell3; but the method, in some scenarios, can produce unacceptably large bias in the estimates.2 To offset the probable bias attributed to Firth bias adjustment, penalization using data augmentation have been suggested.2 In penalization methods, for example, it is assumed that the risk ratio falls between 1:40 and 40, a common range for effect of risk factors on chronic outcomes. Hence, the risk of mortality by fibrosis stage in nonalcoholic fatty liver disease may be different from those reported in the article1 after adjusting for sparse data bias. A take‐home message for the reader is that sparse data bias is a common mistake in biomedical research4 that can be avoided by efficient and recently introduced statistical methods.
A randomized, open-label, multicenter, phase 3 study to compare the efficacy and safety of eribulin to treatment of physician’s choice in patients with advanced non-small cell lung cancer
Authors: N. Katakami, E. Felip, D.R. Spigel, J.-H. Kim, M. Olivo, M. Guo, H. Nokihara, J. C.-H. Yang, N. Iannotti, M. Satouchi, F. Barlesi
Journal: Annals of Oncology (2017)

Eribulin is a microtubule dynamics inhibitor with a novel mechanism of action. This phase 3 study aimed to compare overall survival (OS) in patients with heavily pretreated non-small cell lung cancer (NSCLC) receiving eribulin to treatment of physician's choice (TPC).
Hepatology Highlights – August 2017
Authors: Yecheskel Schneider, Robert S. Brown, Monica Saumoy, Robert E. Schwartz, Vikas Gupta, Russell Rosenblatt
Journal: Hepatology (2017)

Schneider, Yecheskel; Brown, Robert S. Jr.; Saumoy, Monica; Schwartz, Robert E.; Gupta, Vikas; Rosenblatt, Russell Author Information
Immunoprophylaxis Failure of Infants Born to Hepatitis B Carrier Mothers Following Routine Vaccination
Authors: Ka Wang Cheung, Mimi Tin Yan Seto, Anita Sik Yau Kan, Daniel Wong, Kam On Kou, Po Lam So, Wai Lam Lau, Khair Jalal, Yuet Yee Chee, Rosanna Ming Sum Wong, Chin Peng Lee, Ernest Hung Yu Ng
Journal: Clinical Gastroenterology and Hepatology (2017)
PERCUTANEOUS RADIOFREQUENCY THERMAL ABLATION 8 RFTA) OF SMALL HEPATOCELLUALR CARCINOMA: A PROSPECTIVE STUDY
Authors: Mario Latteri, Giuseppe Montalto, Salvatore Pardo, Luigi Sandonato, Vito Di Marco, Calogero Camma, Daniela Cabibi, Pietro Parisi, Camma C, Di Marco, Orlando A, Sandonato L, Parisi P, Sciarrino E, Virdone R, Casaril A, Cabibi D, Pardo S, Di Bona D, Alizzi S, Montalto G, Latteri Ma, Nicoli
Journal: Journal of Hepatology (2004)
Multiple Modes of Positive Selection Shaping the Patterns of Incomplete Selective Sweeps over African Populations of Drosophila melanogaster
Authors: Ha My T. Vy, Yong-Jin Won, Yuseob Kim
Journal: Molecular Biology and Evolution (2017)

It remains a challenge in evolutionary genetics to elucidate how beneficial mutations arise and propagate in a population and how selective pressures on mutant alleles are structured over space and time. By identifying "sweeping haplotypes (SHs)" that putatively carry beneficial alleles and are increasing (or have increased) rapidly in frequency, and surveying the geographic distribution of SH frequencies, we can indirectly infer how selective sweeps unfold in time and thus which modes of positive selection underlie those sweeps. Using population genomic data from African Drosophila melanogaster, we identified SHs from 37 candidate loci under selection. At more than half of loci, we identify single SHs. However, many other loci harbor multiple independent SHs, namely soft selective sweeps, either due to parallel evolution across space or a high beneficial mutation rate. At about a quarter of the loci, intermediate SH frequencies are found across multiple populations, which cannot be explained unless a certain form of frequency-dependent positive selection, such as heterozygote advantage, is invoked given the reasonable range of migration rates between African populations. At one locus, many independent SHs are observed over multiple populations but always together with ancestral haplotypes. This complex pattern is compatible with a large number of mutational targets in a gene and frequency-dependent selection on new variants. We conclude that very diverse modes of positive selection are operating at different sets of loci in D. melanogaster populations.
Abstract P335: Is GSK-3α a Regulator of Aging?
Authors: Jibin Zhou, Hind Lal, Xiying Shang, Ronald Vagnozzi, John Farber, Morgan DeCaul, James R Woodgett, Erhe Gao, Thomas Force
Journal: Circulation Research (2011)

The glycogen synthase kinase-3 (GSK-3) family of protein kinases consists of two highly related isoforms, α and β. The GSK-3 family has been reported to regulate an astonishing variety of physiological and pathophysiological processes, whereas virtually nothing is known as for whether they regulate aging. Aging, defined as the progressive loss of function accompanied by decreasing fertility and increasing mortality with advancing age, is a complex biological process, controlled by multiple genetic, epigenetic and environmental factors. We now present the first studies defining the role of GSK-3α in the aging process using germline GSK-3α knockout (KO) mice at age of 3, 6, 12, and 24 mos. Age-matched wildtype (WT) mice served as control. Kaplan-Meier analysis shows that percent survivals (WT vs. KO) was 73.33 vs. 42.11 ‡ at 24 mos of age. In the heart we find cardiac hypertrophy, marked cell loss with replacement fibrosis, contractile dysfunction with profound abnormalities of mitochondrial structure, and impaired autophagy (assessed by Beclin1/ATG6), all becoming evident after 6 mos of age. Echocardiographic LV mass (in mg) is as follows (4 time points): 124.0±3.15 vs. 132.4±3.93, 136.2±4.75 vs. 171.5±7.57 ‡ , 169.2±8.53 vs. 203.5±8.18 ‡ , 195.4±9.82 vs. 257.4±7.24 ‡ ; ejection factor: 60.6±1.08 vs. 62.5±1.52, 64.3±1.10 vs. 60.7±1.61*, 58.5±1.74 vs. 52.2±1.41 ‡ , 55.5±0.96 vs. 49.4±1.02 ‡ ; invasive hemodynamic dP/dt+: 6863.8±673.8 vs. 6999.4±473.2, 7115.4±392.9 vs. 6012.6±407.3*, 7509.6±419.6 vs. 4291.6±473.5*, 6889.0±460.9 vs. 3955.5±306.9 ‡ . We also observed increased BrdU positive nuclei in isolated cardiomyocytes from the KO at 6 mos of age, and increased stem cells at every time-point, compared with age-matched WT. In the small intestine, we find marked senescence-associated β-galactosidase (SA-β-GAL) activity associated with thinning of the crypts, consistent with reduced cell cycling in this tissue. The results imply accelerated development of age-related pathologies in the KO heart and small bowel. These phenotypes are associated with a reduced lifespan in the mouse. Thus GSK-3α is a novel regulator of aging which retards age-related pathologies and prolongs lifespan of the organism. (*, P&lt;0.05; ‡, P&lt;0.01 KO vs. WT)