tbuckley/cabot-search huggingface dataset:
Deubiquitinating Enzyme USP9X Suppresses Tumor Growth via LATS Kinase and Core Components of the Hippo Pathway
Authors: Aleksandra Toloczko, Fusheng Guo, Hiu-Fung Yuen, Qing Wen, Stephen A. Wood, Yan Shan Ong, Pei Yi Chan, Asfa Alli Shaik, Jayantha Gunaratne, Mark J. Dunne, Wanjin Hong, Siew Wee Chan
Journal: Cancer Research (2017)

Abstract The core LATS kinases of the Hippo tumor suppressor pathway phosphorylate and inhibit the downstream transcriptional co-activators YAP and TAZ, which are implicated in various cancers. Recent studies have identified various E3 ubiquitin ligases that negatively regulate the Hippo pathway via ubiquitination, yet few deubiquitinating enzymes (DUB) have been implicated. In this study, we report the DUB USP9X is an important regulator of the core kinases of this pathway. USP9X interacted strongly with LATS kinase and to a lesser extent with WW45, KIBRA, and Angiomotin, and LATS co-migrated exclusively with USP9X during gel filtration chromatography analysis. Knockdown of USP9X significantly downregulated and destabilized LATS and resulted in enhanced nuclear translocation of YAP and TAZ, accompanied with activation of their target genes. In the absence of USP9X, cells exhibited an epithelial-to-mesenchymal transition phenotype, acquired anchorage-independent growth in soft agar, and led to enlarged, disorganized, three-dimensional acini. YAP/TAZ target gene activation in response to USP9X knockdown was suppressed by knockdown of YAP, TAZ, and TEAD2. Deletion of USP9X in mouse embryonic fibroblasts resulted in significant downregulation of LATS. Furthermore, USP9X protein expression correlated positively with LATS but negatively with YAP/TAZ in pancreatic cancer tissues as well as pancreatic and breast cancer cell lines. Overall, these results strongly indicate that USP9X potentiates LATS kinase to suppress tumor growth. Cancer Res; 77(18); 4921–33. ©2017 AACR.
High expression and persistent activation of STAT1, 3 and 5 predicts resistance to the histone deacetylase (HDAC) inhibitor vorinostat (suberoylanilide hydroxamic acid, SAHA) in cutaneous T cell lymphoma cells.
Authors: Valeria Fantin, Andrey Loboda, Jennifer Roth, Cloud Paweletz, Sophia Randolph, James Hardwick, Jacqueline Pierce, Elizabeth Harrington, Ronald Hendrickson, John Reilly, Christopher Ware, Marshall Kadin, Madeleine Duvic, Stanley Frankel, Victoria Richon
Journal: Cancer Research (2007)

699   Vorinostat is an HDAC inhibitor that induces differentiation, growth arrest and/or apoptosis of malignant cells both  in vitro  and  in vivo , and is currently being tested in the clinic for a variety of indications. In particular, vorinostat has demonstrated an overall response rate of approximately 30% in cutaneous T-cell lymphoma (CTCL). The purpose of this study was to identify biomarkers that predict response to vorinostat in CTCL using gene expression profiling in preclinical model systems. Herein we report the results of our evaluation of the STAT (signal transducer and activator of transcription) signaling pathway. The relative level of mRNA and protein expression as well as activation status of several members of this family has been evaluated in lymphoid cell lines with diverse vorinostat sensitivity (proliferation/ viability IC 50  range:  0.3-14 μM). Among them the more responsive CTCL cells lines HH and HUT102 exhibited an IC 50 ~ 0.8 μM. These cells underwent apoptosis in response to vorinostat as assessed by TUNEL assay, in contrast to Hut78 and MJ cells (IC 50  > 2 μM) that did not show signs of DNA fragmentation upon incubation in vorinostat-containing media for 48 h. Our results indicate that in lymphoma cell lines elevated protein levels and persistent activation of STAT1, 3 and 5 correlate with resistance to vorinostat. Simultaneous treatment with pan-JAK inhibitors resulted in synergistic anti-proliferative effects consistent with a survival, anti-apoptotic role for STAT proteins in the response to vorinostat treatment. Immunohistochemical analysis of STAT1 in skin biopsies isolated from CTCL patients (N=48) enrolled in the vorinostat Phase IIb clinical trial showed that malignant T cells were positively stained in approximately half of the samples and in those cases a relationship between nuclear accumulation of STAT1 and lack of response to treatment exists (p
The Aging Physician and the Medical Profession
Authors: E. Patchen Dellinger, Carlos A. Pellegrini, Thomas H. Gallagher
Journal: JAMA Surgery (2017)

The issue of the aging physician and when to cease practice has been controversial for many years. There are reports of prominent physicians who practiced after becoming dangerous in old age, but the profession has not demonstrated the ability to prevent this. A mandatory retirement age could be discriminatory and take many competent physicians out of practice and risk a physician shortage. An increasing body of evidence regarding the relationship between physicians' age and performance has led organizations, such as the American College of Surgeons, to revisit this challenge.Since 1975, the number of practicing physicians older than 65 years in the United States has increased by more than 374%, and in 2015, 23% of practicing physicians were 65 years or older. Research shows that between ages 40 and 75 years, the mean cognitive ability declines by more than 20%, but there is significant variability from one person to another, indicating that while some older physicians are profoundly impaired, others retain their ability and skills. There are age-based requirements for periodic testing and/or retirement for many professions including pilots, judges, air traffic controllers, Federal Bureau of Investigation employees, and firefighters. While there are not similar requirements for physicians, a few hospitals have introduced mandatory age-based evaluations.As physicians age, a required cognitive evaluation combined with a confidential, anonymous feedback evaluation by peers and coworkers regarding wellness and competence would be beneficial both to physicians and their patients. While it is unlikely that this will become a national standard soon, individual health care organizations could develop policies similar to those present at a few US institutions. In addition, large professional organizations should identify a range of acceptable policies to address the aging physician while leaving institutions flexibility to customize the approach. Absent robust professional initiatives in this area, regulators and legislators may impose more draconian measures.
Erlotinib in the “real life”: Retrospective results in NSCLC in two Italian centers.
Authors: Vito Lorusso, Valeria Saracino, Giampiero Romano, Angelo Nacci, Silvana Assunta Leo, Vincenzo Emanuele Chiuri, Antonio Pellegrino, Pietro Rizzo, Marianna Giampaglia, Margherita Cinefra, Saverio Cinieri
Journal: Journal of Clinical Oncology (2012)

e18048 Background: Erlotinib is an oral tyrosine kinase inhibitor, approved for treatment of advanced NSCLC after the failure of more than 1 or 2 previous chemotherapy regimens. Its efficacy is comparable to that of chemotherapy, however, some concerns have been raised on its activity in pts with poor PS or in those not harboring EGFR mutation. Methods: Wereviewed the medical records of pts treated with erlotinib in the last 5 years in two Oncologic Centers of South Italy, with the aim to correlate response to pts characteristics. Results: Since January 2006 we have treated with erlotinib 388 pts affected by stage IIIb-IV NSCLC as 2 nd , 3 rd or 4 th line of therapy. Median age was 67 (range 23-90), 300 were males and 88 women. Histology was ADK in 214 (55.2 %), SQM in 129 (33.2%) BAL in 12 (3.1%) and other in 33 (8.5%). Stage IIIb/IV was 66/322 (17%/83%). PS was 0 in 90 (23.5%), 1 in 214 (57.4%), 2 in 60 (15.5%) and 3 in 14 (3.6%) pts, respectively. Smoking status was: never smoker 60 (15.6%), ex smoker 276 (71%), currently smoker 52 (13.4%). With regard to the line of therapy, 250 pts (64%) were treated as 2 nd line, 113 (29.1%) as 3 rd line and 25 (6.5%) as 4 th line. Overall, 117 pts (30%) received only the first drug supply and were lost to follow-up, 131 (33.4%) received 2 or 3 drug supplies, 134 (35.7%%) 4-30 drug supplies and 5 pts (0.9%) &gt; 30 drug supplies, respectively. According to RECIST Criteria, 20/256 evaluable pts (11 too early, 121 not evaluable) achieved PR (7.8%), 74 SD (28.9%) and 162 (63.2%) progressed. The characteristics of the responding pts were as follows: 12 women and 8 men, 15 ADK, 4 SQM and 1 other histology (undifferentiated), 9 never smoker, 10 ex smoker and 1 current smoker, PS 0/1/2 in 8/9/3 pts; line of therapy 2 nd /3 rd /4 th in 16/4/0. The median duration of response was 10 months (range 3 to &gt;30). Median duration of SD was 9 months. Responding pts had a median survival of 28 months (range 3-105). Conclusions: These retrospective data suggest a more cautious usage of the drug, in order to avoid the huge number of pts lost to follow-up. In fact, erlotinib should not be prescribed in pts with poor PS and in lines beyond the 3 rd , unless for pts harboring EGFR mutation.
PRDM15 safeguards naive pluripotency by transcriptionally regulating WNT and MAPK–ERK signaling
Authors: Slim Mzoughi, Jingxian Zhang, Delphine Hequet, Shun Xie Teo, Haitong Fang, Qiao Rui Xing, Marco Bezzi, Michelle Kay Yi Seah, Sheena L M Ong, Eun Myoung Shin, Heike Wollmann, Esther S M Wong, Muthafar Al-Haddawi, Colin L Stewart, Vinay Tergaonkar, Yuin-Han Loh, N Ray Dunn, Daniel M Messerschmidt, Ernesto Guccione
Journal: Nature Genetics (2017)
Children are being failed by substandard mental health services
Authors: Matthew Limb
Journal: BMJ (2017)

Many children and young people with mental health problems are still being let down by variable service provision, analysts have warned.

The Education Policy Institute said that one in nine inpatient units in England failed to meet the minimum standard for staff to patient ratios, while a quarter (24%) did not employ enough permanent staff.

It said that increasing numbers of children and young people were being kept in hospitals despite being fit to leave because appropriate specialist or community support wasn’t available.

Between October 2015 and February 2017, children spent nearly 9000 “wasted days” in NHS hospitals when they could not be discharged, according to the analysis.

The number of delayed days was 42% higher between December 2016 and February 2017 than in the same period in 2015-16, the institute said.

The institute, …
Effect of Gonadectomy and Andrenalectomy on the Appearance and Incidence of Spontaneous Lymphoid Leukemia in C58 Mice&lt;xref ref-type="fn" rid="fn1"&gt;&lt;sup&gt;2&lt;/sup&gt;&lt;/xref&gt;
Authors: L. W. Law, Lester E. Bunker, Jr., Betty-Ann Norris, Roscoe B. Jackson
Journal: JNCI Journal of the National Cancer Institute (1947)

Effect of Gonadectomy and Andrenalectomy on the Appearance and Incidence of Spontaneous Lymphoid Leukemia in C58 Mice Get access L. W. Law, L. W. Law Memorial Laboratory, Bar Harbor, Maine Search for other works by this author on: Oxford Academic PubMed Google Scholar Lester E. Bunker, Jr., Lester E. Bunker, Jr. Memorial Laboratory, Bar Harbor, Maine Search for other works by this author on: Oxford Academic PubMed Google Scholar Betty-Ann Norris, Betty-Ann Norris Memorial Laboratory, Bar Harbor, Maine Search for other works by this author on: Oxford Academic PubMed Google Scholar Roscoe B. Jackson Roscoe B. Jackson Memorial Laboratory, Bar Harbor, Maine Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 8, Issue 3, December 1947, Pages 157–159, https://doi.org/10.1093/jnci/8.3.157 Published: 01 December 1947 Article history Published: 01 December 1947 Received: 02 December 1947
Margaret G. Kelly
Authors: David P. Rall
Journal: JNCI Journal of the National Cancer Institute (1968)

Journal Article Margaret G. Kelly Get access David P. Rall David P. Rall Search for other works by this author on: Oxford Academic PubMed Google Scholar JNCI: Journal of the National Cancer Institute, Volume 41, Issue 3, September 1968, Pages III–VI, https://doi.org/10.1093/jnci/41.3.III Published: 01 September 1968
The potential of anti‐infectives and immunomodulators as therapies for asthma and asthma exacerbations
Authors: M. R. Edwards, R. P. Walton, D. J. Jackson, W. Feleszko, C. Skevaki, T. Jartti, H. Makrinoti, A. Nikonova, I. P. Shilovskiy, J. Schwarze, S. L. Johnston, M. R. Khaitov
Journal: Allergy (2017)

Abstract Asthma is responsible for approximately 25,000 deaths annually in Europe despite available medicines that maintain asthma control and reduce asthma exacerbations. Better treatments are urgently needed for the control of chronic asthma and reduction in asthma exacerbations, the major cause of asthma mortality. Much research spanning &gt;20 years shows a strong association between microorganisms including pathogens in asthma onset, severity and exacerbation, yet with the exception of antibiotics, few treatments are available that specifically target the offending pathogens. Recent insights into the microbiome suggest that modulating commensal organisms within the gut or lung may also be a possible way to treat/prevent asthma. The European Academy of Allergy &amp; Clinical Immunology Task Force on Anti‐infectives in Asthma was initiated to investigate the potential of anti‐infectives and immunomodulators in asthma. This review provides a concise summary of the current literature and aimed to identify and address key questions that concern the use of anti‐infectives and both microbe‐ and host‐based immunomodulators and their feasibility for use in asthma.
A single-institution assessment of superficial spreading melanoma (SSM) in the pediatric population: Molecular and histopathologic features compared with adult SSM
Authors: Anna Elisa Verzì, Jeffrey A. Bubley, Alexandra M. Haugh, Bin Zhang, Annette Wagner, Lacey Kruse, Dennis P. West, Jeffrey Wayne, Joan Guitart, Pedram Gerami
Journal: Journal of the American Academy of Dermatology (2017)
Development of local gene therapy using ultrasound and bubble-liposomes in orthotopic models for superficial bladder cancer
Authors: Suguru Fujisawa, Ryo Suzuki, Kazuo Maruyama, Tetsuya Kodama, Masahiro Yasunaga, Yasuhiro Matsumura
Journal: Cancer Research (2008)

1399    Background  The standard treatment method for superficial bladder cancer is transurethral resection followed by chemotherapy or BCG injection. However, half of superficial bladder cancers recur and progress to a higher grade/stage, forming locally invasive cancers that can only be treated using a  radical cystectomy .  Since a  radical cystectomy significantly reduces the  patient’s quality of life, a novel modality for treating superficial bladder cancer is needed. Gene therapy continues to face large technical hurdles, and systemic modes of delivery have not yielded any successful results. Since the bladder is a closed internal organ that is easily accessible from the outside, however, intravesical gene therapy may be feasible. Many efficient methods for gene transfection have been developed for nonclinical experiments, but not for clinical use.  We decided to examine sonoporation because it is relatively nontoxic, fast, and can be performed  extracorporeally .  The aim of the present study was to develop  an effective intravesical gene delivery system for the  treatment of bladder tumors using the transfection of anti-tumor siRNA into cancer cells by sonoporation.   Materials  We established an  orthotopic bladder tumor model by instilling  several human bladder tumor cells transfected with the  luciferase gene into the bladders of nude mice.  We then determined the conditions for ultrasound irradiation in vitro and in vivo. Finally, the effectiveness of siRNA delivery using bubble liposomes and ultrasound  to orthotopic bladder tumors was examined.    Results and Discussion  To date, we have not been able to deliver siRNA to the tumor cells using ultrasound and bubble liposomes effectively. To improve the introduction of siRNA to the orthotopic bladder tumors, we recently established a bladder tumor-related immuno-bubble-liposome. The effectiveness of this system will be discussed.
Clinical Genomics in Inflammatory Bowel Disease
Authors: Holm H. Uhlig, Aleixo M. Muise
Journal: Trends in Genetics (2017)

Genomic technologies inform the complex genetic basis of polygenic inflammatory bowel disease (IBD) as well as Mendelian disease-associated IBD. Aiming to diagnose patients that present with extreme phenotypes due to monogenic forms of IBD, genomics has progressed from 'orphan disease' research towards an integrated standard of clinical care. Advances in diagnostic clinical genomics are increasingly complemented by pathway-specific therapies that aim to correct the consequences of genetic defects. This highlights the exceptional potential for personalized precision medicine. IBD is nevertheless a challenging example for genomic medicine because the overall fraction of patients with Mendelian defects is low, the number of potential candidate genes is high, and interventional evidence is still emerging. We discuss requirements and prospects of explanatory and predictive clinical genomics in IBD.
Half-century After “Summer of Love,” Free Clinics Still Play Vital Role
Authors: Rita Rubin
Journal: JAMA (2017)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA 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
Distinct mouse chromosome 11 (human 17q) amplifications develop in mouse breast tumors induced by oncogenic ERBB2 or polyoma virus middle T antigen
Authors: J. Graeme Hodgson, Sujatmi Hariono, Sophia Bornstein, William J. Muller, Joe W. Gray
Journal: Cancer Research (2005)

1904   We investigated mouse breast tumors induced by expression of oncogenic ERBB2 or PyMT using array comparative genomic hybridization (array CGH) to identify recurrent genome copy number aberrations and reveal cooperative secondary mutational events. We assessed 3 models in this study: 1) TM - contains an activated form of Erbb2 (Neu-NT) knocked into the endogenous mouse Erbb2 locus, 2) MT - expresses PyMT under control of the mouse mammary tumor virus (MMTV) promoter, 3) DB - expresses a mutant variant of PyMT (Y315/322F) unable to activate PI3K, also under control of the MMTV promoter. Our studies using low resolution genome scanning arrays revealed the presence of high level chromosome 11 amplifications in the TM and DB models. This region is syntenic with human 17q21-25, a recurrently gained/amplified locus in human breast cancer. To investigate this locus further, we developed DNA microarrays containing a contig of BAC clones spanning the distal 30Mb of mouse chromosome 11, encompassing the ERBB2 oncogene. Assessment of TM, MT, and DB tumors revealed that the amplifications in the TM and DB models that were spatially distinct. A total of 17/20 TM tumors showed recurrent amplifications of the ERBB2 locus, which generally involved a single peak and encodes multiple genes. We defined a minimal 280kb common amplicon, nearly identical to that observed in human tumors. The conserved amplicon structure in mouse and human breast tumors suggests that multiple genes are co-selected and act in concert to drive tumor formation. In the Db model we observed high level amplifications in 8/16 tumors, ∼15-20Mb distal to the ERBB2 amplicon in TM tumors. Unlike the structured ERBB2 amplicon in the TM model, the Db amplicons were more genomically complex, often containing multiple peaks. These high level amplifications were not observed in Db hyperplasias (n=6) suggesting that they are involved in the hyperplastic to tumor switch in this model. Further, high level amplifications were not observed in PyMT induced tumors, suggesting that the amplified genes play a role in restoring important tumorigenic pathways (e.g. PI3K) and phenotypes (e.g. suppressed apoptosis) inactivated due to the Y315/322F mutation. To determine whether amplification results in over expression we quantitatively assessed mRNA expression levels of amplified genes Grb2 and Itgb4 relative to Gus using Taqman and correlated expression with genome copy number. Both genes showed strong correlations with Grb2 and Itgb4 respectively showing Pearson’s correlations of 0.86 and 0.72. Our results set the stage for detailed studies aimed at characterization of genes mapping to 17q21-25 (mouse chromosome 11) that are functionally important for breast tumor formation.
Public Health and Economic Consequences of Vaccine Hesitancy for Measles in the United States
Authors: Nathan C. Lo, Peter J. Hotez
Journal: JAMA Pediatrics (2017)

Routine childhood vaccination is declining in some regions of the United States due to vaccine hesitancy, which risks the resurgence of many infectious diseases with public health and economic consequences. There are ongoing policy debates on the state and national level, including legislation around nonmedical (personal-belief) exemptions for childhood vaccination and possibly a special government commission on vaccine safety, which may affect vaccine coverage.To estimate the number of measles cases in US children and the associated economic costs under scenarios of different levels of vaccine hesitancy, using the case example of measles, mumps, and rubella (MMR) vaccination and measles.Publicly available data from the US Centers for Disease Control and Prevention were used to simulate county-level MMR vaccination coverage in children (age 2-11 years) in the United States. A stochastic mathematical model was adapted for infectious disease transmission that estimated a distribution for outbreak size as it relates to vaccine coverage. Economic costs per measles case were obtained from the literature. The predicted effects of increasing the prevalence of vaccine hesitancy as well as the removal of nonmedical exemptions were estimated. The model was calibrated to annual measles cases in US children over recent years, and the model prediction was validated using an independent data set from England and Wales.Annual measles cases in the United States and the associated public sector costs.A 5% decline in MMR vaccine coverage in the United States would result in an estimated 3-fold increase in measles cases for children aged 2 to 11 years nationally every year, with an additional $2.1 million in public sector costs. The numbers would be substantially higher if unvaccinated infants, adolescents, and adult populations were also considered. There was variation around these estimates due to the stochastic elements of measles importation and sensitivity of some model inputs, although the trend was robust.This analysis predicts that even minor reductions in childhood vaccination, driven by vaccine hesitancy (nonmedical and personal belief exemptions), will have substantial public health and economic consequences. The results support an urgent need to address vaccine hesitancy in policy dialogues at the state and national level, with consideration of removing personal belief exemptions of childhood vaccination.