tbuckley/cabot-search huggingface dataset:
AAV Gene Therapy Prevents and Reverses Heart Failure in a Murine Knockout Model of Barth Syndrome
Authors: Suya Wang, Yifei Li, Yang Xu, Qing Ma, Zhiqiang Lin, Michael Schlame, Vassilios J. Bezzerides, Douglas Strathdee, William T. Pu
Journal: Circulation Research (2020)

Barth syndrome is an X-linked cardiac and skeletal myopathy caused by mutation of the gene Tafazzin (TAZ). Currently, there is no targeted treatment for Barth syndrome. Lack of a proper genetic animal model that recapitulates the features of Barth syndrome has hindered understanding of disease pathogenesis and therapeutic development.We characterized murine germline TAZ knockout mice (TAZ-KO) and cardiomyocyte-specific TAZ knockout mice models and tested the efficacy of adeno-associated virus (AAV)-mediated gene replacement therapy with human TAZ (hTAZ).TAZ-KO caused embryonic and neonatal lethality, impaired growth, dilated cardiomyopathy, and skeletal myopathy. TAZ-KO mice that survived the neonatal period developed progressive, severe cardiac dysfunction, and fibrosis. Cardiomyocyte-specific inactivation of floxed Taz in cardiomyocytes using Myh6-Cre caused progressive dilated cardiomyopathy without fetal or perinatal loss. Using both constitutive and conditional knockout models, we tested the efficacy and durability of Taz replacement by AAV gene therapy. Neonatal AAV-hTAZ rescued neonatal death, cardiac dysfunction, and fibrosis in TAZ-KO mice, and both prevented and reversed established cardiac dysfunction in TAZ-KO and cardiomyocyte-specific TAZ knockout mice models. However, both neonatal and adult therapies required high cardiomyocyte transduction (≈70%) for durable efficacy.TAZ-KO and cardiomyocyte-specific TAZ knockout mice recapitulate many of the key clinical features of Barth syndrome. AAV-mediated gene replacement is efficacious when a sufficient fraction of cardiomyocytes are transduced.
Chronic myeloid leukemia with variant translocations: A cytogenetic profile
Authors: K. V. Saini, P. Kumari, M. L. Saini, P. Latha, A. Jain, S. KV, U. Batra, A. Attili, V. Lakshmidevi, K. Lakshmaiah, P. Bapsy
Journal: Journal of Clinical Oncology (2007)

17517 Background: Chronic Myeloid Leukemia (CML) is characterized by the translocation between chromosomes 9 and 22. The resulting Philadelphia chromosome is the cytogenetic hallmark of this disease. Occasionally, other variant translocations may be present. Methods: We performed a retrospective analysis of case records between 1999 and 2006 of patients diagnosed with CML at the Kidwai Memorial Institute of Oncology, a tertiary care cancer centre in South India. The cytogenetic profile of CML patients was determined. Results: The total number of CML patients (proven by bone marrow aspiration) diagnosed at our centre during the study period was 1268. Of these, 79 cases (48 M, 31 F) had variant translocations ( Table 1 ). The mean age at diagnosis was 35.9 yrs (SD 11.4). The involved chromosomes were 22 (91.1%), 9 (69.9%), 1 (13.9%), 19 (11.4%), 12 (8.8%), 7 (7.6%), and 6 (7.6%). Other involved chromosomes were 11, 2, 3 13, 15, 17, 16, 20, 21, and 8 in decreasing order of frequency. Table 1 : Cytogenetic Profile of CML Conclusions: Other than chromosomes 22 and 9, the variant translocations commonly involved chromosomes no 1, 19, 12, 7, and 6. The identification of these variant translocations and their co-relation with the clinical behavior may identify new prognostic markers. [Table: see text] No significant financial relationships to disclose.
Abstract P122: P-wave Axis is Associated With All-Cause Mortality in Diabetes: The ACCORD Trial
Authors: Lauren Ehrhardt-Humbert, Matthew J Singleton, Bharathi Upadhya, Muhammad Imtiaz-Ahmad, Elsayed Z SOLIMAN, Prashant Bhave, Elijah H Beaty, Joseph Yeboah
Journal: Circulation (2020)

Introduction: Abnormal P-wave axis (PWA) has emerged as a novel marker of risk for both cardiovascular disease and all-cause mortality in the general population, though this relationship has not been adequately explored among those with type 2 diabetes. Hypothesis: We hypothesized that abnormal PWA is associated with all-cause mortality in a large, well-phenotyped group of participants with type 2 diabetes from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Methods: This analysis included 8,899 ACCORD participants with available PWA data on baseline electrocardiogram. Cox proportional hazards models were used to examine the association between PWA and ACM in models adjusted for demographics, ACCORD trial treatment assignment, and potential confounders. PWA was modeled as either normal (0° - 75°) or abnormal (&lt;0° or &gt;75°). We evaluated the predictive value of PWA by comparing area under the receiver operating characteristic curves in models with and without PWA. Results: Over 44,000 person-years, there were 609 deaths. Participants with abnormal PWA had increased risk of all-cause mortality (HR 1.61, 95% CI 1.25 – 2.08). After multivariable adjustment, the association remained significant (HR 1.32, 95% CI 1.02 – 1.71; see TABLE). Inclusion of abnormal PWA in prediction models afforded a small increase in area under the receiver operating characteristic curves (AUC 0.653 vs. 0.643, p-value for difference of 0.002). Conclusions: In conclusion, among ACCORD trial participants, abnormal PWA was associated with an increased risk of mortality. Abnormal PWA may have added value beyond traditional risk factors in prediction models.
Child Access Prevention Firearm Laws and Firearm Fatalities Among Children Aged 0 to 14 Years, 1991-2016
Authors: Hooman Alexander Azad, Michael C. Monuteaux, Chris A. Rees, Michael Siegel, Rebekah Mannix, Lois K. Lee, Karen M. Sheehan, Eric W. Fleegler
Journal: JAMA Pediatrics (2020)

<h3>Importance</h3> Firearms caused more than 500 pediatric fatalities in 2017—a 50% increase from 2009. Laws regulating firearms are one approach to reducing pediatric firearm fatalities. <h3>Objective</h3> To evaluate the association between state child access prevention (CAP) firearm laws and pediatric firearm fatalities. <h3>Design, Setting, and Participants</h3> A state-level, cross-sectional study of CAP firearm laws throughout the United States, 1991-2016, was conducted using negative binomial regression to analyze differences in state fatality rates in children aged 0 to 14 years. Data analysis was performed from November 21, 2018, to October 18, 2019. <h3>Exposures</h3> Implementation of 2 categories of state CAP firearm laws: recklessness laws, which pertain to providing a firearm to a child, and negligence laws, which pertain to accessibility of a firearm within the home. <h3>Main Outcomes and Measures</h3> Rates of firearm fatalities across all intents and by specific intent (homicide, suicide, and unintentional) per 100 000 children aged 0 to 14 years. <h3>Results</h3> Twenty-five states passed CAP laws between 1989 and 2000. Between 1991 and 2016, 13 697 firearm fatalities occurred in children aged 0 to 14 years. Recklessness laws were not associated with changes in pediatric firearm fatality rates. Negligence laws overall were associated with significant reductions in firearm fatalities in children aged 0 to 14 years, with a 13% relative reduction in all firearm fatalities (95% CI, −18% to −7%), a 15% relative reduction in firearm homicides (95% CI, −22% to −7%), a 12% relative reduction in firearm suicides (95% CI, −20% to −2%), and a 13% relative reduction in unintentional firearm fatalities (95% CI, −24% to −1%). The most stringent negligence laws were associated with unintentional firearm fatality reductions of 59% (95% CI, −68% to −49%). A total of 3929 deaths (29% of all firearm deaths) were associated with states not having passed the most stringent form of negligence CAP laws. <h3>Conclusions and Relevance</h3> In this study, negligence laws were associated with relative reductions in firearm fatality rates in children aged 0 to 14 years. The most stringent negligence laws were associated with the largest reductions in unintentional firearm fatalities. Recklessness laws were not associated with reduced firearm fatality rates. The passage of negligence CAP laws may have the potential to reduce firearm fatalities in children.
NOX4 Inhibition Potentiates Immunotherapy by Overcoming Cancer-Associated Fibroblast-Mediated CD8 T-cell Exclusion from Tumors
Authors: Kirsty Ford, Christopher J. Hanley, Massimiliano Mellone, Cedric Szyndralewiez, Freddy Heitz, Philippe Wiesel, Oliver Wood, Maria Machado, Maria-Antoinette Lopez, Anusha-Preethi Ganesan, Chuan Wang, Ankur Chakravarthy, Tim R. Fenton, Emma V. King, Pandurangan Vijayanand, Christian H. Ottensmeier, Aymen Al-Shamkhani, Natalia Savelyeva, Gareth J. Thomas
Journal: Cancer Research (2020)

Abstract Determining mechanisms of resistance to αPD-1/PD-L1 immune-checkpoint immunotherapy is key to developing new treatment strategies. Cancer-associated fibroblasts (CAF) have many tumor-promoting functions and promote immune evasion through multiple mechanisms, but as yet, no CAF-specific inhibitors are clinically available. Here we generated CAF-rich murine tumor models (TC1, MC38, and 4T1) to investigate how CAFs influence the immune microenvironment and affect response to different immunotherapy modalities [anticancer vaccination, TC1 (HPV E7 DNA vaccine), αPD-1, and MC38] and found that CAFs broadly suppressed response by specifically excluding CD8+ T cells from tumors (not CD4+ T cells or macrophages); CD8+ T-cell exclusion was similarly present in CAF-rich human tumors. RNA sequencing of CD8+ T cells from CAF-rich murine tumors and immunochemistry analysis of human tumors identified significant upregulation of CTLA-4 in the absence of other exhaustion markers; inhibiting CTLA-4 with a nondepleting antibody overcame the CD8+ T-cell exclusion effect without affecting Tregs. We then examined the potential for CAF targeting, focusing on the ROS-producing enzyme NOX4, which is upregulated by CAF in many human cancers, and compared this with TGFβ1 inhibition, a key regulator of the CAF phenotype. siRNA knockdown or pharmacologic inhibition [GKT137831 (Setanaxib)] of NOX4 “normalized” CAF to a quiescent phenotype and promoted intratumoral CD8+ T-cell infiltration, overcoming the exclusion effect; TGFβ1 inhibition could prevent, but not reverse, CAF differentiation. Finally, NOX4 inhibition restored immunotherapy response in CAF-rich tumors. These findings demonstrate that CAF-mediated immunotherapy resistance can be effectively overcome through NOX4 inhibition and could improve outcome in a broad range of cancers. Significance: NOX4 is critical for maintaining the immune-suppressive CAF phenotype in tumors. Pharmacologic inhibition of NOX4 potentiates immunotherapy by overcoming CAF-mediated CD8+ T-cell exclusion.
Results of all-intraperitoneal carboplatin and paclitaxel regimen shows good tolerability and efficacy for advanced ovarian cancer
Authors: C. N. Krasner, M. V. Seiden, A. F. Fuller, J. G. Supko, M. Roche, D. L. Kendall, J. Lee, R. Berkowitz, S. Berlin, U. A. Matulonis
Journal: Journal of Clinical Oncology (2007)

5521 Background: A phase III trial (GOG 172) demonstrated improved survival for patients (pts) with optimally-debulked ovarian cancer treated with intraperitoneal (IP) cisplatin and paclitaxel, as compared with standard IV dosing. Studies to further enhance efficacy and minimize toxicity of IP platinum/taxane regimens are needed. We present the clinical results of a novel IP regimen in follow-up to the pharmacokinetics (pk) results presented last year. Methods: Carboplatin at an AUC 6 on day 1 and paclitaxel 60 mg/m 2 on days 1, 8, 15 was given, IV in cycle 1 and IP in the 5 subsequent 21-day cycles. The initial IV cycle was designed to allow for intra-patient IV vs. IP pk comparison. Pts completing 6 cycles with clinical complete response (CCR) underwent second-look operation (SLO). Results: Accrual is complete with 40 evaluable pts, 8 pts remain on trial. Pts came off study for: port-related complications (7), allergy (2), heme tox (2), vaginal leak (2), and infection (4). Toxicity was mild, with grade 3 or 4 toxicity consisting of neutropenia: 10 (25%), plts: 2 (5%), vomiting: 2 (5%), fatigue: 2 (5%) and anemia: 1 (2.5%). There was no grade 3 or 4 peripheral neuropathy or alopecia. Completion rate was good with 82% of pts completing = 4 cycles, as compared with 52% in GOG 172. All pts completing chemotherapy were judged to be in CCR; there was no progressive disease on trial. Of the pts undergoing SLO, 14 pts were negative, 4 pts were positive, for complete pathological response rate of 78%. Conclusions: Pts were able to complete more cycles of therapy on this regimen as compared with GOG 172. The incidence of gastrointestinal, metabolic, and neurotoxicity is very low. Preliminary SLO rate compares favorably to the 57% seen in GOG 172. Previously reported pk results as well as tolerability and efficacy are encouraging and suggest this regimen should be studied in a larger population. Final toxicity and response data will be available. No significant financial relationships to disclose.
“Stopping the dying”: an interdisciplinary training programme for students
Authors: Frederick J N Stourton, Adam Davis, Dave Hobday, Kevin Priestley
Journal: BMJ (2020)

Park and colleagues make a compelling point about the need for increased joint working during terror incidents.1 We describe a collaborative training concept that lays the foundation for interoperability between police and ambulance services.

In the final week of the initial firearms course for Civil Nuclear Constabulary officers, the students’ tactical and first aid skills are tested with a day of scenarios. Over the past few …
Antitumor activity and biological effects of primary endocrine therapy with GnRH analog and letrozole in premenopausal women with locally advanced operable ER and PgR positive breast cancer
Authors: R. Torrisi, R. Ghisini, C. D'Alessandro, V. Bagnardi, L. Bottiglieri, G. Peruzzotti, A. Rocca, A. Goldhirsch, M. Colleoni
Journal: Journal of Clinical Oncology (2007)

21008 Background: Aromatase inhibitors (AIs) in combination with GnRH analog (A) were never systematically studied in premenopausal women with hormone receptor positive locally advanced operable breast cancer. Methods: We investigated in a two stage phase II trial, the activity of GnRH A plus letrozole (LT), added when E2 levels were in the postmenopausal range, in premenopausal women with T2-T4b N0-N2, endocrine responsive (ER and PgR ≥ 10% of the cells) breast cancer. We also investigated at baseline and at surgery the expression of ERβ, MAPkinases (MAPKs), ERa, EGFR, Her-2/neu, either normal or phosphorylated (p). Results: Thirty-nine patients (pts) were enrolled and 35 (ER &gt;50%, 29 (90%) ; Ki 67 = 20%, 17 (53%); cT2/3, 24/5) are evaluable for response (3 of whom did not receive LT for refusal or failure of achievement of ovarian suppression). There were 16 objective responders (46%, 95% CI 29.5- 62.5), 1 of whom had pCR (3%). Nineteen pts (50%) were stable. Breast conserving surgery became possible for 42% of the patients. Side effects were mild. Endocrine therapy was correlated with grade 2 hot-flashes and arthralgia in 43% and 6% of the patients, respectively. Molecular analysis was performed in 27 pts (13 responders and 14 non responders). Treatment induced a significant decrease of pERa an upregulation of ER-β, which were independent of response. No overexpression of EGFR and HER-2 was registered at baseline and after treatment. Conclusions: The combination of LT and GnRH A is feasible and effective in premenopausal women with locally advanced endocrine responsive operable breast cancer. A biological response to estrogen suppression was observed. Tailored endocrine therapy of longer duration merits further investigations in the preoperative setting. No significant financial relationships to disclose.
Human papillomavirus (HPV) 16/18 l1 AS04 virus-like particle (VLP) cervical cancer vaccine is immunogenic and well-tolerated 18 months after vaccination in women up to age 55 years
Authors: T. F. Schwarz, G. Dubin
Journal: Journal of Clinical Oncology (2007)

3007 Background: Although prevalence of oncogenic HPV infection is highest in women younger than 25, incident infection is estimated to occur in 5% - 10% of women aged 25–55. New infections decrease with age, but the proportion that persists is higher. Therefore, women over 25 also may benefit from HPV vaccination. In a primary Phase III study (GSK 105879/014), an HPV-16/18 AS04 cervical cancer vaccine candidate was highly immunogenic and well tolerated in women up to age 55. This extension study evaluates the persistence of immune response and safety through 18 months after the first vaccine dose. Methods: Healthy women aged 15–55 years in Germany and Poland who had received 3 doses of HPV-16/18 L1 AS04 VLP vaccine at months 0, 1, and 6 in the primary study were invited to participate in a follow-up extension (15–25 years [n=169], 26–35 years [n=83], 36–45 years [n=89], and 46–55 years [n=176]). Immunogenicity and safety were assessed up to 18 months after vaccination. Results: At 18 months, 100% of subjects remained seropositive for both antigens in all age groups. For HPV-16, GMCs were 2,220.1 in women 15–25, 1,276.9 in women 26–35, 905.6 in women 36–45, and 809.0 in women 46–55. For HPV-18, GMCs were 828.2 in women 15–25, 441.8 in women 26–35, 289.7 in women 36–45, and 275.5 in women 46–55. In women over 25, GMCs tended to be higher in those initially seropositive. In the oldest age group, HPV-16 and HPV-18 GMCs remained at least 10-fold higher than natural infection levels reported in another study.The HPV-16/18 AS04 vaccine was well tolerated among all age groups. Conclusions: The HPV-16/18 AS04 vaccine candidate was highly immunogenic and well-tolerated. As with other vaccines, an age- dependent decrease in GMCs was observed, but GMCs remained substantially higher than natural infection levels previously reported in women 15–25. More importantly, GMCs at month 18 for women over 25 remained in the same range as GMCs observed in another study in women 15- 25 that were associated with sustained efficacy up to 4.5 years. Thus, in women up to age 55, an HPV-16/18 AS04 vaccine may protect against new infections with oncogenic HPV types that can cause cervical cancer. [Table: see text]
Abstract P385: Pregnancy Care Must Do More to Meet Women's Social Needs: A Systematic Review of Interventions Addressing the Social Determinants of Health
Authors: Ana Reyes, Rabih Dahdouh, Precious Akanyirige, Araceli Estrada, Maria R Young, Melissa A Simon
Journal: Circulation (2020)

Introduction: Consistent evidence has shown that the social determinants of health (SDoH) play an important role in shaping overall health. As health systems become more focused on improving the health of populations, there is an urgent need for interventions that address upstream factors such as the social determinants of health. Such interventions have not been widely studied and even less work exists in the realm of maternal health. But as maternal and infant mortality remain critical issues, there is great opportunity for the study and development of interventions to address social needs in pregnancy care. Hypothesis: We assessed the hypothesis that most existing interventions addressing the social needs of pregnant women would focus only on identifying social risks, while fewer would connect patients with resources in the community. We expected that most studies would not provide evaluations of effectiveness. Methods: We conducted a database search of MEDLINE, Embase, Cochrane Library, CINAHL, Scopus, and Web of Science to capture literature published between January 1970 and April 2019. A team of reviewers screened titles and abstracts for interventions that were issued in a clinical setting and addressed at least one SDoH as defined by the World Health Organization. Results: Preliminary results revealed 25 studies. All consisted of some form of risk screening and four included a referral process. Interventions addressing intimate partner violence were most numerous followed by psychosocial factors and cigarette smoking. Financial needs were assessed in one study. Eight studies included an evaluation process. Staff carrying out the interventions were primarily research staff, nurse practitioners or nurse midwives. Conclusions: In conclusion, more must be done to connect pregnant women with social resources. As unmet social needs put women at higher risk for poor outcomes in pregnancy, action should be taken to more seamlessly integrate social needs interventions into clinical workflows. Focus should expand beyond traditional social risk screening to capture a wider range of needs including financial stability, housing, and transportation. These are particularly important during pregnancy because adequate prenatal care requires women to be more engaged with the health care system than they would to maintain baseline health.
UK born children are often worse off than those in other rich countries, report finds
Authors: Elisabeth Mahase
Journal: BMJ (2020)

The stalling infant mortality rates in the UK should be a “wake up call” for the nation, according to leading paediatricians.

The UK is fifth from the bottom among 27 European countries for infant mortality. The rate stalled in the UK between 2013 and 2018 at 3.9 per 1000 live births. In England and Wales, the rate is more than twice as high in the most deprived areas (5 per 1000) compared with the least deprived areas (2.7 per 1000).

In the State of Child Health 2020 report,1 the Royal College of Paediatrics and Child Health said the UK is “lagging far behind other countries” in terms of health and wellbeing and that children born …
<i>Notes from the Field:</i> Monkey Bite in a Public Park and Possible Exposure to Herpes B Virus — Thailand, 2018
Authors: Alexander C. Wu, Steven I. Rekant, Elizabeth R. Baca, Renee M. Jenkins, Ludmila M. Perelygina, Julia K. Hilliard, D. Scott Schmid, Richard F. Leman
Journal: MMWR Morbidity and Mortality Weekly Report (2020)