tbuckley/cabot-search huggingface dataset:
Rapid and Complete Reversal of Sensory Ataxia by Gene Therapy in a Novel Model of Friedreich Ataxia
Authors: Françoise Piguet, Charline de Montigny, Nadège Vaucamps, Laurence Reutenauer, Aurélie Eisenmann, Hélène Puccio
Journal: Molecular Therapy (2018)

Friedreich ataxia (FA) is a rare mitochondrial disease characterized by sensory and spinocerebellar ataxia, hypertrophic cardiomyopathy, and diabetes, for which there is no treatment. FA is caused by reduced levels of frataxin (FXN), an essential mitochondrial protein involved in the biosynthesis of iron-sulfur (Fe-S) clusters. Despite significant progress in recent years, to date, there are no good models to explore and test therapeutic approaches to stop or reverse the ganglionopathy and the sensory neuropathy associated to frataxin deficiency. Here, we report a new conditional mouse model with complete frataxin deletion in parvalbumin-positive cells that recapitulate the sensory ataxia and neuropathy associated to FA, albeit with a more rapid and severe course. Interestingly, although fully dysfunctional, proprioceptive neurons can survive for many weeks without frataxin. Furthermore, we demonstrate that post-symptomatic delivery of frataxin-expressing AAV allows for rapid and complete rescue of the sensory neuropathy associated with frataxin deficiency, thus establishing the pre-clinical proof of concept for the potential of gene therapy in treating FA neuropathy.
Open label, non-randomized, multi-cohort pilot study of genetically engineered NY-ESO-1 specific NY-ESO-1<sup>c259</sup>t in HLA-A2<sup>+</sup> patients with synovial sarcoma (NCT01343043).
Authors: Crystal Mackall, William D. Tap, John Glod, Mihaela Druta, Warren Allen Chow, Dejka M. Araujo, Stephan A. Grupp, Brian Andrew Van Tine, Karen Chagin, Erin Van Winkle, Gabor Kari, Trupti Trivedi, Elliot Norry, Tom Holdich, Arundathy N. Bartlett-Pandite, Rafael G. Amado, Sandra P. D'Angelo
Journal: Journal of Clinical Oncology (2017)

3000 Background: NY-ESO-1 is expressed in ~70% of synovial sarcomas (SS). NY-ESO-1 c259 T cells recognizing an NY-ESO-1 derived peptide complexed with HLA-A*02 are being studied in SS. Methods: Eligible patients (pt) are HLA-A*02:01, 02:05 or 02:06, with unresectable, metastatic or recurrent SS expressing NY-ESO-1. Primary endpoint of ORR (CR+PR) is evaluated in high (≥ 50% tumor cells express 2+/3+) and low (≥ 1+ in ≥ 1% cells, not exceeding 2+/3+ in ≥ 50% cells) NY-ESO-1 expressers with different lymphodepleting regimens. Secondary endpoints are safety, DOR, PFS, OS, and gene-marked cell persistence. Lymphocytes are obtained by leukapheresis, isolated, activated, transduced to express NY-ESO-1 c259 T, and expanded. Target dose is 1–6 × 10 9 cells. Disease is assessed at wk 4, 8 and 12 post-T-cell infusion, and then every 3 months. Results: 34 pt have been enrolled with 24 treated. 50% are male; median age is 30 yr (range 15 – 73). 12/15 pt in cohort 1 were treated. ORR was 50% (1 CR; 5 PR). Time to response was 6 wk (range 4-9) and median DOR 31 wk (range 13-72). Cohort 3 was closed due to only 1 PR out of 5 pt. Evaluation is ongoing in cohorts 2 (6 enrolled; 5 treated) and 4 (8 enrolled; 2 treated) as of 1/9/17. The most common AE are leukopenia (96%), nausea and pyrexia (88%), neutropenia (88%), lymphopenia (83%), anemia (79%), and thrombocytopenia (79%). 11 events of CRS were reported (3 G3; 1 G4), with no events of seizure, cerebral edema or fatal neurotoxicity; all resolved with supportive therapy. One fatal SAE (bone marrow failure) occurred in cohort 2; investigations have not identified a mechanism by which NY-ESO-1 c259 T may have caused this event. Conclusions: NY-ESO-1 c259 T has promising efficacy and acceptable safety. CRS is not associated with severe neurotoxicity and appears manageable with appropriate supportive care. Cohort 3 data indicate that Flu may be important for efficacy. Efficacy and safety data will be further evaluated and presented. Clinical trial information: NCT01343043. [Table: see text]
Association of State Alcohol Policies With Alcohol-Related Motor Vehicle Crash Fatalities Among US Adults
Authors: Timothy S. Naimi, Ziming Xuan, Vishnudas Sarda, Scott E. Hadland, Marlene C. Lira, Monica H. Swahn, Robert B. Voas, Timothy C. Heeren
Journal: JAMA Internal Medicine (2018)

Motor vehicle crashes are a leading cause of mortality. However, the association between the restrictiveness of the alcohol policy environment (ie, based on multiple existing policies) and alcohol-related crash fatalities has not been characterized previously to date.To examine the association between the restrictiveness of state alcohol policy environments and the likelihood of alcohol involvement among those dying in motor vehicle crashes in the United States.This investigation was a repeated cross-sectional study in which state alcohol policies (operationalized by the Alcohol Policy Scale [APS]) from 1999 to 2014 were related to motor vehicle crash fatalities from 2000 to 2015 using data from the Fatality Analysis Reporting System (1-year lag). Alternating logistic regression models and generalized estimating equations were used to account for clustering of multiple deaths within a crash and of multiple crashes occurring within states. The study also examined independent associations of mutually exclusive subgroups of policies, including consumption-oriented policies vs driving-oriented policies. The study setting was the 50 US states. Participants were 505 614 decedents aged at least 21 years from motor vehicle crashes from 2000 to 2015.Odds that a crash fatality was alcohol related (fatality stemmed from a crash in which ≥1 driver had a blood alcohol concentration [BAC] ≥0.08%).From 2000 to 2015, there were 505 614 adult motor vehicle crash fatalities in the United States, of which 178 795 (35.4%) were alcohol related. Each 10-percentage point increase in the APS score (corresponding to more restrictive state policies) was associated with reduced individual-level odds of alcohol involvement in a crash fatality (adjusted odds ratio [aOR], 0.90; 95% CI, 0.89-0.91); results were consistent among most demographic and crash-type strata. More restrictive policies also had protective associations with alcohol involvement among crash fatalities associated with BACs from greater than 0.00% to less than 0.08%. After accounting for driving-oriented policies, consumption-oriented policies were independently protective for alcohol-related crash fatalities (aOR, 0.97; 95% CI, 0.96-0.98 based on a 10-percentage point increased APS score).Strengthening alcohol policies, including those that do not specifically target impaired driving, could reduce alcohol-related crash fatalities. Policies may also protect against crash fatalities involving BAC levels below the current legal limit for driving in the United States.
<i>Notes from the Field:</i> Cyclosporiasis Cases Associated with Dining at a Mediterranean-Style Restaurant Chain — Texas, 2017
Authors: Amelia A. Keaton, Noemi Borsay Hall, Rebecca J. Chancey, Vivienne Heines, Venessa Cantu, Varsha Vakil, Stephen Long, Kirstin Short, Elya Franciscus, Natasha Wahab, Aisha Haynie, Laura Gieraltowski, Anne Straily
Journal: MMWR Morbidity and Mortality Weekly Report (2018)
Alfie Evans case: are the notions of best interests and futility just paternalism rebranded?
Authors: Rosemarie Anthony-Pillai
Journal: BMJ (2018)

I always find McCartney’s columns thought provoking, but I think she has focused on one element in the Alfie Evans case.1 One could assume that only those who identify as religious have a belief system, but each of us, even the atheist, has a belief system that invariably colours how we approach life and …
Immune-checkpoint inhibitor-induced diarrhea and colitis in patients with advanced malignancies: retrospective review at MD Anderson
Authors: Yinghong Wang, Hamzah Abu-Sbeih, Emily Mao, Noman Ali, Faisal Shaukat Ali, Wei Qiao, Phillip Lum, Gottumukkala Raju, Gladis Shuttlesworth, John Stroehlein, Adi Diab
Journal: Journal for ImmunoTherapy of Cancer (2018)

<h3>Background</h3> Immune checkpoint inhibitors (ICPIs) are gaining increasing popularity as an efficacious treatment for advanced malignancies. ICPI treatment can be complicated by diarrhea and colitis. Systemic steroids are the first line treatment. Infliximab is reserved for severe refractory cases. We aimed to assess the impact of ICPI-induced diarrhea and colitis and their immunosuppressive treatment on patients’ outcomes. <h3>Methods</h3> This retrospective analysis was conducted in 327 cancer patients who received ICPIs between 2011 and 2017. Patients with ICPI-induced toxicities in other organs were excluded. We collected data about patient demographics, clinical variables, and overall survival. We used descriptive analysis to compare different groups based on the occurrence and the treatment of diarrhea and colitis. Kaplan-Meier and log-rank test were used to estimate and compare overall survival durations between groups. <h3>Results</h3> Diarrhea was recorded in 117 (36%) patients; 79 (24%) of them required immunosuppressive treatment of either systemic corticosteroid without infliximab (<i>n</i>&nbsp;= 44) or with infliximab (<i>n</i>&nbsp;= 35). Caucasian ethnicity, melanoma, stage 3 cancer, and ipilimumab were predictors of colitis that requires immunosuppression. Patients who required immunosuppressants had better overall survival than those who did not require treatment for colitis or diarrhea (<i>P</i>&nbsp;&lt; 0.001). Immunosuppression for diarrhea or colitis did not affect the overall survival significantly (<i>P</i>&nbsp;= 0.232), nor did the choice of treatment (corticosteroids with vs. without infliximab; <i>P</i>&nbsp;= 0.768). Diarrhea was an independent predictor of a favorable overall survival (<i>P</i>&nbsp;&lt; 0.001), irrespective of treatment need (<i>P</i>&nbsp;= 0.003). We confirmed the same results in a subgroup analysis for patients with stage IV malignancies only. Patients who received long duration of steroid treatment (&gt; 30&nbsp;days) had numerically higher infection rate than those who received steroid for shorter duration (40.4 vs. 25.8%, <i>P</i>&nbsp;= 0.160). Likewise, long duration of steroid without infliximab was associated with increased risk of infection compared to short duration of steroid with infliximab (42.9% vs. 14.3%, <i>P</i>&nbsp;= 0.089). <h3>Conclusions</h3> Patients with ICPI-induced diarrhea or colitis have improved survival outcomes. Diarrhea is an independent predictor of an improved survival regardless of treatment requirement. Immunosuppressive treatment for diarrhea did not significantly affect overall survival, however, infection rates were numerically higher among patients who received steroids for a long duration. Therefore, early non-steroid immunosuppressive therapy may ensure a more favorable overall outcome.
Breathlessness measurement should be standardised for the level of exertion
Authors: Magnus Ekström, Viktor Elmberg, Thomas Lindow, Per Wollmer
Journal: European Respiratory Journal (2018)

We would like to thank M. Ekström and colleagues for their correspondence with comments on our article entitled "Effects of inspiratory muscle training on dyspnoea in severe COPD patients during pulmonary rehabilitation: a controlled randomised trial" [1]. We agree with most of the points underlined by M. Ekström and colleagues. Dyspnoea should be measured at a standardised level of exertion <http://ow.ly/kpMQ30jWXau>
Efficacy and tolerability of moxidectin alone and in co-administration with albendazole and tribendimidine versus albendazole plus oxantel pamoate against Trichuris trichiura infections: a randomised, non-inferiority, single-blind trial
Authors: Beatrice Barda, Shaali M Ame, Said M Ali, Marco Albonico, Maxim Puchkov, Jörg Huwyler, Jan Hattendorf, Jennifer Keiser
Journal: The Lancet Infectious Diseases (2018)
Mass cytometry of Hodgkin lymphoma reveals a CD4+ regulatory T-cell–rich and exhausted T-effector microenvironment
Authors: Fathima Zumla Cader, Ron C. J. Schackmann, Xihao Hu, Kirsty Wienand, Robert Redd, Bjoern Chapuy, Jing Ouyang, Nicole Paul, Evisa Gjini, Mikel Lipschitz, Philippe Armand, David Wu, Jonathan R. Fromm, Donna Neuberg, X. Shirley Liu, Scott J. Rodig, Margaret A. Shipp
Journal: Blood (2018)
Is HPV present in specimen of oral cavity carcinomas
Authors: Hans-Robert Metelmann, Axel Schriewer, Wolfram Kaduk, Matthias Evert, Michele Peters, Alexandra Mesko, Frank Dombrowski
Journal: Cancer Research (2008)

4733  There are recent clinical considerations in oral cancer surgery that squamous cell carcinomas of the oral mucosa could be related to HPV like cervix carcinoma and therefore should be included into research for vaccination programs of this kind. In a first view study of the cancer prevention project of ScanBalt 35 tissues specimen from 21 patients (20 male, 1 female, average age 57 years) with oral cavity carcinomas where checked for HPV by use of PCR. PCR was performed as nested PCR with degenerate E6 consensus primers in the first round and with type specific primers for HPV6/11, HPV16 and HPV18 in the second round. As a result, HPV 18 was evident in just one squamous cell carcinoma of the oral cavity in a single patient. The other 20 patients did not show HPV 18, HPV6/11 or HPV 16. At first glance implementation of oral cancer into the cancer prevention programs in accordance with cervix carcinoma prevention does not look very promising.
Phase IB trial of ACY-1215 (Ricolinostat) combined with nab-paclitaxel in metastatic breast cancer.
Authors: Kevin Kalinsky, Maika Onishi, JiYang Yu, Meghna S. Trivedi, Melissa Kate Accordino, Katherine D. Crew, Dawn L. Hershman, Matthew A. Maurer, Jose Silva
Journal: Journal of Clinical Oncology (2018)

1058 Background: HDAC6, a cytoplasmic histone deacetylase, plays an important role in cell-cell interactions, motility, chaperone function, and protein degradation. ACY-1215 is an orally active, selective HDAC6 inhibitor. Preclinical studies have demonstrated ACY-1215 to have synergistic activity with taxanes. We have developed an algorithm (HDAC6 score) based on mRNA expression profiling to evaluate the HDAC6 activity of individual tumor samples. Methods: In this open-label phase Ib, patients (pts) received ACY-1215 daily for 21 days of each 28-day cycle with nab-paclitaxel 100 mg/m2 on days 1, 8, and 15 until progression of disease or unacceptable toxicity. The primary objective was to establish the maximum tolerated dose of ACY-1215 with nab-paclitaxel. Dose escalations were performed according to the time to event continual reassessment method (TITE-CRM), starting at 120 mg to a maximum dose of 240 mg daily (qd). The TITE-CRM used an empirical dose-toxicity model, with a sample size of 15 evaluable patients. HDAC score was performed retrospectively on primary and/or metastatic tissue. Results: 17 pts were accrued between 3/16-2/18: 15 were evaluable. Of evaluable pts, 3 had triple negative BC and 12 hormone receptor (HR)+/HER2-. The mean number of prior lines was 4 (range: 0-9). The first pt started at 120 mg qd, the second at 180 mg qd, and the rest at 240 mg qd. No dose limiting toxicities were seen. The only grade 3 event thought to be medication-related was syncope in 1 pt. No grade IV events were seen. In evaluable pts, the following were best responses: 1 partial response (PR), 9 stable disease (SD), and 3 progressive disease (PD: 2 TNBC, 1 HR+/HER2-). Two pts recently started and were too early to report. In the first 6 evaluable pts, the HDAC6 score (network size = 243) could significantly dichotomize those with PD vs. SD/PR (p = 0.05). Conclusions: ACY-1215 240 mg qd is safe and tolerable with weekly nab-paclitaxel. Clinical activity has been observed, with the majority of pts demonstrating SD and 1 with a PR. Notably, the HDAC6 score appears to preliminarily predict activity. We plan on presenting updated data, including HDAC6 score on additional pts, with data maturity. Clinical trial information: NCT02632071.
Abstract 20588: Urbanization is Associated to Increased Trends in Cardiovascular Mortality Among Indigenous Populations
Authors: Anderson C Armstrong, Ana Marice T Ladeia, Juracy Marques, Dinani Armstrong, Antonio Silva, Luis Claudio L Correia, Manoel Barral Netto, Joao A Lima
Journal: Circulation (2016)

Introduction:  For indigenous living in traditional tribes, urbanization leads to fast changes in CV risk with unknown impact in mortality rates. This is particularly relevant when large governmental interventions occur in the proximity of indigenous areas in developing countries.   Aims:  We investigate the CV mortality profile of indigenous populations during a rapidly urbanization process, largely influenced by governmental infrastructure interventions in Northeast Brazil.   Methods:  We assessed indigenous mortality (≥ 30 y/o) registered by the Brazilian Health Ministry (2007-2011) in states of Northeast Brazil (Bahia and Pernambuco). CV mortality was defined according to ICD-10 and if sudden death in indigenous living in tribes by the Sao Francisco Valley (n = 25,560); then divided according to the degree of urbanization using anthropological criteria: Group 1 - traditional indigenous (Funi-o, Pankararu, Kiriri, and Pankarare); Group 2 - advanced urbanization stages (Tuxa, Truka, and Tumbalala). Mortality rates of highly urbanized cities (Petrolina e Juazeiro) in the proximity of indigenous areas were also evaluated. Analysis explored trends in the percentage of CV mortality for each studied population.   Results:  There were 1,333 indigenous deaths in tribes of Bahia and Pernambuco (2007-2011), with 281 in Group 1 (1.8% of the 2012 group population) and 73 in Group 2 (3.7% of the 2012 group population), CV mortality of 24% and 37% respectively (p=0,02). Between 2007-2009, there were 133 deaths in Group 1 and 44 in Group 2, CV mortality of 23% and 34% respectively. Between 2009-2010, there were 148 deaths in Group 1 and 29 in Group 2, CV mortality of 25% and 41% respectively. Figure 1 shows CV mortality trends over time for indigenous and nearby cities.   Conclusions:  Urbanization appears to influence increases in CV mortality of indigenous living in traditional tribes. Lifestyle changes due to urbanization added to suboptimal health care may increase CV risk in this population.
Reply to Yanagisawa: Treatment of Pulmonary Lymphangioleiomyomatosis during Pregnancy
Authors: Nishant Gupta, Simon R. Johnson, Joel Moss, Francis X. McCormack
Journal: American Journal of Respiratory and Critical Care Medicine (2018)

mammalian target of rapamycin [mTOR]) has become the primary treatment of choice for LAM (5).However, pregnancy is contraindicated during treatment with rapamycin.Recent studies on the molecular pathology of LAM and mTOR pathway signaling have suggested the use of other drugs, such as statins (6), doxycycline (7), and biguanides (8), which are anti-diabetes mellitus drugs and might be promising candidates.Biguanides such as metformin function as activators of adenosine monophosphate-activated protein kinase, which in turn strongly suppresses mTOR (9).In fact, many recent reports have suggested that the use of an adenosine monophosphate-activated protein kinase activator alone or in combination with an mTOR inhibitor may be a promising choice for the treatment of various cancers.In addition, biguanides have been historically used for the treatment of infertility resulting from polycystic ovary syndrome.In patients with this condition, biguanides can be used safely without any concern of fetal teratogenicity.Considering the favorable properties of biguanides, exploration of their use as substitutes or additional drugs for the treatment of LAM may be warranted in the future.So far, no clinical trials of biguanides alone or in combination with other drugs for the treatment of LAM have been reported.One inexpensive study to perform might comprise the subanalysis of previous clinical trials of mTOR inhibitors.These studies would need to include subjects with LAM or renal angiomyolipoma who were also cotreated with biguanides for diabetes mellitus.Such an investigation would also shed new light on the treatment of LAM.
The impact of tumor genomic profile on the effectiveness of adjuvant chemotherapy in resectable intrahepatic cholangiocarcinoma.
Authors: Rebecca Marcus, Heather A. Lillemoe, Reham Abdel-Wahab, Rachna T. Shroff, Milind M. Javle, Thomas A. Aloia
Journal: Journal of Clinical Oncology (2018)

474 Background: The incidence and mortality of ICC is rising in the U.S. While surgical resection currently offers the only potential for cure, the role of adjuvant chemotherapy is not well defined. Tumor genomic profiling is increasingly used to make adjuvant therapy decisions for malignancies. The purpose of this project was to evaluate the correlation between tumor genomic profile and the ability of adjuvant chemotherapy to prevent ICC recurrence after resection. Methods: A retrospective review of 49 patients with ICC undergoing surgical resection and comprehensive tumor genomic profiling was performed. The median age at diagnosis was 56 years (range: 21-72 yrs), 67% were female, and 67% were Caucasian. At resection, 20% had stage I disease, 43% stage II, 29% stage III, and 8% stage IV. Over 90% had moderately or poorly differentiated adenocarcinoma. Clinically relevant genetic mutations (those targeted by anticancer drugs currently on the market or required for entry into a mechanism-driven clinical trial) were evaluated using Foundation Medicine testing. Results: The median recurrence free survival (RFS) for the entire cohort was 9 months (range: 1-55 mo). 59% of patients received adjuvant chemotherapy – 66% gemcitabine-based treatment and 31% capecitabine-based. The most prevalent mutations were FGFR2 (28%), CDKN2A/B (24%), IDH1 (17%), and ARID1A (17%). Median RFS for the adjuvantly treated group was 12 months (range: 3-55 mo), and the presence of any clinically relevant mutation was associated with worse RFS (x vs. y, p = 0.03). IDH1 (30%), BAP1 (25%), and PBRM1 (20%) were most frequently mutated amongst patients who did not receive adjuvant therapy, and their median RFS was 5 months (range: 1-54 mo). Lack of an IDH1 mutation correlated with worse RFS (p = 0.02), while lower stage correlated with improved RFS (p = 0.01). Conclusions: For patients with ICC undergoing resection and adjuvant chemotherapy, the presence of clinically relevant genetic mutations is associated with reduced RFS. To gain further insight into the influence of tumor genomic profile on the effectiveness of adjuvant chemotherapy for this patient population, a multicenter collaborative effort is needed.