tbuckley/cabot-search huggingface dataset:
Phenotypes of Rapid Cystic Fibrosis Lung Disease Progression during Adolescence and Young Adulthood
Authors: Rhonda D. Szczesniak, Dan Li, Weiji Su, Cole Brokamp, John Pestian, Michael Seid, John P. Clancy
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Individuals with cystic fibrosis are at risk for prolonged drops in lung function, clinically termed rapid decline, during discreet periods of the disease.To identify phenotypes of rapid pulmonary decline and determine how these phenotypes are related to patient characteristics.A longitudinal cohort study of patients with cystic fibrosis aged 6-21 years was conducted using the Cystic Fibrosis Foundation Patient Registry. A statistical approach for clustering longitudinal profiles, sparse functional principal components analysis, was used to classify patients into distinct phenotypes by evaluating trajectories of FEV1 decline. Phenotypes were compared with respect to baseline and mortality characteristics.Three distinct phenotypes of rapid decline were identified, corresponding to early, middle, and late timing of maximal FEV1 loss, in the overall cohort (n = 18,387). The majority of variation (first functional principal component, 94%) among patient profiles was characterized by differences in mean longitudinal FEV1 trajectories. Average degree of rapid decline was similar among phenotypes (roughly -3% predicted/yr); however, average timing differed, with early, middle, and late phenotypes experiencing rapid decline at 12.9, 16.3, and 18.5 years of age, respectively. Individuals with the late phenotype had the highest initial FEV1 but experienced the greatest loss of lung function. The early phenotype was more likely to have respiratory infections and acute exacerbations at baseline or to develop them subsequently, compared with other phenotypes.By identifying phenotypes and associated risk factors, timing of interventions may be more precisely targeted for subgroups at highest risk of lung function loss.
Salt and water: not so simple
Authors: Mark L. Zeidel
Journal: Journal of Clinical Investigation (2017)

It has long been viewed that the maintenance of osmotic balance in response to high salt intake is a passive process that is mediated largely by increased water consumption to balance the salt load. Two studies in this issue of the JCI challenge this notion and demonstrate that osmotic balance in response to high salt intake involves a complex regulatory process that is influenced by hormone fluctuation, metabolism, food consumption, water intake, and renal salt and water excretion. Rakova et al. report the unexpected observation that long-term high salt intake did not increase water consumption in humans but instead increased water retention. Moreover, salt and water balance was influenced by glucocorticoid and mineralocorticoid fluctuations. Kitada et al. extend upon these findings in mouse models and determined that increased urea and a corresponding increase in urea transporters in the renal medulla as the result of increased protein intake promote the water retention that is needed to achieve osmotic homeostasis. Together, the results of these two studies lay the groundwork for future studies to determine how, in the face of chronic changes in salt intake, humans maintain volume and osmotic homeostasis.
Multivariate modelling of faecal bacterial profiles of patients with IBS predicts responsiveness to a diet low in FODMAPs
Authors: Sean M P Bennet, Lena Böhn, Stine Störsrud, Therese Liljebo, Lena Collin, Perjohan Lindfors, Hans Törnblom, Lena Öhman, Magnus Simrén
Journal: Gut (2017)

Objective The effects of dietary interventions on gut bacteria are ambiguous. Following a previous intervention study, we aimed to determine how differing diets impact gut bacteria and if bacterial profiles predict intervention response. Design Sixty-seven patients with IBS were randomised to traditional IBS (n=34) or low fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAPs) (n=33) diets for 4 weeks. Food intake was recorded for 4 days during screening and intervention. Faecal samples and IBS Symptom Severity Score (IBS-SSS) reports were collected before (baseline) and after intervention. A faecal microbiota dysbiosis test (GA-map Dysbiosis Test) evaluated bacterial composition. Per protocol analysis was performed on 61 patients from whom microbiome data were available. Results Responders (reduced IBS-SSS by ≥50) to low FODMAP, but not traditional, dietary intervention were discriminated from non-responders before and after intervention based on faecal bacterial profiles. Bacterial abundance tended to be higher in non-responders to a low FODMAP diet compared with responders before and after intervention. A low FODMAP intervention was associated with an increase in Dysbiosis Index (DI) scores in 42% of patients; while decreased DI scores were recorded in 33% of patients following a traditional IBS diet. Non-responders to a low FODMAP diet, but not a traditional IBS diet had higher DI scores than responders at baseline. Finally, while a traditional IBS diet was not associated with significant reduction of investigated bacteria, a low FODMAP diet was associated with reduced Bifidobacterium and Actinobacteria in patients, correlating with lactose consumption. Conclusions A low FODMAP, but not a traditional IBS diet may have significant impact on faecal bacteria. Responsiveness to a low FODMAP diet intervention may be predicted by faecal bacterial profiles. Trial registration number NCT02107625 .
Doctors can withdraw life support from baby with rare genetic disorder, says judge
Authors: Clare Dyer
Journal: BMJ (2017)

Doctors at Great Ormond Street children’s hospital in London are entitled to withdraw life support from a baby with a rare genetic disorder, against his parents’ strenuous opposition, a High Court judge has ruled.

Connie Yates and Chris Gard raised more than £1.2m (€1.4m; $1.5m) from crowdfunding to take 8 month old Charlie, who has mitochondrial DNA depletion syndrome, to the US for nucleoside therapy. But Mr Justice Francis held that the treatment would not be in his interests.

“It is with the heaviest of hearts, but with complete conviction . . . …
The role of cetuximab in induction chemotherapy: Comparison of APF-C (<i>nab-</i>paclitaxel, cisplatin, 5-FU + cetuximab) with APF, both followed by chemoradiation therapy (CRT), in patients with locally advanced head and neck squamous cell carcinoma (HNSCC).
Authors: Douglas Adkins, Jessica C. Ley, Tanya Marya Wildes, Loren S. Michel, Jason Rich, Randal Paniello, Ravi Uppaluri, Wade L. Thorstad, Hiram Alberto Gay, Kathryn Trinkaus, Toni Rachocki, Brian Nussenbaum
Journal: Journal of Clinical Oncology (2015)

6042 Background: Cetuximab (C) improved overall survival (OS) in patients (pts) with HNSCC when added to definitive RT or to palliative chemotherapy; however, the role of cetuximab in induction chemotherapy is unclear. We hypothesized improved OS, disease-specific survival (DSS), and lower relapse rates with the addition of C to APF given as induction chemotherapy before CRT. A nab-Paclitaxel-based induction chemotherapy regimen was chosen because we observed better survival outcomes in comparison to a docetaxel-based regimen (Cancer Medicine2014). Methods: Two consecutive prospective phase II trials (APF and APF+C) were performed: 30 pts were treated with APF (weekly nab-paclitaxel 100 mg/m2 and every 3 week cisplatin 75 mg/m2 and 5-FU 750 mg/m2/day x 3) and 30 pts were treated with APF+C (APF + weekly cetuximab 250 mg/m2). Pts were scheduled to receive three cycles followed by CRT (with cisplatin). Results: Pt and tumor characteristics for all 60 pts are as follows: median age 57 (38-74) yrs, smoking history 83% (50 pts), p16+ Oropharynx (OPSCC) 57% (34 pts), T classification (T2-16 pts; T3-24 pts; T4-20 pts) and N classification (N0/1-11 pts; 2-38 pts; 3-11 pts). The distributions of age, smoking history, p16+ OPSCC, T and N classifications were similar between the two treatment groups. Two year OS (APF-C 90%, APF 93%) and DSS (APF-C 97%, APF 97%) were excellent in both treatment groups and not significantly different (Table); however, disease relapse occurred in five pts in the APF+C group vs 1 pt in the APF group (p = .61, log rank ). When stratified for p16+ OPSCC and p16-HNSCC, no significant differences in 2 year OS or DSS occurred between the two treatment groups. Conclusions: Two year OS and DSS were similar between APF+C and APF, even when stratified for p16 status. These preliminary data do not support the addition of cetuximab to APF. Clinical trial information: NCT01566435 and NCT00736944. Survival Endpoint APF (n = 30) APF+C (n = 30) p value % % 2 yr OS 93% 90% .99* 2 yr DSS 97% 97% .99 p16+ OPSCC 2 yr OS 94% 94% .99 p16+ OPSCC 2 yr DSS 94% 100% .99 p16- HNSCC 2 yr OS 92% 83% .59 p16-HNSCC 2 yr DSS 100% 92% .48 *Fisher's Exact test.
Individuals with progranulin haploinsufficiency exhibit features of neuronal ceroid lipofuscinosis
Authors: Michael E. Ward, Robert Chen, Hsin-Yi Huang, Connor Ludwig, Maria Telpoukhovskaia, Ali Taubes, Helene Boudin, Sakura S. Minami, Meredith Reichert, Philipp Albrecht, Jeffrey M. Gelfand, Andres Cruz-Herranz, Christian Cordano, Marcel V. Alavi, Shannon Leslie, William W. Seeley, Bruce L. Miller, Eileen Bigio, Marek-Marsel Mesulam, Matthew S. Bogyo, Ian R. Mackenzie, John F. Staropoli, Susan L. Cotman, Eric J. Huang, Li Gan, Ari J. Green
Journal: Science Translational Medicine (2017)

Heterozygous mutations in the GRN gene lead to progranulin (PGRN) haploinsufficiency and cause frontotemporal dementia (FTD), a neurodegenerative syndrome of older adults. Homozygous GRN mutations, on the other hand, lead to complete PGRN loss and cause neuronal ceroid lipofuscinosis (NCL), a lysosomal storage disease usually seen in children. Given that the predominant clinical and pathological features of FTD and NCL are distinct, it is controversial whether the disease mechanisms associated with complete and partial PGRN loss are similar or distinct. We show that PGRN haploinsufficiency leads to NCL-like features in humans, some occurring before dementia onset. Noninvasive retinal imaging revealed preclinical retinal lipofuscinosis in heterozygous GRN mutation carriers. Increased lipofuscinosis and intracellular NCL-like storage material also occurred in postmortem cortex of heterozygous GRN mutation carriers. Lymphoblasts from heterozygous GRN mutation carriers accumulated prominent NCL-like storage material, which could be rescued by normalizing PGRN expression. Fibroblasts from heterozygous GRN mutation carriers showed impaired lysosomal protease activity. Our findings indicate that progranulin haploinsufficiency caused accumulation of NCL-like storage material and early retinal abnormalities in humans and implicate lysosomal dysfunction as a central disease process in GRN-associated FTD and GRN-associated NCL.
Modifiable risk factors for ovarian cancer: A multinational case-control study.
Authors: Mohammed Shaik, Terri Lehman, Omar Abed Alkharabsheh, Rama Modali, Borys Hrinczenko
Journal: Journal of Clinical Oncology (2015)

5581 Background: Prior ovarian cancer (OC) epidemiological studies have investigated the relationship of diet, exercise, and smoking. Evidence of these risk factors for ovarian cancer has been inconsistent. In this multinational case control study we evaluated those potential modifiable risk factors. Methods: Data were obtained from the Global Epidemiological Study, a multinational database to assess disease risk factors. A total of 1344 (OC = 672 and controls = 672) matched for age and race, were recruited from Poland, Vietnam, Western Europe and USA. Information regarding risk factors included different diets in number of servings (serv), exercise, and smoking. For categorical and continuous variables chi-square and t-test were used, respectively. Adjusted multivariable logistic regression analysis was used for odds ratios (OR) with 95% confidence intervals (CI) as estimates of the relative risk of OC. Results: Median age was 59 yrs and median BMI for cases and controls was 25.7 and 26, respectively. In the multivariate analysis, OC risk was significantly associated with a self-report of dairy [OR = 1.91; 95% CI (1.4-2.4)], whole grain [OR = 0.64; 95% CI (0.51- 0.87)], fish [OR = 2.7; 95% CI (2.04-3.56)], exercise [OR = 1.54; 95% CI (1.19-1.99)] and tobacco smoking [OR = 0.43; 95% CI (0.25-0.74)], respectively. There was no association with fruits, vegetables, and meat consumption on OC risk (see table). Conclusions: Consumption of fish (any serv/wk), dairy (> 2 serv/day), whole grains (< 2 serv/day) and exercise (> 120 min/wk) were associated with a decreased risk of OC. Smoking > 40 pack-yr (pyr) showed an increased risk for OC. Further prospective studies are needed to validate our findings. Modifiable risk factors in ovarian cancer. Variables Adjusted OR (CI) p-value Fish intake (No vs. Yes) 2.7 (2.04-3.56) < 0.0001 Whole Grain (< 2/day serv vs. ≥ 2/day 0.64 (0.51- 0.87) 0.003 Dairy (< 2/day serv vs. ≥ 2/day) 1.91 (1.4-2.4) < 0.0001 Vegetables (< 2/day serv vs. ≥ 2/day) 0.78 (0.6-1.02) 0.07 Fruits (< 2/day serv vs. ≥ 2/day) 1.16 (0.8-1.5) 0.24 Meat (< 3/wk serv vs. ≥ 3/wk) 1.2 (0.95-1.52) 0.10 BMI 1.001 (0.9-1.02) 0.92 Smoking (<40 pyr vs. ≥ 40 pyr) 0.43 (0.25-0.74) 0.002 Exercise (< 120 min/wk vs. ≥ 120 min/wk) 1.54 (1.19-1.99) 0.0008
Comment on Chen et al. Risk of Developing Type 2 Diabetes in Adolescents and Young Adults With Autism Spectrum Disorder: A Nationwide Longitudinal Study. Diabetes Care 2016;39:788–793
Authors: Yong-Jiang Li, Ya-Min Li
Journal: Diabetes Care (2017)

We read with interest the study by Chen et al. (1) investigating the risk of type 2 diabetes mellitus (DM) among adolescents and young adults with autism spectrum disorder (ASD). The authors reported that adolescents and young adults with ASD had a significantly higher risk of developing type 2 DM (2.7- and 5.3-fold, respectively) compared with those without ASD. However, it seems that important confounding factors, including maternal metabolic conditions, were not adjusted …
Cover Image: Are melanocyte-associated peptides the elusive autoantigens in alopecia areata?
Authors: M. Bertolini, A. Rossi, R. Paus
Journal: British Journal of Dermatology (2017)

Conflicts of interest: none declared. Dear Editor, This section through a lesional alopecia areata hair follicle was double immunostained for c‐Kit, which demarcates hair matrix (HM) melanocytes and mast cells in the hair follicle's connective tissue sheath (CTS), and the T‐cell marker CD8.1 This image catches the rare moment when a CD8+ T cell presumably recognizes an autoantigen presented by a melanocyte and attacks it (red rectangle). While melanogenesis‐related peptides have long been thought to be autoantigens in this CD8+ T‐cell‐dependent autoimmune disease, the key major histocompatibility complex class I‐presented (auto)antigens recognized by these T cells remain to be identified – a prerequisite for developing a curative therapy. This image further supports the hypothesis that melanogenesis‐related peptides are among the elusive autoantigens in alopecia areata.2 DP, dermal papilla; ORS, outer root sheath. Scale bar = 50 μm.
Reply to the letter to the editor ‘Addressing the quality of the ESMO-MCBS’ by Del Paggio
Authors: N.I. Cherny, U. Dafni, J. Bogaerts, G. Pentheroudakis, J. Tabernero, C. Zielinski, M. Piccart, E.G.E. de Vries
Journal: Annals of Oncology (2017)
Emerging therapies for acute myeloid leukemia
Authors: Caner Saygin, Hetty E. Carraway
Journal: Journal of Hematology & Oncology (2017)

Acute myeloid leukemia (AML) is characterized by clinical and biological heterogeneity. Despite the advances in our understanding of its pathobiology, the chemotherapy-directed management has remained largely unchanged in the past 40 years. However, various novel agents have demonstrated clinical activity, either as single agents (e.g., isocitrate dehydrogenase (IDH) inhibitors, vadastuximab) or in combination with standard induction/consolidation at diagnosis and with salvage regimens at relapse. The classes of agents described in this review include novel cytotoxic chemotherapies (CPX-351 and vosaroxin), epigenetic modifiers (guadecitabine, IDH inhibitors, histone deacetylase (HDAC) inhibitors, bromodomain and extraterminal (BET) inhibitors), FMS-like tyrosine kinase receptor 3 (FLT3) inhibitors, and antibody-drug conjugates (vadastuximab), as well as cell cycle inhibitors (volasertib), B-cell lymphoma 2 (BCL-2) inhibitors, and aminopeptidase inhibitors. These agents are actively undergoing clinical investigation alone or in combination with available chemotherapy.
Whole-exome analysis reveals novel somatic genomic alterations associated with cell of origin in diffuse large B-cell lymphoma
Authors: B A Manso, K Wenzl, Y W Asmann, M J Maurer, M Manske, Z-Z Yang, S L Slager, G S Nowakowski, S M Ansell, T E Witzig, A L Feldman, L Rimsza, B Link, J R Cerhan, A J Novak
Journal: Blood Cancer Journal (2017)

Whole-exome analysis reveals novel somatic genomic alterations associated with cell of origin in diffuse large B-cell lymphoma
Expanding the Genotypic Spectrum of Bathing Suit Ichthyosis
Authors: Nareh V. Marukian, Rong-Hua Hu, Brittany G. Craiglow, Leonard M. Milstone, Jing Zhou, Amy Theos, Hande Kaymakcalan, Deniz A. Akkaya, Jouni J. Uitto, Hassan Vahidnezhad, Leila Youssefian, Susan J. Bayliss, Amy S. Paller, Lynn M. Boyden, Keith A. Choate
Journal: JAMA Dermatology (2017)

Bathing suit ichthyosis (BSI) is a rare congenital disorder of keratinization characterized by restriction of scale to sites of relatively higher temperature such as the trunk, with cooler areas remaining unaffected. Fewer than 40 cases have been reported in the literature. Bathing suit ichthyosis is caused by recessive, temperature-sensitive mutations in the transglutaminase-1 gene (TGM1). Clear genotype-phenotype correlations have been difficult to establish because several of the same TGM1 mutations have been reported in BSI and other forms of congenital ichthyosis. We identify novel and recurrent mutations in 16 participants with BSI.To expand the genotypic spectrum of BSI, identifying novel TGM1 mutations in patients with BSI, and to use BSI genotypes to draw inferences about the temperature sensitivity of TGM1 mutations.A total of 16 participants with BSI from 13 kindreds were identified from 6 academic medical centers. A detailed clinical history was obtained from each participant, including phenotypic presentation at birth and disease course. Each participant underwent targeted sequencing of TGM1.Phenotypic and genotypic characteristics in these patients from birth onward.Of the 16 participants, 7 were male, and 9 were female (mean age, 12.6 years; range, 1-39 years). We found 1 novel TGM1 indel mutation (Ile469_Cys471delinsMetLeu) and 8 TGM1 missense mutations that to our knowledge have not been previously reported in BSI: 5 have been previously described in non-temperature-sensitive forms of congenital ichthyosis (Arg143Cys, Gly218Ser, Gly278Arg, Arg286Gln, and Ser358Arg), and 3 (Tyr374Cys, Phe495Leu, and Ser772Arg) are novel mutations. Three probands were homozygous for Arg264Trp, Arg286Gln, or Arg315Leu, indicating that these mutations are temperature sensitive. Seven of 10 probands with a compound heterozygous TGM1 genotype had a mutation at either arginine 307 or 315, providing evidence that mutations at these sites are temperature sensitive and highlighting the importance of these residues in the pathogenesis of BSI.Our findings expand the genotypic spectrum of BSI and the understanding of temperature sensitivity of TGM1 mutations. Increased awareness of temperature-sensitive TGM1 genotypes should aid in genetic counseling and provide insights into the pathophysiology of TGM1 ichthyoses, transglutaminase-1 enzymatic activity, and potential therapeutic approaches.
Disruption of spatiotemporal hypoxic signaling causes congenital heart disease in mice
Authors: Xuejun Yuan, Hui Qi, Xiang Li, Fan Wu, Jian Fang, Eva Bober, Gergana Dobreva, Yonggang Zhou, Thomas Braun
Journal: Journal of Clinical Investigation (2017)

Congenital heart disease (CHD) represents the most prevalent inborn anomaly. Only a minority of CHD cases are attributed to genetic causes, suggesting a major role of environmental factors. Nonphysiological hypoxia during early pregnancy induces CHD, but the underlying reasons are unknown. Here, we have demonstrated that cells in the mouse heart tube are hypoxic, while cardiac progenitor cells (CPCs) expressing islet 1 (ISL1) in the secondary heart field (SHF) are normoxic. In ISL1+ CPCs, induction of hypoxic responses caused CHD by repressing Isl1 and activating NK2 homeobox 5 (Nkx2.5), resulting in decreased cell proliferation and enhanced cardiomyocyte specification. We found that HIF1α formed a complex with the Notch effector hes family bHLH transcription factor 1 (HES1) and the protein deacetylase sirtuin 1 (SIRT1) at the Isl1 gene. This complex repressed Isl1 in the hypoxic heart tube or following induction of ectopic hypoxic responses. Subsequently, reduced Isl1 expression abrogated ISL1-dependent recruitment of histone deacetylases HDAC1/5, inhibiting Nkx2.5 expression. Inactivation of Sirt1 in ISL1+ CPCs blocked Isl1 suppression via the HIF1α/HES1/SIRT1 complex and prevented CHDs induced by pathological hypoxia. Our results indicate that spatial differences in oxygenation of the developing heart serve as signals to control CPC expansion and cardiac morphogenesis. We propose that physiological hypoxia coordinates homeostasis of CPCs, providing mechanistic explanations for some nongenetic causes of CHD.
Restrictions on trans fatty acids are linked to fall in cardiovascular events
Authors: Jacqui Wise
Journal: BMJ (2017)

Counties in the US state of New York that introduced restrictions on trans fatty acids in restaurants and takeaway outlets have seen significantly fewer admissions for cardiovascular events than counties with no restrictions, research in JAMA Cardiology shows.1

The main source of trans fatty acids in the diet is partially hydrogenated oils used in baked goods, yeast breads, fried foods, chips, crackers, and margarine. New York City restricted trans fatty acids in eateries in 2007—the first large US metropolitan area …