tbuckley/cabot-search huggingface dataset:
Extramedullary Infiltration of Acute Lymphoblastic Leukemia in Multiple Organs on FDG PET/CT
Authors: Shuxin Zhang, Wei Wang, Ying Kan, Jie Liu, Jigang Yang
Journal: Clinical Nuclear Medicine (2017)

Abstract Concurrent extramedullary infiltration in multiple organs is uncommon in adults with acute lymphoblastic leukemia. A 21-year-old woman who presented fatigue had a new diagnosis of acute lymphoblastic leukemia underwent FDG PET/CT. The images demonstrated extramedullary infiltration in multiple organs, including the liver, pancreas, kidney and the bone. However, no clinical signs or laboratory tests were suggestive of the involvement of these organs. After four cycles of chemotherapy, the patient’s symptoms were relieved and all previously visualized abnormal activity disappeared on the follow-up FDG PET/CT.
PBX transcription factors drive pulmonary vascular adaptation to birth
Authors: David J. McCulley, Mark D. Wienhold, Elizabeth A. Hines, Timothy A. Hacker, Allison Rogers, Ryan J. Pewowaruk, Rediet Zewdu, Naomi C. Chesler, Licia Selleri, Xin Sun
Journal: Journal of Clinical Investigation (2017)

A critical event in the adaptation to extrauterine life is relaxation of the pulmonary vasculature at birth, allowing for a rapid increase in pulmonary blood flow that is essential for efficient gas exchange. Failure of this transition leads to pulmonary hypertension (PH), a major cause of newborn mortality associated with preterm birth, infection, hypoxia, and malformations including congenital diaphragmatic hernia (CDH). While individual vasoconstrictor and dilator genes have been identified, the coordination of their expression is not well understood. Here, we found that lung mesenchyme–specific deletion of CDH-implicated genes encoding pre–B cell leukemia transcription factors (Pbx) led to lethal PH in mice shortly after birth. Loss of Pbx genes resulted in the misexpression of both vasoconstrictors and vasodilators in multiple pathways that converge to increase phosphorylation of myosin in vascular smooth muscle (VSM) cells, causing persistent constriction. While targeting endothelin and angiotensin, which are upstream regulators that promote VSM contraction, was not effective, treatment with the Rho-kinase inhibitor Y-27632 reduced vessel constriction and PH in Pbx-mutant mice. These results demonstrate a lung-intrinsic, herniation-independent cause of PH in CDH. More broadly, our findings indicate that neonatal PH can result from perturbation of multiple pathways and suggest that targeting the downstream common effectors may be a more effective treatment for neonatal PH.
A phase Ia study of CC-90003, a selective extracellular signal-regulated kinase (ERK) inhibitor, in patients with relapsed or refractory BRAF or RAS-mutant tumors.
Authors: Monica M. Mita, Patricia LoRusso, Grant A. McArthur, Edward S. Kim, Gordon L. Bray, Nanette H Hock, Eric J. Laille, Ida Aronchik, Ellen Filvaroff, Xiaoling Wu, Johanna C. Bendell
Journal: Journal of Clinical Oncology (2017)

2577 Background: CC-90003 is an irreversible inhibitor of ERK 1/2 with potent anti-proliferative activity in KRAS and BRAF mutant tumor models. We conducted a first-in-human study of CC-90003 in patients with RAS or BRAF mutant tumors. Methods: Patients received escalating doses of oral CC-90003 on a 21/28 day cycle. Standard safety (adverse events, chemistry/hematology, physical findings, ECGs and cardiac ECHO/MUGA scans) and PK parameters were assessed. Response was assessed per RECIST 1.1. A proprietary ELISA-based assay measured ERK levels unbound to CC-90003 in peripheral blood mononuclear cells. Results: Nineteen patients (median age: 60 yrs) harboring KRAS (n = 15), NRAS (n = 1), or BRAF (n = 3) mutant tumors received CC-90003 doses from 20 to 160 mg /day. The MTD was 120 mg based on the occurrence of Grade 3 transaminase elevations (n = 2) and hypertension (n = 1) observed at 160 mg (the NTD). Patients completed a median of 2 cycles (range: 1 to 5). AEs (mostly Grade 1 or 2) reported in ≥ 3 patients included constitutional (asthenia, fatigue), gastrointestinal (anorexia, nausea/vomiting, diarrhea), hepatic (transaminase elevations) and neurologic (dizziness, gait disturbance, paresthesias) toxicities. Grade 1-3 neurotoxicity was observed primarily at doses from 80 to 160 mg/day and resolved with dose reduction/interruption. PK parameters were highly variable, with AUC and C max increasing overall, with increasing dose. CC-90003 accumulation was observed after multiple doses. There were no objective responses. Levels of free ERK were reduced by ≥80% compared to baseline by C1D8 at doses ≥ 80 mg/day. Conclusions: ERK inhibition may be an attractive target for the management of mutant RAS or BRAF-driven tumors, however proof-of-concept demonstration for CC-90003 was limited by a lack of objective responses, an unfavorable PK profile and unanticipated neurotoxicity. Clinical trial information: NCT02313012.
Abstract 18384: Hispanic Disparities in PAH: Multi-Modality Validation of Increased Susceptibility to Right Ventricular Dysfunction
Authors: Balaji Natarajan, Vineet Nair, Parinita Dherange, Morgan Whitaker, Irbaz Riaz, Anand Shewale, Vivek Yarlagadda, Kumar Patel, Kenneth Knox, Zain Khalpey, Prakash Suryanarayana, Stephen M Black, Joe G Garcia, Franz Rischard, Jason X Yuan, Ankit A Desai
Journal: Circulation (2016)

Introduction:  Hispanics are known to have increased baseline right ventricular (RV) wall thickness and cardiovascular risk factors compared to non-Hispanics. We, therefore,  hypothesized  that Hispanics have reduced RV function in response to increased pulmonary afterload compared to non-Hispanics.   Methods:  A total of 127 WHO Groups I and IV pulmonary arterial hypertension (PAH) patients were prospectively enrolled and underwent echocardiography and right heart catheterization (RHC) within 4 months, with a subset also performing six-minute walk test (6MWT, n=86). After comparing baseline characteristics between self-reported Hispanics (n=28) and non-Hispanics (n=99), ethnicity effects were assessed using hierarchical linear regression models adjusted for age, gender, indexed pulmonary vascular resistance (PVRi), PAH medication use, and days from echo to RHC.   Results:  Baseline characteristics between the two groups were not significantly different except for age, which was higher in non-Hispanics (60.9+13.7 yrs) compared to Hispanics (51.9+12.2 yrs, P   Conclusions:  Hispanics with PAH exhibit increased pathological RV remodeling and systolic dysfunction validated by both echo and RHC with decreased trends in functional capacity (6MWT) compared to non-Hispanics. This susceptibility may be influenced, in part, by increased pulmonary artery elastance and relatively higher but “normal” wedge pressures.
Microbiota, a key player in alcoholic liver disease
Authors: Anne-Marie Cassard, Dragos Ciocan
Journal: Clinical and Molecular Hepatology (2017)

Alcoholic liver disease (ALD) is a major cause of morbidity and mortality worldwide. Only 20% of heavy alcohol consumers develop alcoholic liver cirrhosis. The intestinal microbiota (IM) has been recently identified as a key player in the severity of liver injury in ALD. Common features of ALD include a decrease of gut epithelial tight junction protein expression, mucin production, and antimicrobial peptide levels. This disruption of the gut barrier, which is a prerequisite for ALD, leads to the passage of bacterial products into the blood stream (endotoxemia). Moreover, metabolites produced by bacteria, such as short chain fatty acids, volatile organic compounds (VOS), and bile acids (BA), are involved in ALD pathology. Probiotic treatment, IM transplantation, or the consumption of dietary fiber, such as pectin, which all alter the ratio of bacterial species, have been shown to improve liver injury in animal models of ALD and to be associated with an improvement in gut barrier function. Although the connections between the microbiota and the host in ALD are well established, the underlying mechanisms are still an active area of research. Targeting the microbiome through the use of prebiotic, probiotic, and postbiotic modalities could be an attractive new approach to manage ALD.
Response to Comment on Dubois-Laforgue et al. Diabetes, Associated Clinical Spectrum, Long-term Prognosis, and Genotype/Phenotype Correlations in 201 Adult Patients With Hepatocyte Nuclear Factor 1B (<i>HNF1B</i>) Molecular Defects. Diabetes Care 2017;40:1436–1443
Authors: Danièle Dubois-Laforgue, Erika Cornu, Cécile Saint-Martin, Joël Coste, Christine Bellanné-Chantelot, José Timsit
Journal: Diabetes Care (2017)

We thank Clissold et al. (1) for their comments on our article (2) that demonstrated genotype/phenotype correlations in patients with HNF1B molecular defects. We reported that, compared with the patients with an HNF1B mutation, those with HNF1B whole-gene deletion due to the 17q12 deletion were leaner at diagnosis and might have a more severe diabetes phenotype. They also had a better renal prognosis as suggested by a higher estimated glomerular filtration rate (eGFR) at diabetes diagnosis and at follow-up, a less frequent need for renal replacement by dialysis or renal transplantation, and a more frequent normal function at follow-up (49% vs. 22%) (2 …
The vaginal microbiome and sexually transmitted infections are interlinked: Consequences for treatment and prevention
Authors: Janneke H. H. M. van de Wijgert
Journal: PLoS Medicine (2017)

In a Perspective for our Collection on STI research, Janneke van de Wijgert discusses the latest on how the vaginal microbiota predisposes women to acquisition of STIs and discusses future potential for clinical intervention.
Ultra-deep targeted sequencing to identify <i>HRAS</i>, <i>TP53</i>, and <i>CDKN2A</i> somatic mutations as molecular prognostic markers in patients with advanced oral squamous cell carcinoma.
Authors: Tzu-Chen Yen, Chien-Hua Peng, Shih-Chi Peng, Chun-Ta Liao, Wen-Ping Hsieh
Journal: Journal of Clinical Oncology (2015)

6024 Background: Ultra-deep targeted sequencing (UDT-Seq) was used to identify somatic mutations predicting disease-specific survival (DSS) in patients with advanced oral squamous cell carcinoma (OSCC). Methods: Formalin-fixed paraffin-embedded primary tumor specimens were collected from 249 node-positive OSCC patients, including 147 patients with (ECS+) and 102 without (ECS-) extracapsular spread. Mutational hotspots of 45 cancer-related genes were examined with UDT-Seq at an average depth of 1000×. Kaplan-Meier plots and Cox regression analyses were used to investigate the association between the mutation status and DSS. Results: Non-synonymous variants were identified in 179 (71.9%) specimens. TP53, CDKN2A, HRAS and PI3KCA were the most frequently mutated genes. The presence of ECS did not statistically significantly influence the mutation spectrum. HRAS mutations were strongly associated with poor DSS independent of ECS. Mutations in TP53 (especially located in the DNA-binding domain) and CDKN2A predicted poor DSS in ECS- and ECS+ patients, respectively. No association between PI3KCA mutations and prognosis was detected. Conclusions: Our findings demonstrate that HRAS, TP53 and CDKN2A mutations identified by UDT-Seq predict DSS in advanced OSCC, potentially serving as molecular markers for individualized patient care through risk-adapted therapy.
Anticancer and immunostimulatory activity of the imipridone ONC201, a selective DRD2 antagonist, in advanced cancer patients.
Authors: Mark N. Stein, Nancy Chan, Ann W. Silk, Jyoti Malhotra, Joseph Aisner, Robert Aiken, Andrew Zloza, Wafik S. El-Deiry, Jenna Newman, Charles Chesson, Rohinton Tarapore, Joshua E. Allen, Wolfgang Oster, Tracie Saunders, Bangning Yu, Siobhan Dickerson, Lorna Rodriguez-Rodriguez, Bruce George Haffty, Howard Kaufman, Janice M. Mehnert
Journal: Journal of Clinical Oncology (2017)

2586 Background: ONC201 is an orally active, small molecule selective antagonist of the G protein-coupled receptor DRD2 that has established a new class of compounds referred to as imipridones. A first-in-human trial of ONC201 defined its recommended phase II dose (RP2D) as 625mg using once every three week administration that was very well tolerated at doses that yielded antitumor effects. ONC201 also showed stimulatory effects on immune cells in preclinical studies, including increased intratumoral NK cell infiltration in xenografts. Based on the exceptional safety profile of ONC201, weekly dosing has been evaluated. Methods: This open-label, 3+3 dose-escalation study used a starting dose of 375mg and escalated to 625mg using a weekly administration schedule. The primary endpoint was to determine the RP2D of ONC201 and secondary endpoints included PD, PK, toxicity, and anti-tumor efficacy. Based on signs of clinical activity and preclinical tumor type sensitivity studies of ONC201, the patient population was enriched for advanced glioblastoma, prostate cancer, and endometrial cancer. Six additional patients were treated at the weekly RP2D. Results: The RP2D for the weekly regimen was defined as 625 mg. Twelve evaluable patients were treated at this dose level and no drug-related AEs &gt; grade 1 occurred. Five patients had stable disease by RECIST criteria for 21-29 weeks. A metastatic prostate cancer who received 375mg ONC201 weekly had significantly diminished intensity in bone scans after 6 doses. PK was consistent with previous reports: Cmax consistently reaches therapeutic micromolar plasma concentrations, ~11 hour half-life, evidence of sustained and delayed activity, no systemic accumulation. In agreement with preclinical observations of ONC201-induced NK cell populations, a 2-10 fold increase in circulating activated NK cells was observed in 5 prostate cancer patients. Conclusions: ONC201 is well tolerated at an oral dose of 625mg weekly, exhibits sustained and late anti-cancer activity, and increases circulating NK cells. Observation in this study, and other clinical studies, warrant further evaluation of the immune oncology effects of ONC201. Clinical trial information: NCT02250781.
Vaginal and anal human papillomavirus infection and seropositivity among female sex workers in Amsterdam, the Netherlands: Prevalence, concordance and risk factors
Authors: E. Marra, N. Kroone, E. Freriks, C.L. van Dam, C.J. Alberts, A.A. Hogewoning, S. Bruisten, A. van Dijk, M.M. Kroone, T. Waterboer, M.F. Schim van der Loeff
Journal: Journal of Infection (2017)
Primary Aspergillosis of the Sphenoid Sinus Observed on Bone SPECT/CT
Authors: Seung Hyun Son, Shin Young Jeong, Sang-Woo Lee, Byeong-Cheol Ahn, Jaetae Lee
Journal: Clinical Nuclear Medicine (2017)

Abstract The bone SPECT/CT allows for precise anatomic delineation of bone activity, which can be valuable for diagnosis of nonmalignant bone diseases. We report an extremely rare case of sphenoid sinus aspergillosis, observed on bone SPECT/CT imaging, as an isolated disease in an immunocompetent individual. A 58-year-old woman with a history of plantar fasciitis was assessed for infection in the tarsal bones. Planar bone scan image revealed incidental focal lesion in skull base, which was considered to be the left sphenoid sinusitis by the bone SPECT/CT scan.
Novel <i>POFUT1</i> mutation associated with hidradenitis suppurativa–Dowling–Degos disease firm up a role for Notch signalling in the pathogenesis of this disorder
Authors: I. González-Villanueva, M. Gutiérrez, P. Hispán, I. Betlloch, J.C. Pascual
Journal: British Journal of Dermatology (2017)
Клініко-сонографічні особливості стеатозу підшлункової залози у дітей з надмірною вагою та ожирінням
Authors: Yu.M. Stepanov, N.Yu. Zavgorodnya, O.Yu. Lukianenko
Journal: GASTROENTEROLOGY (2017)

Актуальність. Своєчасна діагностика стеатозу підшлункової залози (ПЗ) є необхідною умовою виявлення раннього метаболічного ризику та зниження захворюваності на хронічну гастроентерологічну патологію. Мета. Вивчення клініко-інструментальних особливостей стеатозу ПЗ у дітей із надмірною вагою та ожирінням. Матеріали та методи. У 53 дітей із функціональними розладами шлунково-кишкового тракту визначали наявність стеатозу ПЗ за допомогою ультразвукового дослідження. Розподіл за групами відбувся на основі наявності стеатозу ПЗ, ожиріння та надмірної ваги: 1 групу становили 24 пацієнти зі стеатозом ПЗ, ожирінням та надмірною вагою, 2 групу — 18 дітей з ожирінням і надмірною вагою без ознак стеатозу ПЗ, контрольну групу — 11 пацієнтів без стеатозу ПЗ, які мали нормальну вагу. Результати. Клінічна картина у дітей зі стеатозом ПЗ у більшості пацієнтів пояснювалась наявністю супутньої гастроентерологічної патології; 29,1 % хворих основної групи скаржились на біль у лівому підребер’ї. При аналізі диспептичних скарг слід відзначити, що пацієнти зі стеатозом ПЗ частіше скаржились на нудоту (58,3 %), метеоризм (45,8 %) проти пацієнтів, які мали нормальну вагу, однак значущість відмінностей не була достатньою. У пацієнтів 1 групи частіше виявлялась болісність при пальпації за ходом кишечника проти пацієнтів 2 групи. Болісність при пальпації в панкреатичних точках була вірогідно вищою у пацієнтів 1 групи (54,1 %) проти 3 групи. Підвищення ехогенності печінки в 2,4 раза частіше зустрічалось у пацієнтів 1 групи проти 2 групи та в 7 раз частіше, ніж у 3 групі. Зокрема, зміни зернистості печінки втричі частіше зустрічались у пацієнтів зі стеатозом ПЗ (p &lt; 0,05), ніж у пацієнтів без стеатозу та з трофічними розладами, а також дітей, які мають нормальну вагу. Зміни ПЗ при її стеатозі проявлялись не лише змінами ехогенності, але й у майже половини пацієнтів (45,8 %) наявністю нечітких контурів органу, підвищенням зернистості (65,5 %). Об’єм і товщина стінки жовчного міхура були вірогідно вищими у групі дітей зі стеатозом ПЗ проти контрольної групи. Ознаки біліарного сладжу вдвічі частіше зустрічались у дітей зі стеатозом проти групи дітей без стеатозу та в 4 рази частіше, ніж у дітей, які мають нормальну вагу (43,87 % у 1 групі, 21 % у 2 групі та 9 % у 3 групі). Висновки. Клінічні та сонологічні зміни у пацієнтів зі стеатозом ПЗ свідчать про можливість запальних змін у паренхімі залози, що пов’язані із системним запаленням на фоні стеатозу та супутньою патологією органів шлунково-кишкового тракту.
A randomized, crossover phase I study to assess the effects of formulation and meal consumption on the bioavailability of dovitinib (TKI258).
Authors: Sunil Sharma, Ramesh K. Ramanathan, Daniel J. George, Michelle Quinlan, Swarupa Kulkarni, Alaeddin Homsi, Jeffrey W. Scott, Jeffrey R. Infante
Journal: Journal of Clinical Oncology (2013)

2593 Background: Dovitinib (TKI258), an oral multitargeted receptor tyrosine kinase inhibitor, is being studied in a phase 3 trial for renal cell carcinoma. A previous study compared the bioavailability of 2 capsule formulations of dovitinib. Arm 1 of the current study compared relative bioavailability of the final market image (FMI) form (monohydrate tablets) with the clinical service form (CSF; anhydrate capsules) of dovitinib. Arm 2 assessed the effect of food on bioavailability of the FMI tablet in adult patients (pts) with advanced solid tumors. Both arms employed crossover designs. Methods: In arm 1, pts were randomized to receive a single 500-mg dose of dovitinib either as a CSF capsule or FMI tablet, followed by a single 500-mg dose of the other formulation after 7 days of rest. Plasma pharmacokinetic (PK) profiles were determined from blood samples. A linear mixed-effects model fitted to log-transformed PK parameters maximal concentration (C max ) and area under the curve (AUC 0-tlast ) was used to determine the relative bioavailability of FMI vs CSF. In Arm 2, pts received 300 mg of the FMI formulation once daily for 22 days after being randomized to 1 of 6 meal sequences with 3 fed or nonfed states (no meal [NM], low-fat [LF] meal, or high-fat [HF] meal) on days 8, 15, and 22. The relative bioavailability of dovitinib under LF and HF vs NM state was determined using the same model as arm 1 for the PK parameters C max and AUC 0-tlast . Results: The study accrued 21 pts to arm 1 and 42 pts to arm 2. Based on the interim analysis, PK was assessed in 17 evaluable pts in arm 1. The geometric mean ratios (GMRs; 90% CI) for C max and AUC 0-tlast comparing FMI vs CSF were 0.99 (0.91-1.08) and 0.96 (0.89-1.04), respectively. The FMI formulation was used in arm 2; PK was assessed in 19 pts. C max GMR (90% CI) was 0.82 (0.71-0.94) and 0.90 (0.78-1.03) for HF/NM and LF/NM, respectively. AUC 0-tlast GMR (90% CI) was 0.91 (0.81-1.02) and 0.99 (0.88-1.10) for HF/NM and LF/NM, respectively. Conclusions: The oral bioavailability of the FMI tablet and CSF capsule were comparable, and there was no clinically relevant effect of food (HF or LF meals) on the bioavailability of the FMI tablet form of dovitinib. Clinical trial information: NCT01155713.
Cardiovascular and Neuropsychiatric Events after Varenicline Use for Smoking Cessation
Authors: Andrea S. Gershon, Michael A. Campitelli, Steven Hawken, Charles Victor, Beth A. Sproule, Paul Kurdyak, Peter Selby
Journal: American Journal of Respiratory and Critical Care Medicine (2017)

Varenicline aids in smoking cessation but has also been associated with serious adverse events.The aim of this study was to determine the risks of cardiovascular and neuropsychiatric events after varenicline receipt in a real-world setting.A population-based, self-controlled risk interval study using linked universal health administrative data from the diverse, multicultural population of Ontario, Canada, was conducted. In two separate analyses, new varenicline users between September 1, 2011 and February 15, 2014 were observed from 1 year before to 1 year after varenicline receipt. The relative incidences of cardiovascular and neuropsychiatric hospitalizations and emergency department visits in the 12 weeks after varenicline receipt (the risk interval) compared with the remaining observation period (the control interval) were estimated in two separate fixed-effect conditional Poisson regressions. Sensitivity analyses tested the robustness of the results.Among 56,851 new users of varenicline, 6,317 cardiovascular and 10,041 neuropsychiatric hospitalizations and emergency department visits occurred from 1 year before to 1 year after receipt. The incidence of cardiovascular events was 34% higher in the risk compared with the control interval (relative incidence, 1.34; 95% confidence interval, 1.25-1.44). Findings were consistent in sensitivity analyses, most notably in those without any history of previous cardiovascular disease. The relative incidence of neuropsychiatric events was marginally significant in the primary (relative incidence, 1.06; 95% confidence interval, 1.00-1.13) but not all sensitivity analyses.Varenicline appears to be associated with an increased risk of cardiovascular but not neuropsychiatric events.
Yellow fever vaccine in egg-allergic patients: safety of a vaccination protocol
Authors: Gislane S. Juliao, Pamela A. Barbosa, Pryscilla F. Silva, Myllena A. Cunha, Caroline F. Formigari, Antonio C. Pastorino, Ana Paula C. Moschione, Mayra B. Dorna, Cristiane N. Santos
Journal: Journal of Allergy and Clinical Immunology (2018)
Cross-border outbreak of listeriosis caused by cold-smoked salmon, revealed by integrated surveillance and whole genome sequencing (WGS), Denmark and France, 2015 to 2017
Authors: Susanne Schjørring, Sofie Gillesberg Lassen, Tenna Jensen, Alexandra Moura, Jette S Kjeldgaard, Luise Müller, Stine Thielke, Alexandre Leclercq, Mylene M Maury, Mathieu Tourdjman, Marie-Pierre Donguy, Marc Lecuit, Steen Ethelberg, Eva M Nielsen
Journal: Eurosurveillance (2017)

In August 2017, an outbreak of six listeriosis cases in Denmark was traced to cold-smoked salmon, using epidemiological investigations and whole-genome sequencing (WGS) analyses. Exchange of genome sequences allowed identification in France of a food isolate from a salmon-derived product and a human isolate from 2016 within the same cgMLST cluster as the Danish isolates (L2-SL8-ST8-CT771). The salmon product came from a third European Union country. WGS can rapidly link human cases and food isolates across Europe.