tbuckley/cabot-search huggingface dataset:
Aberrant Wnt signaling in multiple myeloma: molecular mechanisms and targeting options
Authors: Harmen van Andel, Kinga A. Kocemba, Marcel Spaargaren, Steven T. Pals
Journal: Leukemia (2019)

Aberrant activation of Wnt/β-catenin signaling plays a central role in the pathogenesis of a wide variety of malignancies and is typically caused by mutations in core Wnt pathway components driving constitutive, ligand-independent signaling. In multiple myelomas (MMs), however, these pathway intrinsic mutations are rare despite the fact that most tumors display aberrant Wnt pathway activity. Recent studies indicate that this activation is caused by genetic and epigenetic lesions of Wnt regulatory components, sensitizing MM cells to autocrine Wnt ligands and paracrine Wnts emanating from the bone marrow niche. These include deletion of the tumor suppressor CYLD, promotor methylation of the Wnt antagonists WIF1, DKK1, DKK3, and sFRP1, sFRP2, sFRP4, sFRP5, as well as overexpression of the co-transcriptional activator BCL9 and the R-spondin receptor LGR4. Furthermore, Wnt activity in MM is strongly promoted by interaction of both Wnts and R-spondins with syndecan-1 (CD138) on the MM cell-surface. Functionally, aberrant canonical Wnt signaling plays a dual role in the pathogenesis of MM: (I) it mediates proliferation, migration, and drug resistance of MM cells; (II) MM cells secrete Wnt antagonists that contribute to the development of osteolytic lesions by impairing osteoblast differentiation. As discussed in this review, these insights into the causes and consequences of aberrant Wnt signaling in MM will help to guide the development of targeting strategies. Importantly, since Wnt signaling in MM cells is largely ligand dependent, it can be targeted by drugs/antibodies that act upstream in the pathway, interfering with Wnt secretion, sequestering Wnts, or blocking Wnt (co)receptors.
Will This Patient Be Difficult to Intubate?
Authors: Michael E. Detsky, Naheed Jivraj, Neill K. Adhikari, Jan O. Friedrich, Ruxandra Pinto, David L. Simel, Duminda N. Wijeysundera, Damon C. Scales
Journal: JAMA (2019)

<h3>Importance</h3> Recognizing patients in whom endotracheal intubation is likely to be difficult can help alert physicians to the need for assistance from a clinician with airway training and having advanced airway management equipment available. <h3>Objective</h3> To identify risk factors and physical findings that predict difficult intubation. <h3>Data Sources</h3> The databases of MEDLINE and EMBASE were searched from 1946 to June 2018 and from 1947 to June 2018, respectively, and the reference lists from the retrieved articles and previous reviews were searched for additional studies. <h3>Study Selection</h3> Sixty-two studies with high (level 1-3) methodological quality that evaluated the accuracy of clinical findings for identifying difficult intubation were reviewed. <h3>Data Extraction and Synthesis</h3> Two authors independently abstracted data. Bivariate random-effects meta-analyses were used to calculate summary positive likelihood ratios across studies or univariate random-effects models when bivariate models failed to converge. <h3>Results</h3> Among the 62 high-quality studies involving 33 559 patients, 10% (95% CI, 8.2%-12%) of patients were difficult to intubate. The physical examination findings that best predicted a difficult intubation included a grade of class 3 on the upper lip bite test (lower incisors cannot extend to reach the upper lip; positive likelihood ratio, 14 [95% CI, 8.9-22]; specificity, 0.96 [95% CI, 0.93-0.97]), shorter hyomental distance (range of &lt;3-5.5 cm; positive likelihood ratio, 6.4 [95% CI, 4.1-10]; specificity, 0.97 [95% CI, 0.94-0.98]), retrognathia (mandible measuring &lt;9 cm from the angle of the jaw to the tip of the chin or subjectively short; positive likelihood ratio, 6.0 [95% CI, 3.1-11]; specificity, 0.98 [95% CI, 0.90-1.0]), and a combination of physical findings based on the Wilson score (positive likelihood ratio, 9.1 [95% CI, 5.1-16]; specificity, 0.95 [95% CI, 0.90-0.98]). The widely used modified Mallampati score (≥3) had a positive likelihood ratio of 4.1 (95% CI, 3.0-5.6; specificity, 0.87 [95% CI, 0.81-0.91]). <h3>Conclusions and Relevance</h3> Although several simple clinical findings are useful for predicting a higher likelihood of difficult endotracheal intubation, no clinical finding reliably excludes a difficult intubation. An abnormal upper lip bite test, which is easily assessed by clinicians, raises the probability of difficult intubation from 10% to greater than 60% for the average-risk patient.
Changes in Screening Practices for Prediabetes and Diabetes Since the Recommendation for Hemoglobin A1c Testing
Authors: Joshua M. Evron, William H. Herman, Laura N. McEwen
Journal: Diabetes Care (2019)

OBJECTIVE Screening involves the presumptive identification of asymptomatic individuals at increased risk for unrecognized disease. We examined changes in screening practices for prediabetes and diabetes since January 2010, when HbA1c was first recommended as an option for screening and diagnosis. RESEARCH DESIGN AND METHODS We studied members without diabetes of an HMO ≥45 years of age continuously enrolled for ≥3 years and assigned to primary care clinicians affiliated with a large academic health system. We defined screening as the first oral glucose tolerance test, HbA1c, or glucose test performed between 2010 and 2014. RESULTS Of 12,772 eligible patients, 9,941 (78%) were screened at least once over 3 years. HbA1c was the initial screening test 14% of the time and glucose 86% of the time. Of those screened with HbA1c, 63% had abnormal results defined as HbA1c ≥5.7% (≥39 mmol/mol). Of those tested with glucose, 30% had abnormal results defined as glucose ≥100 mg/dL, and 5% had abnormal results defined as glucose ≥126 mg/dL. Patients with abnormal HbA1c levels and those with glucose levels ≥126 mg/dL were equally likely to be scheduled for follow-up appointments (41% vs. 39%), but those with abnormal HbA1c levels were more likely to be diagnosed with prediabetes or diabetes (36% vs. 26%). CONCLUSIONS As we observed in 2004, rates of screening are high. HbA1c is still used less frequently than glucose for screening but is more likely to result in a clinical diagnosis. Evidence to support guidelines to define the role of random glucose screening, including definition of appropriate cut points and follow-up, is needed.
IgE and IgG4 Epitope Profiles for the Major Peanut Allergens from Peanut Allergic Patients Undergoing Oral Immunotherapy
Authors: Christina M. Kronfel, Hsiaopo Cheng, Barry K. Hurlburt, Reyna J. Simon, Soheila J. Maleki
Journal: Journal of Allergy and Clinical Immunology (2019)
Abstract 18984: A Challenging Case of Mixed Valvular Dysfunction: From Diagnosis to Intervention
Authors: David J Shim, Lachlan Forrow, Michael C Gavin, Duane S Pinto
Journal: Circulation (2017)

An 86 year old woman with a history of heart failure, atrial fibrillation, coronary artery disease, and mitral regurgitation s/p bioprosthetic valve replacement and LIMA-LAD bypass, was referred to...
Trends and outcomes in laparoscopic versus open surgery for rectal cancer from 2005 to 2016 using the ACS-NSQIP database, a retrospective cohort study
Authors: Catherine H Davis, Tanmay Gaglani, Linda W Moore, Xianglin L Du, Hyunsoo Hwang, Jose-Miguel Yamal, H Randolph Bailey, Marianne V Cusick
Journal: International Journal of Surgery (2019)
Safety of laparoscopic total gastrectomy with splenectomy for upper third advanced gastric cancer.
Authors: Eigo Akimoto, Masanori Tokunaga, Reo Sato, Akio Kaito, Takahiro Kinoshita
Journal: Journal of Clinical Oncology (2019)

139 Background: In patients with locally advanced gastric cancer, total gastrectomy with splenectomy (TGS) is sometimes indicated when a tumor directly infiltrates the spleen or obvious splenic hilar lymph node metastasis exists. However, this procedure is technically demanding and can cause potentially fatal postoperative pancreas-related complications. TGS has increasingly been performed laparoscopically, particularly in East Asia. However, the number of reports regarding laparoscopic TGS (LTGS) is limited, and thus the feasibility of LTGS remains unclear. Methods: The present study included 68 patients with upper-third advanced gastric cancer who underwent LTGS or conventional open TGS (OTGS) between 2012 and 2018. Clinicopathological characteristics and surgical outcomes were retrospectively reviewed and compared between the groups. Results: There were no significant differences in sex, age, tumor size, cN factor, or cStage. cT4 was less frequently included in the LTGS group (21.4 vs 79.6 %, P &lt; 0.01). In the LTGS group, operating time was longer (332 vs 247 min, P &lt; 0.01) and blood loss was less (38 vs 598 ml, P &lt; 0.01). Incidence of Clavien-Dindo grade 3 or higher complication (0 vs 24.1 %, P = 0.05) and median postoperative hospital stay (9 vs 11 days, P = 0.03) were significantly difference between the groups. The median number of harvested No. 10 and No.11d lymph nodes was equivalent between the groups. Conclusions: LTGS can be a safe procedure provided an experienced surgical team performs the surgery. Oncological safety remains unclear, and needs to be confirmed in future trials.
Distinct innate immune cell maturation during the first year of life is associated with farm exposure
Authors: Anna Lang, Samantha R. Fye, Deborah Chasman, Michael D. Evans, Kathrine L. Barnes, Casper G. Bendixsen, Irene Ong, James E. Gern, Christine M. Seroogy
Journal: Journal of Allergy and Clinical Immunology (2019)
Progress and Challenges for Live-Cell Imaging of Genomic Loci using CRISPR-Based Platforms
Authors: Xiaotian Wu, Shiqi Mao, Yachen Ying, Christopher J. Krueger, Antony K. Chen
Journal: Genomics Proteomics & Bioinformatics (2019)

Chromatin conformation, localization, and dynamics are crucial regulators of cellular behaviors. Although fluorescence in situ hybridization-based techniques have been widely utilized for investigating chromatin architectures in healthy and diseased states, the requirement for cell fixation precludes the comprehensive dynamic analysis necessary to fully understand chromatin activities. This has spurred the development and application of a variety of imaging methodologies for visualizing single chromosomal loci in the native cellular context. In this review, we describe currently-available approaches for imaging single genomic loci in cells, with special focus on clustered regularly interspaced short palindromic repeats (CRISPR)-based imaging approaches. In addition, we discuss some of the challenges that limit the application of CRISPR-based genomic imaging approaches, and potential solutions to address these challenges. We anticipate that, with continued refinement of CRISPR-based imaging techniques, significant understanding can be gained to help decipher chromatin activities and their relevance to cellular physiology and pathogenesis.
Decreasing Endoscopy No-Shows Using a Lean Improvement Framework
Authors: Raymond T. Finn, Benjamin Lloyd, Yuval A. Patel, James T. Allen, Jennifer Cornejo, Andrea Davis, Thasha McIntosh, Stephanie Ferguson, Kellie Sims, Shawn Sudaj, Javad Taheri, Nicholas A. Burr, Dawn Provenzale, Ziad F. Gellad
Journal: Clinical Gastroenterology and Hepatology (2019)
Inhalation treatment of cystic fibrosis with lumacaftor and ivacaftor co-delivered by nanostructured lipid carriers
Authors: O.B. Garbuzenko, N. Kbah, A. Kuzmov, N. Pogrebnyak, V. Pozharov, T. Minko
Journal: Journal of Controlled Release (2019)

Cystic fibrosis (CF), a most deadly genetic disorder, is caused by mutations of CF transmembrane receptor (CFTR) - a chloride channel present at the surface of epithelial cells. In general, two steps have to be involved in treatment of the disease: correction of cellular defects and potentiation to further increase channel opening. Consequently, a combinatorial simultaneous treatment with two drugs with different mechanisms of action, lumacaftor and ivacaftor, has been recently proposed. While lumacaftor is used to correct p.Phe508del mutation (the loss of phenylalanine at position 508) and increase the amount of cell surface-localized CFTR protein, ivacaftor serves as a CFTR potentiator that increases the open probability of CFTR channels. Since the main organ that is affected by cystic fibrosis is the lung, the delivery of drugs directly to the lungs by inhalation has a potential to enhance the efficacy of the treatment of CF and limit adverse side effects upon healthy tissues and organs. Based on our extensive experience in inhalation delivering of drugs by different nanocarriers, we selected nanostructured lipid carriers (NLC) for the delivery both drugs directly to the lungs by inhalation and tested NLC loaded with drugs in vitro (normal and CF human bronchial epithelial cells) and in vivo (homozygote/homozygote bi-transgenic mice with CF). The results show that the designed NLCs demonstrated a high drug loading efficiency and were internalized in the cytoplasm of CF cells. It was found that NLC-loaded drugs were able to restore the expression and function of CFTR protein. As a result, the combination of lumacaftor and ivacaftor delivered by lipid nanoparticles directly into the lungs was highly effective in treating lung manifestations of cystic fibrosis.
Abstract P310: Physician Trust and Home Remedy Use Among Low Income Blacks and Whites With Hypertension: Findings From the TRUST Study
Authors: Pamela Payne Foster, Yendelela Cuffee, Noof Alwatban, Maury Minton, Dwight Lewis, Jeroan Allison
Journal: Circulation (2018)

Introduction: Home remedies are used for the treatment of hypertension, despite unsubstantiated claims of their effectiveness. Home remedy use is often attributed to mistrust towards healthcare providers. Few studies have examined the relationship between HR use and physician trust. The objective of this study was to examine the correlates of home remedy use and the relationship between trust in physicians in a cohort of low-income Blacks and Whites with hypertension living in an inner-city in the Deep South. Hypothesis: We hypothesized that White and Black home remedy users with hypertension would report greater mistrust towards physicians than individuals that were not using home remedies. Methods: A cross-sectional examination was conducted among 925 Black and White patients with hypertension receiving care at an urban hospital in the southeastern US. Trust in physicians was self-reported using the Hall General Trust Scale and home remedy use was self-reported using the Brown and Segal scale. Results: Twenty-eight percent (219 of 788) of Black and 15% (20 of 137) of White participants reported home remedy use (p=0.001). Black home remedy users and nonusers had similar trust scores (p=0.582). Whites home remedy users reported lower trust in physicians than white nonusers and Black home remedies users and nonusers (p=0.026). Conclusions: Black home remedy users, non-users, and White non-users reported similar trust scores. The lowest trust scores were found among White home remedy users. Home remedy use was higher among Black than White participants. This study highlights the importance of examining topics of home remedy use and physician trust among low-income White and Black populations. In conclusion, mistrust towards physicians was associated with greater use of home remedies among White participants with hypertension. Home remedy users may benefit from interventions that bolster trust between patients and providers, and facilitate discussion about home remedy use.
Abstract 17382: Gender Difference in Presentation, Management and Outcome of Patients With Acute Myocardial Infarction: A Sub-analysis of J-MINUET Study
Authors: Yasuharu Nakama, Masaharu Ishihara, Masashi Fujino, Hisao Ogawa, Koichi Nakao, Satoshi Yasuda, Teruo Noguchi, Yukio Ozaki, Kazuo Kimura, Satoru Suwa, Kazuteru Fujimoto, Takashi Morita, Wataru Shimizu, Yoshihiko Saito, Atsushi Hirohata, Yasuhiro Morita, Teruo Inoue, Atsunori Okamura, Masaaki Uematsu, Kazuhito Hirata, Kazuhito Hirata, Kengo Tanabe, Yoshisato Shibata, Mafumi Owa, Seiji Hokimoto, Kunihiro Nishimura, Yoshihiro Miyamoto, Takuji Kawagoe, Kazuoki Dai
Journal: Circulation (2015)

Purpose: Several studies have reported gender difference in presentation, management and outcome in patients with acute myocardial infarction (AMI). In this study, we focused the impact of age on gender difference in mortality after AMI. Methods: Between July 2012 and March 2014, 3283 patients were admitted to the 28 hospitals participating to the J-MINUET group within 48 hours after the onset of AMI. AMI was diagnosed by universal definition (type 1 or type 2). Patients were divided into 5 strata according to their age: those with age &lt;55 years, 55-64 years, 65-74 years, 75-84 years and ≥85 years. Results: There were 813 women (24.8%). Women were significantly older than men (74.5±11.8 years vs 66.6±12.3 years, P&lt;0.001). Women had longer time from onset to admission, more NSTEMI, atypical symptom other than chest pain, Killip class ≥2, CKD and type 2 MI. They also had less diabetes and current smoking habits. Although most of the patients received urgent angiography (93.1%), it was less frequent in women (90.4% vs 94.0%, P&lt;0.001). Among patients who underwent primary PCI (85.1%), achievement of final TIMI-3 flow was similar (91.2% vs 92.0%, P=0.53). In-hospital mortality was significantly higher in women than men (9.6% vs 5.5%, P&lt;0.001). When patients were stratified according to their age, there was a liner increase in the prevalence of women as age advanced: 10.6% in &lt;55 years, 15.1% in 55-64 years, 19.8% in 65-74 years, 35.6% in 75-84 years and 53.6% in ≥85 years (P&lt;0.001). There was no significant gender difference in mortality in each stratum (Figure). Multivariate analysis showed that women was no more an independent predictor of death after adjusting age (OR 1.29, 95%CI 0.95-1.75, P=0.10), or age and other variables (OR 1.19, 95%CI 0.79-1.76, P=0.40). Conclusions: Women had higher in-hospital mortality than men after AMI even in the contemporary troponin era. However, their high mortality was mostly explained by their advanced age.
Reply
Authors: Christophe Corpechot, Géraldine Dahlqvist, Olivier Chazouillères, Catherine Johanet
Journal: Hepatology (2017)

We thank Dellavance et al. for their interesting comment.We agree that both their results (1) and ours (2) lend support to the hypothesis that emergence of primary biliary cholangitis (PBC) is not related to antimitochondrial antibodies (AMA) positivity per se, but rather to quantitative and qualitative escalating changes in autoreactivity and humoral response preceding the clinical phase of the disease.Although the two studies differ in terms of initial design and AMA screening methods (cytoplasmic AMA-like pattern in the ANA-Hep-2 immunofluorescence [IF] assay in the Brazilian study and IF assay on rat liver, kidney, and stomach tissue sections in the French study), both found a high proportion of AMA-positive patients with no clinical evidence of PBC (54% and 32%, respectively).In the Brazilian study, higher titers of AMA, high-avidity anti-PDC-E2, and response to three or more antigenic cell domains were independently associated with established PBC. (1)In the French study, female sex, younger age, higher AMA titers, higher rate of AMA-positive dotting/blotting tests, and higher detection rate of PBC-specific (PBC-sp.)antinuclear antibodies (ANAs) were individually associated with definite PBC. (2)In multivariate analysis, AMA titer, PBC-specific ANAs, and female sex were independently associated with established PBC.The optimal AMA titer for distinguishing patients with and without clinical evidence for PBC was 1:320 (c-statistic, 0.69; P < 0.0001).The odds ratio (OR), sensitivity (Se), specificity (Sp), positive predictive value (PPV), and negative predictive value (NPV) associated with AMA titer 1:320, presence of PBC-specific ANAs, or female sex for the identifica-
TCT-90 Predictive Factors and Long-Term Clinical Consequences of Persistent Left Bundle Branch Block Following Transcatheter Aortic Valve Implantation with a Balloon-Expandable Valve
Authors: Marina Urena, Michael Mok, Vicenç Serra, Eric Dumont, Luis Nombela-Franco, Robert De Larochelliere, Daniel Doyle, Albert Igual, Eric Larose, Ignacio Amat-Santos, Melanie Coté, Hug Cuellar, Philippe Pibarot, Peter De Jaegere, François Philippon, Bruno Garcia del Blanco, Josep Rodes-Cabau
Journal: Journal of the American College of Cardiology (2012)
TRYbeCA-1: A randomized, phase III study of eryaspase in combination with chemotherapy versus chemotherapy alone as second-line treatment in patients with pancreatic adenocarcinoma (NCT03665441).
Authors: Pascal Hammel, Rossana Berardi, Geert-Yan Creemers, Antonio Cubillo, Eric Van Cutsem, Richard Greil, Teresa Macarulla, Jean-Philippe Metges, Marcus Smith Noel, Peter Nygren, Pia J. Osterlund, Thomas Seufferlein, Harpreet Singh Wasan, Anu Gupta, Linda Marie Grummer, Nigel Biswas-Baldwin, Richard Kay, Hagop Youssoufian, Iman El-Hariry, Manuel Hidalgo
Journal: Journal of Clinical Oncology (2020)

TPS4666 Background: Second-line treatment options for advanced pancreatic adenocarcinoma are currently limited. Eryaspase, asparaginase (ASNase) encapsulated in red blood cells (RBCs) is an investigational product under development. Following infusion, asparagine and glutamine are actively transported into RBCs where they are hydrolyzed by the encapsulated ASNase. We have recently reported the outcome of a randomized Phase 2b study inpatients with advanced pancreatic cancer whose disease progressed following first-line treatment(NCT02195180). Eryaspase in combination with gemcitabine monotherapy or FOLFOX combination therapy improved overall survival (OS) and progression free survival (PFS). The safety profile of eryaspase was acceptable. The results of this Phase 2b study provided a rationale for initiating this confirmatory Phase 3 pivotal trial (TRYbeCA-1). Methods: TRYbeCA-1 is a randomized, open-label Phase 3 trial (N = ~500) of eryaspase combined with chemotherapy in patients with adenocarcinoma of the pancreas who have failed only one prior line of systemic anti-cancer therapy for advanced pancreatic cancer and have measurable disease. Patients are randomized in a 1:1 ratio to receive gemcitabine/Abraxane or irinotecan-based therapy (FOLFIRI [FOLinic acid-Fluorouracil-IRInotecan regimen] or irinotecan liposome injection/5-fluorouracil/leucovorin) with or without eryaspase, administered as IV infusion on Day 1 and Day 15 of each 4-week cycle. Key eligibility criteria include performance status 0 or 1; stage III-IV disease; documented evidence of disease progression; available tumor tissue; and adequate organ function. The primary endpoint is OS. Key secondary endpoints include PFS and objective response rate, safety, quality of life, pharmacokinetics and pharmacodynamics, and biomarker research. A hazard ratio in OS of 0.725 is being targeted which represents a conservative estimate based on the Phase 2b data and is viewed as being highly clinically relevant. An IDMC is established to review safety at regular intervals andto review efficacy data at the planned interim and final analyses. IDMC last reviewed the trial in October 2019 and suggested the trial continue as planned. Clinical trial information: NCT03665441 .
Quality of Care Indicators in Patients with Sickle Cell Disease (SCD): Influenza Vaccination and Routine Eye Examination Are Associated with Outpatient Utilization but Not Acute Hospital Care, Whereas Comorbidity Indexes Are Strongly Associated with Both
Authors: Tom Adamkiewicz, Peter Baltrus, Chaohua Li, Kitty Carter-Wicker, Anne Gaglioti
Journal: Blood (2018)
Female global health leadership: data-driven approaches to close the gender gap
Authors: Jyoti S Mathad, Lindsey K Reif, Grace Seo, Kathleen F Walsh, Margaret L McNairy, Myung Hee Lee, Adolfine Hokororo, Aarti Kinikar, Claudia T Riche, Marie M Deschamps, Sandy Nerette, Smita Nimkar, Neema Kayange, Hyasinta Jaka, Glory Joseph, Domenica Morona, Thandiwe Yvonne Peter, Nishi Suryavanshi, Daniel W Fitzgerald, Jennifer A Downs
Journal: The Lancet (2019)