bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification and Characterization of Small‐Molecule Ras Modulators and their Impact in Cancer Drug Discovery
Authors: DePaolo Patrick Anthony , Windsor William , Sabio Michael , Tolias Peter 
Published: April 2020

Ras is a small GTPase enzyme that binds guanine diphosphate (GDP), a nucleotide substrate, to its guanine‐nucleotide binding pocket. Ras activation occurs by the coordination of SOS, a guanine nucleotide exchange factor, which catalyzes the substitution of GDP for guanine triphosphate (GTP), rendering the Ras protein in an active state. Oncogenic Ras mutants are constitutively active, propagating proliferative cell signaling that leads to aberrant cell growth and metastatic tumors that are present in 30% of all human cancers. Discovery of a potent, small molecule Ras inhibitor has been challenging. We have characterized a novel class of Ras modulators that exhibit both Ras activation. These small molecules were discovered using Ras‐SOS molecular modeling and computational docking studies focused on identifying potential compound binding to the Ras‐SOS complex interface. Several in‐vitro biochemical assays were performed to elucidate the structural significance, binding kinetics, and nucleotide exchange effects of these small molecule binders. A fluorescence nucleotide exchange assay was optimized to discover compounds that had an atypical nucleotide exchange rate (off‐state to on‐state) in a kinetic assay. Compounds discovered in the assay were then analyzed by Surface Plasmon Resonance (SPR) to further elucidate details on the binding kinetics between Ras and compound as well as between Ras and SOS in the presence of the compound. Of the examined compounds, several exhibited activation of the Ras‐SOS catalytic reaction. An ongoing structure activity relationship (SAR) study has identified essential components that facilitate binding to the Ras:SOS interface. This presumably allosteric interaction may have uncovered an unprobed regulatory site that can be manipulated to create Ras inhibitors. This discovery of activator compounds provides a promising new direction for the development of potent Ras modulators.Support or Funding InformationThe Center for Healthcare Innovation (CHI), Stevens Institute of Technology
ADAM17 Cleaves the Insulin Receptor Ectodomain on Endothelial Cells and Induces Vascular Insulin Resistance
Authors: Ghiarone Thaysa , Castorena-Gonzalez Jorge , Foote Christopher A. , Ramirez-Perez Francisco , Wheeler Andrew A. , Rawlings Arthur L. , Staveley-O’Carrol Kevin F. , Padilla Jaume , Martinez-Lemus Luis A. 
Published: April 2020

Despite efforts to reduce the incidence of type 2 diabetes (T2D) and its cardiovascular consequences, T2D‐associated cardiovascular mortality continues to rise in the US and worldwide. The presence of a pro‐inflammatory state and microvascular insulin resistance are hallmarks of T2D that contribute to cardiovascular disease. The former is associated with increased activity of ADAM17, an enzyme that cleaves the ectodomain of multiple transmembrane proteins, while the latter is characterized by decreased insulin‐induced vasodilatory responses. However, the specific mechanisms, including the potential role(s) of ADAM17, underlying vascular insulin resistance in T2D, remain unknown. We hypothesize that in T2D, increased expression and activation of ADAM17 sheds the insulin receptor ectodomain (IRα) from endothelial cells and thus impairs insulin‐induced vasodilation. We tested this hypothesis using isolated small visceral arteries from T2D and non‐T2D subjects undergoing bariatric surgery and cultured human endothelial cells. Results indicate that arteries from subjects with T2D exhibit increased ADAM17 expression, reduced presence of TIMP3 (the endogenous inhibitor of ADAM17), decreased extracellular IRα, and impaired insulin‐induced vasodilation in comparison with arteries from non‐T2D subjects (P<0.05). In vitro, ADAM17 cleaved insulin receptor recombinant proteins at a specific extracellular site of the IRβ subunit (p<0.05). Exposure of endothelial cells to the PKC activator, PMA, increased the shedding activity of ADAM17 (P<0.05) and decreased the presence of IRα on cell surfaces occupied by ADAM17, as observed using super‐resolution microscopy. Moreover, pharmacological inhibition of ADAM17 with TAPI‐0 rescued PMA‐induced impairments in insulin signaling in endothelial cells and insulin‐stimulated vasodilation in human small visceral arteries (P<0.05). Collectively, these findings suggest that ADAM17‐mediated shedding of IR ectodomains from the endothelial surface impairs insulin‐mediated vasodilation. Therefore, inhibition of ADAM17 sheddase activity should be considered a potential new therapeutic strategy to restore vascular insulin sensitivity in T2D.Support or Funding InformationResearch support: National Institutes of Health grants: R01 HL137769 (JP), R01 HL088105 (LM‐L).
Allelic insufficiency of Znt8 had improved glucose tolerance in male mice after high fat intake
Authors: Cai Yimeng , Kirschke Catherine , Huang Liping 
Published: April 2020

Zinc transporter 8 (ZNT8) is mainly expressed in the pancreatic β‐cell. ZNT8 transports zinc from the cytosol into the insulin‐containing secretory vesicle for insulin crystallization and secretion. Reduced ZNT8 expression affects glucose‐stimulated insulin secretion. Genome Wide‐Association Studies revealed that people with one null allele of ZNT8 are 65% less likely to develop type 2 diabetes (T2D) than those with two normal alleles. The molecular mechanism underling this protective function of ZNT8 allelic insufficiency is not clear. Our specific aim was to uncover this mechanism using Znt8+/− mice. We hypothesized that Znt8 allelic insufficiency caused a decrease in glucose‐stimulated insulin secretion which triggered a compensatory action that ensured normal blood glucose levels after a meal. In the current study, we fed Znt8+/− and control mice a high‐fat diet to induce insulin resistance. The results from this study suggest a gender‐dependent role of Znt8 allelic insufficiency in the protection of mice from T2D. We found that male mice were benefited from Znt8 heterozygosity for controlling glucose levels whereas Znt8 heterozygosity helped female mice for handling dietary lipids. Importantly, we found that glucagon may play a key role in controlling glucose levels in Znt8+/− mice. In conclusion, our data support the notion that allelic Znt8 insufficiency can provide a protective effect against diet‐induced glucose intolerance, possibly through regulation of glucagon secretion.Support or Funding InformationUSDA/ARS 2032‐51000‐005‐00D.
Low Rates of Cascade Genetic Testing Among Families With Hereditary Gynecologic Cancer: An Opportunity to Improve Cancer Prevention
Authors: Griffin Natalie E. , Buchanan Tommy R. , Smith Stephanie H. , Leon Andrea A. , Meyer Melissa F. , Liu Jingxia , Tabak Rachel G. , Fuh Katherine C. , Thaker Premal H. , Powell Matthew A. , Mutch David G. , Massad L. Stewart , Colditz Graham A. , Hagemann Andrea R. 
Published: April 2020

(Abstracted from Gynecol Oncol 2020;156:140–146)
The 2 most common germline mutations causing cancer in the United States are BRCA1/2 mutations associated with hereditary breast and ovarian cancer (HBOC) and mismatch repair (MMR) gene mutations associated with Lynch syndrome (LS). A first-degree relative of a patient with one of these mutations incurs a 50% chance of inheriting the same mutation, and early detection can inform treatment and preventive procedures.
Timing of Office-Based Pessary Care: A Randomized Controlled Trial
Authors: Propst Katie , Mellen Colleen , O'Sullivan David M. , Tulikangas Paul K. 
Published: April 2020

(Abstracted from Obstet Gynecol 2020;135:100–105)
Vaginal pessaries are recommended often as first-line treatment of pelvic organ prolapse and stress urinary incontinence, especially for women who do not desire surgery or who are poor surgical candidates. Several studies have shown that pessaries improve symptoms of prolapse, bowel symptoms, body image perception, and overall quality of life.
Occipital Plate Fixation in the Pediatric Population
Authors: Cohen Lara L. , Yang Brian W. , Glotzbecker Michael P. , Emans John B. , Karlin Lawrence I. , Snyder Brian D. , Hresko Michael T. , Hedequist Daniel J. 
Published: April 2020

Background:
Occipital plate fixation has been shown to improve outcomes in cervical spine fusion. There is a paucity of literature describing occipital plate fixation, especially in the pediatric population. The authors reviewed a case series of 34 patients at a pediatric hospital who underwent cervical spine fusion with occipital plate fixation between 2003 and 2016. This study describes how occipital plates aid the cervical spine union in a case series of diverse, complex pediatric patients.

Methods:
Our orthopaedic database at our institution was queried for patients undergoing an instrumented cervical spine procedure between 2003 and 2016. Medical records were used to collect diagnoses, fusion levels, surgical technique, and length of hospitalization, neurophysiological monitoring, complications, and revision procedures.

Results:
Thirty-four patients met the inclusion criteria. The mean age was 10.9 years (range, 3-21 y). Indications for surgery included cervical instability, basilar invagination, and os odontoideum. These indications were often secondary to a variety of diagnoses, including trisomy 21, Klippel-Feil syndrome, and rheumatoid arthritis. The mean length of hospitalization was 10 days (range, 2 to 80 d). There were no cases of intraoperative dural leak, venous sinus bleeding from occipital screw placement, or implant-related complications. Postoperative complications included 2 cases of nonunion. Eight patients (24%) had follow-up surgery, only 3 (9%) of which were instrumentation revisions. Both patients with nonunion had repeat occipitocervical fixation procedures and achieved union with revision.

Conclusions:
Occipital plate fixation was successful for pediatric cervical spine fusion in this diverse cohort. The only procedure-related complication demonstrated was delayed union or nonunion and implant loosening (4/34, 12%) and there were no plate-related complications. This novel case series shows that occipital plate fixation is safe and effective for pediatric patients with complex diagnoses.

Level of Evidence:
Level IV—case series.
Prolonged Postoperative Intubation After Spinal Fusion in Cerebral Palsy: Are There Modifiable Risk Factors and Associated Consequences?
Authors: LaValva Scott M. , Baldwin Keith , Swarup Ishaan , Flynn John M. , Pahys Joshua M. , Yaszay Burt , Abel Mark F. , Bachmann Keith , Shah Suken A. , Sponseller Paul D. , Cahill Patrick J. 
Published: April 2020

Background:
Instrumented spinal fusion is performed to correct severe spinal deformity that commonly complicates cerebral palsy (CP). Prolonged intubation (PI) is a common perioperative complication, though little is known about the risk factors and consequences of this phenomenon.

Questions/Purposes:
The purpose of this study was to determine (1) the preoperative and intraoperative risk factors associated with PI after spine surgery for CP; (2) the perioperative and postoperative complications associated with PI; and (3) any long-term impacts of PI with respect to health-related quality of life.

Patients and Methods:
A retrospective case-control analysis of prospectively collected, multicenter data was performed on patients with Gross Motor Function Classification System (GMFCS) 4 or 5 CP who underwent instrumented spinal fusion. Patients extubated on postoperative day (POD) 0 were in the early extubation (EE) cohort and those extubated on POD 3 or later were in the PI cohort. Comparisons were made between PI and EE groups with respect to several preoperative and intraoperative variables to identify risk factors for PI. Multivariate logistic regression was performed to identify independent predictors of this outcome. The postoperative hospital course, rate of complications, and health-related quality of life at 2 years were also compared.

Results:
This study included 217 patients (52% male individuals; mean age, 14.0±2.8 y) who underwent spinal fusion for CP. In this cohort, 52 patients (24%) had EE and 58 patients (27%) had PI. There were several independent predictors of PI including history of pneumonia [odds ratio (OR), 6.2; 95% confidence interval (CI), 1.6-24.3; P=0.01], estimated blood loss of >3000 mL (OR, 16.5; 95% CI, 2.0-134; P=0.01), weight of <37 kg (OR, 6.4; 95% CI, 1.5-27.1), and Child Health Index of Life with Disabilities (CPCHILD) Communication and Social Interaction score of <15 (OR, 10.8; 95% CI, 1.1-107.3; P=0.04). In addition, PI was associated with a higher rate of perioperative and postoperative respiratory (P<0.001), cardiovascular (P=0.014), gastrointestinal (P<0.001), and surgical site (0.027) complications, in addition to prolonged hospitalization (P<0.001) and intensive care unit stay (P<0.001).

Conclusions:
Surgeons should seek to optimize nutritional status and pulmonary function, and minimize blood loss in patients with CP to decrease the risk of PI after spinal fusion. Efforts should be made to extubate patients on POD 0 to decrease the risk of complications associated with PI.
Risk of Mortality in Immunocompromised Children With Severe Sepsis and Septic Shock
Authors: Lindell Robert B. , Nishisaki Akira , Weiss Scott L. , Traynor Danielle M. , Fitzgerald Julie C. 
Published: April 2020

Objectives:
To assess the prevalence of immunocompromised diagnoses among children with severe sepsis and septic shock, and to determine the association between immunocompromised diagnoses and clinical outcomes after adjustment for demographics and illness severity.

Design:
Retrospective multicenter cohort study.

Setting:
Eighty-three centers in the Virtual Pediatric Systems database.

Patients:
Children with severe sepsis or septic shock admitted to a participating PICU between January 1, 2012, and December 31, 2016.

Interventions:
None.

Measurements and Main Results:
Across 83 centers, we identified 10,768 PICU admissions with an International Classification of Diseases, 9th Revision, Clinical Modification code for severe sepsis or septic shock; 3,021 of these patients (28%) had an immunocompromised diagnosis. To evaluate variation across centers and determine factors associated with PICU mortality, we used mixed-effect logistic regression models. Among patients without hematopoietic cell transplant, congenital immunodeficiency (adjusted odds ratio, 1.90; 95% CI, 1.24–2.92), multiple prior malignancies (adjusted odds ratio, 1.86; 95% CI, 1.15–2.99), and hemophagocytic lymphohistiocytosis (adjusted odds ratio, 3.09; 95% CI, 1.91–4.98) were associated with an increased odds of PICU mortality. Among patients with prior hematopoietic cell transplant, liquid malignancy (adjusted odds ratio, 3.15; 95% CI, 2.09–4.74), congenital immunodeficiency (adjusted odds ratio, 6.94; 95% CI, 3.84–12.53), multiple prior malignancies (adjusted odds ratio, 3.54; 95% CI, 1.80–6.95), and hemophagocytic lymphohistiocytosis (adjusted odds ratio, 2.79; 95% CI, 1.36–5.71) were associated with an increased odds of PICU mortality. PICU mortality varied significantly by center, and a higher mean number of sepsis patients per month in a center was associated with lower PICU mortality (adjusted odds ratio, 0.94; 95% CI, 0.90–0.98). PICU resource utilization varied by immunocompromised diagnosis and history of hematopoietic cell transplant, and among survivors immunocompromised patients have shorter median PICU length of stay compared with patients without immunocompromised diagnoses (p < 0.001).

Conclusions:
Immunocompromised diagnoses are present in 28% of children with severe sepsis or septic shock. Multiple prior malignancies, hemophagocytic lymphohistiocytosis, congenital immunodeficiency, and hematopoietic cell transplant are independently associated with an increased odds of PICU mortality in children with severe sepsis or septic shock. Significant variation exists in PICU mortality among centers despite adjustment for immunocompromised diagnoses, known risk factors for sepsis-related mortality, and center-level sepsis volume.
Nebulized Bacteriophages for Prophylaxis of Experimental Ventilator-Associated Pneumonia Due to Methicillin-Resistant Staphylococcus aureus
Authors: Prazak Josef , Valente Luca , Iten Manuela , Grandgirard Denis , Leib Stephen L. , Jakob Stephan M. , Haenggi Matthias , Que Yok-Ai , Cameron David R. 
Published: April 2020

Objectives:
There is a need for alternative strategies to combat and prevent antibiotic-resistant bacterial infections. Here, we assessed the potential for bacteriophage prophylaxis in the context of experimental ventilator-associated pneumonia due to methicillin-resistant Staphylococcus aureus in rats.

Design:
Nebulized phages (aerophages) were delivered to the lungs of rats using a modified vibrating mesh aerosol drug delivery system. Animals were intubated and ventilated for 4 hours, at which point they were infected with methicillin-resistant S. aureus strain AW7 via the endotracheal tube, extubated, and then monitored for 96 hours.

Setting:
Ventilator-associated pneumonia.

Subjects:
Male Wistar rats.

Interventions:
A single application of aerophages prior to ventilation at one of two concentrations (~1010 plaque forming units/mL or ~1011 plaque forming units/mL).

Measurements and Main Results:
1) Animal survival at 96 hours, 2) enumeration of bacteria and phages in the lungs and spleen, and 3) lung tissue histopathology. Animals that received aerophages prior to ventilation and methicillin-resistant S. aureus challenge showed a higher survival rate compared with untreated controls (60% for animals that received 3 × 1010 plaque forming units; 70% for animals that received 3 × 1011 plaque forming units; 0% for controls; p < 0.01 for each treatment versus untreated). Surviving animals that received aerophage prophylaxis had fewer methicillin-resistant S. aureus in the lungs compared with untreated control animals that succumbed to pneumonia (1.6 × 106 colony forming units/g vs 8.0 × 108; p < 0.01).

Conclusions:
Prophylactically administered nebulized bacteriophages reduced lung bacterial burdens and improved survival of methicillin-resistant S. aureus infected rats, underscoring its potential in the context of ventilator-associated pneumonia.
Association of cardiovascular diseases with milk intake among general Chinese adults
Authors: Wang Xin-Yan , Liu Fang-Chao , Yang Xue-Li , Li Jian-Xin , Cao Jie , Lu Xiang-Feng , Huang Jian-Feng , Li Ying , Chen Ji-Chun , Zhao Lian-Cheng , Shen Chong , Hu Dong-Sheng , Zhao Ying-Xin , Yu Ling , Liu Xiao-Qing , Wu Xian-Ping , Gu Dong-Feng 
Published: April 2020

Abstract

Background:
The association of milk intake with cardiovascular disease (CVD) and cause-specific mortality remained controversial and evidence among the Chinese population was limited. We aimed to study the relationship between milk intake and CVDs among general Chinese adults.

Methods:
A total of 104,957 participants received questionnaire survey. Results of physical examination such as anthropometric measurements and biochemical tests during 2007 to 2008, demographic data and their information on milk intake were collected through standardized questionnaires. Cox proportional hazard regression models were used to calculate hazard ratios (HRs) and their corresponding 95% confidence intervals (CIs) of CVD incidence, cause-specific mortality and all-cause mortality related to milk intake. Restricted cubic splines (RCSs) were applied to examine dose-response associations.

Results:
Among the 91,757 participants with a median follow-up period of 5.8 years, we documented 3877 CVD cases and 4091 all-cause deaths. Compared with participants who never consumed milk, the multivariate-adjusted HRs (95% CIs) of CVD incidence for 1 to 150 g/day, 151 to 299 g/day, and ≥300 g/day were 0.94 (0.86–1.03) (P > 0.05), 0.77 (0.66–0.89) (P < 0.05), and 0.59 (0.40–0.89) (P < 0.05), respectively; each 100 g increase of daily milk intake was associated with 11% lower risk of CVD incidence (HR, 0.89; 95% CI: 0.85–0.94; P < 0.001), and 11% lower risk of CVD mortality (HR, 0.89; 95% CI: 0.82–0.97; P = 0.008) after adjustment for age, sex, residential area, geographic region, education level, family history of CVD, smoking, alcohol drinking, physical activity level, body mass index, and healthy diet status (ideal or not). RCS analyses also showed a linear dose-response relationship with CVD (P for overall significance of the curve <0.001; P for non-linearity = 0.979; P for linearity <0.001) and stroke (P for overall significance of the curve = 0.010; P for non-linearity = 0.998; P for linearity = 0.002) incidence, and CVD mortality (P for overall significance of the curve = 0.045; P for non-linearity = 0.768; P for linearity = 0.014) within the current range of daily milk intake.

Conclusions:
Daily milk intake was associated with lower risk of CVD incidence and mortality in a linear inverse relationship. The findings provide new evidence for dietary recommendations in CVD prevention among Chinese adults and people with similar dietary pattern in other countries.
Interpretation of Physiologic and Left Ventricular Assist Device Parameters: Implications for Physical Therapist Decision-Making
Authors: Shoemaker Michael J. , Veldman Sarah , Van Dam Ashley , Wainscott Teresa L. 
Published: April 2020

ABSTRACT
As members of the interprofessional team caring for patients with left ventricular assist devices (LVADs), physical therapists need to be able to interpret whether a response to intervention is appropriate and anticipate the impact of changes of medical management to ensure adequate cardiac output to meet task demands, prevent syncope, and prevent suction events. This requires that physical therapist base decision-making on foundational physiologic and pathophysiologic principles and the way in which they are modified by the presence of an LVAD. Unfortunately, the product manuals in use for the most common LVADs do not address interpretation of mobility- and exercise-related LVAD and physiologic parameter changes. Numerous studies exist regarding LVAD and physiologic parameter changes with cardiopulmonary exercise testing, but none provide a singular framework that can be easily referenced by physical therapists to assist in mobilization- and intervention-related decision-making. The present clinical perspective therefore summarizes and synthesizes key concepts regarding interpretation of mobility- and exercise-related LVAD and physiologic parameter changes to help inform physical therapist clinical decision-making across the continuum of care.