Digital Commons Network^™

Current Directions In The Treatment Of Classical Hodgkin Lymphoma, Frank G Keller, Brad Kahl, Jonathan W Friedberg

2020-Current year OA Pubs

Optimal management of patients who present with Hodgkin lymphoma continues to evolve. Most patients are cured with current treatment strategies, some but both short and long-term morbidity and mortality from treatment have particular relevance given the youth of the patient population. Combininations of targeted agents together with conventional chemotherapy have recently been investigated in phase 3 cliniial trials for advanced-stage Hodkgkin lymphoma, and have demonstrated improved efficacy compared with chemotherapy alone. These include both antibody-drug conjugates and PD-1 blockade. Treatment approaches have historically differed between pediatric and adult groups, but recent collaborations between adullt and pediatric groups via the NCTN …

Characteristics Of Post Hoc Subgroup Analyses Of Oncology Clinical Trials: A Systematic Review, Jawad Alrawabdeh, Marah Alzu'bi, Muntaser Alzyoud, Nada Odeh, Yazan Hamadneh, Hira Mian, Ghulam Rehman Mohyuddin, Amar H Kelkar, Aaron M Goodman, Rajshekhar Chakraborty, David A Russler-Germain, Nikita Mehra, Diva Baggio, Edward R Scheffer Cliff, Samer Al Hadidi

2020-Current year OA Pubs

BACKGROUND: Subgroup analyses in clinical trials assess intervention effects on specific patient subgroups, ensuring generalizability. However, they are usually only able to generate hypotheses rather than definitive conclusions. This study examined the prevalence and characteristics of post hoc subgroup analysis in oncology.

METHODS: We systematically reviewed published subgroup analyses from 2000 to 2022. We included articles presenting secondary, post hoc, or subgroup analyses of interventional clinical trials in oncology, cancer survivorship, or cancer screening, published separately from the original clinical trial publication. We collected cancer type, year of publication, where and how subgroup analyses were reported, and funding.

RESULTS: Out …

Mycobacterium Tuberculosis Carrying The Rifampicin Drug-Resistance-Conferring Rpob Mutation H445y Is Associated With Suppressed Immunity Through Type I Interferons, Suhas Bobba, Nicole C Howard, Shibali Das, Mushtaq Ahmed, Linrui Tang, Shyamala Thirunavukkarasu, Michelle H Larsen, Barun Mathema, Maziar Divangahi, Shabaana A Khader

2020-Current year OA Pubs

This study highlights the impact of specific rifampicin-resistance-conferring mutations on the host immune response to

Infants Exposed In Utero To Hurricane Maria Have Gut Microbiomes With Reduced Diversity And Altered Metabolic Capacity, Ai Zhang, David De Ángel Solá, Midnela Acevedo Flores, Lijuan Cao, Leran Wang, Josh G Kim, Phillip I Tarr, Barbara B Warner, Nicolás Rosario Matos, Leyao Wang

2020-Current year OA Pubs

The gut microbiome is a potentially important mechanism that links prenatal disaster exposures with increased disease risks. However, whether prenatal disaster exposures are associated with alterations in the infant's gut microbiome remains unknown. We established a birth cohort study named Hurricane as the Origin of Later Alterations in Microbiome (HOLA) after Hurricane Maria struck Puerto Rico in 2017. We enrolled vaginally born Latino term infants aged 2 to 6 months, including

Volatile Profiling Distinguishes Streptococcus Pyogenes From Other Respiratory Streptococcal Species, Amalia Z Berna, Joseph A Merriman, Leah Mellett, Danealle K Parchment, Michael G Caparon, Audrey R Odom John

2020-Current year OA Pubs

Sore throat is one of the most common complaints encountered in the ambulatory clinical setting. Rapid, culture-independent diagnostic techniques that do not rely on pharyngeal swabs would be highly valuable as a point-of-care strategy to guide outpatient antibiotic treatment. Despite the promise of this approach, efforts to detect volatiles during oropharyngeal infection have yet been limited. In our research study, we sought to evaluate for specific bacterial volatile organic compounds (VOC) biomarkers in isolated cultures

Early Resveratrol Treatment Mitigates Joint Degeneration And Dampens Pain In A Mouse Model Of Pseudoachondroplasia (Psach), Jacqueline T Hecht, Alka C Veerisetty, Debabrata Patra, Mohammad G Hossain, Frankie Chiu, Claire Mobed, Francis H Gannon, Karen L Posey

2020-Current year OA Pubs

Pseudoachondroplasia (PSACH), a severe dwarfing condition associated with early-onset joint degeneration and lifelong joint pain, is caused by mutations in cartilage oligomeric matrix protein (COMP). The mechanisms underlying the mutant-COMP pathology have been defined using the MT-COMP mouse model of PSACH that has the common D469del mutation. Mutant-COMP protein does not fold properly, and it is retained in the rough endoplasmic reticulum (rER) of chondrocytes rather than being exported to the extracellular matrix (ECM), driving ER stress that stimulates oxidative stress and inflammation, driving a self-perpetuating cycle. CHOP (ER stress signaling protein) and TNFα inflammation drive high levels of mTORC1 …

High-Dimensional Deconstruction Of Pancreatic Cancer Identifies Tumor Microenvironmental And Developmental Stemness Features That Predict Survival, Erik P Storrs, Prathamesh Chati, Abul Usmani, Ian Sloan, Bradley A Krasnick, Peter K Harris, Chloe M Sachs, Faridi Qaium, Chris Wetzel, S Peter Goedegebuure, Thomas Hollander, Hephzibah Anthony, Jennifer Ponce, Shahed Badiyan, Hyun Kim, David G Denardo, Gabriel D Lang, Natalie D Cosgrove, Vladimir M Kushnir, Dayna S Early, Kian-Huat Lim, William G Hawkins, Li Ding, Ryan C Fields, Koushik K Das, Aadel A Chaudhuri, Et Al.

2020-Current year OA Pubs

Numerous cell states are known to comprise the pancreatic ductal adenocarcinoma (PDAC) tumor microenvironment (TME). However, the developmental stemness and co-occurrence of these cell states remain poorly defined. Here, we performed single-cell RNA sequencing (scRNA-seq) on a cohort of treatment-naive PDAC time-of-diagnosis endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) samples (n = 25). We then combined these samples with surgical resection (n = 6) and publicly available samples to increase statistical power (n = 80). Following annotation into 25 distinct cell states, cells were scored for developmental stemness, and a customized version of the Ecotyper tool was used to identify communities …

Burosumab Vs Phosphate/Active Vitamin D In Pediatric X-Linked Hypophosphatemia: A Subgroup Analysis By Dose Level, Erik A Imel, Michael P Whyte, Andrew Biggin, Et Al.

2020-Current year OA Pubs

CONTEXT: In an open-label, randomized, controlled, phase 3 trial in 61 children aged 1 to 12 years with X-linked hypophosphatemia (XLH), burosumab improved rickets vs continuing conventional therapy with active vitamin D and phosphate.

OBJECTIVE: We conducted an analysis to determine whether skeletal responses differed when switching to burosumab vs continuing higher or lower doses of conventional therapy.

METHODS: Conventional therapy dose groups were defined as higher-dose phosphate [greater than 40 mg/kg] (HPi), lower-dose phosphate [40 mg/kg or less] (LPi), higher-dose alfacalcidol [greater than 60 ng/kg] or calcitriol [greater than 30 ng/kg] (HD), and lower-dose alfacalcidol [60 ng/kg or less] …

Macrocephaly And Developmental Delay Caused By Missense Variants In Rab5c, Klaas Koop, Weimin Yuan, Bo Zhang, Zachary D Dawson, Anika Lindsey, Huiyan Huang, Dustin Baldridge, Gary A Silverman, Stephen C Pak, Tim Schedl, Et Al.

2020-Current year OA Pubs

Rab GTPases are important regulators of intracellular vesicular trafficking. RAB5C is a member of the Rab GTPase family that plays an important role in the endocytic pathway, membrane protein recycling and signaling. Here we report on 12 individuals with nine different heterozygous de novo variants in RAB5C. All but one patient with missense variants (n = 9) exhibited macrocephaly, combined with mild-to-moderate developmental delay. Patients with loss of function variants (n = 2) had an apparently more severe clinical phenotype with refractory epilepsy and intellectual disability but a normal head circumference. Four missense variants were investigated experimentally. In vitro biochemical …

Manf Stimulates Autophagy And Restores Mitochondrial Homeostasis To Treat Autosomal Dominant Tubulointerstitial Kidney Disease In Mice, Yeawon Kim, Chuang Li, Chenjian Gu, Yili Fang, Eric Tycksen, Terri A Pietka, Jothilingam Sivapackiam, Sun-Ji Park, Fumihiko Urano, Vijay Sharma, Ying Maggie Chen, Et Al.

2020-Current year OA Pubs

Misfolded protein aggregates may cause toxic proteinopathy, including autosomal dominant tubulointerstitial kidney disease due to uromodulin mutations (ADTKD-UMOD), a leading hereditary kidney disease. There are no targeted therapies. In our generated mouse model recapitulating human ADTKD-UMOD carrying a leading UMOD mutation, we show that autophagy/mitophagy and mitochondrial biogenesis are impaired, leading to cGAS-STING activation and tubular injury. Moreover, we demonstrate that inducible tubular overexpression of mesencephalic astrocyte-derived neurotrophic factor (MANF), a secreted endoplasmic reticulum protein, after the onset of disease stimulates autophagy/mitophagy, clears mutant UMOD, and promotes mitochondrial biogenesis through p-AMPK enhancement, thus protecting kidney function in our ADTKD mouse …

Pptc7 Maintains Mitochondrial Protein Content By Suppressing Receptor-Mediated Mitophagy, Natalie M Niemi, Lianjie Wei, Andrew J Smith, Merima Forny, David J Pagliarini, Et Al.

2020-Current year OA Pubs

PPTC7 is a resident mitochondrial phosphatase essential for maintaining proper mitochondrial content and function. Newborn mice lacking Pptc7 exhibit aberrant mitochondrial protein phosphorylation, suffer from a range of metabolic defects, and fail to survive beyond one day after birth. Using an inducible knockout model, we reveal that loss of Pptc7 in adult mice causes marked reduction in mitochondrial mass and metabolic capacity with elevated hepatic triglyceride accumulation. Pptc7 knockout animals exhibit increased expression of the mitophagy receptors BNIP3 and NIX, and Pptc7

Single High Dose Of Liposomal Amphotericin B In Human Immunodeficiency Virus/Aids-Related Disseminated Histoplasmosis: A Randomized Trial, Alessandro C Pasqualotto, Andrej Spec, Et Al.

2020-Current year OA Pubs

BACKGROUND: Histoplasmosis is a major AIDS-defining illness in Latin America. Liposomal amphotericin B (L-AmB) is the drug of choice for treatment, but access is restricted due to the high drug and hospitalization costs of the conventional long regimens.

METHODS: Prospective randomized multicenter open-label trial of 1- or 2-dose induction therapy with L-AmB versus control for disseminated histoplasmosis in AIDS, followed by oral itraconazole therapy. We randomized subjects to: (i) single dose 10 mg/kg of L-AmB; (ii) 10 mg/kg of L-AmB on D1, and 5 mg/kg of L-AmB on D3; (iii) 3 mg/kg of L-AmB daily for 2 weeks (control). The …

Perinatal Murine Cytomegalovirus Infection Reshapes The Transcriptional Profile And Functionality Of Nk Cells, Carmen Rožmanić, Eugene Park, Wayne M Yokoyama, Et Al.

2020-Current year OA Pubs

Infections in early life can elicit substantially different immune responses and pathogenesis than infections in adulthood. Here, we investigate the consequences of murine cytomegalovirus infection in newborn mice on NK cells. We show that infection severely compromised NK cell maturation and functionality in newborns. This effect was not due to compromised virus control. Inflammatory responses to infection dysregulated the expression of major transcription factors governing NK cell fate, such as Eomes, resulting in impaired NK cell function. Most prominently, NK cells from perinatally infected mice have a diminished ability to produce IFN-γ due to the downregulation of long non-coding RNA …

The Inherited Kras-Variant As A Biomarker Of Cetuximab Response In Nsclc, Joanne B Weidhaas, Clifford G Robinson, Et Al.

2020-Current year OA Pubs

PURPOSE: RTOG 0617 was a phase III randomized trial for patients with unresectable stage IIIA/IIIB non-small cell lung cancer comparing standard-dose (60 Gy) versus high-dose (74 Gy) radiotherapy and chemotherapy, plus or minus cetuximab. Although the study was negative, based on prior evidence that patients with the KRAS-variant, an inherited germline mutation, benefit from cetuximab, we evaluated KRAS-variant patients in RTOG 0617.

EXPERIMENTAL DESIGN: From RTOG 0617, 328 of 496 (66%) of patients were included in this analysis. For time-to-event outcomes, stratified log-rank tests and multivariable Cox regression models were used. For binary outcomes, Cochran-Mantel-Haenzel tests and multivariable logistic regression …

A Thermodynamic Analysis Of Clc Transporter Dimerization In Lipid Bilayers, Rahul Chadda, Taeho Lee, Robyn Mahoney-Kruszka, Elizabeth G Kelley, Nathan Bernhardt, Priyanka Sandal, Janice L Robertson

2020-Current year OA Pubs

The CLC-ec1 chloride/proton antiporter is a membrane-embedded homodimer with subunits that can dissociate and associate, but the thermodynamic driving forces favor the assembled dimer at biological densities. Yet, the physical reasons for this stability are confounding as dimerization occurs via the burial of hydrophobic interfaces away from the lipid solvent. For binding of nonpolar surfaces in aqueous solution, the driving force is often attributed to the hydrophobic effect, but this should not apply in the membrane since there is very little water. To investigate this further, we quantified the thermodynamic changes associated with CLC dimerization in membranes by carrying out …

Lipidome Of Mammographic Breast Density In Premenopausal Women, Kayla R Getz, Myung Sik Jeon, Chongliang Luo, Jingqin Luo, Adetunji T Toriola

2020-Current year OA Pubs

BACKGROUND: High mammographic breast density (MBD) is a strong risk factor for breast cancer development, but the biological mechanisms underlying MBD are unclear. Lipids play important roles in cell differentiation, and perturbations in lipid metabolism are implicated in cancer development. Nevertheless, no study has applied untargeted lipidomics to profile the lipidome of MBD. Through this study, our goal is to characterize the lipidome of MBD in premenopausal women.

METHODS: Premenopausal women were recruited during their annual screening mammogram at the Washington University School of Medicine in St. Louis, MO. Untargeted lipidomic profiling for 982 lipid species was performed at Metabolon …

Open Structure And Gating Of The Arabidopsis Mechanosensitive Ion Channel Msl10, Jingying Zhang, Grigory Maksaev, Peng Yuan

2020-Current year OA Pubs

Plants are challenged by drastically different osmotic environments during growth and development. Adaptation to these environments often involves mechanosensitive ion channels that can detect and respond to mechanical force. In the model plant Arabidopsis thaliana, the mechanosensitive channel MSL10 plays a crucial role in hypo-osmotic shock adaptation and programmed cell death induction, but the molecular basis of channel function remains poorly understood. Here, we report a structural and electrophysiological analysis of MSL10. The cryo-electron microscopy structures reveal a distinct heptameric channel assembly. Structures of the wild-type channel in detergent and lipid environments, and in the absence of membrane tension, capture …

Metabolomic Phenotype Of Hepatic Steatosis And Fibrosis In Mexican Children Living With Obesity, Nayely Garibay-Nieto, Karen Pedraza-Escudero, Isabel Omaña-Guzmán, María José Garcés-Hernández, Eréndira Villanueva-Ortega, Mariana Flores-Torres, José Luis Pérez-Hernández, Mireya León-Hernández, Estibalitz Laresgoiti-Servitje, Berenice Palacios-González, Juan Carlos López-Alvarenga, Mauricio Lisker-Melman, Felipe Vadillo-Ortega

2020-Current year OA Pubs

No abstract provided.

Generalization Of Procedural Motor Sequence Learning After A Single Practice Trial, B P Johnson, I Iturrate, R Y Fakhreddine, M Bönstrup, E R Buch, E M Robertson, L G Cohen

2020-Current year OA Pubs

When humans begin learning new motor skills, they typically display early rapid performance improvements. It is not well understood how knowledge acquired during this early skill learning period generalizes to new, related skills. Here, we addressed this question by investigating factors influencing generalization of early learning from a skill A to a different, but related skill B. Early skill generalization was tested over four experiments (N = 2095). Subjects successively learned two related motor sequence skills (skills A and B) over different practice schedules. Skill A and B sequences shared ordinal (i.e., matching keypress locations), transitional (i.e., ordered keypress pairs), …

Characterizing The Patterns Of Electronic Health Record-Integrated Secure Messaging Use: Cross-Sectional Study, Laura R Baratta, Derek Harford, Christine A Sinsky, Thomas Kannampallil, Sunny S Lou

2020-Current year OA Pubs

BACKGROUND: Communication among health care professionals is essential for the delivery of safe clinical care. Secure messaging has rapidly emerged as a new mode of asynchronous communication. Despite its popularity, relatively little is known about how secure messaging is used and how such use contributes to communication burden.

OBJECTIVE: This study aims to characterize the use of an electronic health record-integrated secure messaging platform across 14 hospitals and 263 outpatient clinics within a large health care system.

METHODS: We collected metadata on the use of the Epic Systems Secure Chat platform for 6 months (July 2022 to January 2023). Information …

Immune Cell Deconvolution Reveals Possible Association Of Γδ T Cells With Poor Survival In Head And Neck Squamous Cell Carcinoma, Anuraag S Parikh, Yize Li, Angela Mazul, Wade Thorstad, Jason Rich, Randal C Paniello, Ryan S Jackson, Patrik Pipkorn, Paul Zolkind, Zongtai Qi, Douglas Adkins, Li Ding, Sidharth V Puram, Et Al.

2020-Current year OA Pubs

(1) Background: The role of rare immune cell subtypes in many solid tumors, chief among them head and neck squamous cell carcinoma (HNSCC), has not been well defined. The objective of this study was to assess the association between proportions of common and rare immune cell subtypes and survival outcomes in HNSCC. (2) Methods: In this cohort study, we utilized a deconvolution approach based on the CIBERSORT algorithm and the LM22 signature matrix to infer proportions of immune cell subtypes from 517 patients with untreated HPV-negative HNSCC from The Cancer Genome Atlas. We performed univariate and multivariable survival analysis, integrating …

Yeast Rad52 Is A Homodecamer And Possesses Brca2-Like Bipartite Rad51 Binding Modes, Jaigeeth Deveryshetty, Rahul Chadda, Jenna R Mattice, Simrithaa Karunakaran, Michael J Rau, Katherine Basore, Nilisha Pokhrel, Noah Englander, James A J Fitzpatrick, Brian Bothner, Edwin Antony

2020-Current year OA Pubs

Homologous recombination (HR) is an essential double-stranded DNA break repair pathway. In HR, Rad52 facilitates the formation of Rad51 nucleoprotein filaments on RPA-coated ssDNA. Here, we decipher how Rad52 functions using single-particle cryo-electron microscopy and biophysical approaches. We report that Rad52 is a homodecameric ring and each subunit possesses an ordered N-terminal and disordered C-terminal half. An intrinsic structural asymmetry is observed where a few of the C-terminal halves interact with the ordered ring. We describe two conserved charged patches in the C-terminal half that harbor Rad51 and RPA interacting motifs. Interactions between these patches regulate ssDNA binding. Surprisingly, Rad51 …

Multivariate Gwas Of Alzheimer's Disease Csf Biomarker Profiles Implies Grin2d In Synaptic Functioning, Alexander Neumann, Jigyasha Timsina, Thomas W Marsh, Priyanka Gorijala, Carlos Cruchaga, Et Al.

2020-Current year OA Pubs

BACKGROUND: Genome-wide association studies (GWAS) of Alzheimer's disease (AD) have identified several risk loci, but many remain unknown. Cerebrospinal fluid (CSF) biomarkers may aid in gene discovery and we previously demonstrated that six CSF biomarkers (β-amyloid, total/phosphorylated tau, NfL, YKL-40, and neurogranin) cluster into five principal components (PC), each representing statistically independent biological processes. Here, we aimed to (1) identify common genetic variants associated with these CSF profiles, (2) assess the role of associated variants in AD pathophysiology, and (3) explore potential sex differences.

METHODS: We performed GWAS for each of the five biomarker PCs in two multi-center studies (EMIF-AD …

Association Between Socioeconomic Factors, Race, And Use Of A Specialty Memory Clinic, Abigail Lewis, Aditi Gupta, Inez Oh, Suzanne E. Schindler, Nupur Ghoshal, Zachary Abrams, Randi Foraker, Barbara Joy Snider, John C. Morris, Joyce Balls-Berry, Mahendra Gupta, Philip R. O. Payne, Albert M. Lai

2020-Current year OA Pubs

BACKGROUND AND OBJECTIVES: The capacity of specialty memory clinics in the United States is very limited. If lower socioeconomic status or minoritized racial group is associated with reduced use of memory clinics, this could exacerbate health care disparities, especially if more effective treatments of Alzheimer disease become available. We aimed to understand how use of a memory clinic is associated with neighborhood-level measures of socioeconomic factors and the intersectionality of race.

METHODS: We conducted an observational cross-sectional study using electronic health record data to compare the neighborhood advantage of patients seen at the Washington University Memory Diagnostic Center with the …

Interplay Between Esr1/Pik3ca Codon Variants, Oncogenic Pathway Alterations And Clinical Phenotype In Patients With Metastatic Breast Cancer (Mbc): Comprehensive Circulating Tumor Dna (Ctdna) Analysis, Lorenzo Gerratana, Andrew A Davis, Katherine Clifton, Whitney L Hensing, Cynthia X Ma, Et Al.

2020-Current year OA Pubs

BACKGROUND: although being central for the biology and druggability of hormone-receptor positive, HER2 negative metastatic breast cancer (MBC), ESR1 and PIK3CA mutations are simplistically dichotomized as mutated or wild type in current clinical practice.

METHODS: The study analyzed a multi-institutional cohort comprising 703 patients with luminal-like MBC characterized for circulating tumor DNA through next generation sequencing (NGS). Pathway classification was defined based on previous work (i.e., RTK, RAS, RAF, MEK, NRF2, ER, WNT, MYC, P53, cell cycle, notch, PI3K). Single nucleotide variations (SNVs) were annotated for their oncogenicity through OncoKB. Only pathogenic variants were included in the models. Associations among …

Diagnostic Criteria For Identifying Individuals At High Risk Of Progression From Mild Or Moderate To Severe Alcohol Use Disorder, Alex P Miller, Emma C Johnson, Rebecca Tillman, Vivia V Mccutcheon, Kathleen K Bucholz, Arpana Agrawal, Et Al.

2020-Current year OA Pubs

IMPORTANCE: Current Diagnostic and Statistical Manual of Mental Disorders (Fifth Edition) (DSM-5) diagnoses of substance use disorders rely on criterion count-based approaches, disregarding severity grading indexed by individual criteria.

OBJECTIVE: To examine correlates of alcohol use disorder (AUD) across count-based severity groups (ie, mild, moderate, mild-to-moderate, severe), identify specific diagnostic criteria indicative of greater severity, and evaluate whether specific criteria within mild-to-moderate AUD differentiate across relevant correlates and manifest in greater hazards of severe AUD development.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study involved 2 cohorts from the family-based Collaborative Study on the Genetics of Alcoholism (COGA) with 7 sites …

Il-6 Selectively Suppresses Cdc1 Specification Via C/Ebpβ, Sunkyung Kim, Jing Chen, Suin Jo, Feiya Ou, Stephen T Ferris, Tian-Tian Liu, Ray A Ohara, David A Anderson, Renee Wu, Michael Y Chen, William E Gillanders, William E Gillanders, Theresa L Murphy, Kenneth M Murphy

2020-Current year OA Pubs

Cytokines produced in association with tumors can impair antitumor immune responses by reducing the abundance of type 1 conventional dendritic cells (cDC1), but the mechanism remains unclear. Here, we show that tumor-derived IL-6 generally reduces cDC development but selectively impairs cDC1 development in both murine and human systems through the induction of C/EBPβ in the common dendritic cell progenitor (CDP). C/EBPβ and NFIL3 compete for binding to sites in the Zeb2 -165 kb enhancer and support or repress Zeb2 expression, respectively. At homeostasis, pre-cDC1 specification occurs upon Nfil3 induction and consequent Zeb2 suppression. However, IL-6 strongly induces C/EBPβ expression in …

Reduction Of Sparc Protects Mice Against Nlrp3 Inflammasome Activation And Obesity, Seungjin Ryu, Olga Spadaro, Sviatoslav Sidorov, Aileen H. Lee, Sonia Caprio, Christopher Morrison, Steven R. Smith, Eric Ravussin, Irina Shchukina, Maxim N. Artyomov, Yun-Hee Youm, Vishwa Deep Dixit

2020-Current year OA Pubs

The comprehensive assessment of long-term effects of reducing intake of energy (CALERIE-II; NCT00427193) clinical trial established that caloric restriction (CR) in humans lowers inflammation. The identity and mechanism of endogenous CR-mimetics that can be deployed to control obesity-associated inflammation and diseases are not well understood. Our studies have found that 2 years of 14% sustained CR in humans inhibits the expression of the matricellular protein, secreted protein acidic and rich in cysteine (SPARC), in adipose tissue. In mice, adipose tissue remodeling caused by weight loss through CR and low-protein diet feeding decreased, while high-fat diet-induced (HFD-induced) obesity increased SPARC expression …

Safety And Immunogenicity Of Live Viral Vaccines In A Multicenter Cohort Of Pediatric Transplant Recipients, Amy G Feldman, Stacy Postma, Janis Stoll, Et Al.

2020-Current year OA Pubs

IMPORTANCE: Live vaccines (measles-mumps-rubella [MMR] and varicella-zoster virus [VZV]) have not been recommended after solid organ transplant due to concern for inciting vaccine strain infection in an immunocompromised host. However, the rates of measles, mumps, and varicella are rising nationally and internationally, leaving susceptible immunocompromised children at risk for life-threating conditions.

OBJECTIVE: To determine the safety and immunogenicity of live vaccines in pediatric liver and kidney transplant recipients.

DESIGN, SETTING, AND PARTICIPANTS: This cohort study included select pediatric liver and kidney transplant recipients who had not completed their primary MMR and VZV vaccine series and/or who displayed nonprotective serum antibody …

Tipifarnib Potentiates The Antitumor Effects Of Pi3kα Inhibition In Pik3ca- And Hras-Dysregulated Hnscc Via Convergent Inhibition Of Mtor Activity, Alison E Smith, Douglas R Adkins, Et Al.

2020-Current year OA Pubs

UNLABELLED: Outcomes for patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) are poor, with median overall survival (OS) ranging from 6 to 18 months. For those who progress on standard-of-care (chemo)immunotherapy, treatment options are limited, necessitating the development of rational therapeutic strategies. Toward this end, we targeted the key HNSCC drivers PI3K-mTOR and HRAS via the combination of tipifarnib, a farnesyltransferase (FTase) inhibitor, and alpelisib, a PI3Kα inhibitor, in multiple molecularly defined subsets of HNSCC. Tipifarnib synergized with alpelisib at the level of mTOR in PI3Kα- or HRAS-dependent HNSCCs, leading to marked cytotoxicity in vitro and tumor …