Brian Hernandez - Academia.edu (original) (raw)

Papers by Brian Hernandez

Table S10. RAPID siRNA Screen data - U23674. (XLSX 43 kb)

Figure S1. Heat map of merged chemical screen, RNA-seq, siRNA, and phosphoproteomics results for ... more Figure S1. Heat map of merged chemical screen, RNA-seq, siRNA, and phosphoproteomics results for GlaxoSmithKline (GSK) Orphan Kinome screen. Due to the large number of compounds and protein targets, only a limited scope of compounds and targets is shown here (for full data, see Additional file 15: Table S1). Bright red indicates high sensitivity values, gradating down to white meaning low sensitivity. Gray indicates no interaction or no available data. Asterisk indicates targets later validated in vivo. (TIF 38030 kb)

Table S1. Treatment schedule for PDX models. Table S2. Patient history of PDX eRMS models. Table ... more Table S1. Treatment schedule for PDX models. Table S2. Patient history of PDX eRMS models. Table S3. Statistical summary for CTG-1213/POS-13212. Table S4. Statistical summary for CTG1116/POS-13166. Table S5. Statistical summary for CTG-1628/POS-132166B. Table S6. Statistical summary for J0103366/CF-13A. Table S7. Histological markers of differentiation in PDX eRMS (CTG-1213) mice. Table S8. Patient history of PDX pleoRMS models. Table S9. Statistical summary for CTG-1213/POS-13212. Table S10. Statistical summary for CTG1116/POS-13166. Table S11. Statistical summary for CTG-1628/POS-132166B. Table S12. Histological markers of differentiation in PDX pleoRMS (CTG-800) mice. Table S13. Primers for RT-PCR. (DOCX 41 kb)

Figure S5. Representative immunohistochemistry for CD68 of mouse eRMS tissue and primary cells. N... more Figure S5. Representative immunohistochemistry for CD68 of mouse eRMS tissue and primary cells. Necrotic tissue (a) showed few macrophages present, while viable tumor (b) showed a collection of many macrophages. Macrophage presence was observed as being the same for all treatment groups. (TIF 2929 kb)

American Journal of Obstetrics and Gynecology

BMC Cancer

Background: Cancer patients with advanced disease routinely exhaust available clinical regimens a... more Background: Cancer patients with advanced disease routinely exhaust available clinical regimens and lack actionable genomic medicine results, leaving a large patient population without effective treatments options when their disease inevitably progresses. To address the unmet clinical need for evidence-based therapy assignment when standard clinical approaches have failed, we have developed a probabilistic computational modeling approach which integrates molecular sequencing data with functional assay data to develop patient-specific combination cancer treatments. Methods: Tissue taken from a murine model of alveolar rhabdomyosarcoma was used to perform single agent drug screening and DNA/RNA sequencing experiments; results integrated via our computational modeling approach identified a synergistic personalized two-drug combination. Cells derived from the primary murine tumor were allografted into mouse models and used to validate the personalized two-drug combination. Computational modeling of single agent drug screening and RNA sequencing of multiple heterogenous sites from a single patient's epithelioid sarcoma identified a personalized two-drug combination effective across all tumor regions. The heterogeneity-consensus combination was validated in a xenograft model derived from the patient's primary tumor. Cell cultures derived from human and canine undifferentiated pleomorphic sarcoma were assayed by drug screen; computational modeling identified a resistance-abrogating two-drug combination common to both cell cultures. This combination was validated in vitro via a cell regrowth assay. Results: Our computational modeling approach addresses three major challenges in personalized cancer therapy: synergistic drug combination predictions (validated in vitro and in vivo in a genetically engineered murine cancer model), identification of unifying therapeutic targets to overcome intra-tumor heterogeneity (validated in vivo in a human cancer xenograft), and mitigation of cancer cell resistance and rewiring mechanisms (validated in vitro in a human and canine cancer model).

Frontiers in Cardiovascular Medicine

Background: Code selection is crucial to the accuracy and reproducibility of studies using admini... more Background: Code selection is crucial to the accuracy and reproducibility of studies using administrative data, however a comprehensive assessment of coding trends for major cardiac diagnoses and procedures is lacking. We aimed to evaluate trends in administrative code utilization for major cardiac diagnoses and procedures, and adherence to required methodological practices in cardiac research using the National Inpatient Sample (NIS).Methods: In this observational study of 445 articles, ICD-9-CM codes corresponding to acute myocardial infarction (AMI), heart failure, atrial fibrillation, percutaneous coronary intervention, and coronary artery bypass grafting were collected and analyzed. The NIS was used to compare the number of hospitalizations between the most frequently encountered AMI case definitions. Key elements were abstracted from each article to evaluate adherence to required methodological practices.Results: Variation in code utilization was observed for each diagnosis an...

American Journal of Gastroenterology

Skeletal Muscle

Background: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in the pediatric cancer... more Background: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in the pediatric cancer population. Survival among metastatic RMS patients has remained dismal yet unimproved for years. We previously identified the class I-specific histone deacetylase inhibitor, entinostat (ENT), as a pharmacological agent that transcriptionally suppresses the PAX3:FOXO1 tumor-initiating fusion gene found in alveolar rhabdomyosarcoma (aRMS), and we further investigated the mechanism by which ENT suppresses PAX3:FOXO1 oncogene and demonstrated the preclinical efficacy of ENT in RMS orthotopic allograft and patient-derived xenograft (PDX) models. In this study, we investigated whether ENT also has antitumor activity in fusion-negative eRMS orthotopic allografts and PDX models either as a single agent or in combination with vincristine (VCR). Methods: We tested the efficacy of ENT and VCR as single agents and in combination in orthotopic allograft and PDX mouse models of eRMS. We then performed CRISPR screening to identify which HDAC among the class I HDACs is responsible for tumor growth inhibition in eRMS. To analyze whether ENT treatment as a single agent or in combination with VCR induces myogenic differentiation, we performed hematoxylin and eosin (H&E) staining in tumors. Results: ENT in combination with the chemotherapy VCR has synergistic antitumor activity in a subset of fusionnegative eRMS in orthotopic "allografts," although PDX mouse models were too hypersensitive to the VCR dose used to detect synergy. Mechanistic studies involving CRISPR suggest that HDAC3 inhibition is the primary mechanism of cell-autonomous cytoreduction in eRMS. Following cytoreduction in vivo, residual tumor cells in the allograft models treated with chemotherapy undergo a dramatic, entinostat-induced (70-100%) conversion to non-proliferative rhabdomyoblasts. Conclusion: Our results suggest that the targeting class I HDACs may provide a therapeutic benefit for selected patients with eRMS. ENT's preclinical in vivo efficacy makes ENT a rational drug candidate in a phase II clinical trial for eRMS.

SAMPE 2019 - Charlotte, NC

Journal of Clinical Oncology

e14640 Background: Colorectal cancer (CRC) rarely metastasizes to the brain. With improved surviv... more e14640 Background: Colorectal cancer (CRC) rarely metastasizes to the brain. With improved survival of patients (pts) with metastatic CRC following the advent of targeted agents such as bevacizumab (Bev) and anti-EGFR therapy, the incidence of brain metastases (BM) secondary to CRC is rising. We aimed to evaluate the clinical characteristics of who developed BM secondary to CRC. Methods: A historical cohort analysis of CRC pts with BM treated at our institution from 01/2005-01/2015 was performed. Data collected included primary tumor location (colon/rectum), lymph node (LN) involvement, location of extra-cranial metastases (lung/non-lung), number of BM, KRAS status, CEA levels, Bev or cetuximab (Cet) therapy prior to and after BM, and recursive partitioning analysis (RPA) prognostic class I-III (determined by age, Karnofsky performance status (KPS) and presence of extra-cranial metastases). Overall survival (OS) was estimated from Kaplan-Meier curves and groups were statistically compared with the log ran...

The Journal of surgical research, 2018

Chest tube management protocols, particularly in patients with alveolar-pleural air leak due to r... more Chest tube management protocols, particularly in patients with alveolar-pleural air leak due to recent surgery or trauma, are limited by concerns over safety, especially concerns about rapid and occult development of pneumothorax. A continuous, real-time monitor of pneumothorax could improve the quality and safety of chest tube management. We developed a rat model of pneumothorax to test a novel approach of measuring electrical impedance within the pleural space as a monitor of lung expansion. Anesthetized Sprague-Dawley rats underwent right thoracotomy. A novel impedance sensor and a thoracostomy tube were introduced into the right pleural space. Pneumothorax of varying volumes ranging from 0.2 to 20 mL was created by syringe injection of air via the thoracostomy tube. Electrical resistance measurements from the pleural sensor and fluoroscopic images were obtained at baseline and after the creation of pneumothorax and results compared. A statistically significant, dose-dependent in...

Open Forum Infectious Diseases

Setting Five health care systems in Texas. Objective To describe the epidemiology of inadequate i... more Setting Five health care systems in Texas. Objective To describe the epidemiology of inadequate isolation for pulmonary tuberculosis leading to tuberculosis (TB) exposures from confirmed TB patients and the patient factors that led to the exposures. Design A retrospective cohort and case-control study of adult patients with TB resulting in exposures (cases) vs those TB patients who did not result in exposures (controls) during January 2005 to December 2012. Results There were 335 patients with pulmonary TB disease, 199 cases and 136 controls. There was no difference between groups in age (46 ± 14.6 vs 45 ± 17 years; P > .05), race, or substance abuse. Cases were more likely to be transplant recipients (adjusted odds ratio [AOR], 18.90; 95% CI, 1.9–187.76), have typical TB chest radiograph (AOR, 2.23; 95% CI, 1.1–4.51), and have positive acid-fast bacilli stains (AOR, 2.36; 95% CI, 1.31–4.27). Cases were less likely to have extrapulmonary disease (AOR, 0.47; 95% CI, 0.24–0.95). Co...

The Laryngoscope, 2017

To compare the effectiveness of massed versus interval training when teaching otolaryngology resi... more To compare the effectiveness of massed versus interval training when teaching otolaryngology residents microvascular suturing on a validated microsurgical model. Otolaryngology residents were placed into interval (n = 7) or massed (n = 7) training groups. The interval group performed three separate 30-minute practice sessions separated by at least 1 week, and the massed group performed a single 90-minute practice session. Both groups viewed a video demonstration and recorded a pretest prior to the first training session. A post-test was administered following the last practice session. At an academic medical center, 14 otolaryngology residents were assigned using stratified randomization to interval or massed training. Blinded evaluators graded performance using a validated microvascular Objective Structured Assessment of Technical Skill tool. The tool is comprised of two major components: task-specific score (TSS) and global rating scale (GRS). Participants also received pre- and poststudy surveys to compare subjective confidence in multiple aspects of microvascular skill acquisition. Overall, all residents showed increased TSS and GRS on post- versus pretest. After completion of training, the interval group had a statistically significant increase in both TSS and GRS, whereas the massed group&amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s increase was not significant. Residents in both groups reported significantly increased levels of confidence after completion of the study. Self-directed learning using a chicken thigh artery model may benefit microsurgical skills, competence, and confidence for resident surgeons. Interval training results in significant improvement in early development of microvascular anastomosis skills, whereas massed training does not. NA Laryngoscope, 2017.

Scientific reports, Jun 3, 2016

Risk or presence of metastasis in medulloblastoma causes substantial treatment-related morbidity ... more Risk or presence of metastasis in medulloblastoma causes substantial treatment-related morbidity and overall mortality. Through the comparison of cytokines and growth factors in the cerebrospinal fluid (CSF) of metastatic medulloblastoma patients with factors also in conditioned media of metastatic MYC amplified medulloblastoma or leptomeningeal cells, we were led to explore the bioactivity of IGF1 in medulloblastoma by elevated CSF levels of IGF1, IGF-sequestering IGFBP3, IGFBP3-cleaving proteases (MMP and tPA), and protease modulators (TIMP1 and PAI-1). IGF1 led not only to receptor phosphorylation but also accelerated migration/adhesion in MYC amplified medulloblastoma cells in the context of appropriate matrix or meningothelial cells. Clinical correlation suggests a peri-/sub-meningothelial source of IGF-liberating proteases that could facilitate leptomeningeal metastasis. In parallel, studies of key factors responsible for cell autonomous growth in MYC amplified medulloblastoma...

Background: Several large-scale gene co-expression networks have been constructed successfully fo... more Background: Several large-scale gene co-expression networks have been constructed successfully for predicting gene functional modules and cis-regulatory elements in Arabidopsis (Arabidopsis thaliana). However, these networks are usually constructed and analyzed in an ad hoc manner. In this study, we propose a completely parameter-free and systematic method for constructing gene co-expression networks and predicting functional modules as well as cis-regulatory elements. Results: Our novel method consists of an automated network construction algorithm, a parameter-free procedure to predict functional modules, and a strategy for finding known cis-regulatory elements that is suitable for consensus scanning without prior knowledge of the allowed extent of degeneracy of the motif. We apply the method to study a large collection of gene expression microarray data in Arabidopsis. We estimate that our coexpression network has~94% of accuracy, and has topological properties similar to other biological networks, such as being scale-free and having a high clustering coefficient. Remarkably, among the~300 predicted modules whose sizes are at least 20, 88% have at least one significantly enriched functions, including a few extremely significant ones (ribosome, p < 1E-300, photosynthetic membrane, p < 1.3E-137, proteasome complex, p < 5.9E-126). In addition, we are able to predict cis-regulatory elements for 66.7% of the modules, and the association between the enriched cis-regulatory elements and the enriched functional terms can often be confirmed by the literature. Overall, our results are much more significant than those reported by several previous studies on similar data sets. Finally, we utilize the co-expression network to dissect the promoters of 19 Arabidopsis genes involved in the metabolism and signaling of the important plant hormone gibberellin, and achieved promising results that reveal interesting insight into the biosynthesis and signaling of gibberellin. Conclusions: The results show that our method is highly effective in finding functional modules from real microarray data. Our application on Arabidopsis leads to the discovery of the largest number of annotated Arabidopsis functional modules in the literature. Given the high statistical significance of functional enrichment and the agreement between cis-regulatory and functional annotations, we believe our Arabidopsis gene modules can be used to predict the functions of unknown genes in Arabidopsis, and to understand the regulatory mechanisms of many genes.