Metabolomic and lipidomic pathways in aneurysmal subarachnoid hemorrhage.

Aneurysmal subarachnoid hemorrhage (aSAH) results in a complex systemic response that is critical to the pathophysiology of late complications and has important effects on outcomes. Omics techniques have expanded our investigational scope and depth into this phenomenon. In particular, metabolomics-the study of small molecules, such as blood products, carbohydrates, amino acids, and lipids-can provide a snapshot of dynamic subcellular processes and thus broaden our understanding of molecular-level pathologic changes that lead to the systemic response after aSAH.

Anti-miR-93-5p therapy prolongs sepsis survival by restoring the peripheral immune response.

Sepsis remains a leading cause of death for humans and currently has no pathogenesis-specific therapy. Hampered progress is partly due to a lack of insight into deep mechanistic processes. In the past decade, deciphering the functions of small noncoding miRNAs in sepsis pathogenesis became a dynamic research topic.

Dimeric p53 Mutant Elicits Unique Tumor-Suppressive Activities through an Altered Metabolic Program.

Unlabelled: Cancer-related alterations of the p53 tetramerization domain (TD) abrogate wild-type (WT) p53 function. They result in a protein that preferentially forms monomers or dimers, which are also normal p53 states under basal cellular conditions. However, their physiologic relevance is not well understood.

Molecular Pathways and Mechanisms of HER2 in Cancer Therapy.

The oncogene ERBB2 encoding the receptor tyrosine-protein kinase erbB-2 (HER2) is frequently overexpressed or amplified and occasionally mutated in a variety of human cancers. The early discovery of this oncogene, its established oncogenic relevance in diverse cancers, its substantial expression on the surface of cancer cells, and its druggable catalytic activity have made it one of the most pursued targets in the history of cancer drug development. Initiatives targeting HER2 provided the early stimulus for several transformational pharmaceutical technologies, including mAbs, tyrosine kinase inhibitors, antibody-drug conjugates, and others.

Genomic Correlates of Outcome in Tumor-Infiltrating Lymphocyte Therapy for Metastatic Melanoma.

Purpose: Adoptive cell therapy (ACT) of tumor-infiltrating lymphocytes (TIL) historically yields a 40%-50% response rate in metastatic melanoma. However, the determinants of outcome are largely unknown.

Experimental Design: We investigated tumor-based genomic correlates of overall survival (OS), progression-free survival (PFS), and response to therapy by interrogating tumor samples initially collected to generate TIL infusion products.

Monoclonal Antibodies Generation: Updates and Protocols on Hybridoma Technology.

Since its inception in 1975, the hybridoma technology revolutionized science and medicine, facilitating discoveries in almost any field from the laboratory to the clinic. Many technological advancements have been developed since then, to create these "magical bullets." Phage and yeast display libraries expressing the variable heavy and light domains of antibodies, single B-cell cloning from immunized animals of different species including humans or in silico approaches, all have rendered a myriad of newly developed antibodies or improved design of existing ones.

Isolation and Maintenance of Tumor-Infiltrating Lymphocytes for Translational and Clinical Applications: Established Methods and New Developments.

Adoptive cell transfer (ACT) of in vitro expanded tumor-infiltrating lymphocytes (TIL) for the treatment of patients with advanced stages of metastatic melanoma remains one of the most beneficial therapies eliciting long-lasting responses. Methods and protocols used to expand TIL have evolved over time, utilizing different culture devices and other tools, to streamline and maximize the end product in both numbers and quality. Summarized in this chapter are the latest protocols used in the TIL program at MDACC.

Efficacy of Immune Checkpoint Inhibitors in Upper Tract Urothelial Carcinomas: Current Knowledge and Future Directions.

Upper tract urothelial carcinoma (UTUC) represents a rare and aggressive malignancy arising from the renal pelvis or ureter. It can develop sporadically or have a hereditary origin, such as Lynch syndrome, caused by DNA mismatch repair deficiency, leading to microsatellite instability phenotype. According to molecular characterization studies, UTUC presents different mutational profiles as compared to urinary bladder urothelial carcinomas.

Assessment of In Vivo siRNA Delivery in Cancer Mouse Models.

RNA interference (RNAi) has rapidly become a powerful tool for target discovery and therapeutics. Small interfering RNAs (siRNAs) are highly effective in mediating sequence-specific gene silencing. However, the major obstacle for using siRNAs for cancer therapeutics is their systemic delivery from the administration site to target cells in vivo.

Reducing Skin Toxicities from EGFR Inhibitors with Topical BRAF Inhibitor Therapy.

Treatment of cancer with EGFR inhibitors is limited by on-target skin toxicities induced by inhibition of the MAPK pathway. BRAF inhibitors are known to paradoxically activate the MAPK downstream of EGFR, which we confirmed using human skin keratinocytes. We then conducted a phase I clinical trial testing the hypothesis that topical therapy with the BRAF inhibitor LUT014 could improve skin toxicities induced by EGFR inhibitors.

A Bayesian adaptive randomized phase II multicenter trial of bevacizumab with or without vorinostat in adults with recurrent glioblastoma.

Background: Bevacizumab has promising activity against recurrent glioblastoma (GBM). However, acquired resistance to this agent results in tumor recurrence. We hypothesized that vorinostat, a histone deacetylase (HDAC) inhibitor with anti-angiogenic effects, would prevent acquired resistance to bevacizumab.

Exposure to anti-PD-1 causes functional differences in tumor-infiltrating lymphocytes in rare solid tumors.

The pervasive use of therapeutic antibodies targeting programmed cell death protein 1 (PD-1) to boost anti-tumor immunity has positioned this approach to become the standard-of-care for some solid tumor malignancies. However, little is known as to how blockade of PD-1 may alter the function or phenotype of tumor-infiltrating lymphocytes (TIL). We used our ongoing Phase II clinical trial of pembrolizumab for patients with rare solid tumors from various types (NCT02721732) with matched core biopsies taken at baseline and after initial dose of anti-PD-1 (15-21 days post-dose) to elucidate this question.

Genetic hallmarks of recurrent/metastatic adenoid cystic carcinoma.

BACKGROUNDAdenoid cystic carcinoma (ACC) is a rare malignancy arising in salivary glands and other sites, characterized by high rates of relapse and distant spread. Recurrent/metastatic (R/M) ACCs are generally incurable, due to a lack of active systemic therapies. To improve outcomes, deeper understanding of genetic alterations and vulnerabilities in R/M tumors is needed.

Isolation of Extracellular RNA from Serum/Plasma.

Extracellular RNAs are initiating increased interest due to their potentials in serving as novel biomarkers, mediators of intercellular communication, and therapeutic applications. As a newly emerging field, one of the main obstacles is the lack of standardized protocols for RNA isolations. Here we describe protocols for commercially available kits that have been modified to yield consistent results for isolation of extracellular RNA from both whole serum/plasma and extracellular vesicle-enriched serum/plasma samples.

A Novel Method to Generate and Expand Clinical-Grade, Genetically Modified, Tumor-Infiltrating Lymphocytes.

Following the clinical success achieved with the first generation of adoptive cell therapy (ACT) utilizing expanded tumor-infiltrating lymphocytes (TILs), the second and third generations of TIL ACT are evolving toward the use of genetically modified TIL. TIL therapy generally involves the transfer of a high number of TIL, ranging from 10 to 10 cells. One of the technical difficulties in genetically modifying TIL, using a retroviral vector, is the ability to achieve large expansion of transduced TIL, while keeping the technique suitable to a Good Manufacturing Practices (GMP) environment.

4-1BB-Enhanced Expansion of CD8 TIL from Triple-Negative Breast Cancer Unveils Mutation-Specific CD8 T Cells.

Triple-negative breast cancer (TNBC) highly infiltrated with CD8 tumor-infiltrating lymphocytes (TIL) has been associated with improved prognosis. This observation led us to hypothesize that CD8 TIL could be utilized in autologous adoptive cell therapy for TNBC, although this concept has proven to be challenging, given the difficulty in expanding CD8 TILs in solid cancers other than in melanoma. To overcome this obstacle, we used an agonistic antibody (urelumab) to a TNFR family member, 4-1BB/CD137, which is expressed by recently activated CD8 T cells.

A multicenter assessment of the ability of preoperative computed tomography scan and CA-125 to predict gross residual disease at primary debulking for advanced epithelial ovarian cancer.

Objective: To assess the ability of preoperative computed tomography scan and CA-125 to predict gross residual disease (RD) at primary cytoreduction in advanced ovarian cancer.

Methods: A prospective, non-randomized, multicenter trial of patients who underwent primary debulking for stage III-IV epithelial ovarian cancer previously identified 9 criteria associated with suboptimal (>1cm residual) cytoreduction. This is a secondary post-hoc analysis looking at the ability to predict any RD.

Role of CTGF in Sensitivity to Hyperthermia in Ovarian and Uterine Cancers.

Even though hyperthermia is a promising treatment for cancer, the relationship between specific temperatures and clinical benefits and predictors of sensitivity of cancer to hyperthermia is poorly understood. Ovarian and uterine tumors have diverse hyperthermia sensitivities. Integrative analyses of the specific gene signatures and the differences in response to hyperthermia between hyperthermia-sensitive and -resistant cancer cells identified CTGF as a key regulator of sensitivity.

The beneficial effects of a gas-permeable flask for expansion of Tumor-Infiltrating lymphocytes as reflected in their mitochondrial function and respiration capacity.

Adoptive transfer of autologous expanded tumor-infiltrating lymphocytes (TIL) is a highly successful cell therapy approach in the treatment of late-stage melanoma. Notwithstanding the success of this therapy, only very few centers worldwide can provide it. To make this therapy broadly available, one of the major obstacles to overcome is the complexity of culturing the TIL.

Assessment of In Vivo siRNA Delivery in Cancer Mouse Models.

RNA interference (RNAi) has rapidly become a powerful tool for target discovery and therapeutics. Small interfering RNAs (siRNAs) are highly effective in mediating sequence-specific gene silencing. However, the major obstacle for using siRNAs as cancer therapeutics is their systemic delivery from the administration site to target cells in vivo.

Profiling Long Noncoding RNA Expression Using Custom-Designed Microarray.

Long noncoding RNAs (lncRNAs) are an important class of pervasive genes involved in a variety of biological functions. The abnormal expression of lncRNAs has been implicated in a range of many human diseases, including cancer. But only a small number of functional lncRNAs have been well characterized to date.