Practice Changes in Checkpoint Inhibitor-Induced Immune-Related Adverse Event Management at a Tertiary Care Center.

Understanding of immune-related adverse events (irAEs) has evolved rapidly, and management guidelines are continually updated. We explored temporal changes in checkpoint inhibitor-induced irAE management at a tertiary cancer care center to identify areas for improvement. We conducted a single-center retrospective study of patients who developed a gastrointestinal, pulmonary, renal, or cardiac irAE between July and 1 October in 2019 or 2021.

Development of a Strategic Initiative at MD Anderson Cancer Center to Improve Outcomes in Immune-Related Adverse Events.

Immune checkpoint inhibitors (ICIs) have transformed the treatment paradigm for many cancer types. The clinical use of ICIs is increasing rapidly, including in combinations associated with increased risk of toxicities, termed "immune-related adverse events" (irAEs). Therefore, MD Anderson Cancer Center (MDACC) in Houston, Texas has proactively responded by developing a priority endeavor known as the Immuno-Oncology Toxicity (IOTOX) initiative.

A phase i study of ixazomib and erlotinib in patients with advanced solid tumors.

Preclinical studies have shown that the combined inhibition of EGFR and NF-kB pathways to target the RalB/TBK1 pathway led to synergistic antitumor activity. Based on this rationale, we conducted a Phase I dose-escalation study combining the EGFR inhibitor erlotinib with the NF-kB inhibitor ixazomib in advanced solid tumors. Patients and methods.

HNF1B Loss Exacerbates the Development of Chromophobe Renal Cell Carcinomas.

Chromophobe renal cell carcinoma (ChRCC) is characterized by major changes in chromosomal copy number (CN). No model is available to precisely elucidate the molecular drivers of this tumor type. HNF1B is a master regulator of gene expression.

Resistance to Antiangiogenic Therapy Is Associated with an Immunosuppressive Tumor Microenvironment in Metastatic Renal Cell Carcinoma.

Renal cell carcinoma (RCC) is an immunogenic and proangiogenic cancer, and antiangiogenic therapy is the current mainstay of treatment. Patients with RCC develop innate or adaptive resistance to antiangiogenic therapy. There is a need to identify biomarkers that predict therapeutic resistance and guide combination therapy.

Genetic and pharmacological strategies to refunctionalize the von Hippel Lindau R167Q mutant protein.

Aberrant von Hippel Lindau (VHL) protein function is the underlying driver of VHL-related diseases, including both sporadic and inherited clear cell renal cell carcinoma (ccRCC). About one third of VHL mutations are missense point mutations, with R167Q being the most common VHL point mutation in hereditary VHL disease. Although it has been studied extensively, the ability of VHL-R167Q to downregulate hypoxia-inducible factor 2α (HIF2α) is still controversial.

Speckle-type POZ protein, SPOP, is involved in the DNA damage response.

Speckle-type POZ protein (SPOP) is an adaptor of the cullin 3-based ubiquitin ligase responsible for the degradation of oncoproteins frequently overexpressed in many tumor cells. Altered expression and somatic mutations of SPOP have been observed in various tumor types with chromosomal aberrations, indicating a role of SPOP in maintaining genome stability, although a detailed mechanism remains unclear. Here, we show that SPOP is a component of the DNA damage response (DDR).

DDX3 regulates DNA damage-induced apoptosis and p53 stabilization.

The DEAD box protein family member DDX3 was previously identified as an inhibitor of death receptor-mediated extrinsic apoptotic signaling. However, there had been no studies of the role of DDX3 in regulating the other major type of apoptosis, intrinsic apoptotic signaling, which was examined here. Intrinsic apoptosis was induced in MCF-7 cells by treatment with staurosporine, a general kinase inhibitor, thapsigargin, which induces endoplasmic reticulum (ER) stress, and camptothecin, which causes DNA damage.

Activation of the ATM-Snail pathway promotes breast cancer metastasis.

The DNA damage response (DDR) is critical for the maintenance of genetic stability and serves as an anti-cancer barrier during early tumorigenesis. However, the role of the DDR in tumor progression and metastasis is less known. Here, we demonstrate that the ATM kinase, one of the critical DDR elements, is hyperactive in late stage breast tumor tissues with lymph-node metastasis and this hyperactivity correlates with elevated expression of the epithelial-mesenchymal transition marker, Snail.

The alkylphospholipid, perifosine, radiosensitizes prostate cancer cells both in vitro and in vivo.

Background: Perifosine is a membrane-targeted alkylphospholipid developed to inhibit the PI3K/Akt pathway and has been suggested as a favorable candidate for combined use with radiotherapy. In this study, we investigated the effect of the combined treatment of perifosine and radiation (CTPR) on prostate cancer cells in vitro and on prostate cancer xenografts in vivo.

Methods: Human prostate cancer cell line, CWR22RV1, was treated with perifosine, radiation, or CTPR.

The role of DDX3 in regulating Snail.

DDX3, a DEAD box protein family member, appears to promote the progression of some cancers, which may partly result from its impedance of death receptor-mediated apoptosis. We found that another mechanism by which DDX3 may aid cancer progression is by promoting increased levels of the transcription factor Snail. Snail represses expression of cellular adhesion proteins, leading to increased cell migration and metastasis of many types of cancer.

XIAP associates with GSK3 and inhibits the promotion of intrinsic apoptotic signaling by GSK3.

This study examined if there are interactions between two key proteins that oppositely regulate intrinsic apoptosis, X-linked inhibitor of apoptosis protein (XIAP), a key suppressor of apoptosis that binds to inhibit active caspases, and glycogen synthase kinase-3 (GSK3), which promotes intrinsic apoptosis. Immunoprecipitation of GSK3beta revealed that XIAP associates with GSK3beta, as do two other members of the IAP family, cIAP-1, and cIAP-2. Cell fractionation revealed that XIAP is predominantly cytosolic, cIAP-1 is predominantly nuclear and nearly all of the nuclear cIAP-1 and cIAP-2 are associated with GSK3.

[High throughput screening method of nitric oxide synthase inhibitors and enhancers].

Aim: In order to discover new inhibitors and enhancers of nitric oxide synthase (NOS), an in vitro assay to determine NOS activity was established for high throughput screening.

Methods: The activity of NOS was detected based on the change of nicotinamide-adenine dinucleotide phosphate (NADPH) concentration in the reaction system by the fluorescence density. The enzyme was prepared from bovine brain by gradient centrifugation.