Dynamic Mapping of the Methylproteome Using a Chemoenzymatic Approach.

Dynamic protein post-translational methylation is essential for cellular function, highlighted by the essential role of methylation in transcriptional regulation and its aberrant dysregulation in diseases, including cancer. This underscores the importance of cataloging the cellular methylproteome. However, comprehensive analysis of the methylproteome remains elusive due to limitations in current enrichment and analysis pipelines.

Encorafenib plus binimetinib for BRAF V600E-mutant metastatic NSCLC: clinical implications of the phase 2 PHAROS study.

Drs. Ramalingam and Carlisle discuss the incidence and pathophysiology of BRAF V600E-mutant metastatic non-small cell lung cancer and current treatment options. The podcast provides an overview of the data from the recent Pfizer-sponsored phase 2 PHAROS (NCT03915951) study, which were the basis for the recent US Food and Drug Administration approval of encorafenib plus binimetinib for BRAF V600E-mutant metastatic non-small cell lung cancer.

Tunable fluorescent probes for detecting aldehydes in living systems.

Aldehydes, pervasive in various environments, pose health risks at elevated levels due to their collective toxic effects shared mechanisms. Monitoring total aldehyde content in living systems is crucial due to their cumulative impact. Current methods for detecting cellular aldehydes are limited to UV and visible ranges, restricting their analysis in living systems.

Chemical sensors for imaging total cellular aliphatic aldehydes in live cells.

Aliphatic aldehydes are reactive electrophilic carbonyls that cross-link with DNA and proteins leading to cellular toxicity and disease pathogenesis. This toxicity is due to the cooperative effect of multiple aldehydes a common mechanism. Therefore, live-cell imaging of total aliphatic aldehydes, small-to-long chain (C-C), is highly desired to decipher their physiological and pathological functions.

Cutaneous findings in myotonic dystrophy.

Myotonic dystrophy types 1 and 2 are a group of complex genetic disorders resulting from the expansion of (CTG) nucleotide repeats in the gene. In addition to the hallmark manifestations of myotonia and skeletal muscle atrophy, myotonic dystrophy also affects a myriad of other organs including the heart, lungs, as well as the skin. The most common cutaneous manifestations of myotonic dystrophy are early male frontal alopecia and adult-onset pilomatricomas.

Intraventricular topotecan in the successful treatment of recurrent CNS pleuropulmonary blastoma.

Pleuropulmonary blastoma (PPB) is a rare pediatric tumor of the pleura and pulmonary mesenchyme, associated with pathogenic germline DICER1 mutations. Although the most common site of metastasis is the central nervous system (CNS), patients with CNS metastasis have dismal outcome. We report a case of a patient presenting with type II PPB and intracranial and bone metastases.

Tipifarnib enhances anti-EGFR activity of cetuximab in non-HRas mutated head and neck squamous cell carcinoma cancer (HNSCC).

Objective: To test the potential ability of tipifarnib to impair proliferation and to enhance the activity of the EGFR inhibitor cetuximab in wild-type H-Ras HNSCC, which accounts for the majority of HNSCC.

Materials And Methods: Cell growth, apoptosis and signaling changes in HNSCC cells following tipifarnib exposure in vitro were assessed by SRB, colony formation assay, annexin V staining and Western blot, respectively. A patient-derived xenograft (PDX) animal model was adopted to evaluate the efficacy of tipifarnib in vivo with and without cetuximab.

Immunotherapies in Genitourinary Oncology: Where Are We Now? Where Are We Going?

For decades, limited options existed to treat metastatic genitourinary cancers, including treatment options that could be classified as immunotherapy. Historically, immunotherapy centered on systemic cytokines for the treatment of metastatic kidney cancer, which had several adverse effects, as well as the Bacillus Calmette-Guérin vaccine for non-metastatic bladder cancer. Within the past decade, advances in immunotherapy have led to several approvals from the United States Food and Drug Administration, particularly in the field of immune checkpoint inhibition.

Correlates of financial toxicity in adult cancer patients and their informal caregivers.

Background: Financial toxicity is commonly reported by cancer patients, but few studies have assessed caregiver perceptions. We aimed to validate the modified Comprehensive Score for Financial Toxicity (COST) in cancer caregivers, identify factors associated with financial toxicity in both patients and caregivers, and assess the association of caregiver financial toxicity with patient and caregiver outcomes.

Methods: Using a convenience sampling method, 100 dyads of adult cancer patients and a primary caregiver visiting outpatient oncology clinics (Jan-Sep 2019) were recruited.

Co-expression of fibroblast growth factor receptor 3 with mutant p53, and its association with worse outcome in oropharyngeal squamous cell carcinoma.

Fibroblast growth factor receptor 3 (FGFR3) is expressed in squamous cell carcinoma of the head and neck (SCCHN) including oropharyngeal squamous cell carcinoma (OPSCC) and is a potential therapeutic target. However, information on its correlation with other relevant cancer related proteins stratified by p16 status and its prognostic significance in OPSCC is limited. We examined FGFR3 expression and its correlation with clinical characteristics, p16 status, and mutant p53 (mp53) among 220 retrospectively collected OPSCC cases and 40 prospectively collected SCCHN cases, including a majority of OPSCC.

Cannabinoids in dermatologic surgery.

Though known as a medicinal herb for centuries, the recent legalization of cannabinoids across many states has ushered in a new era where cannabinoids have become a popular treatment option among clinicians and patients alike. Cannabinoids have demonstrated efficacy in wound healing, reducing inflammation, ameliorating pain, and have shown potential as an antitumor agent. As a result, cannabinoids have been rapidly woven into the fabric of modern medicine.

Congenital dyserythropoietic anemia type I: First report from the Congenital Dyserythropoietic Anemia Registry of North America (CDAR).

Congenital dyserythropoietic anemias (CDAs) are characterized by ineffective erythropoiesis and distinctive erythroblast abnormalities; the diagnosis is often missed or delayed due to significant phenotypic heterogeneity. We established the CDA Registry of North America (CDAR) to study the natural history of CDA and create a biorepository to investigate the pathobiology of this heterogeneous disease. Seven of 47 patients enrolled so far in CDAR have CDA-I due to biallelic CDAN1 mutations.

Tumor derived UBR5 promotes ovarian cancer growth and metastasis through inducing immunosuppressive macrophages.

Immunosuppressive tumor microenvironment (TME) and ascites-derived spheroids in ovarian cancer (OC) facilitate tumor growth and progression, and also pose major obstacles for cancer therapy. The molecular pathways involved in the OC-TME interactions, how the crosstalk impinges on OC aggression and chemoresistance are not well-characterized. Here, we demonstrate that tumor-derived UBR5, an E3 ligase overexpressed in human OC associated with poor prognosis, is essential for OC progression principally by promoting tumor-associated macrophage recruitment and activation via key chemokines and cytokines.

Combinatorial approaches targeting the EGFR family and c-Met in SCCHN.

Objective: We aimed to develop novel combinations of inhibitors targeting EGFR family members and c-Met for the treatment of recurrent SCCHN.

Materials And Methods: Three different c-Met inhibitors in combination with a pan-HER inhibitor (crizotinib/afatinib, tivantinib/afatinib and cabozantinib/afatinib) were investigated for their anti-tumor effects on SCCHN cell lines in vitro. In vivo activity of the combinations was tested in SCCHN cell line xenografts and patient-derived xenograft (PDX) animal models generated from patients with recurrent SCCHN.

Excessive Costimulation Leads to Dysfunction of Adoptively Transferred T Cells.

Although clinical responses with CD19-targeting chimeric antigen receptor (CAR) T-cell treatment have been observed in patients with certain hematologic malignancies, high rates of disease relapse highlight the necessity to understand and improve mechanisms of CAR T-cell failure. Because T-cell dysfunction is thought to contribute to CAR T-cell treatment failure, understanding what mechanisms drive T cells into this dysfunctional state may aid optimal design of efficacious CAR T cells. Dysfunctional CAR T cells have been characterized as having upregulated inhibitory receptors and decreased cytolytic capabilities.

Optimization of T-cell Receptor-Modified T Cells for Cancer Therapy.

T-cell receptor (TCR)-modified T-cell gene therapy can target a variety of extracellular and intracellular tumor-associated antigens, yet has had little clinical success. A potential explanation for limited antitumor efficacy is a lack of T-cell activation We postulated that expression of proinflammatory cytokines in TCR-modified T cells would activate T cells and enhance antitumor efficacy. We demonstrate that expression of interleukin 18 (IL18) in tumor-directed TCR-modified T cells provides a superior proinflammatory signal than expression of interleukin 12 (IL12).

Phosphoinositide 3-Kinase Signaling Can Modulate MHC Class I and II Expression.

Molecular events activating the PI3K pathway are frequently detected in human tumors and the activation of PI3K signaling alters numerous cellular processes including tumor cell proliferation, survival, and motility. More recent studies have highlighted the impact of PI3K signaling on the cellular response to interferons and other immunologic processes relevant to antitumor immunity. Given the ability of IFNγ to regulate antigen processing and presentation and the pivotal role of MHC class I (MHCI) and II (MHCII) expression in T-cell-mediated antitumor immunity, we sought to determine the impact of PI3K signaling on MHCI and MHCII induction by IFNγ.

Combined BRAF and HSP90 Inhibition in Patients with Unresectable -Mutant Melanoma.

BRAF inhibitors are clinically active in patients with advanced BRAF-mutant melanoma, although acquired resistance remains common. Preclinical studies demonstrated that resistance could be overcome using concurrent treatment with the HSP90 inhibitor XL888. Vemurafenib (960 mg p.