Oncogenic composite mutations can be predicted by co-mutations and their chromosomal location.

Genetic heterogeneity in tumors can show a remarkable selectivity when two or more independent genetic events occur in the same gene. This phenomenon, called composite mutation, points toward a selective pressure, which frequently causes therapy resistance to mutation-specific drugs. Since composite mutations have been described to occur in sub-clonal populations, they are not always captured through biopsy sampling.

A Real-world Toxicity Atlas Shows that Adverse Events of Combination Therapies Commonly Result in Additive Interactions.

Purpose: Combination therapies are a promising approach for improving cancer treatment, but it is challenging to predict their resulting adverse events in a real-world setting.

Experimental Design: We provide here a proof-of-concept study using 15 million patient records from the FDA Adverse Event Reporting System (FAERS). Complex adverse event frequencies of drugs or their combinations were visualized as heat maps onto a two-dimensional grid.

Screening of predicted synergistic multi-target therapies in glioblastoma identifies new treatment strategies.

Background: IDH-wildtype glioblastoma (GBM) is a highly malignant primary brain tumor with a median survival of 15 months after standard of care, which highlights the need for improved therapy. Personalized combination therapy has shown to be successful in many other tumor types and could be beneficial for GBM patients.

Methods: We performed the largest drug combination screen to date in GBM, using a high-throughput effort where we selected 90 drug combinations for their activity onto 25 patient-derived GBM cultures.

Review: A Roadmap to Use Nonstructured Data to Discover Multitarget Cancer Therapies.

Therapy resistance to single agents has led to the realization that combination therapies could become the cornerstone of cancer treatment. To operationalize the selection of effective and safe multitarget therapies, we propose to integrate chemical and preclinical therapeutic information with clinical efficacy and toxicity data, allowing a new perspective on the drug target landscape. To assess the feasibility of this approach, we evaluated the publicly available chemical, preclinical, and clinical therapeutic data, and we addressed some potential limitations while integrating the data.

Investigation of the Metal Pollution Sources in Lake Mogan, Ankara, Turkey.

It is important to investigate the monthly level of trace metals in freshwater systems to assess environmental health. This information can be used to support effective management and control of natural areas in regard to the introduction and bioavailability of chemicals in the aquatic environment. We aimed to determine monthly changes in the levels of aluminum (Al), arsenic (As), cadmium (Cd), chromium (Cr), copper (Cu), iron (Fe), lead (Pb), mercury (Hg), zinc (Zn), nickel (Ni), and selenium (Se) in water, sediment, and fish samples from Lake Mogan.

The TICking clock of EGFR therapy resistance in glioblastoma: Target Independence or target Compensation.

Targeted therapy against driver mutations responsible for cancer progression has been shown to be effective in many tumor types. For glioblastoma (GBM), the epidermal growth factor receptor (EGFR) gene is the most frequently mutated oncogenic driver and has therefore been considered an attractive target for therapy. However, so far responses to EGFR-pathway inhibitors have been disappointing.

Radiosensitivity Is an Acquired Vulnerability of PARPi-Resistant BRCA1-Deficient Tumors.

The defect in homologous recombination (HR) found in BRCA1-associated cancers can be therapeutically exploited by treatment with DNA-damaging agents and PARP inhibitors. We and others previously reported that BRCA1-deficient tumors are initially hypersensitive to the inhibition of topoisomerase I/II and PARP, but acquire drug resistance through restoration of HR activity by the loss of end-resection antagonists of the 53BP1/RIF1/REV7/Shieldin/CST pathway. Here, we identify radiotherapy as an acquired vulnerability of 53BP1;BRCA1-deficient cells and .

WINDOW consortium: A path towards increased therapy efficacy against glioblastoma.

Glioblastoma is the most common and malignant form of brain cancer, for which the standard treatment is maximal surgical resection, radiotherapy and chemotherapy. Despite these interventions, mean overall survival remains less than 15 months, during which extensive tumor infiltration throughout the brain occurs. The resulting metastasized cells in the brain are characterized by chemotherapy resistance and extensive intratumoral heterogeneity.

Loss of p53 suppresses replication-stress-induced DNA breakage in G1/S checkpoint deficient cells.

In cancer cells, loss of G1/S control is often accompanied by p53 pathway inactivation, the latter usually rationalized as a necessity for suppressing cell cycle arrest and apoptosis. However, we found an unanticipated effect of p53 loss in mouse and human G1-checkpoint-deficient cells: reduction of DNA damage. We show that abrogation of the G1/S-checkpoint allowed cells to enter S-phase under growth-restricting conditions at the expense of severe replication stress manifesting as decelerated DNA replication, reduced origin firing and accumulation of DNA double-strand breaks.

Subunit composition of VRAC channels determines substrate specificity and cellular resistance to Pt-based anti-cancer drugs.

Although platinum-based drugs are widely used chemotherapeutics for cancer treatment, the determinants of tumor cell responsiveness remain poorly understood. We show that the loss of subunits LRRC8A and LRRC8D of the heteromeric LRRC8 volume-regulated anion channels (VRACs) increased resistance to clinically relevant cisplatin/carboplatin concentrations. Under isotonic conditions, about 50% of cisplatin uptake depended on LRRC8A and LRRC8D, but neither on LRRC8C nor on LRRC8E.

ABCC6 prevents ectopic mineralization seen in pseudoxanthoma elasticum by inducing cellular nucleotide release.

Pseudoxanthoma elasticum (PXE) is an autosomal recessive disease characterized by progressive ectopic mineralization of the skin, eyes, and arteries, for which no effective treatment exists. PXE is caused by inactivating mutations in the gene encoding ATP-binding cassette sub-family C member 6 (ABCC6), an ATP-dependent efflux transporter present mainly in the liver. Abcc6(-/-) mice have been instrumental in demonstrating that PXE is a metabolic disease caused by the absence of an unknown factor in the circulation, the presence of which depends on ABCC6 in the liver.