PSCA-targeted BPX-601 CAR T cells with pharmacological activation by rimiducid in metastatic pancreatic and prostate cancer: a phase 1 dose escalation trial.

Here we report results of a phase 1 multi-institutional, open-label, dose-escalation trial (NCT02744287) of BPX-601, an investigational autologous PSCA-directed GoCAR-T® cell product containing an inducible MyD88/CD40 ON-switch responsive to the activating dimerizer rimiducid, in patients with metastatic pancreatic (mPDAC) or castration-resistant prostate cancer (mCRPC). Primary objectives were to evaluate safety and tolerability and determine the recommended phase 2 dose/schedule (RP2D). Secondary objectives included the assessment of efficacy and characterization of the pharmacokinetics of rimiducid.

Transforming Primary Care Data Into the Observational Medical Outcomes Partnership Common Data Model: Development and Usability Study.

Background: Patient-monitoring software generates a large amount of data that can be reused for clinical audits and scientific research. The Observational Health Data Sciences and Informatics (OHDSI) consortium developed the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM) to standardize electronic health record data and promote large-scale observational and longitudinal research.

Objective: This study aimed to transform primary care data into the OMOP CDM format.

Phase 1 dose-escalation study of SEA-CD40: a non-fucosylated CD40 agonist, in advanced solid tumors and lymphomas.

Background: SEA-CD40 is an investigational, non-fucosylated, humanized monoclonal IgG antibody that activates CD40, an immune-activating tumor necrosis factor receptor superfamily member. SEA-CD40 exhibits enhanced binding to activating FcγRIIIa, possibly enabling greater immune stimulation than other CD40 agonists. A first-in-human phase 1 trial was conducted to examine safety, pharmacokinetics, and pharmacodynamics of SEA-CD40 monotherapy in patients with advanced solid tumors and lymphoma.

DGCR8 Mediates Repair of UV-Induced DNA Damage Independently of RNA Processing.

Ultraviolet (UV) radiation is a carcinogen that generates DNA lesions. Here, we demonstrate an unexpected role for DGCR8, an RNA binding protein that canonically functions with Drosha to mediate microRNA processing, in the repair of UV-induced DNA lesions. Treatment with UV induced phosphorylation on serine 153 (S153) of DGCR8 in both human and murine cells.

NEK8 regulates DNA damage-induced RAD51 foci formation and replication fork protection.

Proteins essential for homologous recombination play a pivotal role in the repair of DNA double strand breaks, DNA inter-strand crosslinks and replication fork stability. Defects in homologous recombination also play a critical role in the development of cancer and the sensitivity of these cancers to chemotherapy. RAD51, an essential factor for homologous recombination and replication fork protection, accumulates and forms immunocytochemically detectable nuclear foci at sites of DNA damage.

The Development of Object Function and Manipulation Knowledge: Evidence from a Semantic Priming Study.

Object semantics include object function and manipulation knowledge. Function knowledge refers to the goal attainable by using an object (e.g.

Investigation of PD-L1 Biomarker Testing Methods for PD-1 Axis Inhibition in Non-squamous Non-small Cell Lung Cancer.

Inhibitors of the programmed cell death 1 (PD-1) signaling axis have recently demonstrated efficacy and are rapidly being incorporated into the treatment of non-small cell lung cancers (NSCLCs). Despite clear benefits to certain patients, the association of these responses with a predictive biomarker remains uncertain. Several different biomarkers have been proposed, with differing results and conclusions.

FANCI Regulates Recruitment of the FA Core Complex at Sites of DNA Damage Independently of FANCD2.

The Fanconi anemia (FA)-BRCA pathway mediates repair of DNA interstrand crosslinks. The FA core complex, a multi-subunit ubiquitin ligase, participates in the detection of DNA lesions and monoubiquitinates two downstream FA proteins, FANCD2 and FANCI (or the ID complex). However, the regulation of the FA core complex itself is poorly understood.

Non-specific chemical inhibition of the Fanconi anemia pathway sensitizes cancer cells to cisplatin.

Background: Platinum compounds such as cisplatin and carboplatin are DNA crosslinking agents widely used for cancer chemotherapy. However, the effectiveness of platinum compounds is often tempered by the acquisition of cellular drug resistance. Until now, no pharmacological approach has successfully overcome cisplatin resistance in cancer treatment.

Functional restoration of BRCA2 protein by secondary BRCA2 mutations in BRCA2-mutated ovarian carcinoma.

Acquired platinum resistance is a serious problem in the treatment of ovarian carcinomas. However, the mechanism of the drug resistance has not been elucidated. Here, we show functional significance of restoration of BRCA2 protein by secondary BRCA2 mutations in acquired drug resistance of BRCA2-mutated ovarian carcinoma.

Secondary mutations as a mechanism of cisplatin resistance in BRCA2-mutated cancers.

Ovarian carcinomas with mutations in the tumour suppressor BRCA2 are particularly sensitive to platinum compounds. However, such carcinomas ultimately develop cisplatin resistance. The mechanism of that resistance is largely unknown.

The Fanconi anemia pathway and ubiquitin.

Fanconi anemia (FA) is a rare genetic disorder characterized by aplastic anemia, cancer/leukemia susceptibility and cellular hypersensitivity to DNA crosslinking agents, such as cisplatin. To date, 12 FA gene products have been identified, which cooperate in a common DNA damage-activated signaling pathway regulating DNA repair (the FA pathway). Eight FA proteins form a nuclear complex harboring E3 ubiquitin ligase activity (the FA core complex) that, in response to DNA damage, mediates the monoubiquitylation of the FA protein FANCD2.

Proteasome function is required for DNA damage response and fanconi anemia pathway activation.

Proteasome inhibitors sensitize tumor cells to DNA-damaging agents, including ionizing radiation (IR), and DNA cross-linking agents (melphalan and cisplatin) through unknown mechanisms. The Fanconi anemia pathway is a DNA damage-activated signaling pathway, which regulates cellular resistance to DNA cross-linking agents. Monoubiquitination and nuclear foci formation of FANCD2 are critical steps of the Fanconi anemia pathway.

A new model of pre-B acute lymphoblastic leukemia chemically induced in rats.

Objective: Although B acute lymphoblastic leukemia (B-ALL) is the most common leukemia among children, no chemically inducible model of this leukemia has yet been described in vivo.

Methods: Leukemia was chemically induced in male WKAH/Hkm rats by a nitrosourea derivative, N-butylnitrosourea (BNU), an alkylating agent, administered orally 5 days a week for 24 weeks. Development of leukemia was monitored by clinical observation, follow-up of blood parameters, and appearance of blast cells in peripheral blood samples.

A single mutated BRCA1 allele leads to impaired fidelity of double strand break end-joining.

Heterozygosity for mutations in the BRCA1 gene in humans confers high risk for developing breast cancer, but a biochemical basis for this phenotype has not yet been determined. Evidence has accumulated implicating BRCA1, in the maintenance of genomic integrity and the protection of cells against DNA double strand breaks (DSB). Here we present evidence that human cells heterozygous for BRCA1 mutations exhibit impaired DNA end-joining, which is the major DSB repair pathway in mammalian somatic cells.

Can 50 Hz magnetic fields alter iron metabolism and induce anaemia?

Unlabelled: PURPOSE. Some changes in tissue iron concentration have been reported in animals exposed to electromagnetic fields. In other studies, variations in the haemoglobin level were occasionally observed.