The evaluation of treat and release attitudes of pre-hospital emergency healthcare professionals in case of hypoglycemia.

AIM: It is aimed to evaluate the knowledge of Pre-Hospital Emergency Health Services (PHEMS) staff about the treat and release criteria in hypoglycemia cases and their attitudes in the decision-making processes related to hospitalization. MATERIALS AND METHODS: The sample of this descriptive cross-sectional study consisted of 714 paramedics working in PHEMS in Turkey. A survey developed in Microsoft Forms, which includes various features such as age, gender, years of professional experience, developed in line with the literature, and questions covering treat and release in hypoglycemia cases and absolute hospital transport criteria, was used in the collection of data. Participants who agreed to participate in the study answered the online survey. FINDINGS: Of the 714 participants, 402 (56.30%) were female and 312 (43.70%) were male. 598 (83.75%) of the participants, who had a dilemma regarding the transfer of hypoglycemia cases that became stable after treatment to the hospital, decide to transfer the patient to the emergency room. 706 (98.88%) reported that the presence of another emergency that needs intervention in addition to hypoglycemia was decisive in the decision to transfer to the absolute hospital, and 586 (82.07%) reported that the patient's who did not return to his normal mental state after emergency medical intervention was decisive in the treatment and release decision. CONCLUSION: PHEMS employees have high knowledge and awareness related to treat and release criteria in hypoglycemia cases with which they have high experience. PHEMS employee, who has a dilemma related to making a treat and release decision, decides to transfer to the hospital with a high rate. PHEMS systems should define the treat and release protocols for hypoglycemia cases more clearly in order to use emergency services and health resources effectively.

A first-in-class Polymerase Theta Inhibitor selectively targets Homologous-Recombination-Deficient Tumors.

DNA polymerase theta (POLθ) is synthetic lethal with Homologous Recombination (HR) deficiency and thus a candidate target for HR-deficient cancers. Through high-throughput small molecule screens we identified the antibiotic Novobiocin (NVB) as a specific POLθ inhibitor that selectively kills HR-deficient tumor cells in vitro and in vivo. NVB directly binds to the POLθ ATPase domain, inhibits its ATPase activity, and phenocopies POLθ depletion. NVB kills HR-deficient breast and ovarian tumors in GEMM, xenograft and PDX models. Increased POLθ levels predict NVB sensitivity, and BRCA-deficient tumor cells with acquired resistance to PARP inhibitors (PARPi) are sensitive to NVB in vitro and in vivo. Mechanistically, NVB-mediated cell death in PARPi-resistant cells arises from increased double-strand break end resection, leading to accumulation of single-strand DNA intermediates and non-functional RAD51 foci. Our results demonstrate that NVB may be useful alone or in combination with PARPi in treating HR-deficient tumors, including those with acquired PARPi resistance. (151/150).

Correction: Neoadjuvant olaparib targets hypoxia to improve radioresponse in a homologous recombination-proficient breast cancer model.

[This corrects the article DOI: 10.18632/oncotarget.20936.].

Neoadjuvant olaparib targets hypoxia to improve radioresponse in a homologous recombination-proficient breast cancer model.

Clinical trials are studying the benefits of combining the PARP-1 inhibitor olaparib with chemotherapy and radiotherapy treatment in a variety of cancer increasing the therapeutic ratio for olaparib may come from its ability to modify the tumour microenvironment by targeting homologous recombination-deficient, hypoxic tumour clonogens, and/or increasing tumour-associated vasodilation to improve oxygenation. Herein, we investigated the effect of prolonged neoadjuvant exposure to olaparib on the tumor microenvironment using a genetically-engineered mouse p53-/- syngeneic breast cancer model, which is proficient in homology-directed DNA repair. We observed increased in vivo growth delay and decreased ex vivo clonogenic survival following pre-treatment with olaparib 50 mg/kg bid Olaparib for 7 days ending 48 hours prior to a radiation dose of 12Gy. This increased in vivo radioresponse was associated with a decreased hypoxic fraction. This study suggests that the radiation response in patients can be improved with limited toxicity if olaparib is given in a purely neoadjuvant setting to modify the tumor microenviroment prior to the start of the radiotherapy treatment. Consequently a significant gain can be achieved in therapeutic window and clinical studies are needed to confirm this preclinical data.

EZH2 promotes degradation of stalled replication forks by recruiting MUS81 through histone H3 trimethylation.

The emergence of resistance to poly-ADP-ribose polymerase inhibitors (PARPi) poses a threat to the treatment of BRCA1 and BRCA2 (BRCA1/2)-deficient tumours. Stabilization of stalled DNA replication forks is a recently identified PARPi-resistance mechanism that promotes genomic stability in BRCA1/2-deficient cancers. Dissecting the molecular pathways controlling genomic stability at stalled forks is critical. Here we show that EZH2 localizes at stalled forks where it methylates Lys27 on histone 3 (H3K27me3), mediating recruitment of the MUS81 nuclease. Low EZH2 levels reduce H3K27 methylation, prevent MUS81 recruitment at stalled forks and cause fork stabilization. As a consequence, loss of function of the EZH2/MUS81 axis promotes PARPi resistance in BRCA2-deficient cells. Accordingly, low EZH2 or MUS81 expression levels predict chemoresistance and poor outcome in patients with BRCA2-mutated tumours. Moreover, inhibition of Ezh2 in a murine Brca2-/- breast tumour model is associated with acquired PARPi resistance. Our findings identify EZH2 as a critical regulator of genomic stability at stalled forks that couples histone modifications to nuclease recruitment. Our data identify EZH2 expression as a biomarker of BRCA2-deficient tumour response to chemotherapy.

Modeling invasive lobular breast carcinoma by CRISPR/Cas9-mediated somatic genome editing of the mammary gland.

Large-scale sequencing studies are rapidly identifying putative oncogenic mutations in human tumors. However, discrimination between passenger and driver events in tumorigenesis remains challenging and requires in vivo validation studies in reliable animal models of human cancer. In this study, we describe a novel strategy for in vivo validation of candidate tumor suppressors implicated in invasive lobular breast carcinoma (ILC), which is hallmarked by loss of the cell-cell adhesion molecule E-cadherin. We describe an approach to model ILC by intraductal injection of lentiviral vectors encoding Cre recombinase, the CRISPR/Cas9 system, or both in female mice carrying conditional alleles of the Cdh1 gene, encoding for E-cadherin. Using this approach, we were able to target ILC-initiating cells and induce specific gene disruption of Pten by CRISPR/Cas9-mediated somatic gene editing. Whereas intraductal injection of Cas9-encoding lentiviruses induced Cas9-specific immune responses and development of tumors that did not resemble ILC, lentiviral delivery of a Pten targeting single-guide RNA (sgRNA) in mice with mammary gland-specific loss of E-cadherin and expression of Cas9 efficiently induced ILC development. This versatile platform can be used for rapid in vivo testing of putative tumor suppressor genes implicated in ILC, providing new opportunities for modeling invasive lobular breast carcinoma in mice.

Prevalence of glaucoma in patients with vitiligo.

Vitiligo is an acquired idiopathic disease characterized by depigmented maculae and melanocytic destruction. We determined the prevalence of glaucoma in 49 patients who had presented to the dermatology polyclinic with vitiligo and compared that with the prevalence of glaucoma in 20 age- and sex-matched healthy controls. All patients were given an ophthalmologic examination to identify any glaucomatous changes. In the vitiligo group, 9 patients (18.4%) were found to have signs of normal-tension glaucoma (NTG), while there were no signs of NTG in the control group. This difference between the 2 groups was statistically significant (P=.04). Because glaucoma can cause permanent vision loss when left untreated, its greater prevalence among patients with vitiligo suggests that these patients should be carefully monitored.