Ulriksenchambers9438

DNA mismatch repair (MMR) proteins are essential for the recognition and correction of sporadic genetic mutations that occur during DNA replication. Deficient MMR function (dMMR) leads to an increased risk of development of neoplasia. Identification of dMMR within tumours can suggest a high chance of the inherited cancer condition Lynch syndrome and predicts poor clinical response to certain conventional chemotherapies but an increased likelihood of response to immunotherapy. This review provides an update on the biology of MMR proteins, their encoding genes and mechanisms for the development of dMMR. This is followed by a discussion of the identification and significance of dMMR in routine clinical practice.Containment of the COVID-19 pandemic requires reducing viral transmission. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is initiated by membrane fusion between the viral and host cell membranes, which is mediated by the viral spike protein. We have designed lipopeptide fusion inhibitors that block this critical first step of infection and, on the basis of in vitro efficacy and in vivo biodistribution, selected a dimeric form for evaluation in an animal model. Epigallocatechin Daily intranasal administration to ferrets completely prevented SARS-CoV-2 direct-contact transmission during 24-hour cohousing with infected animals, under stringent conditions that resulted in infection of 100% of untreated animals. These lipopeptides are highly stable and thus may readily translate into safe and effective intranasal prophylaxis to reduce transmission of SARS-CoV-2.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive disease with a poor cure rate for relapsed/resistant patients. Due to the lack of T-cell restricted targetable antigens, effective immune-therapeutics are not presently available and the treatment of chemo-refractory T-ALL is still an unmet clinical need. To develop novel immune-therapy for T-ALL, we generated an afucosylated monoclonal antibody (mAb) (ahuUMG1) and two different bispecific T-cell engagers (BTCEs) against UMG1, a unique CD43-epitope highly and selectively expressed by T-ALL cells from pediatric and adult patients.

UMG1 expression was assessed by immunohistochemistry (IHC) on a wide panel of normal tissue microarrays (TMAs), and by flow cytometry on healthy peripheral blood/bone marrow-derived cells, on 10 different T-ALL cell lines, and on 110 T-ALL primary patient-derived cells. CD43-UMG1 binding site was defined through a peptide microarray scanning. ahuUMG1 was generated by Genetic Glyco-Engineering technology from a novel humeffect was specifically exerted by engaged activated T cells. Moreover, UMG1-BTCEs effectively antagonized tumor growth at concentrations >2 log lower as compared with ahuUMG1, with significant mice survival advantage in different T-ALL models in vivo.

Altogether our findings, including the safe UMG1-epitope expression profile, provide a framework for the clinical development of these innovative immune-therapeutics for this still orphan disease.

Altogether our findings, including the safe UMG1-epitope expression profile, provide a framework for the clinical development of these innovative immune-therapeutics for this still orphan disease.

Little is known regarding the efficacy of immune checkpoint inhibitors (ICI) in patients with advanced large-cell neuroendocrine lung carcinoma (aLCNEC).

125 consecutive patients with aLCNEC were identified in the electronic databases of 4 participating cancer centers. The patients were divided into group A (patients who received ICI, n=41) and group B (patients who did not receive ICI, n=84). Overall survival since advanced disease diagnosis (OS DX) and OS since ICI initiation (OS ICI) were captured.

With a median follow-up of 11.8 months (mo) (IQR 7.5-17.9) and 6.0mo (IQR 3.1-10.9), 66% and 76% of patients died in groups A and B, respectively. Median OS DX was 12.4mo (95% CI 10.7 to 23.4) and 6.0mo (95% CI 4.7 to 9.4) in groups A and B, respectively (log-rank test, p=0.02). For ICI administration, HR for OS DX was 0.59 (95% CI 0.38 to 0.93, p=0.02-unadjusted), and 0.58 (95% CI 0.34 to 0.98, p=0.04-adjusted for age, Eastern Cooperative Oncology Group (ECOG) performance status (PS), presence of liver metastases and chemotherapy administration). In a propensity score matching analysis (n=74; 37 patients in each group matched for age and ECOG PS), median OS DX was 12.5 mo (95% CI 10.6 to 25.2) and 8.4 mo (95% CI 5.4 to 16.9) in matched groups A and B, respectively (log-rank test, p=0.046). OS ICI for patients receiving ICI as monotherapy (n=36) was 11.0 mo (95% CI 6.1 to 19.4).

With the limitations of retrospective design and small sample size, the results of this real-world cohort analysis suggest a positive impact of ICI on OS in aLCNEC.

With the limitations of retrospective design and small sample size, the results of this real-world cohort analysis suggest a positive impact of ICI on OS in aLCNEC.

This study aimed to determine the rate of scalpel cricothyroidotomy conducted by a physician-paramedic prehospital trauma service over 20 years and to identify indications for, and factors associated with the intervention.

A retrospective observational study was conducted from 1 January 2000 to 31 December 2019 using clinical database records. This study was conducted in a physician-paramedic prehospital trauma service, serving a predominantly urban population of approximately 10 million in an area of approximately 2500 km

.

Over 20 years, 37 725 patients were attended by the service, and 72 patients received a scalpel cricothyroidotomy. An immediate 'primary' cricothyroidotomy was performed in 17 patients (23.6%), and 'rescue' cricothyroidotomies were performed in 55 patients (76.4%). Forty-one patients (56.9%) were already in traumatic cardiac arrest during cricothyroidotomy. Thirty-two patients (44.4%) died on scene, and 32 (44.4%) subsequently died in hospital. Five patients (6.9%) survived to hosph trauma receiving this procedure was 88.9% in our service.

This study identifies a number of indications leading to scalpel cricothyroidotomy both as a primary procedure or after failed intubation. The main indication for scalpel cricothyroidotomy in our service was as a rescue airway for failed laryngoscopy due to a large volume of blood in the airway. Despite high levels of procedural success, 56.9% of patients were already in traumatic cardiac arrest during cricothyroidotomy, and overall mortality in patients with trauma receiving this procedure was 88.9% in our service.