Cereblon-based Bifunctional Degrader of SOS1, BTX-6654, Targets Multiple KRAS Mutations and Inhibits Tumor Growth.

Mutations within the oncogene KRAS drive an estimated 25% of all cancers. Only allele-specific KRAS G12C inhibitors are currently available and are associated with the emergence of acquired resistance, partly due to upstream pathway reactivation. Given its upstream role in the activation of KRAS, son of sevenless homolog 1 (SOS1), has emerged as an attractive therapeutic target. Agents that target SOS1 for degradation could represent a potential pan-KRAS modality that may be capable of circumventing certain acquired resistance mechanisms. Here, we report the development of two SOS1 cereblon-based bifunctional degraders, BTX-6654 and BTX-7312, cereblon-based bifunctional SOS1 degraders. Both compounds exhibited potent target-dependent and -specific SOS1 degradation. BTX-6654 and BTX-7312 reduced downstream signaling markers, pERK and pS6, and displayed antiproliferative activity in cells harboring various KRAS mutations. In two KRAS G12C xenograft models, BTX-6654 degraded SOS1 in a dose-dependent manner correlating with tumor growth inhibition, additionally exhibiting synergy with KRAS and MEK inhibitors. Altogether, BTX-6654 provided preclinical proof of concept for single-agent and combination use of bifunctional SOS1 degraders in KRAS-driven cancers.

Hemoglobin A1c as a Predictor of Surgical Site Infection in Patients With Orthopaedic Trauma.

INTRODUCTION: Previous research involving diabetes mellitus (DM), glycemic control, and complications in orthopaedic patients has primarily focused on elective procedures. The purpose of this study was to evaluate hemoglobin A1c (A1c) as a predictor of postoperative surgical site infection (SSI) in patients with orthopaedic trauma. METHODS: Patients aged 18 years or older treated surgically for an acute fracture by a fellowship-trained orthopaedic trauma surgeon at a single academic tertiary referral center with a laboratory value for A1c available within 3 months of their surgery were identified retrospectively. Postoperative SSI was defined according to 'Fracture related infection: A consensus on definition from an international expert group,' by Metsemakers et al. RESULTS: A total of 925 patients met criteria for analysis. A receiver operating characteristic curve was calculated using A1c as a predictor for signs suggestive and confirmatory of SSI and demonstrated an area under the curve of 0.535 and 0.539, respectively. No significant difference was found in the rate of signs suggestive or confirmatory of SSI in patients with normal A1c levels (<6.5) compared with patients with A1c levels consistent with a diagnosis of DM (>6.5), P-value = 0.199 and P-value = 0.297, respectively. No significant difference was found in the rate of signs suggestive or confirmatory of SSI in patients with completely uncontrolled DM (A1c > 10) compared with patients with A1c levels <10, P-value 0.528 and P-value = 0.552, respectively. CONCLUSION: Existing literature has demonstrated an association with postoperative infection in orthopaedic patients who have elevated A1c values. In this cohort of patients with orthopaedic trauma, hemoglobin A1c was not a valuable tool to predict postoperative SSI. Given these findings, routine A1c monitoring is not a reliable predictor of SSI criteria in patients with orthopaedic trauma based on the current consensus definition of SSI in fracture surgery.

Counter-stereotypical messaging and partisan cues: Moving the needle on vaccines in a polarized United States.

This paper reports results from a large-scale randomized controlled trial assessing whether counter-stereotypical messaging and partisan cues can induce people to get COVID-19 vaccines. The study used a 27-s video compilation of Donald Trump's comments about the vaccine from Fox News interviews and presented the video to millions of U.S. YouTube users through a $100,000 advertising campaign in October 2021. Results indicate that the number of vaccines increased in the average treated county by 103 (with a one-tailed P value of 0.097). Based on this average treatment effect and totaling across our 1014 treated counties, the total estimated effect was 104,036 vaccines.

A Recipe for Madness: Parenthood in the Era of Covid-19.

Objectives: This article seeks to understand the economic, mental health, and political impacts on American parents in the era of Covid-19. Methods: We draw on survey data from a diverse national sample collected in September 2020 and employ multivariate analysis to explore how Covid-19 has uniquely affected the attitudes and life experiences of American parents. Results: We find that Covid-19 has been unusually burdensome for parents as they are more likely to have experienced negative physical and mental health outcomes and suffer more negative financial impacts. Despite the challenges parents face, they also remain cautious about in-person school and vaccinations. Although mothers have been the focus of much news coverage, we find that both mothers and fathers have been similarly and negatively impacted by Covid-19. Conclusion: American parents are suffering at distinctively high levels during this pandemic. In order to recover, policymakers will need to target outreach and support tailored to the needs and issues facing parents.

P2Y2 Nucleotide Receptor Prompts Human Cardiac Progenitor Cell Activation by Modulating Hippo Signaling.

RATIONALE: Autologous stem cell therapy using human c-Kit+ cardiac progenitor cells (hCPCs) is a promising therapeutic approach for treatment of heart failure (HF). However, hCPCs derived from aged patients with HF with genetic predispositions and comorbidities of chronic diseases exhibit poor proliferative and migratory capabilities, which impair overall reparative potential for injured myocardium. Therefore, empowering functionally compromised hCPCs with proregenerative molecules ex vivo is crucial for improving the therapeutic outcome in patients with HF. OBJECTIVE: To improve hCPC proliferation and migration responses that are critical for regeneration by targeting proregenerative P2Y2 nucleotide receptor (P2Y2R) activated by extracellular ATP and UTP molecules released following injury/stress. METHODS AND RESULTS: c-Kit+ hCPCs were isolated from cardiac tissue of patients with HF undergoing left ventricular assist device implantation surgery. Correlations between P2 nucleotide receptor expression and hCPC growth kinetics revealed downregulation of select P2 receptors, including P2Y2R, in slow-growing hCPCs compared with fast growers. hCPC proliferation and migration significantly improved by overexpressing or stimulating P2Y2R. Mechanistically, P2Y2R-induced proliferation and migration were dependent on activation of YAP (yes-associated protein)-the downstream effector of Hippo signaling pathway. CONCLUSIONS: Proliferation and migration of functionally impaired hCPCs are enhanced by P2Y2R-mediated YAP activation, revealing a novel link between extracellular nucleotides released during injury/stress and Hippo signaling-a central regulator of cardiac regeneration. Functional correlations exist between hCPC phenotypic properties and P2 purinergic receptor expression. Lack of P2Y2R and other crucial purinergic stress detectors could compromise hCPC responsiveness to presence of extracellular stress signals. These findings set the stage for subsequent studies to assess purinergic signaling modulation as a potential strategy to improve therapeutic outcome for use of hCPCs in patients with HF.

Cosmic ray radiography of the damaged cores of the Fukushima reactors.

The passage of muons through matter is dominated by the Coulomb interaction with electrons and nuclei. The interaction with the electrons leads to continuous energy loss and stopping of the muons. The interaction with nuclei leads to angle "diffusion." Two muon-imaging methods that use flux attenuation and multiple Coulomb scattering of cosmic-ray muons are being studied as tools for diagnosing the damaged cores of the Fukushima reactors. Here, we compare these two methods. We conclude that the scattering method can provide detailed information about the core. Attenuation has low contrast and little sensitivity to the core.

Insulin injection regimens and metabolic control in an international survey of adolescents with type 1 diabetes over 3 years: results from the Hvidore study group.

UNLABELLED: The optimal insulin regimen for paediatric patients with type 1 diabetes remains controversial. Therefore this multicentre study was performed in adolescents over a 3-year period to assess metabolic control, severe hypoglycaemia, and weight gain in relation to insulin injection regimens. Out of 2873 children and adolescents in an international survey in 1995, 872 adolescents (433 boys, 439 girls, mean age in 1995 11.3+/-2.2 years) were restudied in 1998, relating insulin regimens to HbA(1c) measured in a central laboratory. In addition, the daily dose of insulin, changes in body mass index (BMI), and events of severe hypoglycaemia were evaluated. Over 3 years, the use of multiple injection regimens increased from 42% to 71%: 251 patients remained on twice daily insulin, 365 remained on multiple injections and 256 shifted from twice daily insulin to multiple injections. In all three subgroups an increase in insulin dose, a deterioration of metabolic control, and an increase in BMI were observed. Metabolic control deteriorated less than expected over 3 years during adolescence (HbA(1c) 1995: 8.7+/-1.6%; 1998 observed: 8.9+/-1.6%, HbA(1c) expected for 1998: 9.0%). BMI increased more than expected, the increase was greatest in patients switching from twice daily to multiple injections, and higher in females compared to males. CONCLUSION: in this international study, metabolic control was unsatisfactory in many adolescents with type 1 diabetes irrespective of the insulin regimen. No improvement in metabolic control was observed in this cross-sectional survey, over 3 years in any of the subgroups. Even the group switching from twice to multiple injections did not improve blood glucose control and the increase in body mass index was most pronounced in this group. Conclusive evidence, however, should be based on prospectively planned, randomised therapeutic trials in paediatric patients.