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Fusions between protein-coding genes are common oncogenic drivers across cancers, typically pairing a proto-oncogene with partner that does not independently drive cancer. In all therapeutically actionable fusions, the proto-oncogene is the drug target, the contributions to oncogenicity of the fusion partner have largely been ignored. We studied the role of BRAF fusion partners and found that they are necessary for transformation. In the setting of KIAA1549::BRAF, the most common fusion protein across brain tumors, we found that KIAA1549 is necessary for the oncogenicity of KIAA1549::BRAF and engenders a striking and specific dependency on the protein O-mannosyltransferase complex (POMT1/2). Specifically, we show that genetic silencing or pharmacologic inhibition of the protein O-mannosyltransferase complex (POMT1/2) reverses fusion-induced transformation, thereby representing a novel and MAPK independent therapeutic target. Furthermore, POMT1/2 is required to glycosylate and enable maturation of the K::B fusion protein. These findings represent a proof-of-concept for targeting the partners in oncogenic fusions as a potential cancer therapeutic strategy.

Studies of acute kidney injury usually lack data on pre-admission kidney function and often substitute an inpatient or imputed serum creatinine as an estimate for baseline renal function. In this study, we compared the potential error introduced by using surrogates such as (1) an estimated glomerular filtration rate of 75 ml/min per 1.73 m2 (suggested by the Acute Dialysis Quality Initiative), (2) a minimum inpatient serum creatinine value, and (3) the first admission serum creatinine value, with values computed using pre-admission renal function. The study covered a 12-month period and included a cohort of 4863 adults admitted to the Vanderbilt University Hospital. Use of both imputed and minimum baseline serum creatinine values significantly inflated the incidence of acute kidney injury by about half, producing low specificities of 77–80%. In contrast, use of the admission serum creatinine value as baseline significantly underestimated the incidence by about a third, yielding a low sensitivity of 39%. Application of any surrogate marker led to frequent misclassification of patient deaths after acute kidney injury and differences in both in-hospital and 60-day mortality rates. Our study found that commonly used surrogates for baseline serum creatinine result in bi-directional misclassification of the incidence and prognosis of acute kidney injury in a hospital setting.

Immunotherapies that produce durable responses in some malignancies have failed in pancreatic ductal adenocarcinoma (PDAC) due to rampant immune suppression and poor tumor immunogenicity. We and others have demonstrated that induction of the senescence-associated secretory phenotype (SASP) can be an effective approach to activate anti-tumor natural killer (NK) cell and T cell immunity. In the present study, we found that the pancreas tumor microenvironment suppresses NK cell and T cell surveillance after therapy-induced senescence through enhancer of zeste homolog 2 (EZH2)-mediated epigenetic repression of proinflammatory SASP genes. EZH2 blockade stimulated production of SASP chemokines CCL2 and CXCL9/10, leading to enhanced NK cell and T cell infiltration and PDAC eradication in mouse models. EZH2 activity was also associated with suppression of chemokine signaling and cytotoxic lymphocytes and reduced survival in patients with PDAC. These results demonstrate that EZH2 represses the proinflammatory SASP and that EZH2 inhibition combined with senescence-inducing therapy could be a powerful means to achieve immune-mediated tumor control in PDAC.

(R,S)-ketamine (ketamine) and its enantiomer (S)-ketamine (esketamine) can produce rapid and substantial antidepressant effects. However, individual response to ketamine/esketamine is variable, and there are no well-accepted methods to differentiate persons who are more likely to benefit. Numerous potential peripheral biomarkers have been reported, but their current utility is unclear. We conducted a systematic review/meta-analysis examining the association between baseline levels and longitudinal changes in blood-based biomarkers, and response to ketamine/esketamine. Of the 5611 citations identified, 56 manuscripts were included (N = 2801 participants), and 26 were compatible with meta-analytical calculations. Random-effect models were used, and effect sizes were reported as standardized mean differences (SMD). Our assessments revealed that more than 460 individual biomarkers were examined. Frequently studied groups included neurotrophic factors (n = 15), levels of ketamine and ketamine metabolites (n = 13), and inflammatory markers (n = 12). There were no consistent associations between baseline levels of blood-based biomarkers, and response to ketamine. However, in a longitudinal analysis, ketamine responders had statistically significant increases in brain-derived neurotrophic factor (BDNF) when compared to pre-treatment levels (SMD [95% CI] = 0.26 [0.03, 0.48], p = 0.02), whereas non-responders showed no significant changes in BDNF levels (SMD [95% CI] = 0.05 [−0.19, 0.28], p = 0.70). There was no consistent evidence to support any additional longitudinal biomarkers. Findings were inconclusive for esketamine due to the small number of studies (n = 2). Despite a diverse and substantial literature, there is limited evidence that blood-based biomarkers are associated with response to ketamine, and no current evidence of clinical utility.

We examined key influences on STEM college seniors’ postgraduate plans. Using data from the National Longitudinal Study of Freshmen we utilized multilevel modeling to identify variables associated with planning to pursue a STEM-related job or STEM graduate study after graduation. Key findings emphasize the importance of volunteering and extracurricular activities for women, as well as lower-income and underrepresented racially minoritized students, as well as the relevance of interaction with faculty. Findings also suggest that a certain amount of “opportunity hoarding” exists among majority-status students. We conclude with implications for creating more welcoming, inclusive, and diverse STEM environments.

Phenytoin is the recommended second-line intravenous anticonvulsant for treatment of paediatric convulsive status epilepticus in the UK; however, some evidence suggests that levetiracetam could be an effective and safer alternative. This trial compared the efficacy and safety of phenytoin and levetiracetam for second-line management of paediatric convulsive status epilepticus. This open-label, randomised clinical trial was undertaken at 30 UK emergency departments at secondary and tertiary care centres. Participants aged 6 months to under 18 years, with convulsive status epilepticus requiring second-line treatment, were randomly assigned (1:1) using a computer-generated randomisation schedule to receive levetiracetam (40 mg/kg over 5 min) or phenytoin (20 mg/kg over at least 20 min), stratified by centre. The primary outcome was time from randomisation to cessation of convulsive status epilepticus, analysed in the modified intention-to-treat population (excluding those who did not require second-line treatment after randomisation and those who did not provide consent). This trial is registered with ISRCTN, number ISRCTN22567894. Between July 17, 2015, and April 7, 2018, 1432 patients were assessed for eligibility. After exclusion of ineligible patients, 404 patients were randomly assigned. After exclusion of those who did not require second-line treatment and those who did not consent, 286 randomised participants were treated and had available data: 152 allocated to levetiracetam, and 134 to phenytoin. Convulsive status epilepticus was terminated in 106 (70%) children in the levetiracetam group and in 86 (64%) in the phenytoin group. Median time from randomisation to cessation of convulsive status epilepticus was 35 min (IQR 20 to not assessable) in the levetiracetam group and 45 min (24 to not assessable) in the phenytoin group (hazard ratio 1·20, 95% CI 0·91–1·60; p=0·20). One participant who received levetiracetam followed by phenytoin died as a result of catastrophic cerebral oedema unrelated to either treatment. One participant who received phenytoin had serious adverse reactions related to study treatment (hypotension considered to be immediately life-threatening [a serious adverse reaction] and increased focal seizures and decreased consciousness considered to be medically significant [a suspected unexpected serious adverse reaction]). Although levetiracetam was not significantly superior to phenytoin, the results, together with previously reported safety profiles and comparative ease of administration of levetiracetam, suggest it could be an appropriate alternative to phenytoin as the first-choice, second-line anticonvulsant in the treatment of paediatric convulsive status epilepticus. National Institute for Health Research Health Technology Assessment programme.

Germline mutations in BRCA1/2 predispose individuals to breast cancer (termed germline-mutated BRCA1/2 breast cancer, gBRCA-BC) by impairing homologous recombination (HR) and causing genomic instability. HR also repairs DNA lesions caused by platinum agents and PARP inhibitors. Triple-negative breast cancers (TNBCs) harbor subpopulations with BRCA1/2 mutations, hypothesized to be especially platinum-sensitive. Cancers in putative ‘BRCAness’ subgroups—tumors with BRCA1 methylation; low levels of BRCA1 mRNA ( BRCA1 mRNA-low); or mutational signatures for HR deficiency and those with basal phenotypes—may also be sensitive to platinum. We assessed the efficacy of carboplatin and another mechanistically distinct therapy, docetaxel, in a phase 3 trial in subjects with unselected advanced TNBC. A prespecified protocol enabled biomarker–treatment interaction analyses in gBRCA-BC and BRCAness subgroups. The primary endpoint was objective response rate (ORR). In the unselected population (376 subjects; 188 carboplatin, 188 docetaxel), carboplatin was not more active than docetaxel (ORR, 31.4% versus 34.0%, respectively; P  = 0.66). In contrast, in subjects with gBRCA-BC, carboplatin had double the ORR of docetaxel (68% versus 33%, respectively; biomarker, treatment interaction  P  = 0.01). Such benefit was not observed for subjects with BRCA1 methylation, BRCA1 mRNA-low tumors or a high score in a Myriad HRD assay. Significant interaction between treatment and the basal-like subtype was driven by high docetaxel response in the nonbasal subgroup. We conclude that patients with advanced TNBC benefit from characterization of BRCA1/2 mutations, but not BRCA1 methylation or Myriad HRD analyses, to inform choices on platinum-based chemotherapy. Additionally, gene expression analysis of basal-like cancers may also influence treatment selection. The phase 3 TNT Trial in subjects with triple-negative breast cancer supports the superiority of carboplatin over docetaxel in BRCA1/2 -mutated tumors and a greater response to taxanes in the nonbasal subtype.

Background There has been a lack of updated epidemiological data on the incidence and survival outcomes for patients with small cell lung cancer (SCLC) in the United States over the last two decades. Methods A retrospective, population‐based study was conducted utilizing the Surveillance, Epidemiology, and End Results (SEER) program to identify patients with SCLC from 2000 to 2020. Trends in cancer incidence, incidence‐based mortality rates, 1‐year relative survival rates and 1‐year observed survival were evaluated utilizing the SEER database. Results The database identified a total of 188,426 SCLC patients during the study period from 2000 through 2020. The age‐adjusted incidence rate slowly declined, on average, by 3% (95% CI: −3.2% to −2.8%) each year from 9 per 100,000 in 2000 to 4.6 per 100,000 in 2020. The decline is evident for all age groups, sexes, and races. Incidence‐based mortality also declined slowly from 6.6 in 2005 to 3.5 in 2020. However, survival outcomes, including 1‐year relative survival and 1‐year observed survivals, have not improved significantly over the last two decades. Conclusion This study found that the incidence of SCLC has decreased from 2000 to 2020, likely due to a reduction in smoking rates, underscoring the importance of smoking abstinence. An improvement in incidence‐based mortality is likely related to an enhanced medical care and a decrease in the incidence of SCLC, but the lack of improvement in survival outcomes reflects the need for more effective systemic therapy.

While numerous studies have highlighted the consequences of exclusion in STEM, fewer studies have empirically tested the benefits of inclusion in peer relationships. We focus on the impact of having cross-racial or cross-gender study partners among one’s close friends in a national sample of 408 STEM majors. Using structural equation modeling, we examined the direct and indirect relationships between having diverse study partners, key background and college experience variables, and college GPA. We identified a significant positive relationship, both direct and indirect, between studying with a close friend of a different race and GPA. We also found that having a cross-gender study partner is positively linked to organizing study groups and study-faculty interaction, which in turn improves GPA. However, Black students were less likely to have either cross-racial or cross-gender study partners among their close friends. We discuss implications for equity and the need to encourage positive intergroup relations in STEM.