Summary Inflammation is a recognised hallmark of cancer that substantially contributes to the development and progression of malignancies. In established cancers, there is increasing evidence for the ...roles that local immune response and systemic inflammation have in progression of tumours and survival of patients with cancer. This knowledge provides an opportunity to target these inflammatory responses to improve patient outcomes. In this Review, we examine the complex interplay between local immune responses and systemic inflammation, and their influence on clinical outcomes, and propose potential anti-inflammatory interventions for patients with cancer.
Circular RNAs (circRNAs) are a large class of transcripts in the mammalian genome. Although the translation of circRNAs was reported, additional coding circRNAs and the functions of their translated ...products remain elusive. Here, we demonstrate that an endogenous circRNA generated from a long noncoding RNA encodes regulatory peptides. Through ribosome nascent-chain complex-bound RNA sequencing (RNC-seq), we discover several peptides potentially encoded by circRNAs. We identify an 87-amino-acid peptide encoded by the circular form of the long intergenic non-protein-coding RNA p53-induced transcript (LINC-PINT) that suppresses glioblastoma cell proliferation in vitro and in vivo. This peptide directly interacts with polymerase associated factor complex (PAF1c) and inhibits the transcriptional elongation of multiple oncogenes. The expression of this peptide and its corresponding circRNA are decreased in glioblastoma compared with the levels in normal tissues. Our results establish the existence of peptides encoded by circRNAs and demonstrate their potential functions in glioblastoma tumorigenesis.
Among patients with acute myeloid leukemia, gene sequencing during remission revealed that persistent mutations in genes associated with clonal hematopoiesis did not have value for predicting relapse ...but that persistent mutations in other leukemia-associated genes had such value.
Background: Currently, children face the highest risk of death during the neonatal phase. UNICEF data shows that in 2022, globally, approximately 2.3 million children died in the first month of life, ...accounting for about 6,400 neonatal deaths per day. The aim is determining the survival proportion of neonates, hazard ratios, and maternal factors influencing the survival of low-birth-weight neonates. Methodology: A retrospective cohort study design using secondary data from 183 medical records of low-birth-weight neonates from 2020 to 2022. Kaplan-Meier analysis and life table were used to observe the time frame and survival proportion, as well as differences among independent variable groups. Cox regression analysis was conducted to estimate hazard ratios and the influence of independent variables. Results: Gestational age (p=0.028, HR=2.7948, CI 95% = 1.1197-6.9757), ANC visits (p=0.000, HR=2.7057, CI 95% = 1.6320-4.4857), and maternal employment status (p=0.023, HR=2.6546, CI 95% = 1.1430-6.1651) are statistically significant variables that influence the survival of low-birth-weight neonates. Conclusions: The survival proportion of low-birth-weight neonates is 60.80%. Gestational age, ANC visits, and maternal employment status significantly contribute to the survival of low-birth-weight neonates.
IMPORTANCE Out-of-hospital cardiac arrest is a major health problem associated with poor outcomes. Early recognition and intervention are critical for patient survival. Bystander cardiopulmonary ...resuscitation (CPR) is one factor among many associated with improved survival. OBJECTIVE To examine temporal changes in bystander resuscitation attempts and survival during a 10-year period in which several national initiatives were taken to increase rates of bystander resuscitation and improve advanced care. DESIGN, SETTING, AND PARTICIPANTS Patients with out-of-hospital cardiac arrest for which resuscitation was attempted were identified between 2001 and 2010 in the nationwide Danish Cardiac Arrest Registry. Of 29 111 patients with cardiac arrest, we excluded those with presumed noncardiac cause of arrest (n = 7390) and those with cardiac arrests witnessed by emergency medical services personnel (n = 2253), leaving a study population of 19 468 patients. MAIN OUTCOMES AND MEASURES Temporal trends in bystander CPR, bystander defibrillation, 30-day survival, and 1-year survival. RESULTS The median age of patients was 72 years; 67.4% were men. Bystander CPR increased significantly during the study period, from 21.1% (95% CI, 18.8%-23.4%) in 2001 to 44.9% (95% CI, 42.6%-47.1%) in 2010 (P < .001), whereas use of defibrillation by bystanders remained low (1.1% 95% CI, 0.6%-1.9% in 2001 to 2.2% 95% CI, 1.5%-2.9% in 2010; P = .003). More patients achieved survival on hospital arrival (7.9% 95% CI, 6.4%-9.5% in 2001 to 21.8% 95% CI, 19.8%-23.8% in 2010; P < .001). Also, 30-day survival improved (3.5% 95% CI, 2.5%-4.5% in 2001 to 10.8% 95% CI, 9.4%-12.2% in 2010; P < .001), as did 1-year survival (2.9% 95% CI, 2.0%-3.9% in 2001 to 10.2% 95% CI, 8.9%-11.6% in 2010; P < .001). Despite a decrease in the incidence of out-of-hospital cardiac arrests during the study period (40.4 to 34.4 per 100 000 persons in 2001 and 2010, respectively; P = .002), the number of survivors per 100 000 persons increased significantly (P < .001). For the entire study period, bystander CPR was positively associated with 30-day survival, regardless of witnessed status (30-day survival for nonwitnessed cardiac arrest, 4.3% 95% CI, 3.4%-5.2% with bystander CPR and 1.0% 95% CI, 0.8%-1.3% without; odds ratio, 4.38 95% CI, 3.17-6.06). For witnessed arrest the corresponding values were 19.4% (95% CI, 18.1%-20.7%) vs 6.1% (95% CI, 5.4%-6.7%); odds ratio, 3.74 (95% CI, 3.26-4.28). CONCLUSIONS AND RELEVANCE In Denmark between 2001 and 2010, an increase in survival following out-of-hospital cardiac arrest was significantly associated with a concomitant increase in bystander CPR. Because of the co-occurrence of other related initiatives, a causal relationship remains uncertain.
Estimates of biological age based on DNA methylation patterns, often referred to as "epigenetic age", "DNAm age", have been shown to be robust biomarkers of age in humans. We previously demonstrated ...that independent of chronological age, epigenetic age assessed in blood predicted all-cause mortality in four human cohorts. Here, we expanded our original observation to 13 different cohorts for a total sample size of 13,089 individuals, including three racial/ethnic groups. In addition, we examined whether incorporating information on blood cell composition into the epigenetic age metrics improves their predictive power for mortality. All considered measures of epigenetic age acceleration were predictive of mortality (p≤8.2x10
, independent of chronological age, even after adjusting for additional risk factors (p<5.4x10
, and within the racial/ethnic groups that we examined (non-Hispanic whites, Hispanics, African Americans). Epigenetic age estimates that incorporated information on blood cell composition led to the smallest p-values for time to death (p=7.5x10
). Overall, this study a) strengthens the evidence that epigenetic age predicts all-cause mortality above and beyond chronological age and traditional risk factors, and b) demonstrates that epigenetic age estimates that incorporate information on blood cell counts lead to highly significant associations with all-cause mortality.
Patients with surgically resected stage III melanoma are at high risk for recurrence. The 5-year survival rate with ipulimumab was 11 percentage points higher than that with placebo (65% vs. 54%), ...but there were substantial immune-related toxic effects.
Ipilimumab, a fully human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen 4 (CTLA-4) to augment antitumor immune responses, was approved by the Food and Drug Administration (FDA) and the European Medicines Agency in 2011 at a dose of 3 mg per kilogram of body weight for the treatment of advanced melanoma.
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On the basis of data from a phase 2 trial that indicated the potential for a dose of 10 mg per kilogram to have higher efficacy than the dose of 0.3 mg or 3 mg per kilogram in patients with advanced melanoma, although at a cost of more . . .
We generated
drug-response and multiomics profiling data for a prospective series of 252 samples from 186 patients with acute myeloid leukemia (AML). A functional precision medicine tumor board ...(FPMTB) integrated clinical, molecular, and functional data for application in clinical treatment decisions. Actionable drugs were found for 97% of patients with AML, and the recommendations were clinically implemented in 37 relapsed or refractory patients. We report a 59% objective response rate for the individually tailored therapies, including 13 complete responses, as well as bridging five patients with AML to allogeneic hematopoietic stem cell transplantation. Data integration across all cases enabled the identification of drug response biomarkers, such as the association of
overexpression with resistance to FLT3 inhibitors. Integration of molecular profiling and large-scale drug response data across many patients will enable continuous improvement of the FPMTB recommendations, providing a paradigm for individualized implementation of functional precision cancer medicine. SIGNIFICANCE: Oncogenomics data can guide clinical treatment decisions, but often such data are neither actionable nor predictive. Functional
drug testing contributes significant additional, clinically actionable therapeutic insights for individual patients with AML. Such data can be generated in four days, enabling rapid translation through FPMTB.
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Bruton tyrosine kinase is a clinically validated target in mantle cell lymphoma. Acalabrutinib (ACP-196) is a highly selective, potent Bruton tyrosine kinase inhibitor developed to minimise ...off-target activity.
In this open-label, phase 2 study, oral acalabrutinib (100 mg twice per day) was given to patients with relapsed or refractory mantle cell lymphoma, until disease progression or unacceptable toxicity. The primary endpoint was overall response assessed according to the Lugano classification, and safety analyses were done in all participants. This trial is registered with ClinicalTrials.gov, number NCT02213926.
From March 12, 2015, to Jan 5, 2016, 124 patients with relapsed or refractory mantle cell lymphoma were enrolled and all patients received treatment; median age 68 years. Patients received a median of two (IQR 1–2) previous therapies. At a median follow-up of 15·2 months, 100 (81%) patients achieved an overall response and 49 (40%) patients achieved a complete response. The Kaplan-Meier estimated medians for duration of response, progression-free survival, and overall survival were not reached; the 12-month rates were 72% (95% CI 62–80), 67% (58–75), and 87% (79–92%), respectively. The most common adverse events were primarily grade 1 or 2 and were headache (47 38%), diarrhoea (38 31%), fatigue (34 27%), and myalgia (26 21%). The most common grade 3 or worse adverse events were neutropenia (13 10%), anaemia (11 9%), and pneumonia (six 5%). There were no cases of atrial fibrillation and one case of grade 3 or worse haemorrhage. The median duration of treatment was 13·8 months. Treatment was discontinued in 54 (44%) patients, primarily due to progressive disease (39 31%) and adverse events (seven 6%).
Acalabrutinib treatment provided a high rate of durable responses and a favourable safety profile in patients with relapsed or refractory mantle cell lymphoma. These findings suggest an important role for acalabrutinib in the treatment of this disease population.
Acerta Pharma, a member of the AstraZeneca Group.
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