Limited understanding of the biological processes that govern metastatic dissemination hinders its prevention and treatment[1]. Here, using 501 longitudinally collected primary and metastatic tumour samples from 24 patients with non-small cell lung cancer (NSCLC) enrolled in the TRACERx lung study and PEACE autopsy programme, we infer tumour evolution from diagnosis to death. With DNA-sequencing data encompassing 70% of the metastases that were radiologically detected before death and paired multi-region sampled primary tumours, we show that the genomes of metastases diverge markedly from those of their ancestral primary tumour, with additional driver alterations and genome doubling events occurring after metastatic dissemination. In 62.5% of patients, multiple primary tumour subclones disseminated, each founding a distinct metastasis. These metastases served as sources of onward spread: more than half of the metastases sampled were seeded by other metastases. The duration that metastases existed in situ influenced their likelihood of seeding further metastases. Most metastatic migrations started and ended in the same anatomical cavity. The few subclones that exited the thorax to seed metastases disseminated widely and were enriched for somatic copy-number alterations, suggesting that chromosomal instability may facilitate extrathoracic spread. This spatial and temporal evolutionary analysis sheds light on the extent of metastatic diversity and seeding in advanced NSCLC-which tends to be underestimated in single metastasis biopsies-and identifies genomic and clinical mediators of metastatic progression.

The tumor suppressor p53 is the most frequently mutated protein in tumors and a target for drug development. More than 2000 cancer-associated p53 missense mutations have been reported, most of them located in the DNA-binding domain (DBD). Due to the low intrinsic thermostability of the latter, they often lead to unfolding at physiological temperature. Stabilizing the DBD with small molecules has been shown to be effective in reactivating the cavity-creating cancer mutant Y220C. Unfortunately, the majority of p53 mutants seem to lack druggable binding pockets for small molecules. Here we show that a designed ankyrin repeat protein (DARPin) that binds to the p53 DBD stabilizes temperature-sensitive (TS) p53 cancer mutants, thereby compensating for mutation-induced loss of stability. We determined high-resolution crystal structures of multiple DARPin-mutant p53 complexes, providing mechanistic insights into this mode of stabilization. Reporter gene assays across a comprehensive panel of cancer-associated mutants revealed reactivation of the majority of TS mutants, whereas DNA-contact mutants and those with local misfolding of the DNA-binding surface remained inactive, as expected. We demonstrate that this reactivation induces the transcription of canonical p53 target genes and elicits antiproliferative effects in cancer cell lines. A combination of this DARPin with an mRNA/lipid nanoparticle-based transfection approach may have the potential to reactivate most TS p53 mutants and resensitize cancer cells to chemotherapy.

Hydatid cyst disease, caused by Echinococcus granulosus, primarily affects the liver and lungs, while cardiac involvement, especially the right atrium (RA), is extremely rare. We report the case of a 21-year-old woman who presented with massive haemoptysis and hypoxemia. Transthoracic echocardiography demonstrated a large multicystic mass occupying the RA cavity, adherent to the atrial wall and interatrial septum, strongly suggestive of a hydatid cyst. Chest computed tomography angiography confirmed multiple pulmonary cystic lesions, intravascular filling defects consistent with pulmonary embolism, and a large hepatic hydatid cyst (5 × 4 cm). Serological testing for echinococcosis was positive. The patient underwent successful surgical excision of the RA cyst and pulmonary embolectomy under cardiopulmonary bypass. This case illustrates the rare presentation of an RA hydatid cyst with multiorgan involvement and associated pulmonary embolism, emphasizing the critical role of comprehensive imaging and timely surgical intervention in the management of complex echinococcosis.

Corynebacterium striatum, a commensal of skin and mucosa, is an emerging opportunistic pathogen. We report a rare case of postoperative incision and thoracic infection caused by C. striatum with concurrent pulmonary colonization by carbapenem-resistant Klebsiella pneumoniae (CRKP). Following resection of lung and bladder tumours, the patient developed fever, pleural effusion, and poor wound healing. Sputum cultures suggested CRKP colonization, while pleural fluid cultures identified C. striatum as the true pathogen. Clinical pharmacy consultation was pivotal in resolving this diagnostic dilemma. Guided by literature review and clinical presentation, targeted vancomycin therapy against C. striatum was initiated, leading to successful infection control. This case highlights that C. striatum should be considered a potential pathogen in postoperative patients with malignancy or invasive procedures. It is often multidrug-resistant but susceptible to glycopeptides like vancomycin. When multidrug-resistant organisms such as CRKP are also present, a comprehensive assessment integrating clinical, microbiological, and imaging data is essential to distinguish colonization from infection. This precision prevents unnecessary broad-spectrum antibiotic use, curbs resistance, and underscores the critical role of clinical pharmacists in managing complex infections through multidisciplinary collaboration.

This umbrella review examined the certainty and validity of available meta-analyses for the association between food insecurity (FI) and adverse health outcomes (AHOs) in children and adolescents. A comprehensive systematic search was conducted using three databases: PubMed/MEDLINE, Web of Science, and Scopus, until August 20, 2024. Effect sizes were recalculated using random effects models. The GRADE tool assessed evidence certainty, while AMSTAR-2 and the Newcastle-Ottawa Scale evaluated study quality. Twelve meta-analyses comprising of 108 pooled analyses (557,700 individuals) were included in this umbrella review. Food insecurity was found to be significantly associated with the increased risk of several AHOs in children and adolescents: anemia (OR: 1.50, 95% CI: 1.23 to 1.82; moderate certainty), obesity (OR: 1.16, 95% CI: 1.06 to 1.27; moderate certainty), stunting (OR: 1.12, 95% CI: 1.05 to 1.19; moderate certainty), and dental caries (OR: 1.70, 95% CI: 1.43 to 2.03; low certainty). Regarding mental health in children and adolescents, FI was found to be associated with an increased risk of suicidal ideation (OR: 1.08, 95% CI: 1.01 to 1.16; moderate certainty) and suicide plans (OR: 1.32, 95% CI: 1.14 to 1.54; moderate certainty). Further, there was found to be an increased risk in developmental outcomes (OR: 1.32, 95% CI: 1.10 to 1.59; moderate certainty) and externalizing behaviors (OR: 1.25, 95% CI: 1.08 to 1.44; low certainty). A protective association was observed for cognitive/math development disorders (OR: 0.84, 95% CI: 0.73 to 0.96; low certainty), which may be attributed to methodological limitations, though this finding requires further investigation. Food insecurity was shown to be associated with multiple AHOs in children and adolescents, with moderate to low certainty evidence. Findings should be interpreted cautiously due to substantial heterogeneity and the inclusion of low-quality meta-analyses. The observed heterogeneity and methodological limitations of the included meta-analyses suggest cautious application in designing prevention programs, particularly in designing evidence-informed nutritional and lifestyle interventions.

ObjectiveCancer and other noncommunicable diseases (NCDs) are increasingly recognized as a global development challenge. The most recent UN high-level meeting on NCDs underscored insufficient progress toward the Political Declaration on NCDs. Key barriers-including gaps in situational analysis, priority setting, and budgeting-all hinge on localized cancer epidemiology data. The Global Burden of Disease (GBD) study is uniquely positioned to provide this essential information.MethodsThis study estimated global malignant tumor burden and trends across 5 socio-demographic index (SDI) areas and 21 regions from 1990-2021 and projected trends to 2041 using GBD 2021 data for 33 tumor groups.ResultsIn 2021, there were 23.4 million (95% UI: 22.3-23.6 million) new cases, 9.8 million (9.1-10.5 million) deaths, and 251 million (235-268 million) DALYs attributable to malignant tumors, ranking them third globally for DALYs after respiratory infections and tuberculosis. Tracheal, bronchus, and lung (TBL) cancer was the leading cause of cancer mortality in both genders combined (15/21 regions) and in males (14/21 regions), while breast cancer led female mortality (12/21 regions). In high-SDI areas, malignant tumors ranked first for DALYs. TBL, colon and rectum cancer (CRC), and breast cancer comprised the top three DALY causes for both genders combined and for females; for high-SDI males, the top three were TBL, CRC, and pancreatic cancer. Projections to 2041 (Bayesian age-period-cohort [BAPC] model) indicated decreasing age-standardized incidence rates (ASIR) and case numbers for stomach and esophageal cancers. Conversely, rising ASIR and incidence numbers were projected for CRC, breast cancer, prostate cancer, lip/oral cavity cancer, multiple myeloma, thyroid cancer, and testicular cancer.ConclusionsThe cancer burden profile is strongly influenced by SDI level and gender, with high-SDI regions characterized by TBL and CRC, while lower-SDI regions face a higher burden from gender-specific and infection-related cancers. TBL cancer remains the dominant driver of cancer mortality worldwide, particularly among males. Breast cancer shows remarkable consistency as the leading female-specific cancer across most regions by both incidence and mortality.