Explore the vast range of titles available.

In mouse models of patient-derived breast cancer brain metastases, combined inhibition of PI3K and mTOR resulted in regression, and therapeutic response was correlated with a reduction in 4EBP1 phosphorylation. Brain metastases represent the greatest clinical challenge in treating HER2-positive breast cancer. We report the development of orthotopic patient-derived xenografts (PDXs) of HER2-expressing breast cancer brain metastases (BCBM), and their use for the identification of targeted combination therapies. Combined inhibition of PI3K and mTOR resulted in durable tumor regressions in three of five PDXs, and therapeutic response was correlated with a reduction in the phosphorylation of 4EBP1, an mTORC1 effector. The two nonresponding PDXs showed hypermutated genomes with enrichment of mutations in DNA-repair genes, which suggests an association of genomic instability with therapeutic resistance. These findings suggest that a biomarker-driven clinical trial of PI3K inhibitor in combination with an mTOR inhibitor should be conducted for patients with HER2-positive BCBM.

Activation of the unfolded protein response (UPR) sustains protein homeostasis (proteostasis) and plays a fundamental role in tissue maintenance and longevity of organisms. Long-range control of UPR activation has been demonstrated in invertebrates, but such mechanisms in mammals remain elusive. Here, we show that the female sex hormone estrogen regulates the UPR in hematopoietic stem cells (HSCs). Estrogen treatment increases the capacity of HSCs to regenerate the hematopoietic system upon transplantation and accelerates regeneration after irradiation. We found that estrogen signals through estrogen receptor α (ERα) expressed in hematopoietic cells to activate the protective Ire1α-Xbp1 branch of the UPR. Further, ERα-mediated activation of the Ire1α-Xbp1 pathway confers HSCs with resistance against proteotoxic stress and promotes regeneration. Our findings reveal a systemic mechanism through which HSC function is augmented for hematopoietic regeneration.

The CLOVES syndrome is an overgrowth disease arising from mosaic activating somatic mutations in the PIK3CA gene. These mutations occur during fetal development producing malformation and overgrowth of a variety of tissues. It has recently been shown that treatment with low doses of a selective inhibitor of Class I PI3K catalytic subunit p110α, the protein product of the PIK3CA gene, can yield dramatic therapeutic benefits for patients with CLOVES and PROS (a spectrum of PIK3CA-related overgrowth syndromes). To assess the long-term effects of moderate loses of p110α activity, we followed development and growth of mice with heterozygous loss of p110α ( Pik3ca +/− ) over their entire lifetimes, paying particular attention to effects on the brain. While homozygous deletion of the Pik3ca gene is known to result in early embryonic lethality, these Pik3ca +/− mice displayed a longer lifespan compared to their wild-type littermates. These mice appeared normal, exhibited no obvious behavioral abnormalities, and no body weight changes. However, their brains showed a significant reduction in size and weight. Notably, mice featuring deletion of one allele of Pik3ca only in the brain also showed gradually reduced brain size and weight. Mechanistically, either deletion of p110α or pharmacological inhibition of p110α activity reduced neurosphere size, but not numbers, in vitro , suggesting that p110α activity is critical for neuronal stem cells. The phenotypes observed in our two genetically engineered mouse models suggest that the sustained pharmacological inhibition of the PIK3CA activity in human patients might have both beneficial and harmful effects, and future treatments may need to be deployed in a way to avoid or minimize adverse effects.

Brain metastases represent the greatest clinical challenge in treating HER2-positive breast cancer. We report the development of orthotopic patient-derived xenografts (PDXs) of HER2-expressing breast cancer brain metastases (BCBM), and their use for the identification of targeted combination therapies. Combined inhibition of PI3K and mTOR resulted in durable tumor regressions in three of five PDXs, and therapeutic response correlated with reduction of 4EBP1 phosphorylation. The two non-responding PDXs showed hypermutated genomes with enrichment of mutations in DNA repair genes, suggesting an association of genomic instability with therapeutic resistance. These findings suggest that a biomarker-driven clinical trial of PI3K inhibitor plus an mTOR inhibitor should be conducted for patients with HER2-positive BCBM.

Trever Bivona and colleagues show that the Hippo pathway effector YAP promotes resistance to RAF and MEK inhibitor therapy in multiple types of BRAF -mutant tumors. The findings suggest that combined suppression of YAP and RAF-MEK signaling might enhance treatment response and prevent drug resistance. Resistance to RAF- and MEK-targeted therapy is a major clinical challenge 1 , 2 , 3 , 4 . RAF and MEK inhibitors are initially but only transiently effective in some but not all patients with BRAF gene mutation and are largely ineffective in those with RAS gene mutation because of resistance 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 . Through a genetic screen in BRAF-mutant tumor cells, we show that the Hippo pathway effector YAP (encoded by YAP1 ) acts as a parallel survival input to promote resistance to RAF and MEK inhibitor therapy. Combined YAP and RAF or MEK inhibition was synthetically lethal not only in several BRAF-mutant tumor types but also in RAS-mutant tumors. Increased YAP in tumors harboring BRAF V600E was a biomarker of worse initial response to RAF and MEK inhibition in patients, establishing the clinical relevance of our findings. Our data identify YAP as a new mechanism of resistance to RAF- and MEK-targeted therapy. The findings unveil the synthetic lethality of combined suppression of YAP and RAF or MEK as a promising strategy to enhance treatment response and patient survival.

Oncogenic mutations in the BRAF kinase occur in 6–8% of nonsmall cell lung cancers (NSCLCs), accounting for more than 90,000 deaths annually worldwide. The biological and clinical relevance of these BRAF mutations in NSCLC is incompletely understood. Here we demonstrate that human NSCLC cells with BRAF ⱽ⁶⁰⁰ᴱ, but not other BRAF mutations, initially are sensitive to BRAF-inhibitor treatment. However, these BRAF ⱽ⁶⁰⁰ᴱ NSCLC cells rapidly acquire resistance to BRAF inhibition through at least one of two discrete molecular mechanisms: (i) loss of full-length BRAF ⱽ⁶⁰⁰ᴱ coupled with expression of an aberrant form of BRAF ⱽ⁶⁰⁰ᴱ that retains RAF pathway dependence or (ii) constitutive autocrine EGF receptor (EGFR) signaling driven by c-Jun–mediated EGFR ligand expression. BRAF ⱽ⁶⁰⁰ᴱ cells with EGFR-driven resistance are characterized by hyperphosphorylated protein kinase AKT, a biomarker we validated in BRAF inhibitor-resistant NSCLC clinical specimens. These data reveal the multifaceted molecular mechanisms by which NSCLCs establish and regulate BRAF oncogene dependence, provide insights into BRAF–EGFR signaling crosstalk, and uncover mechanism-based strategies to optimize clinical responses to BRAF oncogene inhibition.

Ferns belong to species-rich group of land plants, encompassing more than 11,000 extant species, and are crucial for reflecting terrestrial ecosystem changes. However, our understanding of their biodiversity hotspots, particularly in Southeast Asia, remains limited due to scarce genetic data. Despite harboring around one-third of the world’s fern species, less than 6% of Southeast Asian ferns have been DNA-sequenced. In this study, we addressed this gap by sequencing 1,496 voucher-referenced and expert-identified fern samples from (sub)tropical Asia, spanning Malaysia, the Philippines, Taiwan, and Vietnam, to retrieve their rbcL and trnL-F sequences. This DNA barcode collection of Asian ferns encompasses 956 species across 152 genera and 34 families, filling major gaps in fern biodiversity understanding and advancing research in systematics, phylogenetics, ecology and conservation. This dataset significantly expands the Fern Tree of Life to over 6,000 species, serving as a pivotal and global reference for worldwide barcoding identification of ferns.

Chiea Chuen Khor, Tin Aung and colleagues report the results of a large genome-wide association study of primary angle closure glaucoma. They identify five new susceptibility loci and provide insights into disease pathogenesis. Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study (GWAS) followed by replication in a combined total of 10,503 PACG cases and 29,567 controls drawn from 24 countries across Asia, Australia, Europe, North America, and South America. We observed significant evidence of disease association at five new genetic loci upon meta-analysis of all patient collections. These loci are at EPDR1 rs3816415 (odds ratio (OR) = 1.24, P = 5.94 × 10 −15 ), CHAT rs1258267 (OR = 1.22, P = 2.85 × 10 −16 ), GLIS3 rs736893 (OR = 1.18, P = 1.43 × 10 −14 ), FERMT2 rs7494379 (OR = 1.14, P = 3.43 × 10 −11 ), and DPM2 – FAM102A rs3739821 (OR = 1.15, P = 8.32 × 10 −12 ). We also confirmed significant association at three previously described loci ( P < 5 × 10 −8 for each sentinel SNP at PLEKHA7 , COL11A1 , and PCMTD1 – ST18 ) 1 , providing new insights into the biology of PACG.

Background: In this study, we examined the effectiveness of transfer learning in improving automatic segmentation of brain metastases on magnetic resonance imaging scans, with potential applications in preventive exams and remote diagnostics. Methods: We trained three deep learning models on a public dataset from the ASNR-MICCAI Brain Metastasis Challenge 2024, fine-tuned them on a small private dataset, and compared their performance to models trained from scratch. Results: Results showed that models using transfer learning performed better than scratch-trained models, though the improvement was not statistically substantial. The custom Tversky and Binary Cross-Entropy loss function helped manage class imbalance and reduce false negatives, limiting missed tumor regions. Medical experts noted that, while fine-tuned models worked well with larger, well-defined tumors, they struggled with tiny, scattered tumors in complex cases. Conclusions: This study highlights the potential of transfer learning and tailored loss functions in medical imaging, while also pointing out the models’ limitations in detecting very small tumors in challenging cases.

Risk factors for severe outcomes of SARS-CoV-2 infection are not well established in children. We sought to describe pediatric hospital admissions associated with SARS-CoV-2 infection in Canada and identify risk factors for more severe disease. We conducted a national prospective study using the infrastructure of the Canadian Paediatric Surveillance Program (CPSP). Cases involving children who were admitted to hospital with microbiologically confirmed SARS-CoV-2 infection were reported from Apr. 8 to Dec. 31 2020, through weekly online questionnaires distributed to the CPSP network of more than 2800 pediatricians. We categorized hospital admissions as related to COVID-19, incidental, or for social or infection control reasons and determined risk factors for disease severity in hospital. Among 264 hospital admissions involving children with SARS-CoV-2 infection during the 9-month study period, 150 (56.8%) admissions were related to COVID-19 and 100 (37.9%) were incidental infections (admissions for other reasons and found to be positive for SARS-CoV-2 on screening). Infants (37.3%) and adolescents (29.6%) represented most cases. Among hospital admissions related to COVID-19, 52 (34.7%) had critical disease, 42 (28.0%) of whom required any form of respiratory or hemodynamic support, and 59 (39.3%) had at least 1 underlying comorbidity. Children with obesity, chronic neurologic conditions or chronic lung disease other than asthma were more likely to have severe or critical COVID-19. Among children who were admitted to hospital with SARS-CoV-2 infection in Canada during the early COVID-19 pandemic period, incidental SARS-CoV-2 infection was common. In children admitted with acute COVID-19, obesity and neurologic and respiratory comorbidities were associated with more severe disease.