Sarcoma incidence worldwide: regional differences in histology and molecular subtypes.

PURPOSE OF REVIEW: There are numerous sarcoma subtypes and vary widely in terms of epidemiology, clinical characteristics, genetic profiles, and pathophysiology. They also differ widely between ethnic groups. This review focuses on the different incidence rates of sarcomas in different regions and the potential explanations for these disparities. RECENT FINDINGS: In an intercontinental study using national cancer registry databases from France and Taiwan, the French population had a higher risk of liposarcomas, leiomyosarcomas, and synovial sarcomas, whereas the Taiwanese population had a higher incidence of angiosarcomas and malignant peripheral nerve sheath tumors. The anatomical distribution of these sarcomas also varied between these two regions. In France, most angiosarcoma cases occurred in the extremities and trunk, whereas in Taiwan, angiosarcoma cases in the abdomen and pelvis were more common. Another international study showed that in addition to the common known TP53 and NF1 germline mutations, genes involved in centromere and telomere maintenance were also involved in sarcomagenesis. We reviewed factors related to genetics, environmental effects, chemical exposure, and radiation exposure that could explain the differences in sarcoma incidence among different geographical or ethnic regions. SUMMARY: Our understanding of the potential cause of sarcomas with different subtypes is limited. Establishing a comprehensive global database for patients with sarcomas from all ethnic groups is essential to deepen our understanding of the potential risk factors and the pathophysiology of all sarcoma subtypes.

A case of primary pleural epithelioid hemangioendothelioma achieving stable disease with paclitaxel treatment: A case report and literature review.

Epithelioid hemangioendothelioma (EHE) is a rare vascular neoplasm with a clinical behaviour that falls between a benign hemangioma and a high-grade angiosarcoma. Pleural EHE is exceptionally rare, and its prognosis is grim, with most patients experiencing survival of less than 1 year. Here, we present a case of pleural EHE in a 45-year-old woman with a month-long history of right-sided pleuritic chest pain. Chest computed tomography revealed consolidation, atelectasis of the right lung, right pleural thickening, and pleural effusion. She underwent video-assisted thoracoscopic surgery for decortication and was diagnosed with conclusively pleural EHE, showing a CAMTA1 rearrangement. Paclitaxel treatment, administered once weekly on days 1, 8 and 15 of a 28-day cycle, resulted in a stable disease after 12 cycles. Managing patients with pleural EHE is challenging because there are still no established standard treatments. Our case achieved 11-month progression-free survival following paclitaxel treatment.

The Influence of Precipitated Particles on the Grain Size in Cold-Rolled Al-Mn Alloy Foils upon Annealing at 100-550 °C.

The Al-Mn alloy heat exchanger fin production process includes a brazing treatment at s high temperature of 600 °C, in which coarse grains are preferred for their high resistance to deformation at elevated temperatures by decreasing the grain boundary sliding. In this study, Al-1.57Mn-1.57Zn-0.58Si-0.17Fe alloy foils cold rolled by 81.7% (1.1 mm in thickness) and 96.5% (0.21 mm in thickness) were annealed at 100-550 °C for 1 h to investigate their recrystallization behavior, grain sizes, and precipitates by increasing the annealing temperature, using micro-hardness measurement, electron back-scattered diffraction (EBSD), scanning electron microscopy (SEM), and transmission electron microscopy (TEM) techniques. The micro-hardness results showed that the recrystallization finishing temperatures for the two samples were almost the same, 323 ± 2 °C. The EBSD results showed that when the annealing temperature decreased from 550 to 400 °C, the recrystallized grain sizes of the two samples were nearly identical-both increased slightly. Further decreasing the annealing temperature from 400 to 330 °C caused the grain sizes to increase more, with the thinner foil sample having a more significant increase. The SEM and TEM observations showed that the micron-sized primary-phase remained unchanged during the annealing process. The nano-sized secondary phase precipitates formed during the hot-rolling process experienced a coarsening and dissolving process upon annealing. The particle size of the secondary phase increased from 32 nm to 44 nm and the area fraction decreased from 4.2% to 3.8%. The nucleation analysis confirmed that the large primary-phase could act as a nucleation site through particle stimulated nucleation (PSN) mode. The relatively dense secondary phase precipitates with small sizes at lower temperatures could provide higher Zener drag to the grain boundaries, leading to fewer nuclei and thereafter coarser grains. The coarsening of the recrystallized grains in the foils could be implemented through thickness reduction and/or precipitation processes to form densely distributed nano-sized precipitates.

Age and aging process alter the gut microbes.

BACKGROUND: Gut microbes and age are both factors that influence the development of disease. The community structure of gut microbes is affected by age. OBJECTIVE: To plot time-dependent gut microbe profiles in individuals over 45 years old and explore the correlation between age and gut microbes. METHODS: Fecal samples were collected from 510 healthy individuals over 45 years old. Shannon index, Simpson index, Ace index, etc. were used to analyze the diversity of gut microbes. The beta diversity analysis, including non-metric multidimensional scaling (NMDS), was used to analyze community distribution. Linear discriminant analysis (LDA) and random forest (RF) algorithm were used to analyze the differences of gut microbes. Trend analysis was used to plot the abundances of characteristic gut microbes in different ages. RESULTS: The individuals aged 45-49 had the highest richness of gut bacteria. Fifteen characteristic gut microbes, including Siphoviridae and Bifidobacterium breve, were screened by RF algorithm. The abundance of Ligiactobacillus and Microviridae were higher in individuals older than 65 years. Moreover, the abundance of Blautia_A massiliensis, Lubbockvirus and Enterocloster clostridioformis decreased with age and the abundance of Klebsiella variicola and Prevotella increased with age. The functional genes, such as human diseases and aging, were significantly different among different aged individuals. CONCLUSIONS: The individuals in different ages have characteristic gut microbes. The changes in community structure of gut microbes may be related to age-induced diseases.

Sequential multimodal treatments with chemotherapy and surgery for advanced soft tissue sarcoma may be associated with better survival than chemotherapy.

BACKGROUND: In patients with advanced soft tissue sarcoma (STS), surgery had been reported to be associated with superior overall survival (OS). Chemotherapy details for such patients were less reported, and whether multimodal treatment with surgery and chemotherapy provides extra survival benefit remains unclear. METHODS: We retrospectively reviewed patients with newly diagnosed advanced STS treated at National Taiwan University Hospital from January 1, 2011, to December 31, 2017. OS was calculated from the day of diagnosis of advanced STS to the day of death or last follow-up. Baseline patient characteristics and details regarding surgery and chemotherapy were recorded. RESULTS: A total of 545 patients were diagnosed with STS from 2011 to 2017, of which 226 patients had advanced STS. The median age was 54.7 years, and 54% of patients were women. Approximately 38% of patients with advanced STS underwent surgery and exhibited a trend of longer OS compared with who did not (median = 18.6 vs. 11.9 months, p = 0.083). In the chemotherapy subgroup, the benefit of surgery was more prominent (median = 21.9 vs. 16.5 months, p = 0.037). Patients who received chemotherapy prior to surgery exhibited numerically longer OS than those who underwent surgery first (median = 33.9 vs. 18.3 months, p = 0.155). After adjusting other clinical factors, chemotherapy remained an independent factor associated with favourable OS. CONCLUSION: Surgery may be more beneficial for the patients who receive chemotherapy. Our results support evaluation of sequential multimodal treatments strategy including surgery and chemotherapy in patients with advanced STS.

Characterizing the Efficacy and Safety of Chemotherapy Plus Everolimus in HER2-Negative Metastatic Breast Cancer Harboring Altered PI3K/AKT/mTOR.

BACKGROUND: The clinical outcomes of chemotherapy (CT) for the treatment of metastatic triple-negative (TN) and hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC) have proven to be disappointing. The phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway, a tumor-promoting signaling cascade frequently mutated in breast cancer (BC), has been implicated in chemoresistance. In this study, our objective is to investigate the efficacy and safety of combining everolimus with chemotherapy in mBC patients exhibiting mutations in the PI3K/AKT/mTOR pathway. METHODS: We conducted a retrospective analysis to characterize the efficacy, safety, and their association with clinical and molecular characteristics of metastatic lesions in 14 patients with HER2- mBC. These patients harbored at least one altered member of the PI3K/AKT/mTOR signaling pathway and were treated with a combination of a chemotherapy agent and the mTOR inhibitor everolimus (CT+EVE). RESULTS: The majority of patients belonged to the triple-negative (TN) subtype (9/14, 64.3%), having already undergone 2 lines of chemotherapy (CT) in the metastatic setting (11, 78.6%). These patients carried altered phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) and were administered a vinorelbine-containing regimen (10, 71.4%). The objective response rate (ORR) was 42.9%, with a disease control rate of 92.9%. The median progression-free survival (PFS) and overall survival (OS) were 5.9 (95% confidence interval (CI): 4.9-13.6) months and 14.3 (95% CI: 8.5-not reached (NR)) months, respectively. Patients with fewer prior treatment lines tended to exhibit longer PFS. OS, PFS, and ORR were comparable between hormone receptor-positive (HR+) and triple-negative breast cancer (TNBC) patients, but numerical improvements were noted in patients with a single PI3K pathway alteration compared to those with more than one alteration. Genomic alterations that surfaced upon progression on CT+EVE included cyclin dependent kinase 4 (CDK4) and epidermal growth factor receptor (EGFR) amplification, as well as neurofibromin 1 (NF1) mutation, suggesting potential mechanisms of acquired resistance. An analysis of adverse events indicated manageable toxicities. CONCLUSIONS: The findings of this study suggest both activity and safety for the combination of chemotherapy and the mTOR inhibitor everolimus (CT+EVE) in patients with HER2- mBC who have alterations in the PI3K pathway, particularly those who have received fewer prior chemotherapy. However, it is crucial to note that large-scale, randomized control studies are warranted to more comprehensively characterize the efficacy and safety of this combination therapy.

Pericyte signaling via soluble guanylate cyclase shapes the vascular niche and microenvironment of tumors.

Pericytes and endothelial cells (ECs) constitute the fundamental components of blood vessels. While the role of ECs in tumor angiogenesis and the tumor microenvironment is well appreciated, pericyte function in tumors remains underexplored. In this study, we used pericyte-specific deletion of the nitric oxide (NO) receptor, soluble guanylate cyclase (sGC), to investigate via single-cell RNA sequencing how pericytes influence the vascular niche and the tumor microenvironment. Our findings demonstrate that pericyte sGC deletion disrupts EC-pericyte interactions, impairing Notch-mediated intercellular communication and triggering extensive transcriptomic reprogramming in both pericytes and ECs. These changes further extended their influence to neighboring cancer-associated fibroblasts (CAFs) and tumor-associated macrophages (TAMs) through paracrine signaling, collectively suppressing tumor growth. Inhibition of pericyte sGC has minimal impact on quiescent vessels but significantly increases the vulnerability of angiogenic tumor vessels to conventional anti-angiogenic therapy. In conclusion, our findings elucidate the role of pericytes in shaping the tumor vascular niche and tumor microenvironment and support pericyte sGC targeting as a promising strategy for improving anti-angiogenic therapy for cancer treatment.

Deep learning models incorporating endogenous factors beyond DNA sequences improve the prediction accuracy of base editing outcomes.

Adenine base editors (ABEs) and cytosine base editors (CBEs) enable the single nucleotide editing of targeted DNA sites avoiding generation of double strand breaks, however, the genomic features that influence the outcomes of base editing in vivo still remain to be characterized. High-throughput datasets from lentiviral integrated libraries were used to investigate the sequence features affecting base editing outcomes, but the effects of endogenous factors beyond the DNA sequences are still largely unknown. Here the base editing outcomes of ABE and CBE were evaluated in mammalian cells for 5012 endogenous genomic sites and 11,868 genome-integrated target sequences, with 4654 genomic sites sharing the same target sequences. The comparative analyses revealed that the editing outcomes of ABE and CBE at endogenous sites were substantially different from those obtained using genome-integrated sequences. We found that the base editing efficiency at endogenous target sites of both ABE and CBE was influenced by endogenous factors, including epigenetic modifications and transcriptional activity. A deep-learning algorithm referred as BE_Endo, was developed based on the endogenous factors and sequence information from our genomic datasets, and it yielded unprecedented accuracy in predicting the base editing outcomes. These findings along with the developed computational algorithms may facilitate future application of BEs for scientific research and clinical gene therapy.

High-throughput mapping of single-neuron projection and molecular features by retrograde barcoded labeling.

Deciphering patterns of connectivity between neurons in the brain is a critical step toward understanding brain function. Imaging-based neuroanatomical tracing identifies area-to-area or sparse neuron-to-neuron connectivity patterns, but with limited throughput. Barcode-based connectomics maps large numbers of single-neuron projections, but remains a challenge for jointly analyzing single-cell transcriptomics. Here, we established a rAAV2-retro barcode-based multiplexed tracing method that simultaneously characterizes the projectome and transcriptome at the single neuron level. We uncovered dedicated and collateral projection patterns of ventromedial prefrontal cortex (vmPFC) neurons to five downstream targets and found that projection-defined vmPFC neurons are molecularly heterogeneous. We identified transcriptional signatures of projection-specific vmPFC neurons, and verified Pou3f1 as a marker gene enriched in neurons projecting to the lateral hypothalamus, denoting a distinct subset with collateral projections to both dorsomedial striatum and lateral hypothalamus. In summary, we have developed a new multiplexed technique whose paired connectome and gene expression data can help reveal organizational principles that form neural circuits and process information.

Clinical factors for delayed neuropsychiatric sequelae from acute carbon monoxide poisoning: a retrospective study.

Background: Delayed neuropsychiatric sequelae (DNS), which seriously affect the daily lives of patients, are the most common complications of carbon monoxide (CO) poisoning. No uniform screening tool is available for identifying high-risk groups. Therefore, in this study, we aimed to explore whether conventional laboratory indicators and imaging data from primary hospitals could predict the occurrence of DNS. Methods: This retrospective observational study was conducted in a single-center primary hospital from January 1, 2021 to May 31, 2023. Participants included patients aged >18 years with acute CO poisoning. Patients with complete recovery in the acute phase were followed up by telephone and outpatient visits, and the presence of DNS was determined according to the occurrence of new neurological symptoms within 6 weeks after discharge. We obtained demographic, laboratory, and imaging data from the medical records and performed a univariate analysis. A multivariate logistic regression model was used to identify independent clinical predictors of DNS. Results: A total of 73 patients were included in the study, of whom 25 (34.2%) developed DNS. Multivariate logistic regression analysis revealed that a longer duration of CO exposure (adjusted odds ratio (AOR): 1.262, 95% confidence interval (CI): 1.069-1.490) and the presence of acute brain lesions on diffusion-weighted imaging (DWI) (AOR: 5.117, 95% CI: 1.430-18.315) were independent risk factors for DNS. Receiver operating characteristic analyses of the duration of CO exposure were performed (area under the curve (AUC): 0.825; 95% CI: 0.731-0.918) with a cut-off value of 5.5 h, and DNS was predicted with a sensitivity of 96% and a specificity of 66.7%. Conclusion: High cranial DWI signal within 24 h and duration of poisoning longer than 5.5 h are independent predictors of DNS. The predictive effects of conventional laboratory indicators require further standardized and large-sample studies.

Cluster energy prediction based on multiple strategy fusion whale optimization algorithm and light gradient boosting machine.

BACKGROUND: Clusters, a novel hierarchical material structure that emerges from atoms or molecules, possess unique reactivity and catalytic properties, crucial in catalysis, biomedicine, and optoelectronics. Predicting cluster energy provides insights into electronic structure, magnetism, and stability. However, the structure of clusters and their potential energy surface is exceptionally intricate. Searching for the global optimal structure (the lowest energy) among these isomers poses a significant challenge. Currently, modelling cluster energy predictions with traditional machine learning methods has several issues, including reliance on manual expertise, slow computation, heavy computational resource demands, and less efficient parameter tuning. RESULTS: This paper introduces a predictive model for the energy of a gold cluster comprising twenty atoms (referred to as Au20 cluster). The model integrates the Multiple Strategy Fusion Whale Optimization Algorithm (MSFWOA) with the Light Gradient Boosting Machine (LightGBM), resulting in the MSFWOA-LightGBM model. This model employs the Coulomb matrix representation and eigenvalue solution methods for feature extraction. Additionally, it incorporates the Tent chaotic mapping, cosine convergence factor, and inertia weight updating strategy to optimize the Whale Optimization Algorithm (WOA), leading to the development of MSFWOA. Subsequently, MSFWOA is employed to optimize the parameters of LightGBM for supporting the energy prediction of Au20 cluster. CONCLUSIONS: The experimental results show that the most stable Au20 cluster structure is a regular tetrahedron with the lowest energy, displaying tight and uniform atom distribution, high geometric symmetry. Compared to other models, the MSFWOA-LightGBM model excels in accuracy and correlation, with MSE, RMSE, and R2 values of 0.897, 0.947, and 0.879, respectively. Additionally, the MSFWOA-LightGBM model possesses outstanding scalability, offering valuable insights for material design, energy storage, sensing technology, and biomedical imaging, with the potential to drive research and development in these areas.

Perovskite Oxides Alleviate Microstrain and Anion Loss of Radially-Aligned Ni-Rich Ncm811 Cathodes under High-Voltage Operations.

The energy density of Ni-rich cathodes is expected to be further unlocked by increasing the cut-off voltage to above 4.3 V, which nevertheless come with significantly increased irreversible phase transition and abundant side reactions. In this study, the perovskite oxides enhanced radial-aligned LiNi0.8 Co0.1 Mn0.1 O2 (NCM811) cathodes are reported, in which the coherent-growth La2 [LiTM]O4 clusters are evenly riveted into the crystals and the stable Lax Ca1- x [TM]O3- x protective layer is concurrently formed on the surface. The reciprocal interactions greatly reduce the lattice strain during de-/lithiation. Meantime, the abundant oxygen vacancies of the coating layer are proved to reversibly capture (state of charge) and re-release (state of discharge) the oxygen radicals, fully avoiding their correlative side reactions. The resultant NCM811 displays negligible O2 and CO2 emissions when charging to 4.5 V as well as a thinner CEI film, therefore delivering a large capacity of 225 mAh g-1 at 0.1C in coin-type half-cells and a high retention of 88.3% after 1000 cycles at 1C in pouch-type full-cells within 2.7-4.5 V. The development of high-voltage Ni-rich cathodes exhibits a highly effective pathway to further increase their energy density.

Whole-Brain Radiotherapy Alone vs Preceded by Bevacizumab, Etoposide, and Cisplatin for Untreated Brain Metastases From Breast Cancer: A Randomized Clinical Trial.

Importance: The incidence of brain metastasis is increasing in patients with metastatic breast cancer. Treatments to extend the control of brain metastasis are urgently required. Objective: To investigate whether the addition of an induction treatment of bevacizumab, etoposide, and cisplatin (BEEP) improves brain-specific progression-free survival (PFS) after whole-brain radiotherapy (WBRT). Design, Setting, and Participants: This open-label, randomized, multicenter clinical trial assessed patients with brain metastases from breast cancer (BMBC) in Taiwan from September 9, 2014, to December 24, 2018, with survival follow-up until December 31, 2021. Key inclusion criteria included metastatic brain tumors not suitable for focal treatment, WBRT naivety, age 20 to 75 years, and at least 1 measurable brain metastatic lesion. The primary end point was brain-specific PFS, with an expected hazard ratio of 0.60, a 2-sided α ≤ .20, and power of 0.8. Interventions: Eligible patients were randomly assigned at a ratio of 2:1 to the experimental arm, which involved 3 cycles of BEEP followed by WBRT, or the control arm, which involved WBRT alone. Main Outcomes and Measures: The primary end point was the determination of brain-specific PFS by local investigators according to the Response Evaluation Criteria in Solid Tumors, version 1.1, the initiation of other brain-directed treatment after WBRT, or death. Other key end points included brain-specific objective response rate after 8 weeks of BEEP treatment or WBRT and 8-month brain-specific PFS rate, PFS, and overall survival. Results: A total of 118 patients with BMBC were randomized, with the intention-to-treat cohort comprising 112 patients. The median age was 56 years (range, 34-71 years), and 61 patients (54.5%) had ERBB2 (formerly HER2 or HER2/neu)-positive disease. The median (range) brain-specific PFS was 8.1 (0.3-29.5) vs 6.5 (0.9-25.5) months in the experimental and control arms, respectively (hazard ratio, 0.71; 95% CI, 0.44-1.13; P = .15; significant at predefined α ≤ .20). The brain-specific objective response rate at 2 months was not significantly different (BEEP treatment vs WBRT, 41.9% vs 52.6%), but the 8-month brain-specific PFS rate was significantly higher in the experimental group (48.7% vs 26.3%; P = .03). Adverse events were generally manageable with prophylactic granulocyte colony-stimulating factor treatment. Conclusions and Relevance: The findings show that induction BEEP before WBRT may improve the control of BMBC compared with using upfront WBRT, which could address an unmet need for an effective systemic treatment for intractable brain and extracranial metastases from metastatic breast cancer. Trial Registration: ClinicalTrials.gov Identifier: NCT02185352.

Effect of the Solid Solution and Aging Treatment on the Mechanical Properties and Microstructure of a Novel Al-Mg-Si Alloy.

A novel Al-Mg-Si aluminum alloy with the addition of the micro-alloying element Er and Zr that was promptly quenched after extrusion has been studied. The solid solution and aging treatment of the novel alloy are studied by observing the microstructure, mechanical properties, and strengthening mechanism. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) techniques are employed to examine the changes in the microstructure resulting from various solid solution treatments and aging treatments. The best strengthening effect can be achieved when the solubility of the MgSi phase and precipitate ß″ (Mg2Si phase) is at their maximum. The addition of Er and Zr elements promotes the precipitation of the ß″ phase and makes the b″ phase more finely dispersed. The aging strengthening of alloys is a comprehensive effect of the dislocation cutting mechanism and bypass mechanism, the joint effect of diffusion strengthening of Al3(Er,Zr) particles and the addition of Er and Zr elements promoting the precipitation strengthening of ß″ phases. In this paper, by adding Er and Zr elements and exploring the optimal heat treatment system, the yield strength of the alloy reaches 437 MPa and the tensile strength reaches 453 MPa after solid solution treatment at 565 °C/30 min and aging at 175 °C/10 h.

Identification and quantification of small exon-containing isoforms in long-read RNA sequencing data.

Small exons are pervasive in transcriptomes across organisms, and their quantification in RNA isoforms is crucial for understanding gene functions. Although long-read RNA-seq based on Oxford Nanopore Technologies (ONT) offers the advantage of covering transcripts in full length, its lower base accuracy poses challenges for identifying individual exons, particularly microexons (≤ 30 nucleotides). Here, we systematically assess small exons quantification in synthetic and human ONT RNA-seq datasets. We demonstrate that reads containing small exons are often not properly aligned, affecting the quantification of relevant transcripts. Thus, we develop a local-realignment method for misaligned exons (MisER), which remaps reads with misaligned exons to the transcript references. Using synthetic and simulated datasets, we demonstrate the high sensitivity and specificity of MisER for the quantification of transcripts containing small exons. Moreover, MisER enabled us to identify small exons with a higher percent spliced-in index (PSI) in neural, particularly neural-regulated microexons, when comparing 14 neural to 16 non-neural tissues in humans. Our work introduces an improved quantification method for long-read RNA-seq and especially facilitates studies using ONT long-reads to elucidate the regulation of genes involving small exons.

C21 steroidal glycosides from the root bark of Periploca sepium and their NO production inhibitory and cytotoxic activity.

A series of C21 steroidal glycosides were isolated from the root bark of Periploca sepium, including a new compound, perisepiumoside A1 (1), and six known compounds (2-7). Their structures were elucidated by analysis of HR-ESI-MS, and 1D and 2D NMR spectroscopic data. All these compounds were tested for their NO production inhibitory activity in LPS-stimulated RAW 264.7 cells. Results showed that these C21 steroidal glycosides could remarkably inhibit NO production, particularly 1 and 2 with IC50 values of 30.81 ± 0.18 µM and 44.39 ± 0.21 µM, respectively. In addition, the cytotoxicity of these compounds was measured on A549, MCF-7, and HeLa cancer cell lines. Among them, compounds 1 and 7 displayed cytotoxicity against the A549 cell line with IC50 values of 28.41 ± 0.12 µM and 39.06 ± 0.05 µM, respectively.

Long-Read Sequencing Reveals Alternative Splicing-Driven, Shared Immunogenic Neoepitopes Regardless of SF3B1 Status in Uveal Melanoma.

Tumor-specific neoepitopes are promising targets in cancer immunotherapy. However, the identification of functional tumor-specific neoepitopes remains challenging. In addition to the most common source, single-nucleotide variants (SNV), alternative splicing (AS) represents another rich source of neoepitopes and can be utilized in cancers with low SNVs such as uveal melanoma (UM). UM, the most prevalent adult ocular malignancy, has poor clinical outcomes due to a lack of effective therapies. Recent studies have revealed the promise of harnessing tumor neoepitopes to treat UM. Previous studies have focused on neoepitope targets associated with mutations in splicing factor 3b subunit 1 (SF3B1), a key splicing factor; however, little is known about the neoepitopes that are commonly shared by patients independent of SF3B1 status. To identify the AS-derived neoepitopes regardless of SF3B1 status, we herein used a comprehensive nanopore long-read-sequencing approach to elucidate the landscape of AS and novel isoforms in UM. We also performed high-resolution mass spectrometry to further validate the presence of neoepitope candidates and analyzed their structures using the AlphaFold2 algorithm. We experimentally evaluated the antitumor effects of these neoepitopes and found they induced robust immune responses by stimulating interferon (IFN)γ production and activating T cell-based UM tumor killing. These results provide novel insights into UM-specific neoepitopes independent of SF3B1 and lay the foundation for developing therapies by targeting these actionable neoepitopes.

Disparity in survival benefits of pembrolizumab between Asian and non-Asian patients with advanced cancers: A systematic review and meta-regression analysis.

BACKGROUND: Immune checkpoint inhibitors have revolutionized the treatment of malignancies. However, disproportionate enrollment among races and ethnicities places the generalizability of global trial results in doubt. METHODS: In this systematic review, phase 3 randomized controlled trials investigating pembrolizumab in advanced cancers and providing subgroup analyses of Asian and non-Asian participants were included. The primary and secondary effect measures were the mean differences (MDs) in the natural logarithms of the hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) between these two subgroups, respectively. We used random-effects meta-analysis to calculate the pooled ratios of HRs (i.e., exp(MD)) and implemented a meta-regression analysis to identify significant covariates. RESULTS: A total of 17 and 11 trials were included in the meta-analyses of OS and PFS, respectively. These trials included 2732 (25.49%) Asian and 7000 (65.32%) non-Asian participants in the OS analysis and 1438 (22.5%) Asian and 4129 (64.61%) non-Asian participants in the PFS analysis. The pooled ratio of HRs for OS was 0.87 (95% CI: 0.76-0.99; p = 0.0391), favoring Asian participants, but no significant difference was found in PFS (pooled ratio of HRs: 0.93; 95% CI: 0.82-1.07; p = 0.2391). Both linear meta-regression analyses revealed an open-label design as a crucial covariate, which indicated more benefits for non-Asian participants. CONCLUSIONS: Compared with non-Asian patients, Asian patients with advanced cancers may derive superior OS benefits from pembrolizumab. Although the results warrant further exploration, this meta-analysis provides insight into clinical research design.

A comprehensive analysis of Fanconi anemia genes in Chinese patients with high-risk hereditary breast cancer.

BACKGROUND: Four Fanconi anemia (FA) genes (BRCA1, BRCA2, PALB2 and RAD51C) are defined as breast cancer (BC) susceptibility genes. Other FA genes have been inconsistently associated with BC. Thus, the role of other FA genes in BC should be explored in specific populations. METHODS: Mutations in 16 FA genes were screened with a 98-gene panel sequencing assay in a cohort of 1481 Chinese patients with high-risk hereditary BC. The association between mutations and clinicopathological characteristics as well as prognosis was analyzed. The risk of BC in carriers of FA gene mutations was assessed in the Genome Aggregation Database and the Westlake Biobank for Chinese cohort. RESULTS: A total of 2.57% (38/1481) BC patients were identified who had 12 other FA gene germline mutations. Among them, the most frequently mutated gene was FANCA (8/1481, 0.54%). These 38 patients carried 35 distinct pathogenic/likely pathogenic variants, of which 21 were novel. We found one rare FANCB deleterious variant (c.1327-3dupT) in our cohort. There was a statistically significant difference in lymph node status between FA gene mutation carriers and non-carriers (p = 0.041). We observed a trend that mutation carriers had larger tumor sizes, lower estrogen receptor (ER) and progesterone receptor (PR) positivity rates, and lower 3.5-year invasive disease-free survival (iDFS) and distant recurrence-free survival (DRFS) rates than non-carriers (tumor size > 2 cm: 51.43% vs. 45.63%; ER positivity rates: 51.43% vs. 60.81%; PR positivity rates: 48.57% vs. 55.16%; 3.5-year iDFS rates: 58.8% vs. 66.7%; 3.5-year DRFS rates: 58.8% vs. 68.8%). The frequency of the mutations in FANCD2, FANCM and BRIP1 trended to be higher among BC cases than that in controls (p = 0.055, 0.08 and 0.08, respectively). CONCLUSION: This study comprehensively estimated the prevalence, clinicopathological characteristics, prognosis and risk of BC associated with deleterious variants in FA genes in Chinese high-risk hereditary BC patients. It enriches our understanding of the role of FA genes with BC.