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Lynch syndrome (LS) carriers develop mismatch repair–deficient neoplasia with high neoantigen (neoAg) rates. No detailed information on targetable neoAgs from LS precancers exists, which is crucial for vaccine development and immune-interception strategies. We report a focused somatic mutation and frameshift-neoAg landscape of microsatellite loci from colorectal polyps without malignant potential (PWOMP), precancers, and early-stage cancers in LS carriers. We generated paired whole-exome and transcriptomic sequencing data from 8 colorectal PWOMP, 41 precancers, 8 advanced precancers, and 12 early-stage cancers of 43 LS carriers. A computational pipeline was developed to predict, rank, and prioritize the top 100 detected mutated neoAgs that were validated in vitro using ELISpot and tetramer assays. Mutation calling revealed >10 mut/Mb in 83% of cancers, 63% of advanced precancers, and 20% of precancers. Cancers displayed an average of 616 MHC-I neoAgs/sample, 294 in advanced precancers, and 107 in precancers. No neoAgs were detected in PWOMP. A total of 65% of our top 100 predicted neoAgs were immunogenic in vitro, and were present in 92% of cancers, 50% of advanced precancers, and 29% of precancers. We observed increased levels of naïve CD8+ and memory CD4+ T cells in mismatch repair–deficient cancers and precancers via transcriptomics analysis. Shared frameshift-neoAgs are generated within unstable microsatellite loci at initial stages of LS carcinogenesis and can induce T-cell responses, generating opportunities for vaccine development, targeting LS precancers and early-stage cancers. This study provides the combined mutational and transcriptomic landscape along with a catalog of immunologically validated neoantigens in Lynch syndrome colonic precancers and tumors that will facilitate cancer immunoprevention strategies. [ABSTRACT FROM AUTHOR]

KRAS mutations, microsatellite instability, and tumor location have been found to be significant prognostic factors in colorectal cancer. The interaction between these variables and its effect on overall survival in nonmetastatic colon cancer has not been well elucidated. The National Cancer Database (2010–2016) was queried for patients with stage I–III colon cancer and known microsatellite instability and KRAS status undergoing curative resection. A total of 5,292 patients were identified: 60.4% had right-sided cancers, 36.4% had KRAS mutations, and 15.6% had microsatellite instability. Right-sided tumors were more likely to have microsatellite instability and KRAS mutations compared to left-sided tumors. On univariable analysis, KRAS mutations and microsatellite instability status were not associated with differences in survival, whereas right-sided cancers had worse overall survival compared to left-sided cancers (hazard ratio 1.32, 95% confidence interval: 1.18–1.47). On multivariable analysis, right-sided location, KRAS mutations, and microsatellite instability were not independent prognostic factors. However, a significant interaction between laterality and KRAS status was observed. In patients with mutated KRAS cancers, left-sided tumors were at increased risk of death compared to right-sided tumors (hazard ratio: 1.30, 95% confidence interval: 1.03–1.63), whereas in patients with wild-type KRAS cancers, left-sided tumors were at decreased risk of death (hazard ratio: 0.81, 95% confidence interval: 0.67–0.97). In patients with stage I–III colon cancer, laterality, KRAS mutation, and microsatellite instability status were not independently prognostic after curative resection. However, the effect of laterality was opposite based on KRAS status, with left-sided (compared to right-sided) tumors associated with worse overall survival in mutated KRAS patients and better overall survival in wild-type KRAS individuals. Laterality itself may not be an independent prognostic factor but a reflection of differing genetic profiles within the colon. [ABSTRACT FROM AUTHOR]

We aimed to evaluate the practice and the associated outcomes of surgical treatment for young-onset colorectal cancer (YOCRC) patients presenting with synchronous liver metastases. The study cohort was divided into two groups according to surgery date: 131 patients in the early era (EE, 1998–2011) and 179 in the contemporary era (CE, 2012–2020). The CE had a higher rate of node-positive primary tumors, higher carcinoembryonic antigen level, and lower rate of RAS/BRAF mutations. The CE had higher rates of reverse or combined resection, multi-drug prehepatectomy chemotherapy, and two-stage hepatectomy. The median survival was 8.4 years in the CE and 4.3 years in the EE (p = 0.011). On multivariate analysis, hepatectomy in the CE was independently associated with improved overall survival (HR 0.48, p = 0.001). With a combination of perioperative systemic therapy, careful selection of treatment approach, and coordinated resections, durable cure can be achieved in YOCRC patients. [ABSTRACT FROM AUTHOR]

Purpose: Definitive radiation therapy with concurrent chemotherapy is curative for nonmetastatic squamous cell carcinoma of the anus (SCCA). However, the true effect of chemoradiation on long-term functional outcomes is poorly understood owing to limited follow-up and patient-reported outcomes (PROs).Methods and Materials: We conducted a cross-sectional survey of 248 patients with SCCA treated with definitive intensity modulated radiation and concurrent chemotherapy from 2010 to 2018 who were alive and without recurrence. PRO measures were collected, including Functional Assessment of Cancer Therapy-General (FACT-G7), Fecal Incontinence Quality of Life (FIQoL), Low Anterior Resection Syndrome (LARS), and International Consultation on Incontinence Questionnaires (ICIQ). Models were used to determine the association between demographic, tumor, treatment, and dosimetric data with PROs.Results: One hundred twelve (45%) patients completed PROs. Median [interquartile range (IQR)] time from radiation completion to survey was 51 [37-85] months. The median scores [IQR] for FACT-G7, FIQoL, and LARS were 21 [15-24], 14 [11-16], and 32 [25-37], respectively. For men, median subscores [IQR] for ICIQ voiding and incontinence subscores were 5 [2-6] and 1 [1-3], respectively. For women, median subscores [IQR] for ICIQ voiding, incontinence, and filling were 1 [1-3], 5 [3-8], and 4 [2-5], respectively. Higher (better) FIQoL scores were associated with higher (better) FACT-G7 scores (β = 0.83; 95% confidence interval, 0.58-1.09; P < .001), and higher (worse) LARS scores were associated with lower (worse) FACT-G7 scores (β = -0.22; 95% confidence interval, -0.31 to -0.13; P < .001). A separate multivariable analysis revealed higher bowel bag D1% was associated with lower (worse) FIQoL (P = .001) and higher (worse) LARS (P = .003) scores. Higher bladder V40 Gy was associated with increased (worse) ICIQ voiding subscore (P = .001).Conclusions: Patients treated with modern chemoradiation for SCCA experience significant long-term bowel toxic effects with considerable effect on quality of life. Minimizing bowel hotspots and bladder V40 Gy may improve bowel and urinary function. Other interventions to reduce long-term toxic effects and improve quality of life are needed. [ABSTRACT FROM AUTHOR]

Glioblastoma is the most prevalent and lethal primary intrinsic tumor in the central nervous system. Glioblastoma stem cells (GSCs) reprogram the transcriptional and metabolic machinery to mediate therapeutic resistance to radiation. Understanding the regulatory mechanism of GSCs may inform novel approaches to improve the clinical outcome for glioblastoma patients. Nuclear pore complex (NPC) is an evolutionarily conserved structure that maintains the traffic between the nucleus and cytoplasm. In current study, we aim to interrogate the aberrant regulation of NPC in GSCs and develop novel targeted approach to sensitize GSC to radiation. Patient-derived GSCs were validated using functional assays. Transcriptional analysis of GSCs and matched differentiated glioblastoma cells (DGCs) were performed using RNA sequencing to identify aberrant regulatory pathways upregulated in GSCs. The clinical impact of target genes on patient survival was assessed using the glioblastoma dataset from The Cancer Genome Atlas (TCGA). Quantitative RT-PCR and Western blotting were performed to assess the relative expression between GSCs and DGCs. Radiation sensitivity was measured using Cs-137 irradiator. Validation of the stem-like function of target genes was performed using RNA interference followed by in vitro neurosphere formation assay and in vivo tumorigenesis with xenograft mouse model. 27 of the total 31 NPC genes were found to be upregulated in the primary glioblastoma patient specimens compared to non-tumor brain tissue in the TCGA dataset. Among them, a systematic approach combining transcriptional profiling and clinical validation linked nucleoporin 98 (NUP98) to a nexus between GSC phenotype and radiation resistance. GSCs preferentially express NUP98, which is essential for GSC maintenance and tumorigenesis in vitro and in vivo. RNA sequencing demonstrated that NUP98 regulates the expression of key DNA repair genes, including BRCA1, BRCA2, and RAD51. NUP98 forms a complex with the transcription factor P65, and directly stimulates the active transcription of genes involved in homologous recombination. Attenuation of NUP98 or P65 expression leads to the accumulation of unrepaired intrinsic DNA damage and sensitizes GSC to the treatment of ionizing radiation. Clinically, overexpression of NUP98 informs poor clinical outcome among patients with glioblastoma. Combining transcriptional discovery and clinical validation, we discovered that NUP98, an essential NPC component, maintains GSC proliferation and tumorigenesis through modulating the transcriptional control of homologous recombination pathway. Our results demonstrated a novel therapeutic approach of sensitizing GSC to radiation through targeting the nexus between aberrant transcriptional regulation and therapeutic resistance in stem-like glioma cells. [ABSTRACT FROM AUTHOR]

Aqueous zinc-ion batteries (AZIBs) are attracting worldwide attention due to their multiple merits such as extreme safety, low cost, feasible assembly, and environmentally friendly enabled by water-based electrolytes. At present, AZIBs have experienced systematic advances in battery components including cathode, anode, and electrolyte, whereas research involving separators is insufficient. The separator is the crucial component of AZIBs through providing ion transport, forming contact with electrodes, serving as a container for electrolyte, and ensuring the efficient battery operation. Considering this great yet ignored significance, it is timely to present the latest advances in design strategies, the systematic classification and summary of separators. We summarize the separator optimization strategies mainly along two approaches including the modification of the frequently used glass fiber and the exploitation of new separators. The advantages and disadvantages of the two strategies are analyzed from the material types and the characteristics of different strategies. The effects and mechanisms of various materials on regulating the uniform migration and deposition of Zn 2+ , balancing the excessively concentrated nucleation points, inhibiting the growth of dendrites, and the occurrence of side reactions were discussed using confinement, electric field regulation, ion interaction force, desolvation, etc. Finally, potential directions for further improvement and development of AZIBs separators are proposed, aiming at providing helpful guidance for this booming field., (Copyright © 2024 Science China Press. Published by Elsevier B.V. All rights reserved.)

Competing Interests: Conflict of interest The authors declare that they have no conflict of interest.