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Alzheimer's disease (AD) is a progressive neurological disorder and the leading cause of dementia. Despite significant efforts, treatment strategies targeting amyloid-β have been less successful than anticipated. Recently, the role of neuroinflammation and adaptive immune response in AD pathogenesis has gained attention. Here, we performed immune cell-enriched single-cell RNA sequencing of brain parenchymal cells from 12-month-old 5xFAD, an AD mouse model. We analyzed 11,587 single cells and found distinct differences in T cell and choroid plexus cell populations between 5xFAD mouse and littermate control. Subsequent sub-clustering of T cells in the 5xFAD mouse revealed distinct subtypes, with CD8 + resident memory T cells (T RM ) being the most prevalent T cell type. In addition, we observed an increase in T cell exhaustion markers, including Pdcd1, Ctla4, and Havcr2, with a particularly significant elevation of PD-1 and TIM-3 in CD8 + T RM in 5xFAD mouse. Furthermore, choroid plexus (ChP) epithelial cells showed altered gene expression patterns, with higher expression of MHC class I and Type I IFN-stimulated genes in 5xFAD mouse compared to the control mouse, suggesting an association with clonal expansion of AD-specific T cells in the brain. Through single-cell RNA sequencing (scRNA-seq) analysis, our study highlights the potential role of resident memory CD8 + T cell and their possible interactions with ChP epithelial cells. This study provides an exploration of the brain microenvironment landscape in AD, revealing critical insights into its underlying mechanisms., Competing Interests: Declaration of competing interest The authors declare that they have no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Tumor-infiltrating CD8 + T cell is a robust predictor of outcome and immunotherapy response in patients with CRC. However, limited introduction of intratumoral CD8 + T cells remains a barrier for treatment of CRC. One of the most effective but difficult therapy for CD8 + T cells entering the tumor is activating chemokine receptors. This study observed a decrease in the expression level of interferon regulator factor 1(IRF1) in CRC tumor tissues compared to matched non-tumor tissues. Furthermore, it found a positive correlation between low IRF1 expression and unfavorable prognosis in CRC patients. The present study also demonstrated that overexpression of IRF1 attenuated tumor growth by promoting the accumulation of facilitating CD8 + T cells at the tumor site in mouse models. Additionally, this study identified IRF1 response elements in the promoter region of CXCL10 and show that the binding of IRF1 promoted the transcription of CXCL10. Of note, it was discovered that an increase in CXCL10 was positively associated with improved survival in CRC. These findings strongly suggest that IRF1 serves as a key transcription factor for CXCL10, highlighting its potential as a therapeutic target for CRC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Liposomes, especially polyethylene glycol (PEG)-modified long-circulating liposomes, have been approved for market use, due to good biocompatibility, passive tumor targeting, and sustained drug release. PEG-modified long-circulating liposomes address issues such as poor stability and rapid clearance by the reticuloendothelial system. However, they still face challenges like hindering drug uptake by tumor cells and preventing tumor penetration. Inspired by the hypoxic tumor microenvironment, we constructed a hypoxia-responsive liposome (PAO-L) to enhance the intracellular uptake and photodynamic therapy (PDT) effect of chlorin e6 (Ce6). The intelligent hypoxia-cleavable PEG-AZO-OA (PAO) was prepared by coupling PEG and octadecylamine (OA) to hypoxia-sensitive azobenzene-4,4'-dicarboxylic acid (AZO) through amide reaction. The synthesized PAO was further incorporated into Ce6-loaded liposomes to enhance the circulation stability, while promote the tumor penetration and internalization by the responsive shedding of PEG from liposome surface upon reaching the hypoxic tumor tissue. PAO-L mediated PDT significantly inhibited the growth of B16F10 and 4T1 tumors, as well as lung metastasis of 4T1 breast cancer. The excellent therapeutic effect and good tolerability make PAO-L a promising candidate for enhanced PDT., Competing Interests: Declaration of competing interest The authors declared that there are no known competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

As the global population continues to age, understanding the complex role of cellular senescence and its implications in healthy lifespans has gained increasing prominence. Cellular senescence is defined as the irreversible cessation of cell proliferation, accompanied by the secretion of a range of pro-inflammatory factors, collectively termed the senescence-associated secretory phenotype (SASP), in response to various cellular stresses. While the accumulation of senescent cells has been strongly implicated in the aging process and the pathogenesis of age-related diseases owing to their pro-inflammatory properties, recent research has also highlighted their essential roles in processes such as tumour suppression, tissue development, and repair. This review provides a comprehensive examination of the dual nature of senescent cells, evaluating their deleterious contributions to chronic inflammation, tissue dysfunction, and disease, as well as their beneficial roles in maintaining physiological homeostasis. Additionally, we explored the therapeutic potential of senolytic agents designed to selectively eliminate detrimental senescent cells while considering the delicate balance between transient and beneficial senescence and the persistence of pathological senescence. A deeper understanding of these dynamics is critical to develop novel interventions aimed at mitigating age-related dysfunctions and enhancing healthy life expectancies., (© The Author(s) 2025. Published by Oxford University Press on behalf of the Japanese Biochemical Society. All rights reserved.)

Metal-organic frameworks (MOFs) provide diverse applications across a wide range of scientific disciplines, including drug/nucleic acid (NA) delivery. In the subclass of MOFs, zeolitic imidazolate framework-8 (ZIF-8) is well regarded due to its exceptional physicochemical properties. Biomolecules can be encapsulated and released under precise conditions within ZIF, making it an important material for materials science and biomedical applications. Different solvents and synthesis methods influence the ZIF's topologies and framework structures. The physicochemical properties of plasmid-encapsulated ZIF (plasmid@ZIF) can be controlled by tuning the precursors and biomolecular concentration. Using plasmid@ZIF, this study demonstrated that nucleic acids can be loaded precisely and released with a controlled bioactivity within cells. It was found that the ZIF phases substantially influenced both NA delivery into the cell and physicochemical properties. As a result of this study, we better understand MOFs' potential in NA delivery, and it emphasizes the importance of precisely controlling their physicochemical properties.

Wilms tumors are commonly associated with predisposition syndromes. Many of these syndromes are associated with specific phenotypic features and are discussed in the related article from the AACR Pediatric Cancer Working Group. Guidelines for surveillance in this population were published in 2017, but since then several studies have identified new genes with recurrent pathogenic variants associated with increased risk for Wilms tumor development. In general, variants in these genes are less likely to be associated with other phenotypic features. Recently, members of the AACR Pediatric Cancer Working Group met to update surveillance guidelines for patients with a predisposition to Wilms tumors with a review of recently published evidence and risk estimates. Risk estimates for Wilms tumor for the more recently described genes are discussed here along with suggested surveillance guidelines for these populations. Several other emerging clinical scenarios associated with Wilms tumor predisposition are also discussed, including patients with family histories of Wilms tumor and no identified causative gene, patients with bilateral tumors, and patients with somatic mosaicism for chromosome 11p15.5 alterations. This perspective serves to update pediatric oncologists, geneticists, radiologists, counselors, and other health care professionals on emerging evidence and harmonize updated surveillance recommendations in the North American and Australian context for patients with emerging forms of Wilms tumor predisposition., (©2024 American Association for Cancer Research.)

After the World Health Organization established a precise definition of mucinous cystic neoplasm (MCN) in 2000, based on the presence of ovarian-type stroma, its clinical features became more apparent. Surgery for MCN, which primarily affects middle-aged women with long life expectancies, is likely to negatively impact the patient's quality of life. Although recent studies have reported a low proportion of advanced neoplasia among resected MCN (≤15%), many clinicians still recommend surgery for patients with presumed MCN without considering risk stratification for advanced neoplasia. Recent studies have demonstrated that, when appropriate patient groups are established based on high-risk characteristics, there is no difference in long-term prognosis between a surveillance strategy and surgery. Additionally, while most guidelines do not recommend post-resection surveillance for MCN, research indicates that surveillance of non-resected MCN is more cost-effective than surgery when considering the expenses of post-pancreatectomy diabetic care. It is time to carefully consider a surveillance strategy, despite the significant misdiagnosis rates associated with MCN diagnosis based solely on imaging without histology., (© 2025 Japanese Society of Hepato‐Biliary‐Pancreatic Surgery.)

Genome-wide association studies have identified approximately 200 genetic risk loci for breast cancer, but the causal variants and target genes are mostly unknown. We sought to fine-map all known breast cancer risk loci using genome-wide association study data from 172,737 female breast cancer cases and 242,009 controls of African, Asian and European ancestry. We identified 332 independent association signals for breast cancer risk, including 131 signals not reported previously, and for 50 of them, we narrowed the credible causal variants down to a single variant. Analyses integrating functional genomics data identified 195 putative susceptibility genes, enriched in PI3K/AKT, TNF/NF-κB, p53 and Wnt/β-catenin pathways. Single-cell RNA sequencing or in vitro experiment data provided additional functional evidence for 105 genes. Our study uncovered large numbers of association signals and candidate susceptibility genes for breast cancer, uncovered breast cancer genetics and biology, and supported the value of including multi-ancestry data in fine-mapping analyses., Competing Interests: Competing interests: O.I.O is co-founder at CancerIQ, serves as Scientific Advisor at Tempus and is on the Board of 54gene. The other authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Nature America, Inc.)

In this issue of Molecular Cell, studies by Xu et al., 1 Kimble et al., 2 and Elango et al. 3 examine how yeast and mammalian cells process DNA double-strand breaks that arise when the DNA replication machinery encounters a DNA nick., Competing Interests: Declaration of interests The authors declare no conflicts of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Nuclear speckles are dynamic nuclear bodies characterized by high concentrations of factors involved in RNA production. Although the contents of speckles suggest multifaceted roles in gene regulation, their biological functions are unclear. Here we investigate speckle variation in human cancer, finding two main signatures. One speckle signature was similar to healthy adjacent tissues, whereas the other was dissimilar, and considered an aberrant cancer speckle state. Aberrant speckles show altered positioning within the nucleus, higher levels of the TREX RNA export complex and correlate with poorer patient outcomes in clear cell renal cell carcinoma (ccRCC), a cancer typified by hyperactivation of the HIF-2α transcription factor. We demonstrate that HIF-2α promotes physical association of certain target genes with speckles depending on HIF-2α protein speckle-targeting motifs, defined in this study. We identify homologous speckle-targeting motifs within many transcription factors, suggesting that DNA-speckle targeting may be a general gene regulatory mechanism. Integrating functional, genomic and imaging studies, we show that HIF-2α gene regulatory programs are impacted by speckle state and by abrogation of HIF-2α-driven speckle targeting. These findings suggest that, in ccRCC, a key biological function of nuclear speckles is to modulate expression of select HIF-2α-regulated target genes that, in turn, influence patient outcomes. Beyond ccRCC, tumour speckle states broadly correlate with altered functional pathways and expression of speckle-associated gene neighbourhoods, exposing a general link between nuclear speckles and gene expression dysregulation in human cancer., Competing Interests: Competing interests: A.R. receives royalties from LGC/Biosearch Technologies related to Stellaris RNA-FISH. The other authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Nature Limited.)

Nasopharyngeal carcinoma (NPC) presents a substantial clinical challenge due to the limited understanding of its genetic underpinnings. Here we conduct the largest scale whole-exome sequencing association study of NPC to date, encompassing 6,969 NPC cases and 7,100 controls. We unveil 3 germline genetic variants linked to NPC susceptibility: a common rs2276868 in RPL14, a rare rs5361 in SELE, and a common rs1050462 in HLA-B. We also underscore the critical impact of rare genetic variants on NPC heritability and introduce a refined composite polygenic risk score (rcPRS), which outperforms existing models in predicting NPC risk. Importantly, we reveal that the polygenic risk for NPC is mediated by EBV infection status. Utilizing a comprehensive multiomics approach that integrates both bulk-transcriptomic (n = 356) and single-cell RNA sequencing (n = 56) data with experimental validations, we demonstrate that the RPL14 variant modulates the EBV life cycle and NPC pathogenesis. Furthermore, our data indicate that the SELE variant contributes to modifying endothelial cell function, thereby facilitating NPC progression. Collectively, our study provides crucial insights into the intricate genetic architecture of NPC, spotlighting the vital interplay between genetic variations and tumor microenvironment components, including EBV and endothelial cells, in predisposing to NPC. This study opens new avenues for advancements in personalized risk assessments, early diagnosis, and targeted therapies for NPC.

Importance: The current standard-of-care salvage therapy in relapsed/refractory classic Hodgkin lymphoma (cHL) includes consolidation high-dose chemotherapy (HDCT)/autologous stem cell transplant (aSCT)., Objective: To investigate whether presalvage risk factors and fludeoxyglucose-18 (FDG) positron emission tomography (PET) response to reinduction chemotherapy can guide escalation or de-escalation between HDCT/aSCT or transplant-free consolidation with radiotherapy to minimize toxic effects while maintaining high cure rates., Design, Setting, and Participants: EuroNet-PHL-R1 was a nonrandomized clinical trial that enrolled patients younger than 18 years with first relapsed/refractory cHL across 68 sites in 13 countries in Europe between January 2007 and January 2013. Data were analyzed between September 2022 and July 2024., Intervention: Reinduction chemotherapy consisted of alternating IEP (ifosfamide, etoposide, prednisolone) and ABVD (adriamycin, bleomycin, vinblastine, dacarbazine). Patients with low-risk disease (late relapse after 2 cycles of first-line chemotherapy and any relapse with an adequate response after 1 IEP/ABVD defined as complete metabolic response on FDG-PET and at least 50% volume reduction) received a second IEP/ABVD cycle and radiotherapy (RT) to all sites involved at relapse. Patients with high-risk disease (all primary progressions and relapses with inadequate response after 1 IEP/ABVD cycle) received a second IEP/ABVD cycle plus HDCT/aSCT with or without RT., Main Outcomes and Measures: The primary end point was 5-year event-free survival. Secondary end points were overall survival (OS) and progression-free survival (PFS). PFS was identical to event-free survival because no secondary cancers were observed. PFS data alone are presented for simplicity., Results: Of 118 patients analyzed, 58 (49.2%) were female, and the median (IQR) age was 16.3 () years. The median (IQR) follow-up was 67.5 (58.5-77.0) months. The overall 5-year PFS was 71.3% (95% CI, 63.5%-80.1%), and OS was 82.7% (95% CI, 75.8%-90.1%). For patients in the low-risk group (n = 59), 41 received nontransplant salvage with a 5-year PFS of 89.7% (95% CI, 80.7%-99.8%) and OS of 97.4% (95% CI, 92.6%-100%). In contrast, 18 received HDCT/aSCT off protocol, with a 5-year PFS of 88.9% (95% CI, 75.5%-100%) and OS of 100%. All 59 patients with high-risk disease received HDCT/aSCT (and 23 received post-HDCT/aSCT RT) with a 5-year PFS of 53.3% (95% CI, 41.8%-67.9%) and OS of 66.5% (95% CI, 54.9%-80.5%)., Conclusion and Relevance: In this nonrandomized clinical trial, FDG-PET response-guided salvage in relapsed cHL may identify patients in whom transplant-free salvage achieves excellent outcomes. HDCT/aSCT may be reserved for primary progression and relapsed cHL with inadequate response., Trial Registration: ClinicalTrials.gov Identifier: NCT00433459.

Background/aims: Hepatocellular carcinoma (HCC) exhibits significant sex disparities in incidence, yet its molecular mechanisms remain unclear. We explored the role of telomerase reverse transcriptase (TERT) genetic alterations and hepatitis B virus (HBV) integration, both known major contributors to HCC, in sex-specific risk for HBV-related HCC., Methods: We examined 310 HBV-related HCC tissues to investigate sex-specific TERT promoter (TERT-pro) mutations and HBV integration profiles, stratified by sex and age, and validated with single-cell RNA sequencing (scRNA-seq) data., Results: Tumors predominantly exhibited TERT-pro mutations (26.0% vs. 0%) and HBV-TERT integration (37.0% vs. 3.0%) compared to non-tumorous tissues. While TERT-pro mutations increased with age in both sexes, younger males (≤60 years) showed marked predominance compared to younger females. Males had significantly more HBV integrations at younger ages, while females initially had fewer integrations that gradually increased with age. Younger males' integrations showed significantly greater enrichment in the TERT locus compared to younger females, alongside a preference for promoters, PreS/S regions, and CpG islands. Overall, TERT genetic alterations were significantly sex-differential in younger individuals (75.3% in males vs. 23.1% in females) but not in older individuals (76.9% vs. 83.3%, respectively). These alterations were associated with increased TERT expression. The skewed TERT abnormalities in younger males were further corroborated by independent scRNA-seq data., Conclusions: Our findings highlight the critical role of TERT alterations and HBV integration patterns in the male predominance of HCC incidence among younger HBV carriers, offering insights for future exploration to optimize sex-specific patient care and HCC surveillance strategies.

Replication fork collision with a DNA nick can generate a one-ended break, fostering genomic instability. The opposing fork's collision with the nick could form a second DNA end, enabling conservative repair by homologous recombination (HR). To study mechanisms of nickase-induced HR, we developed the Flp recombinase "step arrest" nickase in mammalian cells. A Flp-nick induces two-ended, BRCA2/RAD51-dependent short tract gene conversion (STGC), BRCA2/RAD51-independent long tract gene conversion, and discoordinated two-ended invasions. HR pathways induced by a replication-independent break and the Flp-nickase differ in their dependence on BRCA1, MRE11, and CtIP. To determine the origin of the second DNA end during Flp-nickase-induced STGC, we blocked the opposing fork using a Tus/Ter replication fork barrier (RFB). Flp-nickase-induced STGC remained robust and two ended. Thus, a single replication fork's collision with a Flp-nick triggers two-ended HR, possibly reflecting replicative bypass of lagging strand nicks. This response may limit genomic instability during replication of nicked DNA., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Competing Interests: HH serves without remuneration on an external advisory board of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, on the International Advisory Board of the University of Vienna, and on the external Executive Advisory Committee of the Sylvester Comprehensive Cancer Center, University of Miami Health System, and as a member of the Standing Advisory Group on Nuclear Applications of the International Atomic Energy Agency. Until Oct 31, 2024, HH also served without remuneration on the Scientific Committee of the German Cancer Research Center (DKFZ) and the Board of Trustees of the DKFZ. She is remunerated for serving on the Board of Directors of Ion Beam Applications and receives stock options for serving on the Board of Directors of iCAD. Her work is partly supported by funding to her institution (Memorial Sloan-Kettering Center support grant/core grant P30 CA008748) from the US National Institutes of Health (NIH)–National Cancer Institute (NCI). JOP reports uncompensated service as President of the Swiss Society of Nuclear Medicine, service to the World Federation of Nuclear Medicine and Biology as the focal point for technical collaboration with WHO, and service as the President of Section and Board of Nuclear Medicine of the European Union of Medical Specialists. AM reports that her work is partly supported by funding to her institution (Memorial Sloan-Kettering Center support grant/core grant P30 CA008748) from NIH–NCI. BA reports support for attending meetings or travel from the International Society of Radiology and the American College of Radiology. AMS reports institutional research funding from the Australian National Health and Medical Research Council, Medical Research Future Fund, and National Imaging Facility; patents planned, issued or pending for his role as an inventor of antibodies to HER2, ADAMs, EGFR, and Ephs; uncompensated participation on data safety monitoring or advisory boards for Telix and ImunOs; uncompensated service as a board member for the Australia and New Zealand Society of Nuclear Medicine and World Federation of Nuclear Medicine and Biology and as theme chair of the National Imaging Facility; stock holdings as founder and Director of Certis Therapeutics; and research and trial funding to his institution from Telix, Clarity, Fusion, Antengene, EMD Serono, ITM, Avid/Lily, Medimmune, and Cyclotek. All other authors declare no competing interests.

Technological innovations in genomics and related fields have facilitated large sequencing efforts, supported new biological discoveries in cancer, and spawned an era of liquid biopsy biomarkers. Despite these advances, precision oncology has practical constraints, partly related to cancer's biological diversity and spatial and temporal complexity. Advanced imaging technologies are being developed to address some of the current limitations in early detection, treatment selection and planning, drug delivery, and therapeutic response, as well as difficulties posed by drug resistance, drug toxicity, disease monitoring, and metastatic evolution. We discuss key areas of advanced imaging for improving cancer outcomes and survival. Finally, we discuss practical challenges to the broader adoption of precision imaging in the clinic and the need for a robust translational infrastructure., Competing Interests: Declaration of interests HH serves on the board of directors for Ion Beam Applications; the external advisory board of the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University; the international advisory board of the University of Vienna; the scientific committee and board of trustees of the DKFZ (German Cancer Research Center); the board of directors of iCAD; the advisory board of The Lancet Oncology; and receives stock options from iCAD. KH receives grants from Novartis and Sofie Biosciences; has consulted for Advanced Accelerator Applications, Amgen, AstraZeneca, Bain Capital, Bayer, Boston Scientific, Convergent, Curium, Debiopharm, EcoR1, Fusion, GE Healthcare, Immedica, Isotopen Technologien München, Janssen Pharmaceuticals, Merck, Molecular Partners, NVision, POINT Biopharma, Pfizer, Radiopharm Theranostics, Rhine Pharma, Siemens Healthineers, Sofie Biosciences, Telix, Theragnostics, and Y-mAbs Therapeutics; has stock options in Sofie Biosciences, Pharma15, Vision, Convergent, Aktis Oncology, AdvanCell; is an advisory board member of Fusion and GE Healthcare; receives honoraria from PeerView; and has received travel support from Janssen Pharmaceuticals. JSL reports research support from Clarity Pharmaceuticals and Avid Radiopharmaceuticals; has acted as an advisor for Alpha-9 Theranostics, Boxer, Clarity Pharmaceuticals, Earli, Curie Therapeutics, Evergreen Theragnostics, West Street Life Sciences, Inhibrx, Luminance Biosciences, NexTech Venture, Sanofi US Services, Solve Therapeutics, Suba Therapeutics, TPG Capital, Telix Pharmaceuticals, pHLIP, and Precirix; is a co-inventor on technologies licensed to Diaprost, Elucida Oncology, Theragnostics, CheMatech, Daiichi Sankyo, and Samus Therapeutics; is the co-founder of pHLIP; holds equity in Summit Biomedical Imaging, Telix Pharmaceuticals, Clarity Pharmaceuticals, and Evergreen Theragnostics; and is supported by National Institutes of Health grant R35 CA232130. MGP has consulted for CraniUS, UCLA Cancer Center, Ventyx, Einseca, and ModeX; receives royalties from Lantheus Holdings, Novartis, Intuitive Surgical and Cyclotek; has 70 patents issued or filed related to imaging or informatics; and has stock options in D&D Pharmatech, PlenaryAI, Earli, and Immunosity. AMS reports trial funding from EMD Serono, ITM, Telix Pharmaceuticals, AVID Radiopharmaceuticals, Fusion Pharmaceuticals, and Cyclotek; research funding from Medimmune, AVID Radiopharmaceuticals, Adalta, Antengene, Humanigen, Telix Pharmaceuticals, and Theramyc; and payment for participation in advisory boards of Imagion and Immunos. RW has consulted for ModeRNA, Boston Scientific, Lumicell, Seer Biosciences, Earli, and Accure Health. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Introduction: Long-acting injectable cabotegravir (CAB-LA) for pre-exposure prophylaxis significantly reduced HIV acquisition in HPTN 084. We report on the safety and CAB-LA pharmacokinetics in pregnant women during the blinded period of HPTN 084., Methods: Participants were randomized 1:1 to either active cabotegravir (CAB) plus tenofovir disoproxil fumarate/emtricitabine (TDF/FTC) placebo or active TDF/FTC plus CAB placebo. Pregnancy testing was performed at each visit; participants with a positive test had study product withheld and were offered open-label TDF/FTC. Pregnancies were confirmed on two tests at least 4 weeks apart. All participants with a positive pregnancy test prior to November 5, 2020 are included in this analysis. Pregnancy incidence, maternal adverse event (AE) incidence, pregnancy outcomes (including composite outcome of spontaneous abortion <20 weeks, intrauterine foetal death or stillbirth ≥20 weeks, premature birth <37 weeks, or small for gestational age) were assessed. The apparent terminal phase half-life (t 1/2app ) of CAB-LA in pregnant women in HPTN 084 was compared to non-pregnant women from the phase 2a HPTN 077 trial. Multivariable models assessed associations with t 1/2app. RESULTS: Fifty-seven pregnancies (30 CAB-LA, 27 TDF/FTC) were confirmed over 3845 person-years [py] (incidence 1.5/100 py, 95% CI 1.1-1.9). CAB-LA group participants had a median 342 days (IQR 192, 497) of CAB-LA exposure prior to pregnancy detection. Grade 2 or higher maternal AE incidence did not differ by study arm (CAB 157, 95% CI 91-271 per 100 py vs. TDF/FTC 217, 95% CI 124-380 per 100 py; p = 0.256). Most pregnancies (81%) resulted in live births (25 CAB-LA, 22 TDF/FTC). Composite poor pregnancy outcomes did not differ significantly by group (CAB 6/30 vs. TDF/FTC 4/27; p = 0.476). No congenital anomalies were observed. The CAB t 1/2app geometric mean was 52.8 days (95% CI 40.7-68.4) in pregnant women compared to 60.3 days (95% CI 47.7-76.3; p = 0.66) in non-pregnant women; neither pregnancy nor body mass index were significantly associated with t 1/2app ., Conclusions: CAB-LA concentrations post-cessation of injections were generally well tolerated in pregnant women. The t 1/2app was comparable between pregnant and non-pregnant women. Ongoing studies will examine the safety and pharmacology of CAB-LA in women who choose to continue CAB-LA through pregnancy and lactation., (© 2025 The Author(s). Journal of the International AIDS Society published by John Wiley & Sons Ltd on behalf of the International AIDS Society.)

Competing Interests: Competing interests: The authors declare no competing interests.

Dioscin is a natural plant-derived steroidal saponin that exerts antitumor effects in multiple cancers. It is widely involved in multiple apoptotic pathways and exerts its anti-tumor effects. In this study, we discovered that Dioscin treatment increased the expression of Noxa, thereby inducing the apoptosis of OSCC cells. Previous reports indicate that dysfunction of the BMI1-Noxa axis is frequently observed in multiple cancers. Our study revealed that Dioscin upregulates Noxa by impairing the protein expression of BMI1 in OSCC cells. Dioscin promotes the ubiquitination of BMI1 and facilitates its degradation, leading to upregulation of Noxa expression at the mRNA level and activation of apoptosis. Additionally, Dioscin exhibited potent tumor suppression in xenograft tumor models. In conclusion, our research provides new insights and strategies for inhibiting OSCC cells by investigating the ant-tumor mechanism of the natural compound Dioscin., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Malignant tumors have been a serious threat to human health with their increasing incidence. Difficulties with conventional treatments are toxicity, drug resistance, and recurrence. For this reason, non-invasive treatment modalities such as photothermal therapy (PTT), photodynamic therapy (PDT), chemodynamic therapy (CDT), and others have received much attention. Among them, Ferrocene (Fc)-based nanomedicines for enhanced Chemodynamic Therapy (ECDT) is a new therapeutic strategy based on the Fenton reaction. Based on ferrocene's good biocompatibility, potentiation in medicinal chemistry, and good stability of divalent iron ions, scientists are increasingly using it as a Fenton's iron donor for tumor therapy. Such ferrocene-based ECDT nanoplatforms have shown remarkable promise for clinical applications and have significantly increased the efficacy of CDT treatment. Ferrocene-based nanomedicines exhibit exceptional consistency owing to their low toxicity, high stability, enhanced bioavailability, and a multitude of advantages over conventional approaches to cancer treatment. As a consequence, a number of tactics have been investigated in recent years to raise the effectiveness of ferrocene-based ECDT. In this review, we detail the different forms and strategies used to enhance Ferrocene-based ECDT efficiency., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Cancer research has been significantly advanced by the integration of transcriptomic data through high-throughput sequencing technologies like RNA sequencing (RNA-seq). This paper reviews the transformative impact of transcriptomics on understanding cancer biology, focusing on the use of extensive datasets such as The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx). While transcriptomic data provides crucial insights into gene expression patterns and disease mechanisms, the analysis is fraught with technical and biological biases. Technical biases include issues related to microarray, RNA-seq, and nanopore sequencing methods, while biological biases arise from factors like tumor heterogeneity and sample purity. Additionally, misinterpretations often occur when correlational data is erroneously assumed to imply causality or when bulk data is misattributed to specific cell types. This review emphasizes the need for researchers to understand and mitigate these biases to ensure accurate data interpretation and reliable clinical outcomes. By addressing these challenges, the paper aims to enhance the robustness of cancer research and improve the application of transcriptomic data in developing effective therapies and diagnostic tools., Competing Interests: Competing Interests: The authors have declared that no competing interest exists., (© The author(s).)

Stem cells reside in specialized microenvironments, termed niches, at several different locations in tissues 1-3 . The differential functions of heterogeneous stem cells and niches are important given the increasing clinical applications of stem-cell transplantation and immunotherapy. Whether hierarchical structures among stem cells at distinct niches exist and further control aspects of immune tolerance is unknown. Here we describe previously unknown new hierarchical arrangements in haematopoietic stem cells (HSCs) and bone marrow niches that dictate both regenerative potential and immune privilege. High-level nitric oxide-generating (NO hi ) HSCs are refractory to immune attack and exhibit delayed albeit robust long-term reconstitution. Such highly immune-privileged, primitive NO hi HSCs co-localize with distinctive capillaries characterized by primary ciliated endothelium and high levels of the immune-checkpoint molecule CD200. These capillaries regulate the regenerative functions of NO hi HSCs through the ciliary protein IFT20 together with CD200, endothelial nitric oxide synthase and autophagy signals, which further mediate immunoprotection. Notably, previously described niche constituents, sinusoidal cells and type-H vessels 2-10 co-localize with less immune-privileged and less potent NO low HSCs. Together, we identify highly immune-privileged, late-rising primitive HSCs and characterize their immunoprotective niches comprising specialized vascular domains. Our results indicate that the niche orchestrates hierarchy in stem cells and immune tolerance, and highlight future immunotherapeutic targets., Competing Interests: Competing interests: S.C.R. is a scientific founder of Purinomia Biotech and consults for eGenesis; his interests are reviewed and managed by HMFP at the Beth Israel Deaconess Medical Center following their conflict-of-interest policies. All other authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Nature Limited.)

Hepatocellular carcinoma (HCC) originates from differentiated hepatocytes undergoing compensatory proliferation in livers damaged by viruses or metabolic-dysfunction-associated steatohepatitis (MASH) 1 . While increasing HCC risk 2 , MASH triggers p53-dependent hepatocyte senescence 3 , which we found to parallel hypernutrition-induced DNA breaks. How this tumour-suppressive response is bypassed to license oncogenic mutagenesis and enable HCC evolution was previously unclear. Here we identified the gluconeogenic enzyme fructose-1,6-bisphosphatase 1 (FBP1) as a p53 target that is elevated in senescent-like MASH hepatocytes but suppressed through promoter hypermethylation and proteasomal degradation in most human HCCs. FBP1 first declines in metabolically stressed premalignant disease-associated hepatocytes and HCC progenitor cells 4,5 , paralleling the protumorigenic activation of AKT and NRF2. By accelerating FBP1 and p53 degradation, AKT and NRF2 enhance the proliferation and metabolic activity of previously senescent HCC progenitors. The senescence-reversing and proliferation-supportive NRF2-FBP1-AKT-p53 metabolic switch, operative in mice and humans, also enhances the accumulation of DNA-damage-induced somatic mutations needed for MASH-to-HCC progression., Competing Interests: Competing interests: M.K. is a founder and stockholder in Elgia Pharmaceuticals and received research support from Merck and Janssen Pharmaceuticals and holds a patent for the use of MUP-uPA mice as a NASH-HCC model. L.B.A. is a compensated consultant and has equity interest in io9 and Genome Insight; his spouse is an employee of Biotheranostics. L.B.A. is also listed as an inventor on US Patent 10,776,718 for source identification by non-negative matrix factorization. L.B.A. declares US provisional applications with the following serial numbers: 63/289,601, 63/269,033, 63/483,237, 63/366,392 and 63/367,846. L.B.A. and S.P.N. also declare US provisional applications with serial numbers 63/412,835 and 63/492,348. The other authors declare no competing interests., (© 2025. The Author(s), under exclusive licence to Springer Nature Limited.)

While immunotherapy with immune checkpoint inhibitors (ICIs) has revolutionized the clinical management of various malignancies, a large fraction of patients are refractory to ICIs employed as standalone therapeutics, necessitating the development of combinatorial treatment strategies. Immunogenic cell death (ICD) inducers have attracted considerable interest as combinatorial partners for ICIs, at least in part owing to their ability to initiate a tumor-targeting adaptive immune response. However, compared with either approach alone, combinatorial regimens involving ICD inducers and ICIs have not always shown superior clinical activity. Here, we discuss accumulating evidence on the therapeutic interactions between ICD inducers and immunotherapy with ICIs in oncological settings, identify key factors that may explain discrepancies between preclinical and clinical findings, and propose strategies that address existing challenges to increase the efficacy of these combinations in patients with cancer., Competing Interests: Competing interests: LG holds research contracts with Lytix Biopharma, Promontory and Onxeo; Has received consulting/advisory honoraria from Boehringer Ingelheim, AstraZeneca, AbbVie, OmniSEQ, Onxeo, The Longevity Labs, Inzen, Imvax, Sotio, Promontory, Noxopharm, EduCom, and the Luke Heller TECPR2 Foundation; and holds Promontory stock options. The other authors have no conflicts of interest to declare., (© 2024. The Author(s).)

Significance: There is intratumor heterogeneity in the stabilization of missense mutant p53, and it has been thought that only cells with nuclear accumulation of mutant p53 have oncogenic function. However, using mouse intestinal tumor-derived organoids, we show that mutant p53-stabilized cells transactivate Wnt/β-catenin signaling in neighboring p53-destabilized cells through activating the COX-2/PGE2 pathway. These results suggest that both p53-stabilized cells and p53-destabilized cells contribute to malignant progression through interaction within the intratumor microenvironment., (©2024 The Authors; Published by the American Association for Cancer Research.)

Cellular iron plays a crucial role in many crucial physiological processes. Excessive iron retention due to iron influx and efflux imbalance contributes to cancer development and proliferation, as well as malignant conversion. Membrane-type 1 matrix metalloproteinase (MT1-MMP) plays a crucial role in tumor invasion and metastasis, because this enzyme can degrade various extracellular matrix components and cleave membrane tethered proteins on the cell surface. Herein, we demonstrate that cellular iron regulates MT1-MMP-mediated proMMP-2 activation and thereby cancer cell invasion. Iron depletion downregulated MT1-MMP expression in cancer cells, accompanied by inhibition of proMMP-2 activation. Conversely, iron loading stimulated MT1-MMP expression and MT1-MMP-containing extracellular vesicle secretion, thereby promoting proMMP-2 activation, which was inhibited through antioxidant treatment. Iron chelator deferasirox suppressed cancer cell invasion but not fibroblasts. Thus, this study indicated that iron accumulation in cancer may contribute to not only cell proliferation but also invasion by activating the MT1-MMP-MMP-2 axis., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Store-operated calcium (Ca 2+ ) entry (SOCE) represents a major route of Ca 2+ permeation across the plasma membrane (PM) in nonexcitable cells, which plays an indispensable role in maintaining intracellular Ca 2+ homeostasis. This process is orchestrated through the dynamic coupling between the endoplasmic reticulum (ER)-localized Ca 2+ sensor stromal interaction molecule 1 (STIM1) and the PM-resident ORAI1 channel. Upon depletion of ER Ca 2+ stores, STIM1 undergoes conformational rearrangements and oligomerization, leading to the translocation of activated STIM1 toward the PM. This movement is facilitated by the physical interactions between positively charged cytosolic domains within STIM1 and negatively charged phospholipids embedded in the PM, ultimately enabling its binding to and activation of the PM-embedded ORAI1 channel. In this mini-review, we provide an overview of STIM1-mediated Ca 2+ signaling at ER-PM contact sites, highlighting the regulatory roles of phospholipids in the inner leaflet and sphingolipids in the outer leaflet of the PM. We also discuss the development of molecular tools that enable real-time visualization and manipulation of membrane contact sites (MCSs) at ER-PM junctions. Finally, we highlight recent progress in developing targeted therapies for human diseases linked to STIM1 mutations and dysregulated Ca 2+ signaling at ER-PM MCSs.

Introduction: Social support can play an important role in the care of older adults living with cancer. However, different patterns of social support, such as emotional, instrumental, informational, appraisal, and giving support need to be considered to facilitate adjustments to cancer. This study aimed to explore the distinct patterns of social support among older adults with cancer and examine the socio-demographic variables and patient-reported outcomes that may be associated with patterns of social support., Materials and Methods: Data were used from 7,097 respondents from the Experience of Cancer Patients in Transition Study administered in 2016. Socio-demographic variables included sex, age, marital status, place of residence, and income, alongside patient-reported outcomes. Latent class analysis was used to identify distinct social support patterns. Multivariable multinomial regression models were then used to determine predictors of these latent classes., Results: Three latent classes of social support were identified: "low," "moderate," and "high" emotional support. Having "high" emotional support did not necessarily mean patients had the highest levels of all social support attributes. For example, the "low" emotional support group exhibited the highest appraisal support (16 % of class members) and giving support (42 % of class members). While most socio-demographic variables were not significant predictors of the latent classes, statistically significant differences were found in emotional health., Discussion: Assessing social support requires consideration of the different patterns of support, as the presence of one attribute (e.g., appraisal or giving support) does not ensure the coverage of others (e.g., emotional support). Comprehensive assessments of these varied support patterns are recommended to better address the psychological and emotional challenges associated with a cancer diagnosis and to inform subsequent interventions., Competing Interests: Declaration of Competing Interest There is no conflicts of interest to report., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Our previous studies have shown that estrogen receptor beta (ERβ) can promote the progression of clear cell renal cell carcinoma (ccRCC) by downregulating the expression of circATP2B1 and miR-204-3p. Here, we found that ERβ might promote the epithelial-mesenchymal transition(EMT) of ccRCC by modulating the circATP2B1/miR-204-3p/TWIST1(Twist family basic helix-loop-helix transcription factor 1) signaling pathway., Methods: We utilized bioinformatics analysis to determine the clinical significance of TWIST1 in ccRCC. The expression of TWIST1 in ccRCC tissues and cells was examined using immunohistochemistry, real-time quantitative polymerase chain reaction and western blotting assay. Chromatin Immunoprecipitation assay were conducted to validate the relationship between ERβ and TWIST1. Luciferase reporter gene assays were employed to validate the binding targets of TWIST1 and miR-204-3p. The role of TWIST1 in ccRCC was studied through in vitro and in vivo experiments. Transwell assays and wound healing assays were used to assess the impact of TWIST1 on the invasive and migratory abilities of ccRCC cells., Results: Mechanism analysis revealed that miR-204-3p can inhibit TWIST1 by targeting its 3' untranslated region. Additionally, TWIST1 can promote ERβ transcription by directly binding to transcription factor binding site in the ERβ promoter region, forming a positive feedback loop. These in vitro data were further validated in an in vivo mouse model. Importantly, analysis of data from the TCGA-KIRC database further confirmed the above in vitro/in vivo findings., Conclusions: Together, our results suggest that ERβ/circATP2B1/miR-204-3p/TWIST1 can promote EMT by forming a positive feedback loop, thus promoting the progression of ccRCC. Targeting this newly identified signaling pathway may more effectively control the progression of ccRCC., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024. Published by Elsevier Inc.)

Cancer cell membrane-derived nanoparticle drug delivery system enables precise drug delivery to tumor tissues and is a new effective way to treat solid tumors. The aim of this study is to develop a safe and effective cancer cell membrane-derived nano-delivery system targeting gastric cancer. We previously reported that EPH receptor A2 (EphA2) is an important target for gastric cancer. RNA m6A methyltransferases METTL3 is upregulated in multiple cancers and promotes cancer development by increasing the expression of multiple oncogenes. We design a new nano-delivery system PLGA-STM-TAT: nanoparticles PLGA (poly lactic acid-hydroxyacetic acid) loaded with METTL3 inhibitor STM2457 and cell-penetrating peptide TAT, and then covered with gastric cancer cell membranes equipped with YSA peptides by means of click chemistry, which targeting EphA2. The nanoparticles are specifically enriched in gastric cancer tissues, significantly increased drug accumulation, and inhibited cancer cell proliferation by decreasing key oncogenes c-MYC and BRD4. During drug administration, we found that the expression of the immune checkpoint molecule PD-L1 was suppressed, and the anti-tumor immune effect was enhanced by the nano-delivery system in combination with anti-PD1. This cancer cell membrane-derived nano-delivery system provides a new biological strategy to treat gastric cancer through effective m6A modulation and EphA2 targeting. STATEMENT OF SIGNIFICANCE: M6A modifications have important biological roles, especially in tumors. Targeting highly modified m6A in gastric cancer becomes a challenge. We developed a nano-drug delivery system for modulating m6A that could produce an effective anti-cancer therapeutic effect and that the nanoparticles enhanced antitumor immunity when combined with anti-PD1.This cancer cell membrane-derived new nano-drug delivery system shows great promise as an antitumor approach by modulating m6A modification and targeting EphA2 in gastric cancers., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Non-Hodgkin lymphoma (NHL) represents the fourth most common malignant disease among children and adolescents. Current disease classifications, including the most recent World Health Organization (WHO) classification and the International Consensus Classification (ICC), rely on a combination of clinical, epidemiological, histologic, immunophenotypic, and molecular data to define discrete clinicopathologic entities. There is growing evidence that children, adolescents, and young adults (CAYA) with B-cell NHL display unique clinical and epidemiologic characteristics. This may be explained by distinct age-related developmental plasticity, immune and haematopoietic repertoires, environmental exposures and social determinants of health, and germline or acquired genetic and molecular features, including those associated with inborn errors of immunity (IEI). Here, we discuss the unique clinical and biological characteristics of several distinct paediatric B-cell NHL types to indicate a path forward in classification of these CAYA NHL to optimally support multidisciplinary patient care and personalized treatment. We propose a potential "arising in CAYA" classification qualifier to denote the distinct clinicopathologic characteristics of B-cell NHLs that, otherwise, histologically and immunophenotypically resemble those arising in middle-aged and older adults. We also discuss how haemopathology diagnoses are evolving to incorporate the most current scientific knowledge into future classification systems of CAYA B-cell NHL., (© 2024 The Author(s). Histopathology published by John Wiley & Sons Ltd.)

Protein phosphorylation is a dynamic, reversible posttranslational modification that plays an important role in the regulation of cell signaling. Recently, label-free quantitative (LFQ) phosphoproteomics has become a powerful tool to analyze the phosphorylation of proteins within complex samples. In this chapter, we describe how to apply LFQ phosphoproteomics that is based on Fe-IMAC phosphopeptide enrichment followed by strong anion exchange (SAX) and porous graphitic carbon (PGC) fractionation strategies for identification and quantification of changes in the phosphoproteome in the fission yeast Schizosaccharomyces pombe., (© 2025. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

According to morphological features, tumor-infiltrating B cells (TIL-Bs) can be classified as lympho-myeloid aggregates (LMAs) and tertiary lymphoid structures (TLSs). As a disease with high incidence and mortality, research on esophageal squamous cell carcinoma (ESCC) TIL-Bs is still unclear. Thus, we aimed to investigate the prognostic value and functional involvement of TIL-Bs in ESCC. Based on CD20 immunohistochemical staining of 147 ESCC samples, the TIL-Bs at different anatomic subregions (intra-tumor (T), invasive margin (IM) and peri-tumor (P)) were quantified and correlated with survival by Kaplan-Meier analyses. We found that LMAs were widely distributed throughout the whole section and were associated with poor prognosis, especially those located in the T subregion, which was contrary to the positive clinical significance of TLSs. Based on the number of LMAs and TLSs, a four-level immune type was constructed as an independent predictor for survival. Using multiplexed immunofluorescence (mIF) staining, we found that the main phenotype of infiltrating B cells in LMAs was CD20 + IgD - CD27 - double-negative (DN) B cells. DN B cells were abundant in ESCC tumor tissue, and their high expression was related to shortened overall survival time. Subsequently, we demonstrate a close relationship between DN B cells and regulatory T cells (Tregs) using single cell RNA-seq data, bulk RNA-seq data and flow cytometry, and verified the spatial proximity of DN B cells and Tregs by mIF staining. Trajectory analysis and flow cytometry revealed that DN B cells highly expressed genes involved in the antigen processing and presentation pathway, such as HLA-DR. The abundance of DN B cells and LMAs in ESCC provides novel potential targets for optimal immunotherapy against ESCC., Competing Interests: Declaration of competing interest The authors declare no conflict of interest and all authors have read the journal's authorship statement., (Copyright © 2024. Published by Elsevier Inc.)

The rational design of nanozymes with highly efficient reactive oxygen species (ROS) generation to overcome the resistant infection microenvironment still faces a significant challenge. Herein, the highly active Fe single-atom nanozymes (Fe SAzymes) with a hierarchically porous nanostructure were prepared through a colloidal silica-induced template method. The proposed Fe SAzymes with satisfactory oxidase (OD)-like and peroxidase (POD)-like activity can transform O 2 and H 2 O 2 to superoxide anion free radical (•O 2 - ) and hydroxyl radical (•OH), which possess an excellent bactericidal effect. Also, the glutathione peroxidase (GPX)-like activity of Fe SAzymes can consume glutathione in the infection microenvironment, thus facilitating ROS generation to enhance the sterilization effect. Besides, the intrinsic photothermal effect of Fe SAzymes further significantly boosts the enzyme-like activity to generate much more reactive oxygen species for efficient antibacterial therapy. Accordingly, both in vitro and in vivo results indicate that the Fe SAzymes with synergistically photothermal-catalytic performances exhibit satisfactory antibacterial effects and biocompatibility. This work provides new insights into designing highly efficient SAzymes for effective sterilization applications by an amount of ROS generation., Competing Interests: Declaration of Competing Interest We declare that we do not have any commercial or associative interest that represents a conflict of interest in connection with the work submitted., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Pancreatoduodenectomy in elderly patients may be associated with increased postoperative mortality, but studies in minimally invasive pancreatoduodenectomy (MIPD) are scarce., Methods: International multicenter retrospective study including patients aged >60 years undergoing MIPD (robot-assisted and laparoscopic) and open pancreatoduodenectomy (OPD), were categorized by age: 60-69, 70-79, and 80+ years. In each category, propensity score matching (PSM) was performed (1:1 ratio) between MIPD and OPD. Primary outcome was 30-day/in-hospital mortality., Results: Among 3820 patients, we matched 1468 patients aged 60-69, 1154 patients aged 70-79, and 196 patients aged 80+ years. In patients aged 60-69 and 70-79 years, MIPD was associated with longer operative time, less blood loss and a longer length of stay. Major morbidity was higher after MIPD with similar 30-day/in-hospital mortality. The R0 resection rate was higher after MIPD. In patients aged 80+ years, besides a longer operative time in MIPD, outcomes were comparable between both groups., Conclusion: This study found no evidence that increasing age worsens mortality of MIPD. MIPD was associated with longer operative time, higher rate of major morbidity, prolonged length of stay versus less blood loss and a higher R0 resection in patients aged 60-69 and 70-79 years. These differences continue in patients aged 80+ years, but became less evident., Competing Interests: Conflict of interest LRJ and MGB received funding from the Intuitive Surgical® for the investigator-initiated LEARNBOT study on safe implementation and training of robot pancreatoduodenectomy in Europe. MGB and MAH received funding from Intuitive Surgical® (LEARNBOT 24445; DIPLOMA-2 24904) and Ethicon EndoSurgery (994492729) to support the ongoing quality registry for minimally invasive pancreatic surgery in Europe and from Intuitive Surgical® for the investigator-initiated DIPLOMA-2 randomized trial comparing minimally invasive and open pancreaticoduodenectomy. The other authors have nothing to disclose relevant to this study or manuscript., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The endoplasmic reticulum (ER) is a dynamic organelle that is a site of the synthesis of proteins and lipids, contributing to the regulation of proteostasis, lipid metabolism, redox balance, and calcium storage/-dependent signaling events. The disruption of ER homeostasis due to the accumulation of misfolded proteins in the ER causes ER stress which activates the unfolded protein response (UPR) system through the activation of IRE1, PERK, and ATF6. Activation of UPR is observed in various cancers and therefore, its association with process of carcinogenesis has been of importance. Tumor cells effectively utilize the UPR system to overcome ER stress. Moreover, ER stress and autophagy are the stress response mechanisms operating together to maintain cellular homeostasis. In human cancers, ER stress-driven autophagy can function as either pro-survival or pro-death in a context-dependent manner. ER stress-mediated autophagy can have crosstalk with other types of cell death pathways including apoptosis and ferroptosis. In this connection, the present review has evaluated the role of ER stress in the regulation of autophagy-mediated tumorigenesis and its interactions with other cell death mechanisms such as apoptosis and ferroptosis. We have also comprehensively discussed the effect of ER stress-mediated autophagy on cancer progression and chemotherapeutic resistance., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Jadomycin B, a natural product isolated from Streptomyces venezuelae , exerts an anti-cancer effect on human triple negative breast cancer cells in vitro and has anti-tumoral effects in vivo in animal models of breast cancer. One proposed mechanism for this anti-cancer effect is through interaction with topoisomerase 2 (TOP2). Based on the previously described interactions between jadomycin B and TOP2 we hypothesized that jadomycin B will act additively with TOP2 poisons and produce a similar functional outcome in eliciting cell cycle arrest. Combined treatments of jadomycin B and the TOP2 poisons doxorubicin or mitoxantrone produced moderately synergistic to additive cytotoxicity (combination index values ranging from 0.72-0.94) in MDA-MB-231 cells. In comparison, combined mitoxantrone and doxorubicin produced additive cytotoxicity (combination index values 0.96-1.11). Jadomycin B combined with the proteosome inhibitor MG132 had additive cytotoxicity (combination index values 0.76-1.18). In contrast, mitoxantrone or doxorubicin cytotoxicity was antagonized by MG132 (combination index values 1.21-2.31). Jadomycin B treatment arrested cells in S-phase ( P  = 0.0024) as opposed to mitoxantrone which caused G 2 /M-phase arrest ( P  < 0.0001). In conclusion, jadomycin B interacts differently than known TOP2 poisons in combination, supporting a novel pharmacological mechanism(s) of action for jadomycin B cytotoxicity., Competing Interests: The authors declare there are no competing interests

Background: Auer rods (AuRs) are prominent intracellular structures found almost exclusively in myeloid cell malignancies, such as acute myeloid leukemia (AML), chronic and juvenile myelomonocytic leukemia and myelodysplastic syndrome. Extremely rare AuRs have been reported in patients with acute lymphoblastic leukemia (ALL) or among ambiguous lineage leukemia patients with a dominantly lymphoblastic immunophenotype., Procedure: We report diagnostic and follow-up data of an international cohort of 11 children suffering from leukemias with AuRs and with significant presence of T and myeloid markers, majority of whom categorized as early T-cell precursor (ETP, n = 7); or T-ALL (ETP status unknown, n = 2), ALAL (acute leukemia of ambiguous lineage, n = 1), and AML reclassified from ALAL (n = 1). We described other diagnostic details and treatment types and responses. Moreover, we summarize previously published data., Results: Among the four patients who started and remained on ALL-type therapy, all were in the first complete remission, whereas both patients who started and remained on AML-type therapy relapsed and died. Of the patients who followed either a combined ALL/AML protocol (Interfant 06) or who switched from one of the two types of therapy to the other, one patient died, and the remaining four were in first complete remission at the most recent follow-up. We also searched for similar cases in the literature and found only three additional children with nonmyeloid leukemia and AuRs and 10 adults with this type of leukemia., Conclusions: Briefly, ALL- or combined ALL/AML-type therapy may be effective for treating AuR-positive leukemia patients with a lymphoid immunophenotype., (© 2024 The Author(s). Pediatric Blood & Cancer published by Wiley Periodicals LLC.)

Purpose: Screening for nasopharyngeal carcinoma (NPC) has shown an improvement in early detection and survival rates of NPC in endemic regions. It is critical to evaluate whether NPC screening can reduce NPC-specific mortality in the population., Methods: Sixteen towns in Sihui and Zhongshan cities, China, were selected; eight were randomly allocated to the screening group and eight to the control group. Residents age 30-69 years with no history of NPC were included from January 1, 2008, to December 31, 2015. Residents in the screening towns were invited to undergo serum Epstein-Barr virus (EBV) viral capsid antigen/nuclear antigen 1-immunoglobulin A antibody tests; others received no intervention. The population was followed until December 31, 2019. Nonparametric tests and Poisson regression models were used to estimate the screening effect on NPC mortality, accounting for the cluster-randomized design. The trial is registered with ClinicalTrials.gov (identifier: NCT00941538)., Results: A total of 174,943 residents in the screening group and 186,263 residents in the control group were included. NPC incidence and overall mortality were similar between the two groups. A total of 52,498 (30.0% of 174,943) residents participated in the serum EBV antibody test. The overall compliance rate for endoscopic examination and/or biopsies among baseline and ever-classified high-risk participants was 65.9% (1,110 of 1,685) and 67.6% (1,703 of 2,518), respectively. A significant 30% reduction in NPC mortality was observed in the screening group compared with the control group (standardized NPC-specific mortality rate of 8.2 NPC deaths per 1,000 person-years versus 12.5; adjusted rate ratio [RR], 0.70 [95% CI, 0.49 to 0.997]; P = .048). This benefit was most evident among individuals age 50 years and older (RR, 0.56 [95% CI, 0.37 to 0.85]; P = .007) compared with those younger than 50 years (RR, 0.96 [95% CI, 0.64 to 1.46]; P = .856)., Conclusion: In this 12-year trial, EBV antibody testing resulted in a significant reduction in NPC mortality.

Background: Pan-immune inflammation value (PIV) is a newly defined biomarker that includes whole cellular components that are indicators of systemic inflammation in complete blood count (CBC), easily accessible and has the potential to reflect both the body's immune response and systemic inflammation status. This study evaluated the pretreatment PIV for its prognostic impact on overall survival (OS) in patients with metastatic castration-resistant prostate cancer (mCRPC) treated with Lutetium-177 ( 177 Lu)-PSMA-617., Methods: The PIV was based on the earliest CBC obtained within 1 month before treatment initiation. Patients were categorized into low and high PIV groups based on the median pretreatment PIV, and the relationship between OS and PIV groups was assessed by multivariable analysis., Results: A total of 43 patients with mCRPC treated with ( 177 Lu)-PSMA-617 were included. The median OS was longer in the low PIV group (15.1 months [95% confidence interval [CI] 10.6-19.5]) than in the high PIV group (4.2 months [95% CI 1.7-6.6]) (p < 0.001). In multivariable analysis, high PIV (hazard ratio [HR]: 4.3, 95% CI 1.194-15.93, p = 0.026) and high Eastern Cooperative Oncology Group performance score (HR: 7.05, 95% CI 1.48-33.46, p = 0.014) were associated with shorter OS., Conclusion: This study showed that pretreatment PIV might be a prognostic factor in patients with mCRPC treated with ( 177 Lu)-PSMA-617., (© 2024 Wiley Periodicals LLC.)

Background: The rapid increase in the number of patients with chronic diseases and depression, as well as the rapid spread of their effects, have led to these two health problems gradually developing into major public health issues in China and around the world. Currently, many individuals with chronic diseases are experiencing depressive symptoms one after another. Therefore, it is imperative to conduct research on how to prevent depression in this growing population of individuals with chronic diseases in a timely manner., Methods: Based on the data of the 2015 and 2018 national follow-up surveys of the China Health and Retirement Longitudinal Study, a total of 7641 patients with short-term increase in the number of chronic diseases were selected as the study objects, and a binary logistic regression model was constructed according to the five dimensions of the health ecology model. The neural network model was used to explore the main (first two) factors affecting the increase in the number of chronic diseases in China in the short term, and the random forest and extreme value gradient lifting algorithm were used to verify them, and effective suggestions were put forward., Results: The detection rate of depression in the population with increasing number of chronic diseases from 2015 to 2018 was 42.13 %. The model was established based on five dimensions of the health ecology model: Model 1 (Personal trait layer), Model 2 (Personal trait layer plus Behavioral feature layer), Model 3 (Personal trait layer plus Behavioral feature layer plus Living and working conditions layer), Model 4 (Personal trait layer plus Behavioral feature layer plus Living and working conditions layer plus Networking layer) and Model 5 (Personal trait layer plus Behavioral feature layer plus Living and working conditions layer plus Networking layer plus Policy environment layer).The prediction accuracy of the five models was 66.4 %, 68.3 %, 70.7 %, 71.6 % and 71.6 %, respectively, and Model 5 showed that the P values of gender, self-rated health, night's sleep time (h), disability, life satisfaction, child satisfaction, place of residence and highest level of education were all <0.05, life satisfaction and self-rated health importance were 0.249 (100 %) and 0.226 (90.8 %)., Conclusion: Gender, self-rated health, night sleep duration, disability, satisfaction with life, satisfaction with children, place of residence and highest level of education were the main influencing factors for the increase of depressive symptoms in the population with chronic diseases in the short term, among which life satisfaction and self-rated health have the greatest impact on depressive symptoms, and there is an interaction between the two., Competing Interests: Declaration of competing interest The authors declare that they have no competing interests., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Genetic interactions are adaptive within a species. Hybridization can disrupt such species-specific genetic interactions and creates novel interactions that alter the hybrid progeny overall fitness. Hybrid incompatibility, which refers to degenerative genetic interactions that decrease the overall hybrid survival and sterility, is one of the results from combining two diverged genomes in hybrids. The discovery of spontaneous lethal tumorigenesis and underlying genetic interactions in select hybrids between diverged Xiphophorus species showed that lethal pathological process can result from degenerative genetic interactions. Such genetic interactions leading to lethal phenotype are thought to shield gene flow between diverged species. However, hybrids between certain Xiphophorus species do not develop such tumors. Here we report the identification of a locus residing in the genome of one Xiphophorus species that represses an oncogene from a different species. Our finding provides insights into normal and pathological pigment cell development, regulation and a molecular mechanism in hybrid incompatibility., (© 2024 The Author(s). Pigment Cell & Melanoma Research published by John Wiley & Sons Ltd.)

Familial progressive hyperpigmentation with or without hypopigmentation (FPHH) is an autosomal dominant disorder characterized by widespread skin hyperpigmentation, café-au-lait spots, and hypopigmented circular macules, resulting from KITLG variants. KITLG, expressed by keratinocytes, binds to KIT on melanocytes, stimulating melanogenesis. Disturbances in the KITLG-KIT interaction result in diffuse hyperpigmentation in FPHH. However, the mechanisms behind hypopigmented macule formation remain unclear. This report presents a unique FPHH case in a patient with a novel KITLG mutation (Ser78Leu). Notably, the patient showed multiple hypopigmented macules and striae along the lines of Blaschko. Digital polymerase chain reaction analysis of the DNA from skin and blood tissues indicated a copy-neutral loss of heterozygosity at the KITLG locus, only in the hypopigmented macule. These findings suggest that the hypopigmented macules might result from revertant mosaicism. Conversely, café-au-lait spots do not follow the lines of Blaschko and can superimpose on the hypopigmented striae, indicating a distinct pathogenesis. This case contributes to the understanding of the genetic mechanisms in FPHH., (© 2024 Japanese Dermatological Association.)

Five cases of patients with systemic connective tissue diseases (CTD) who developed connective tissue disease-associated interstitial lung disease (CTD-ILD) with progressive pulmonary fibrosis (PPF) are reported here. Unspecified ILD was diagnosed using high-resolution computed tomography (HRCT). Histologically, all cases were usual interstitial pneumonia (UIP) with findings of advanced (3/5) to diffuse (2/5) fibrosis, with a partially (4/5) to completely (1/5) formed image of a honeycomb lung. The fibrosis itself spread subpleurally and periseptally to more central parts (2/5) of the lung, around the alveolar ducts (2/5), or even without predisposition (1/5). Simultaneously, there was architectural reconstruction based on the mutual fusion of fibrosis without compression of the surrounding lung parenchyma (1/5), or with its compression (4/5). The whole process was accompanied by multifocal (1/5), dispersed (2/5), or organized inflammation in aggregates and lymphoid follicles (2/5). As a result of continuous fibroproduction and maturation of the connective tissue, the alveolar septa thickened, delimiting groups of alveoli that merged into air bullae. Few indistinctly visible (2/5), few clearly visible (1/5), multiple indistinctly visible (1/5), and multiple clearly visible (1/5) fibroblastic foci were present. Among the concomitant changes, areas of emphysema, bronchioloectasia, and bronchiectasis, as well as bronchial and vessel wall hypertrophy, and mucostasis in the alveoli and edema were observed. The differences in the histological appearance of usual interstitial pneumonia associated with systemic connective tissue diseases (CTD-UIP) versus the pattern associated with idiopathic pulmonary fibrosis (IPF-UIP) are discussed here. The main differences lie in spreading lung fibrosis, architectural lung remodeling, fibroblastic foci, and inflammatory infiltrates., (©The Author(s) 2024. Open Access. This article is licensed under a Creative Commons CC-BY International License.)

Multiple hereditary infundibulocystic basal cell carcinoma syndrome (MHIBCC), an autosomal dominant disorder caused by variants in SUFU, is characterized by numerous infundibulocystic basal cell carcinomas (IBCCs). In this report, we present a possible case of mosaic MHIBCC. A 57-year-old woman underwent the removal of four papules on her face, which were diagnosed as IBCCs. Exome sequencing revealed a SUFU c.1022+1G>A mutation within the skin tumor. The same mutation was detected in her blood but at a lower allele frequency. TA cloning revealed that the allele frequency of the mutation in the blood was 0.07. Additionally, tumor assessment revealed loss of heterozygosity (LOH) in chromosome 10, including the SUFU locus. These results indicate the patient had mosaicism for the SUFU mutation in normal tissues, aligning with the mosaic MHIBCC diagnosis. This, combined with LOH, likely contributed to IBCC development. Mosaic MHIBCC may present with milder symptoms. However, it may still increase the risk of developing brain tumors and more aggressive basal cell carcinoma. The possibility of mosaicism should be investigated in mild MHIBCC cases, where standard genetic tests fail to detect SUFU germline variants., (© 2024 Japanese Dermatological Association.)