Sleep, physical activity, and sedentary behaviors in relation to overall cancer and site-specific cancer risk: A prospective cohort study.

Large prospective studies are required to better elucidate the associations of physical activity, sedentary behaviors (SBs), and sleep with overall cancer and site-specific cancer risk, accounting for the interactions with genetic predisposition. The study included 360,271 individuals in UK Biobank. After a median follow-up of 12.52 years, we found higher total physical activity (TPA) level and higher sleep scores were related to reduced risk of cancer while higher SB level showed a positive association with cancer. Compared with high TPA-healthy sleep group and low SB-healthy sleep group, low TPA-poor sleep group and high SB-poor sleep group had the highest risk for overall cancer, breast cancer, and lung cancer. Adherence to a more active exercise pattern was associated with a lower risk of cancer irrespective of genetic risk. Our study suggests that improving the quality of sleep and developing physical activity habits might yield benefits in mitigating the cancer risk.

Ni2P active site ensembles tune electrocatalytic nitrate reduction selectivity.

We demonstrate that active site ensembles on transition metal phosphides tune the selectivity of the nitrate reduction reaction. Using Ni2P nanocrystals as a case study, we report a mechanism involving competitive co-adsorption of H* and NOx* intermediates. A near 100% faradaic efficiency for nitrate reduction over hydrogen evolution is observed at -0.4 V, while NH3 selectivity is maximized at -0.2 V vs. RHE.

Life's Essential 8, genetic susceptibility, and the risk of psoriatic disease: a prospective cohort study.

BACKGROUND: Psoriatic disease (PsD) is closely associated with cardiovascular diseases. The Life's Essential 8 (LE8) score is a new metric for assessing cardiovascular health (CVH), where a higher score indicates better CVH. However, the longitudinal association between LE8 score and the risk of PsD remains uncertain. The main aim of the present study was to explore the association between LE8 scores and the risk of PsD. OBJECTIVE: To investigate the associations between LE8 score, genetic susceptibility, and the risk of PsD within a cohort design. METHODS: This cohort study included 261,642 participants from the UK Biobank without PsD at baseline. LE8 comprises eight indicators: diet, physical activity, nicotine exposure, sleep health, body mass index, blood lipids, blood glucose, and blood pressure. Cox proportional hazard models were employed to examine the association between the participants' LE8 scores, PsD genetic risk, and the risk of PsD. Hazard ratios (HRs) and 95% confidential intervals (CIs) were calculated. RESULTS: During an average follow-up of 12.32 years, 1,501 participants developed PsD. Compared to participants with low LE8 scores, the HRs (95% CIs) of developing PsD for those with moderate and high LE8 scores were 0.51 (0.43, 0.59) and 0.34 (0.27, 0.42) after adjustments, respectively. Dose-response analysis revealed a linear negative association between continuous LE8 score and the risk of developing PsD (P < 0.001), with no evidence of non-linear association detected. The genetic susceptibility to PsD did not modify this association (P for interaction = 0.63). Subgroup analyses revealed that women demonstrated a more pronounced beneficial association between LE8 scores and PsD risk (P for interaction = 0.02). CONCLUSIONS: Our study suggests that a higher LE8 score, regardless of genetic risk, was associated with a lower risk of PsD, particularly among women. Consequently, maintaining a high CVH status is recommended to prevent PsD and assess associated risks.

Celecoxib Augments Paclitaxel-Induced Immunogenic Cell Death in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) is a highly aggressive malignancy that lacks effective targeted therapies. Inducing immunogenic cell death (ICD) in tumor cells represents a promising strategy to enhance therapeutic efficacy by promoting antitumor immunity. Paclitaxel (PTX), a commonly used chemotherapy drug for TNBC, can induce ICD; however, the resulting immunogenicity is limited. Thus, there is an urgent need to explore strategies that improve the effectiveness of ICD in TNBC by incorporating immunoregulatory agents. This study investigated the potential of celecoxib (CXB) to enhance PTX-induced ICD by blocking the biosynthesis of PGE2 in the tumor cells. We observed that the combination of CXB and PTX promoted the maturation of dendritic cells and primed a T cell-dependent immune response, leading to enhanced tumor rejection in a vaccination assay. To further optimize drug delivery in vivo, we developed cRGD-modified liposomes for the targeted codelivery of CXB and PTX. This delivery system significantly improved drug accumulation and triggered robust antitumor immunity in an orthotopic mouse model of TNBC. Moreover, it served as an in situ vaccine to inhibit tumor recurrence and lung metastasis. Overall, our findings provide in-depth insights into the therapeutic mechanism underlying the combination of CXB and PTX, highlighting their potential as effective immune-based therapies for TNBC.

Comprehensive analysis of cuproptosis-related genes involved in immune infiltration and their use in the diagnosis of hepatic ischemia‒reperfusion injury: an experimental Study.

BACKGROUND: Hepatic ischemia reperfusion injury (HIRI) is a common injury not only during liver transplantation but also during major hepatic surgery. HIRI causes severe complications and affects the prognosis and survival of patients. Cuproptosis, a newly identified form of cell death, plays an important role in a variety of illnesses. However, its role in HIRI remains unknown. MATERIALS AND METHODS: The GSE151648 dataset was mined from the Gene Expression Omnibus (GEO) database, and differences were analyzed for intersections. Based on the differentially expressed genes (DEGs), functional annotation, differentially expressed cuproptosis-related genes (DE-CRGs) identification and lasso logistic regression were conducted. Correlation analysis of DE-CRGs and immune infiltration was further conducted, and DE-CRGs were applied to construct an HIRI diagnostic model. The hierarchical clustering method was used to classify the specimens of HIRI, and functional annotation was conducted to verify the accuracy of these DE-CRGs in predicting HIRI progression. The GSE14951 microarray dataset and GSE171539 single-cell sequencing dataset were chosen as validation datasets. At the same time, the significance of DE-CRGs was verified using a mouse model of HIRI with cuproptosis inhibitors and inducers. Finally, a network of transcription-factor-DE-CRGs and miRNA-DE-CRGs was constructed to reveal the regulation mechanisms. And potential drugs for DE-CRGs were predicted using Drug Gene Interaction Database (DGIdb). RESULTS: Overall, 2390 DEGs and 19 DE-CRGs were identified. Through machine learning algorithms, 8 featured DE-CRGs (GNL3, ALAS1, TSC22D2, KLF5, GTF2B, DNTTIP2, SLFN11 and HNRNPU) were screened, and 2 cuproptosis-related subclusters were defined. Based on the 8 DE-CRGs obtained from the HIRI model (AUC=0.97), the nomogram model demonstrated accuracy in predicting HIRI. Eight DE-CRGs were highly expressed in HIRI samples and were negatively related to immune cell infiltration. A higher level of immune infiltration and expression of CRG group B was found in the HIRI population. Differences in cell death and immune regulation were found between the 2 groups. The diagnostic value of the 8 DE-CRGs was confirmed in the validation of two datasets. The identification of 7 DE-CRGs (SLFN11 excluded) by HIRI animal model experiments was also confirmed. Using hTFtarget, miRWalk and DGIDB database, we predicted that 17 transcription factors, 192 miRNAs and 10 drugs might interact with the DE-CRGs. CONCLUSION: This study shows that cuproptosis may occur in HIRI and is correlated with immune infiltration. Additionally, a cuproptosis-related predictive model was constructed for studying the causes of HIRI and developing targeted treatment options for HIRI.

A Cascade-Amplified Pyroptosis Inducer: Optimizing Oxidative Stress Microenvironment by Self-Supplying Reactive Nitrogen Species Enables Potent Cancer Immunotherapy.

Selective generation of sufficient pyroptosis inducers at the tumor site without external stimulation holds immense significance for a longer duration of immunotherapy. Here, we report a cascade-amplified pyroptosis inducer CSCCPT/SNAP that utilizes reactive nitrogen species (RNS), self-supplied from the diffusion-controlled reaction between reactive oxygen species (ROS) and nitric oxide (NO) to potentiate pyroptosis and immunotherapy, while both endogenous mitochondrial ROS stimulated by released camptothecin and released NO initiate pyroptosis. Mechanistically, cascade amplification of the antitumor immune response is prompted by the cooperation of ROS and NO and enhanced by RNS with a long lifetime, which could be used as a pyroptosis trigger to effectively compensate for the inherent drawbacks of ROS, resulting in long-lasting pyroptosis for favoring immunotherapy. Tumor growth is efficiently inhibited in mouse melanoma tumors through the facilitation of reactive oxygen/nitrogen species (RONS)-NO synergy. In summary, our therapeutic approach utilizes supramolecular engineering and nanotechnology to integrate ROS producers and NO donors of tumor-specific stimulus responses into a system that guarantees synchronous generation of these two reactive species to elicit pyroptosis-evoked immune response, while using self-supplied RNS as a pyroptosis amplifier. RONS-NO synergy achieves enhanced and sustained pyroptosis and antitumor immune responses for robust cancer immunotherapy.

A conjoint analysis of renal structure and omics characteristics reveal new insight to yak high-altitude hypoxia adaptation.

BACKGROUND: Yaks have unique adaptive mechanisms to the hypoxic environment, in which the kidney plays an important role. The aim of this study was to explore the histological changes of yak kidney at different altitudes and the metabolites and genes associated with adaptation to the hypoxic environment. METHODS: We analyzed the tissue structure and transcriptomic metabolomic data of yak kidney tissue at two altitudes, 2600 and 4400 m. We compared and identified the morphological adaptations of the kidney and the metabolites and genes associated with hypoxia adaptation in yaks. Changes in renal morphological adaptations, differential metabolites and genes were compared and identified, combining the two in a joint analysis. RESULTS: High-altitude yak kidneys showed significant adaptive changes: increased mitochondria, increased glomerular thylakoid area, and decreased localized ribosomes. Transcriptomics and metabolomics identified 69 DAMs (Differential metabolites) and 594 DEGs (differential genes). Functional enrichment analysis showed that the DAMs were associated with protein digestion and absorption, ABC transporter, and MTOR signaling pathway; the DEGs were significantly enriched in Cholesterol metabolism and P53 signaling pathway. The joint analysis indicated that metabolites such as lysine and arginine, as well as key genes such as ABCB5 and COL1A2, were particularly affected under hypoxic conditions, whereas changes in mitochondria in the tissue structure may be related to the expression of MFN1 and OPA1, and changes in glomerular thylakoid membranes are related to VEGFA and TGFB3. CONCLUSION: The kidney regulates metabolites and gene expression related to hormone synthesis, protein metabolism, and angiogenesis by adjusting the mitochondrial and glomerular thylakoid membrane structure to support the survival of yaks in high-altitude environments.

LncRNA SNHG14 silencing attenuates the progression of diabetic nephropathy via the miR-30e-5p/SOX4 axis.

BACKGROUND: Diabetic nephropathy (DN) is a diabetic complication. LncRNAs are reported to participate in the pathophysiology of DN. Here, the function and mechanism of lncRNA small nucleolar RNA host gene 14 (SNHG14) in DN were explored. METHODS: Streptozotocin (STZ)-induced DN mouse models and high glucose (HG)-treated human mesangial cells (MCs) were used to detect SNHG14 expression. SNHG14 silencing plasmids were applied to examine the function of SNHG14 on proliferation and fibrosis in HG-treated MCs. Potential targets of SNHG14 were predicted using bioinformatics tools and verified by luciferase reporter, RNA pulldown, and northern blotting assays. The functional role of SNHG14 in DN in vivo was detected by injection with adenoviral vector carrying sh-SNHG14 into DN mice. Serum creatinine, blood urea nitrogen, blood glucose, 24-h proteinuria, relative kidney weight, and renal pathological changes were examined in DN mice. RESULTS: SNHG14 expression was elevated in the kidneys of DN mice and HG-treated MCs. SNHG14 silencing inhibited proliferation and fibrosis of HG-stimulated MCs. SNHG14 bound to miR-30e-5p to upregulate SOX4 expression. In rescue assays, SOX4 elevation diminished the effects of SNHG14 silencing in HG-treated MCs, and SOX4 silencing reversed the effects of SNHG14 overexpression. In in vivo studies, SNHG14 downregulation significantly ameliorated renal injuries and renal interstitial fibrosis in DN mice. CONCLUSIONS: SNHG14 silencing attenuates kidney injury in DN mice and reduces proliferation and fibrotic phenotype of HG-stimulated MCs via the miR-30e-5p/SOX4 axis.

Insufficiency of quality of life as the treatment endpoint for balloon pulmonary angioplasty in inoperable chronic thromboembolic pulmonary hypertension.

Background and Objectives: The ability of a quality of life (QoL) to guide balloon pulmonary angioplasty (BPA) among patients with inoperable chronic thromboembolic pulmonary hypertension (CTEPH) has not been fully investigated. This study explored the relationship between QoL scores and hemodynamics in CTEPH patients after BPA and examined whether QoL could be applied as a treatment endpoint. Materials and Methods: This cohort study included patients with inoperable CTEPH who had undergone at least four sessions of BPA. The patients' demographic and clinical data as well as hemodynamic parameters and scores from the RAND 36-item short-form QoL questionnaire were recorded and compared before and after BPA. Results: After BPA treatments, clinical characteristics, hemodynamic parameters, as well as QoL score improved significantly. A physical component summary (PCS) score of 35 or 46 can be used as the cutoff value for predicting better World Health Organization functional classification (WHO FC). Patients who had a higher PCS would have longer 6-min walk distance (6MWD), lower pulmonary vascular resistance (PVR), and better cardiac output (CO) both before and after BPA. However, 19 patients (55.9%) with a higher PCS score after BPA did not achieve the goal of mean pulmonary arterial pressure (mPAP) ≤30 mmHg. During the follow-up period, a significant reduction of PVR was observed, but the PCS score improved a little. Conclusions: QoL is a useful tool for assessing the exercise endurance of patients with inoperable CTEPH treated with BPA, but is insufficient to serve as a treatment endpoint for BPA.

Photoacoustic Imaging-Guided Self-Adaptive Hyperthermia Supramolecular Cascade Nano-Reactor for Diabetic Periodontal Bone Regeneration.

Commencing with the breakdown of the diabetic osteoimmune microenvironment, multiple pathogenic factors, including hyperglycemia, inflammation, hypoxia, and deleterious cytokines, are conjointly involved in the progression of diabetic periodontal bone regeneration. Based on the challenge of periodontal bone regeneration treatment and the absence of real-time feedback of blood oxygen fluctuation in diabetes mellitus, a novel self-adaptive hyperthermia supramolecular cascade nano-reactor ACFDG is constructed via one-step supramolecular self-assembly strategy to address multiple factors in diabetic periodontal bone regeneration. Hyperthermia supramolecular ACFDG possesses high photothermal conversion efficiency (32.1%), and it can effectively inhibit the vicious cycle of ROS-inflammatory cascade through catalytic cascade reactions, up-regulate the expression of heat shock proteins (HSPs) under near-infrared (NIR) irradiation, which promotes periodontal bone regeneration. Remarkably, ACFDG can provide real-time non-invasive diagnosis of blood oxygen changes during periodontal bone regeneration through photoacoustic (PA) imaging, thus can timely monitor periodontal hypoxia status. In conclusion, this multifunctional supramolecular nano-reactor combined with PA imaging for real-time efficacy monitoring provides important insights into the biological mechanisms of diabetic periodontal bone regeneration and potential clinical theranostics.

Expression Localization of the KRT32 Gene and Its Association of Genetic Variation with Wool Traits.

Changes in keratin gene expression and spatiotemporal regulation determine the compositional content and cellular localization of wool keratin, thereby affecting wool traits. Therefore, keratin gene family member 32 (KRT32) was selected for a study using RT-qPCR, immunofluorescence, and penta-primer amplification refractory mutation system (PARMS) techniques. The results showed that KRT32 mRNA was highly expressed in the skin and localized to the inner root sheath (IRS), outer root sheath (ORS) and dermal papilla (DP). Sequencing results identified eight SNPs in KRT32, and association analyses revealed that the variations were significantly associated with multiple traits in wool (p < 0.05), including MFD, CF and MFC. The constructed haplotype combination H2H3 has higher CF and smaller MFD than other haplotype combination (p < 0.05). In conclusion, KRT32 can be used as a candidate gene for molecular genetic improvement of wool in Gansu Alpine Fine-wool sheep.

Impact of Interfering Substances on the Bactericidal Efficacy of Different Commercially Available Hypochlorous Acid-Based Wound Irrigation Solutions Commonly Found in South-East Asia.

The high prevalence of chronic wounds is a growing concern. Recently, hypochlorous acid (HOCl)-based solutions were introduced as an alternative antimicrobial for wound cleansing. In this study, we assessed the in vitro bactericidal activities of seven commercially available wound irrigation products commonly found in South-East Asia. The evaluation was conducted using quantitative suspension method, EN 13727 in either low or high protein conditions. Under low protein conditions, four out of the five HOCl products achieved bactericidal activity (≥5 log10 reduction factor; RF) within 2-5 min, and only one product achieved 5 log10 RF at 15 s. None of the HOCl achieved 5 log10 RF under high protein, even after 30 min of exposure time. In contrast, protein interference on the antimicrobial activities of polyhexamethylene biguanide-based product is less pronounced (low protein: 60 s vs. high protein: 2 min to attain ≥5 log10 RF). Octenidine dihydrochloride is the only active not affected by protein interference achieving ≥5 log10 RF within 15 s in both low and high protein conditions. These findings warrant the need to screen antimicrobial wound care products, especially HOCl-based products, in high protein condition to better reflect the antimicrobial activities in wound care.

All-stage targeted red blood cell membrane-coated docetaxel nanocrystals for glioma treatment.

Challenges for glioma treatment with nanomedicines include physio-anatomical barriers (the blood-brain barrier and blood-brain tumor barrier), low drug loading capacity, and limited circulation time. Here, a red blood cell membrane-coated docetaxel drug nanocrystal (pV-RBCm-NC(DTX)), modified with pHA-VAP (pV) for all-stage targeting of glioma, was designed. The NC(DTX) core exhibited a high drug loading capacity but low in vivo stability, and the RBCm coating significantly enhanced the stability and prolonged in vivo circulation. Moreover, the Y-shaped targeting ligand pV was modified by a mild avidin-biotin interaction, which endowed RBCm-NC(DTX) with superior barrier-crossing ability and therapeutic efficacy. The integration of nanocrystal technology, cell membrane coating, and the avidin-biotin insertion method into this active targeting biomimetic formulation represents a promising drug delivery strategy for glioma.

A novel peptide-drug conjugate for glioma-targeted drug delivery.

The existence of the blood-brain barrier (BBB) and blood-brain tumor barrier (BBTB) greatly limits the application of chemotherapy in glioma. To address this challenge, an optimal drug delivery system must efficiently cross the BBB/BBTB and specifically deliver therapeutic drugs into glioma cells while minimizing systemic toxicity. Here we demonstrated that glucose-regulated protein 78 (GRP78) and dopamine receptor D2 were highly expressed in patient-derived glioma tissues, and dopamine receptors were highly expressed on the BBB. Subsequently, we synthesized a novel "Y"-shaped peptide and compared the effects of different linkers on the receptor affinity and targeting ability of the peptide. A peptide-drug conjugate (pHA-AOHX-VAP-doxorubicin conjugate, pHA-AOHX-VAP-DOX) with a better affinity for glioma cells and higher solubility was derived for glioma treatment. pHA-AOHX-VAP-DOX could cross both BBB and BBTB via dopamine receptor and GRP78 receptor, and finally target glioma cells, significantly prolonging the survival time of nude mice bearing intracranial glioma. Furthermore, pHA-AOHX-VAP-DOX significantly reduced the toxicity of DOX and increased the maximum tolerated dose (MTD). Collectively, this work paves a new avenue for overcoming multiple barriers and effectively delivering chemotherapeutic agents to glioma cells while providing key evidence to identify potential receptors for glioma-targeted drug delivery.

Dual rare genetic diseases in five pediatric patients: insights from next-generation diagnostic methods.

BACKGROUND: Clinicians traditionally aim to identify a singular explanation for the clinical presentation of a patient; however, in some cases, the diagnosis may remain elusive or fail to comprehensively explain the clinical findings. In recent years, advancements in next-generation sequencing, including whole-exome sequencing, have led to the incidental identification of dual diagnoses in patients. Herein we present the cases of five pediatric patients diagnosed with dual rare genetic diseases. Their natural history and diagnostic process were explored, and lessons learned from utilizing next-generation diagnostic technologies have been reported. RESULTS: Five pediatric cases (3 boys, 2 girls) with dual diagnoses were reported. The age at diagnosis was from 3 months to 10 years. The main clinical presentations were psychomotor retardation and increased muscular tension, some accompanied with liver dysfunction, abnormal appearance, precocious puberty, dorsiflexion restriction and varus of both feet, etc. After whole-exome sequencing, nine diseases were confirmed in these patients: Angelman syndrome and Krabbe disease in case 1, Citrin deficiency and Kabuki syndrome in case 2, Homocysteinemia type 2 and Copy number variant in case 3, Isolated methylmalonic acidemia and Niemann-Pick disease type B in case 4, Isolated methylmalonic acidemia and 21-hydroxylase deficiency in case 5. Fifteen gene mutations and 2 CNVs were identified. Four novel mutations were observed, including c.15292de1A in KMT2D, c.159_164inv and c.1427G > A in SLC25A13, and c.591 C > G in MTHFR. CONCLUSIONS: Our findings underscore the importance of clinicians being vigilant about the significance of historical and physical examination. Comprehensive clinical experience is crucial for identifying atypical clinical features, particularly in cases involving dual rare genetic diseases.

Care-seeking delay of patients with heart failure in China: a mixed-method study.

AIM: This study aims to explore the duration and influencing factors of care-seeking delay among patients with heart failure (HF) in China. METHODS AND RESULTS: A convergent mixed method containing a cross-sectional study and two parts of qualitative studies was designed, following the STROBE and COREQ guidelines. Convenience sampling was applied to recruit patients with HF from two general hospitals from December 2021 to December 2022. Purposive sampling was used to enrol healthcare professionals from two general hospitals and two community hospitals from June to November 2022. Among the 258 patients with HF in the cross-sectional study, the median duration of care-seeking delay was 7.5 days. The result integration indicated that the delay duration was influenced by the dyspnoea symptom burden, the oedema symptom burden, and the depression status. The lower dyspnoea symptom burden, the higher oedema symptom burden, and the higher depression score were related to the prolonged care-seeking delay duration. The duration was also affected by the COVID-19 pandemic, level of support from medical system, and the symptom management abilities of the caregivers. The COVID-19 pandemic, low level of support from medical system, and limited symptom management abilities of caregivers were related to the prolonged care-seeking delay duration. CONCLUSIONS: Care-seeking delay among patients with HF needs attention in China. The duration of care-seeking delay of patients with HF was influenced by the dyspnoea symptom burden, the oedema symptom burden, and depression status, as well as the COVID-19 pandemic, level of support from medical system, and the symptom management abilities of the caregivers.

A novel method for precise implantation of tracheal Y-shaped stent.

The tracheal Y-shaped stent is mainly used for the treatment of critical patients with airway stenosis or esophagotracheal fistula near carina. A novel method for precise implantation of Y-shaped tracheal stents was developed using double-lumen endotracheal intubation and flexible bronchoscopy. This approach aims to address the limitations associated with X-ray or rigid bronchoscopy guidance, such as operational difficulties and the risk of inaccurate stent placement leading to implantation failure or suffocation. With this new technique, 13 tracheal Y-shaped stents were successfully implanted. This method shows promise in reducing the complexity of stent implantation and facilitating timely treatment for patients in need. Additionally, it has the potential to update current operating standards and guidelines for this procedure.

Large-scale genome-wide association study of 398,238 women unveils seven novel loci associated with high-grade serous epithelial ovarian cancer risk.

Background: Nineteen genomic regions have been associated with high-grade serous ovarian cancer (HGSOC). We used data from the Ovarian Cancer Association Consortium (OCAC), Consortium of Investigators of Modifiers of BRCA1/BRCA2 (CIMBA), UK Biobank (UKBB), and FinnGen to identify novel HGSOC susceptibility loci and develop polygenic scores (PGS). Methods: We analyzed >22 million variants for 398,238 women. Associations were assessed separately by consortium and meta-analysed. OCAC and CIMBA data were used to develop PGS which were trained on FinnGen data and validated in UKBB and BioBank Japan. Results: Eight novel variants were associated with HGSOC risk. An interesting discovery biologically was finding that TP53 3'-UTR SNP rs78378222 was associated with HGSOC (per T allele relative risk (RR)=1.44, 95%CI:1.28-1.62, P=1.76×10-9). The optimal PGS included 64,518 variants and was associated with an odds ratio of 1.46 (95%CI:1.37-1.54) per standard deviation in the UKBB validation (AUROC curve=0.61, 95%CI:0.59-0.62). Conclusions: This study represents the largest GWAS for HGSOC to date. The results highlight that improvements in imputation reference panels and increased sample sizes can identify HGSOC associated variants that previously went undetected, resulting in improved PGS. The use of updated PGS in cancer risk prediction algorithms will then improve personalized risk prediction for HGSOC.

Lyophilized lymph nodes for improved delivery of chimeric antigen receptor T cells.

Lymph nodes are crucial organs of the adaptive immune system, orchestrating T cell priming, activation and tolerance. T cell activity and function are highly regulated by lymph nodes, which have a unique structure harbouring distinct cells that work together to detect and respond to pathogen-derived antigens. Here we show that implanted patient-derived freeze-dried lymph nodes loaded with chimeric antigen receptor T cells improve delivery to solid tumours and inhibit tumour recurrence after surgery. Chimeric antigen receptor T cells can be effectively loaded into lyophilized lymph nodes, whose unaltered meshwork and cytokine and chemokine contents promote chimeric antigen receptor T cell viability and activation. In mouse models of cell-line-derived human cervical cancer and patient-derived pancreatic cancer, delivery of chimeric antigen receptor T cells targeting mesothelin via the freeze-dried lymph nodes is more effective in preventing tumour recurrence when compared to hydrogels containing T-cell-supporting cytokines. This tissue-mediated cell delivery strategy holds promise for controlled release of various cells and therapeutics with long-term activity and augmented function.