Development, validation and reliability testing of the hospice care environment scale.

BACKGROUND: WHO stated the environment is an important factor affecting the development of hospice care. The environment is the sum of factors affecting behavior besides the individual factors. Currently, a scale to comprehensively assess the hospice environment of nurse is still lacking. This study aimed to develop an instrument to investigate the environmental factors affecting hospice care of nurses. METHODS: Literature review and a semi-structured interview were conducted to form the items pool of the Hospice Care Environment Scale. Two rounds of Delphi expert consultation were conducted by 16 experts to revise the scale dimensions and entries to form the Hospice Care Environment Scale. A psychometric evaluation was then performed among 530 oncology nurses in a large tertiary oncology hospital in Hubei Province. The 500 valid questionnaires were randomly divided into two groups in a 1:1 ratio, sample 1 (n1 = 250) for item screening and sample 2 (n2 = 250) for quality evaluation of the resulting scale. Item analysis, reliability analysis, validity analysis and acceptability analysis were performed. RESULT: The Hospice Care Environment Scale consists of two dimensions and 13 entries. The Cronbach's α coefficient of the Hospice Care Environment Scale was 0.970, and the Cronbach's α coefficient of the two dimensions were 0.952 and 0.969, respectively, with the Item-content validity index and average Scale- content validity index of the scale was both 1.000. The validation factor analysis showed the standardized path coefficients of each item were basically above 0.5, and the factor structure model was stable and suitable. The average completion time of the scale was about 3 min, which had good feasibility. CONCLUSION: The Hospice Care Environment Scale to assess the environment of hospice care services, has good content and construct validity and reliability. This scale can provide guidance to evaluate the hospice care environment.

PICK1 inhibits the malignancy of nasopharyngeal carcinoma and serves as a novel prognostic marker.

Although many important advances have been made in the treatment of nasopharyngeal carcinoma (NPC) in recent years, local recurrence and distant metastasis remain the main factors affecting NPC prognosis. Biomarkers for predicting the prognosis of NPC need to be urgently identified. Here, we used whole-exon sequencing (WES) to determine whether PICK1 mutations are associated with the prognosis of NPC. Functionally, PICK1 inhibits the proliferation and metastasis of NPC cells both in vivo and in vitro. Mechanistically, PICK1 inhibited the expression of proteins related to the Wnt/ß-catenin signaling pathway. PICK1 restrained the nuclear accumulation of ß-catenin and accelerated the degradation of ß-catenin through the ubiquitin-proteasome pathway. The reduced PICK1 levels were significantly associated with poor patient prognosis. Hence, our study findings reveal the mechanism by which PICK1 inactivates the Wnt/ß-catenin signaling pathway, thereby inhibiting the progression of NPC. They support PICK1 as a potential tumor suppressor and prognostic marker for NPC.

MEF2D facilitates liver metastasis of gastric cancer cells through directly inducing H1X under IL-13 stimulation.

Liver metastasis is the most common metastatic occurrence in gastric cancer patients, although the precise mechanism behind it remains unclear. Through a combination of proteomics and quantitative RT-PCR, our study has revealed a significant correlation between the upregulation of myocyte enhancer factor-2D (MEF2D) and both distant metastasis and poor prognosis in gastric cancer patients. In mouse models, we observed that overexpressing or knocking down MEF2D in gastric cancer cells respectively promoted or inhibited liver metastasis. Furthermore, our research has demonstrated that MEF2D regulates the transcriptional activation of H1X by binding to the H1X promoter. This regulation leads to the upregulation of H1X, which, in turn, promotes the in vivo metastasis of gastric cancer cells along with the upregulation of the downstream gene ß-CATENIN. Additionally, we found that the expression of MEF2D and H1X at both mRNA and protein levels can be induced by the inflammatory factor IL-13, and this induction exhibits a time gradient dependence. In human gastric cancer tissues, the expression of IL13RA1, the receptor for IL-13, positively correlates with the expression of MEF2D and H1X. IL13RA1 has been identified as an intermediate receptor through which IL-13 regulates MEF2D. In conclusion, our findings suggest that MEF2D plays a crucial role in promoting liver metastasis of gastric cancer by upregulating H1X and downstream target ß-CATENIN in response to IL-13 stimulation. Targeting MEF2D could therefore be a promising therapeutic strategy for the clinical management of gastric cancer. STATEMENT OF SIGNIFICANCE: MEF2D promotes its transcriptional activation in gastric cancer cells by binding to the H1X promoter and is upregulated by IL-13-IL13RA1, thereby promoting distant metastasis of gastric cancer.

Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 3 Expression and Its Correlation with Prognosis and Growth of Serous Ovarian Cancer: Correlation of DYRK3 with Ovarian Cancer Survival.

Background: Epithelial ovarian cancer, primarily serous ovarian cancer (SOC), stands as a predominant cause of cancer-related mortality among women globally, emphasizing the urgent need for comprehensive research into its molecular underpinnings. Within this context, the dual-specificity tyrosine phosphorylation-regulated kinase 3 (DYRK3) has emerged as a potential key player with implications for prognosis and tumor progression. Methods: This study conducted a meticulous retrospective analysis of 254 SOC cases from our medical center to unravel the prognostic significance of DYRK3. Survival analyses underscored DYRK3 as an independent adverse prognostic factor in SOC, with a hazard ratio of 2.60 (95% CI 1.67-4.07, P < 0.001). Experimental investigations involved DYRK3 knockdown in serous ovarian cancer cell lines (CAOV3 and OVCAR-3) through a shRNA strategy, revealing substantial decreases in cell growth and invasion capabilities. Bioinformatics analyses further hinted at DYRK3's involvement in modulating the tumor immune microenvironment. In vivo experiments with DYRK3-knockdown cell lines validated these findings, demonstrating a notable restriction in the growth of ovarian cancer xenografts. Results: Our findings collectively illuminate DYRK3 as a pivotal tumor-promoting oncogene in SOC. Beyond its adverse prognostic implications, DYRK3 knockdown exhibited promising therapeutic potential by impeding cancer progression and potentially influencing the tumor immune microenvironment. Conclusions: This study establishes a compelling foundation for further research into DYRK3's intricate role and therapeutic potential in ovarian cancer treatment. As we unravel the complexities surrounding DYRK3, our work not only contributes to the understanding of SOC pathogenesis but also unveils new prospects for targeted therapeutic interventions, holding promise for improved outcomes in ovarian cancer management.

Biodegradable and flame-retardant cellulose-based wearable triboelectric nanogenerator for mechanical energy harvesting in firefighting clothing.

Integrating flexible triboelectric nanogenerators (TENGs) into firefighting clothing offers exciting opportunities for wearable portable electronics in personal protective technology. However, it is still a grand challenge to produce eco-friendly TENGs from biodegradable and low-cost natural polymers for mechanical-energy harvesting and self-powered sensing. Herein, conductive polypyrrole (PPy) and natural chitosan (CS)/phytic acid (PA) tribonegative materials were employed onto the Lycra fabric (LC) in turn to assemble the biodegradable and flame-retardant single-electrode mode LC/PPy/CS/PA TENG (abbreviated as LPCP-TENG). The resultant LPCP-TENG exhibits truly wearable breathability (1378.6 mm/s), elasticity (breaking elongation 291 %), and shape adaptivity performance that can produce an open circuit voltage of 0.3 V with 2 N contact pressure at a working frequency of 5 Hz with a limiting oxygen index of 35.2 %. Furthermore, facile monitoring for human motion of firefighters on fireground is verified by LPCP-TENG when used as self-powered flexible tactile sensor. In addition, degradation experiments have shown that waste LPCP-TENG can be fully degraded in soil within 120 days. This work broadens the applicational range of wearable TENG to reduce the environmental effects of abandoned TENG, exhibiting prosperous applications prospects in the field of wearable power source and self-powered motion detection sensor for personal protection application on fireground.

Circ_0098823 binding with IGF2BP3 regulates DNM1L stability to promote metastasis of hepatocellular carcinoma via mitochondrial fission.

Hepatocellular carcinoma (HCC) is highly metastatic and invasive. CircRNA participates in gene regulation of multiple tumor metastases, but little is known whether it is a bystander or an actual player in HCC metastasis. We aim to explore the molecular mechanisms of novel circRNAs in HCC metastasis. RT-qPCR was used to detect the expression of 13 circRNAs derived by the ERBB3 gene. The function of circ_0098823 and DNM1L in HCC cells were estimated by CCK-8, transwell assays, flow cytometry, electron microscope, and in vivo experiments. RNA binding protein of circ_0098823 was confirmed by RNA pull-down, mass spectrometry, and RNA immunoprecipitation. The expression of DNM1L after IGF2BP3 knockdown was detected by RT-qPCR and western blot. Circ_0098823 was significantly up-regulated both in HCC tissues and HGF induced cell lines. Circ_0098823 overexpression significantly enhanced proliferation, migration, and invasion but decreased apoptosis of HCC cells, particularly promoted mitochondrial fission. Compared with the control group, the tumors in the circ_0098823 knockdown mice were significantly smaller and lighter. Circ_0098823 silencing suppressed DNM1L expression, a key molecule for fission, which enhanced proliferation, migration and invasion, and inhibited apoptosis of HCC cell. IGF2BP3 was a binding protein of circ_0098823. The expression and mRNA stability of DNM1L were down-regulated by IGF2BP3 knockdown. IGF2BP3 knockdown significantly alleviated the excessive migration, invasion and apoptosis of HCC cells caused by circ_0098823 overexpression. This study uncovered a novel circ_0098823 with tumor-promoting effect, and the mechanism by which circ_0098823 participates in HCC progression through IGF2BP3-guided DNM1L. Our study broadens molecular understanding of HCC progression.

Digital Health Psychosocial Intervention in Adult Patients With Cancer and Their Families: Systematic Review and Meta-Analysis.

BACKGROUND: Patients with cancer and their families often experience significant distress and deterioration in their quality of life. Psychosocial interventions were used to address patients' and families' psychosocial needs. Digital technology is increasingly being used to deliver psychosocial interventions to patients with cancer and their families. OBJECTIVE: A systematic review and meta-analysis were conducted to review the characteristics and effectiveness of digital health interventions on psychosocial outcomes in adult patients with cancer and their family members. METHODS: Databases (PubMed, Cochrane Library, Web of Science, Embase, CINAHL, PsycINFO, ProQuest Dissertations and Theses Global, and ClinicalTrials.gov) were searched for randomized controlled trials (RCTs) or quasi-experimental studies that tested the effects of a digital intervention on psychosocial outcomes. The Joanna Briggs Institute's critical appraisal checklists for RCTs and quasi-experimental studies were used to assess quality. Standardized mean differences (ie, Hedges g) were calculated to compare intervention effectiveness. Subgroup analysis was planned to examine the effect of delivery mode, duration of the intervention, type of control, and dosage on outcomes using a random-effects modeling approach. RESULTS: A total of 65 studies involving 10,361 patients (mean 159, SD 166; range 9-803 patients per study) and 1045 caregivers or partners (mean 16, SD 54; range 9-244 caregivers or partners per study) were included in the systematic review. Of these, 32 studies were included in a meta-analysis of the effects of digital health interventions on quality of life, anxiety, depression, distress, and self-efficacy. Overall, the RCT studies' general quality was mixed (applicable scores: mean 0.61, SD 0.12; range 0.38-0.91). Quasi-experimental studies were generally of moderate to high quality (applicable scores: mean 0.75, SD 0.08; range 0.63-0.89). Psychoeducation and cognitive-behavioral strategies were commonly used. More than half (n=38, 59%) did not identify a conceptual or theoretical framework. Most interventions were delivered through the internet (n=40, 62%). The median number of intervention sessions was 6 (range 1-56). The frequency of the intervention was highly variable, with self-paced (n=26, 40%) being the most common. The median duration was 8 weeks. The meta-analysis results showed that digital psychosocial interventions were effective in improving patients' quality of life with a small effect size (Hedges g=0.05, 95% CI -0.01 to 0.10; I2=42.7%; P=.01). The interventions effectively reduced anxiety and depression symptoms in patients, as shown by moderate effect sizes on Hospital Anxiety and Depression Scale total scores (Hedges g=-0.72, 95% CI -1.89 to 0.46; I2=97.6%; P<.001). CONCLUSIONS: This study demonstrated the effectiveness of digital health interventions on quality of life, anxiety, and depression in patients. Future research with a clear description of the methodology to enhance the ability to perform meta-analysis is needed. Moreover, this study provides preliminary evidence to support the integration of existing digital health psychosocial interventions in clinical practice. TRIAL REGISTRATION: PROSPERO CRD42020189698; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=189698.

The Experience of Uncertainty in Individuals With High Risk for Pancreatic Cancer.

BACKGROUND: Individuals with a strong family history of pancreatic cancer or a known hereditary cancer syndrome that is associated with pancreatic cancer are considered at high risk for developing pancreatic cancer. Living with a high risk for often fatal cancer is accompanied by high levels of uncertainty. Uncertainty is also independently associated with negative health outcomes. By understanding issues, sources, and responses to uncertainty, targeted supportive care strategies can be provided. OBJECTIVES: This study aimed to examine how uncertainty manifests in the experience of being at high risk to develop pancreatic cancer and to describe issues, sources of, and responses to uncertainty. METHODS: In this secondary qualitative descriptive study, we analyzed 19 interviews with persons living with inherited pancreatic cancer risk. Analysis was guided by a conceptual framework of uncertainty and responses to uncertainty. RESULTS: Participants described multiple personal, practical, and scientific issues of uncertainty, centering on what to expect for their future health. Participants also expressed positive and negative cognitive, emotional, and behavioral responses to uncertainty, including engaging in surveillance. Uncertainty sources were both individual experiences as well as perceptions of healthcare provider uncertainty with managing pancreatic cancer risk. CONCLUSION: Pancreatic cancer risk includes issues of uncertainty related to personal mortality, defining and managing risk, and experiencing surveillance. Positive and negative responses to this uncertainty could be targeted through interventions. IMPLICATION FOR PRACTICE: The oncology nurse should assess for sources of and responses to uncertainty in persons at risk for pancreatic cancer and offer psychosocial and educational support.

Cathelicidin (LL-37) causes expression of inflammatory factors in coronary artery endothelial cells of Kawasaki disease by activating TLR4-NF-κB-NLRP3 signaling.

BACKGROUND: Kawasaki disease (KD) is a type of vasculitis with an unidentified etiology. Cathelicidin (LL-37) may be involved in the development of the KD process; therefore, further research to investigate the molecular mechanism of LL-37 involvement in KD is warranted. METHODS: Enzyme-linked immunosorbent assay (ELISA) was used to detect the levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, NLRP3, and LL-37 in the sera of healthy subjects, children with KD, and children with pneumonia. Subsequently, human recombinant LL-37 or/and toll-like receptors 4 (TLR4)-specific inhibitor TAK-242 stimulated human coronary artery endothelial cells (HCAECs), CCK-8 was used to detect cell proliferation, flow cytometry to detect apoptosis, transmission electron microscopy to observe cytoskeletal changes, Transwell to measure cell migration ability, ELISA to detect inflammatory factor levels, Western blot analysis to analyze protein levels of toll-like receptors 4 (TLR4) and NF-κB p-65, and quantitative real-time polymerase chain reaction (qRT-PCR) to determine LL-37, NLRP3 mRNA levels. RESULTS: In this study, we found that the level of LL-37 was highly expressed in the serum of children with KD, and after LL-37 stimulation, apoptosis was significantly increased in HCAECs, and the expression levels of TLR4, NLRP3 and inflammatory factors in cells were significantly enhanced. Intervention with the TLR4-specific inhibitor TAK-242 significantly alleviated the LL-37 effects on cellular inflammation, TLR4, NLRP3 promotion effect. CONCLUSIONS: Our data suggest that LL-37 induces an inflammatory response in KD coronary endothelial cells via TLR4-NF-κB-NLRP3, providing a potential target for the treatment of KD.

Anti-PD-1/Her2 Bispecific Antibody IBI315 Enhances the Treatment Effect of Her2-Positive Gastric Cancer through Gasdermin B-Cleavage Induced Pyroptosis.

The majority of patients with human epidermal growth factor receptor 2 (Her2)-positive gastric cancer develop refractory to Her2-targeted therapy, where upregulation of immune checkpoints plays an essential role. Herein, a recombinant fully human IgG1 bispecific antibody IBI315 targeting both PD-1 and Her2 is developed  and its antitumor efficacy as well as the underlying mechanism is investigated. IBI315 crosslinks the physical interaction between Her2-positive tumor cells and PD-1-positive T cells, resulting in significantly enhanced antitumor effects compared to each parent antibody or their combination, both in vitro and in vivo mouse tumor models reconstituted with human immune cells using patient-derived xenografts and organoids. Moreover, IBI315 treatment also induces the recruitment and activation of immune cells in tumors. Mechanistically, IBI315 triggers gasdermin B (GSDMB)-mediated pyroptosis in tumor cells, leading to the activation and recruiments of T cells. The activated T cells secret IFNγ, enhancing GSDMB expression and establishing a positive feedback loop of T cell activation and tumor cell killing. Notably, GSDMB is found to be elevated in Her2-positive gastric cancer cells, providing a rationale for IBI315's efficacy. IBI315 is supported here as a promising bispecific antibody-based immunotherapy approach for Her2-positive gastric cancer in preclinical studies, broadening the therapeutic landscape of this patient population.

Quantitative haplotype-resolved analysis of mitochondrial DNA heteroplasmy in Human single oocytes, blastoids, and pluripotent stem cells.

Maternal mitochondria are the sole source of mtDNA for every cell of the offspring. Heteroplasmic mtDNA mutations inherited from the oocyte are a common cause of metabolic diseases and associated with late-onset diseases. However, the origin and dynamics of mtDNA heteroplasmy remain unclear. We used our individual Mitochondrial Genome sequencing (iMiGseq) technology to study mtDNA heterogeneity, quantitate single nucleotide variants (SNVs) and large structural variants (SVs), track heteroplasmy dynamics, and analyze genetic linkage between variants at the individual mtDNA molecule level in single oocytes and human blastoids. Our study presented the first single-mtDNA analysis of the comprehensive heteroplasmy landscape in single human oocytes. Unappreciated levels of rare heteroplasmic variants well below the detection limit of conventional methods were identified in healthy human oocytes, of which many are reported to be deleterious and associated with mitochondrial disease and cancer. Quantitative genetic linkage analysis revealed dramatic shifts of variant frequency and clonal expansions of large SVs during oogenesis in single-donor oocytes. iMiGseq of a single human blastoid suggested stable heteroplasmy levels during early lineage differentiation of naïve pluripotent stem cells. Therefore, our data provided new insights of mtDNA genetics and laid a foundation for understanding mtDNA heteroplasmy at early stages of life.

Hypoxia-induced degradation of PICK1 by RBCK1 promotes the proliferation of nasopharyngeal carcinoma cells.

AIMS: Hypoxia is an important feature of nasopharyngeal carcinoma (NPC). "Protein interacting with PRKCA 1" (PICK1) is commonly downregulated in human malignancies and is functionally related to poor prognosis. However, there is a limited understanding of the upstream mechanisms regulating PICK1 currently. MAIN METHODS: PICK1 and HIF-1α expression levels were analyzed by Immunohistochemistry (IHC), western blotting, and quantitative real-time PCR assay. Protein stability and ubiquitin assays were used to investigate PICK1 protein degradation. Immunofluorescence and co-immunoprecipitation assays were used to demonstrate the interaction between RBCK1 and PICK1. Gene knockdown by siRNA transfection was used to investigate the role of HIF-1α and RBCK1 in hypoxia-induced PICK1 degradation. Cell Counting Kit-8 (CCK-8), 5-Ethynyl-2'-deoxyuridine (EdU) assays and subcutaneous xenograft nude models were used to explore the roles of RBCK1 and PICK1 in NPC cell proliferation. KEY FINDINGS: PICK1 expression in NPC tissue was negatively relative to that of HIF-1α. HIF-1α downregulated PICK1 expression by facilitating its ubiquitination by the E3 ligases RANBP2-type and C3HC4-type zinc finger containing 1 (RBCK1), thereby enhancing proteasome-mediated PICK1 degradation. RBCK1 knockdown inhibited NPC cell proliferation, which was ameliorated by double knockdown of RBCK1/PICK1. SIGNIFICANCE: These data provide evidence for an NPC cell adaptation mechanism to hypoxia, where HIF-1α regulates RBCK1, which targets PICK1 for degradation to promote cell proliferation.

Nonstructural N- and C-tails of Dbp2 confer the protein full helicase activities.

Human DDX5 and its yeast ortholog Dbp2 are ATP-dependent RNA helicases that play a key role in normal cell processes, cancer development, and viral infection. The crystal structure of the RecA1-like domain of DDX5 is available but the global structure of DDX5/Dbp2 subfamily proteins remains to be elucidated. Here, we report the first X-ray crystal structures of the Dbp2 helicase core alone and in complex with ADP at 3.22 Å and 3.05 Å resolutions, respectively. The structures of the ADP-bound post-hydrolysis state and apo-state demonstrate the conformational changes that occur when the nucleotides are released. Our results showed that the helicase core of Dbp2 shifted between open and closed conformation in solution but the unwinding activity was hindered when the helicase core was restricted to a single conformation. A small-angle X-ray scattering experiment showed that the disordered amino (N) tail and carboxy (C) tails are flexible in solution. Truncation mutations confirmed that the terminal tails were critical for the nucleic acid binding, ATPase, and unwinding activities, with the C-tail being exclusively responsible for the annealing activity. Furthermore, we labeled the terminal tails to observe the conformational changes between the disordered tails and the helicase core upon binding nucleic acid substrates. Specifically, we found that the nonstructural terminal tails bind to RNA substrates and tether them to the helicase core domain, thereby conferring full helicase activities to the Dbp2 protein. This distinct structural characteristic provides new insight into the mechanism of DEAD-box RNA helicases.

A Feedback Loop of LINC00665 and the Wnt Signaling Pathway Expedites Osteosarcoma Cell Proliferation, Invasion, and Epithelial-Mesenchymal Transition.

OBJECTIVES: Osteosarcoma (OS) is a malignant tumor with frequent occurrence among teenagers. Long non-coding RNAs (lncRNAs) play pro-cancer roles in many tumors. The purpose of this study was to figure out the functional role of a novel lncRNA long intergenic non-protein coding RNA 665 (LINC00665) in OS by observing the OS cell behaviors. METHODS: Quantitative reverse transcription polymerase chain reaction (RT-qPCR) was used to analyze LINC00665 expression in OS cells. Cell function assays assessed the impacts of LINC00665 on OS cell phenotype. Immunofluorescence and western blot analyzed the function of LINC00665 on epithelial-mesenchymal transition (EMT) in OS. Moreover, mechanistic assays analyzed the downstream mechanism of LINC00665 in OS cells. RESULTS: LINC00665 was significantly up-regulated in OS cells. LINC00665 silence facilitated OS cell proliferation, migration, invasion, and EMT while inhibiting cell apoptosis. Mechanically, LINC00665 acted as a competing endogenous RNA (ceRNA) to sponge miR-1249-5p and thereby modulated Wnt family member 2B (WNT2B) to activate Wnt pathway. Wnt pathway activated LINC00665 expression transcriptionally. CONCLUSIONS: Our study uncovered the cancer-promoting role of LINC00665 in OS, and the feedback loop of LINC00665/miR-1249-5p/WNT2B/Wnt might be a potential target for OS treatment.

PD-L1: Biological mechanism, function, and immunotherapy in gastric cancer.

Gastric cancer (GC) is one of the main causes of cancer incidence rate and mortality worldwide. As the main breakthrough direction, the application of immune checkpoint inhibitors makes patients with GC have better prognosis, where PD-L1/PD-1 inhibitors in immunotherapy have good anti-tumor immune efficacy. Further understanding of the regulatory mechanism of PD-L1 in GC may bring substantial progress to the immunotherapy. In this review, we provide information on the endogenous and exogenous regulatory mechanisms of PD-L1 and its biological functions combined with current clinical trials of PD-L1/PD-1 inhibitors in GC. The malignant biological phenotypes caused by PD-L1 and the corresponding clinical combined treatment scheme have been reported. Identifying the biomarkers of the potential efficacy of immunotherapy and specifying the clinical immunotherapy scheme in combination with molecular characteristics of patients may maximize clinical benefits and better prognosis.

Microbiota and metabolites alterations in proximal and distal gastric cancer patients.

BACKGROUND: Globally, gastric cancer is the third most common cancer and the third leading cause of cancer death. Proximal and distal gastric cancers have distinct clinical and biological behaviors. The microbial composition and metabolic differences in proximal and distal gastric cancers have not been fully studied and discussed. METHODS: In this study, the gastric microbiome of 13 proximal gastric cancer tissues, 16 distal gastric cancer tissues, and their matched non-tumor tissues were characterized using 16S rRNA amplicon sequencing. Additionally, 10 proximal gastric cancer tissues, 11 distal gastric cancer tissues, and their matched non-tumor tissues were assessed by untargeted metabolomics. RESULTS: There was no significant difference in microbial diversity and richness between the proximal and distal gastric cancer tissues. At the genus level, the abundance of Rikenellaceae_RC9_gut_group, Porphyromonas, Catonella, Proteus, Oribacterium, and Moraxella were significantly increased in Proximal T, whereas that of Methylobacterium_Methylorubrum was significantly increased in Distal T. The untargeted metabolomics analysis revealed 30 discriminative metabolites between Distal T and Distal N. In contrast, there were only 4 discriminative metabolites between Proximal T and Proximal N. In distal gastric cancer, different metabolites were scattered through multiple pathway, including the sphingolipid signaling pathway, arginine biosynthesis, protein digestion and absorption, alanine, aspartate and, glutamate metabolism, etc.In proximal gastric cancer, differential microbial metabolites were mainly related to hormone metabolism. CONCLUSION: Methylobacterium-Methylorubrum was significantly increased in Distal T, positively correlated with cancer-promoting metabolites, and negatively correlated with cancer-inhibiting metabolites. Rikenellaceae_RC_gut_group was significantly increased in Proximal T and positively correlated with cancer-promoting metabolites. Further studies regarding the functions of the above-mentioned microorganisms and metabolites were warranted as the results may reveal the different mechanisms underlying the occurrence and development of proximal and distal gastric cancers and provide a basis for future treatments. IMPORTANCE: First, the differences in microbial composition and metabolites between the proximal and distal gastric cancers were described; then, the correlation between microbiota and metabolites was preliminarily discussed. These microbes and metabolites deserve further investigations as they may reveal the different mechanisms involved in the occurrence and development of proximal and distal gastric cancers and provide a basis for future treatments.

Hypoxic Cell-Derived Extracellular Vesicles Aggravate Rectal Injury Following Radiotherapy via MiR-122-5p.

Radiation-induced rectal injury is a common side effect of radiotherapy. Hypoxia often occurs after radiotherapy. This study aimed to explore the bystander effect of hypoxia on radiation-induced rectal injury. In vivo, apoptosis increased nearby the highly hypoxic area in the rectal tissues in the mouse models of radiation-induced rectal injury, indicating the potential involvement of hypoxia. In vitro, flow cytometry and Western blotting showed that both hypoxia and hypoxic human intestinal epithelial crypt (HIEC) cell supernatant promoted apoptosis in normoxic HIEC cells. The pro-apoptotic effect of extracellular vesicles (EVs) derived from hypoxic HIEC cell to normoxic HIEC cells was then determined. MiR-122-5p was chosen for further studies through a microRNA (miRNA) microarray assay and apoptosis was alleviated in cells receiving miR-122-5p inhibiting hypoxic EVs. Together, our study demonstrated that the miR-122-5p containing-EVs derived from hypoxic HIEC cells promoted apoptosis in normoxic HIEC cells. Hypoxic EV-derived miR-122-5p plays a critical pathologic role in radiation-induced rectal injury and may be a potential therapeutic target.

Low-dose X-ray irradiation combined with FAK inhibitors improves the immune microenvironment and confers sensitivity to radiotherapy in pancreatic cancer.

Radiation therapy offers limited clinical benefits for patients with pancreatic cancer, partly as a result of the predominantly immunosuppressive microenvironment characteristic of this specific type of cancer. A large number of abnormal blood vessels and high-density fibrous matrices in pancreatic cancer will lead to hypoxia within tumor tissue and hinder immune cell infiltration. We used low-dose X-ray irradiation, also known as low-dose radiation therapy (LDRT), to normalize the blood vessels in pancreatic cancer, while simultaneously administering an inhibitor of focal adhesion kinase (FAK) to reduce pancreatic cancer fibrosis. We found that this treatment successfully reduced pancreatic cancer hypoxia, increased immune cell infiltration, and increased sensitivity to radiation therapy for pancreatic cancer.

Gold nanorods modified by endogenous protein with light-irradiation enhance bone repair via multiple osteogenic signal pathways.

Fracture is one of the most common clinical diseases that reduce the quality of patients' lives significantly. In this study, we prepared gold nanorods modified by endogenous proteins which collected from the autologous blood of individual mice for enhanced photothermal therapy (PTT) to treat fracture. Due to the outermost layer being endogenous proteins, we find that GNRs neither activate the immune cells in vitro nor cause any rejection immune responses after entering the body as compared with PEG modification. In addition, the internal bleeding and edema of the fracture site result in a rapid enrichment of GNRs after intravenous injection. Under near infrared (NIR) light irradiation, the mild photothermal effect of the accumulated GNRs can effectively promote healing of fracture in mice. The molecular mechanism of osteogenic capability is revealed by transcriptome sequencing and subsequent confirmatory experiments, indicating enhanced two key osteogenic signal transduction (MAPK, PI3K-Akt) and multiple key osteogenesis related factors expression following the treatment. Our strategy offers an alternative way to promote bone regeneration following a fracture.

The shared uncertainty experience of older adults with advanced cancer and their caregivers.

OBJECTIVE: One primary source of psychological distress in patients with cancer and their caregivers is uncertainty. However, the uncertainty trajectory and its relationship between older adults with advanced cancer and their caregivers have rarely been examined. This study describes the uncertainty trajectory in patient-caregiver dyads, explores the effect of geriatric assessment (GA) intervention on trajectory, and examines the interdependent relationship of uncertainty. METHODS: This secondary analysis used longitudinal data from a national cluster-randomized controlled trial examining a GA intervention compared to usual care. Participants completed the modified 9-item Mishel Uncertainty in Illness Scale at enrollment, 4-6 weeks, 3 months, and 6 months. The dyadic growth model and cross-lagged actor-partner interdependence model were used. RESULTS: A total of 397 dyads (patient age M = 76.81 ± SD5.43; caregiver age M = 66.69 ± SD12.52) were included. Both had a trend of decreased uncertainty over time (b = -0.16, p < 0.01). There was a greater decrease in uncertainty among caregivers in the GA group than those in the usual care group (b = -0.46, p = 0.02). For both patients and caregivers, their past uncertainty was a significant predictor of their own current uncertainty (i.e., actor effect, p < 0.01). The individual's past uncertainty was a significant predictor of the other dyad member's current uncertainty (i.e., partner effect, p < 0.05), indicating an interdependent relationship between patient and caregiver uncertainty over time. CONCLUSIONS: Findings suggest patient and caregiver function as a unit with uncertainty levels affecting each other. Future interventions could build on GA to address uncertainty for older patients with advanced cancer and caregivers.