Spatially Resolved Niche and Tumor Microenvironmental Alterations in Gastric Cancer Peritoneal Metastases.

BACKGROUND AND AIMS: Peritoneal metastasis (PM) in gastric cancer (GC) is associated with poor prognosis and significant morbidity. We sought to understand the genomic, transcriptomic, and tumor microenvironment (TME) features that contribute to peritoneal organotropism in GC. METHODS: We conducted a comprehensive multi-omic analysis of 548 samples from 326 patients, including primary tumors, matched normal tissues; peritoneal metastases, and adjacent-normal peritoneal tissues. We used whole exome sequencing, whole transcriptome sequencing, and digital spatial profiling to investigate molecular alterations, gene expression patterns, and TME characteristics associated with PM. RESULTS: Our analysis identified specific genomic alterations in primary tumors, including mutations in ELF3, CDH1, and PIGR, and TME signatures, such as stromal infiltration and M2 macrophage enrichment, associated with increased risk of PM. We observed distinct transcriptional programs and immune compositions in GCPM compared with liver metastases, highlighting the importance of the TME in transcoelomic metastasis. We found differential expression of therapeutic targets between primary tumors and PM, with lower CLDN18.2 and FGFR2b expression in PM. We unravel the roles of the TME in niche reprogramming within the peritoneum, and provide evidence of pre-metastatic niche conditioning even in early GC without clinical PM. These findings were further validated using a humanized mouse model, which demonstrated niche remodeling in the peritoneum during transcoelomic metastasis. CONCLUSION: Our study provides a comprehensive molecular characterization of GCPM and unveils key biological principles underlying transcoelomic metastasis. The identified predictive markers, therapeutic targets, and TME alterations offer potential avenues for targeted interventions and improved patient outcomes.

TC2N inhibits distant metastasis and stemness of breast cancer via blocking fatty acid synthesis.

BACKGROUND: Tandem C2 domains, nuclear (TC2N) is a C2 domain-containing protein that belongs to the carboxyl-terminal type (C-type) tandem C2 protein family, and acts as an oncogenic driver in several cancers. Previously, we preliminarily reported that TC2N mediates the PI3K-Akt signaling pathway to inhibit tumor growth of breast cancer (BC) cells. Beyond that, its precise biological functions and detailed molecular mechanisms in BC development and progression are not fully understood. METHODS: Tumor tissues of 212 BC patients were subjected to tissue microarray and further assessed the associations of TC2N expression with pathological parameters and FASN expression. The protein levels of TC2N and FASN in cell lines and tumor specimens were monitored by qRT-PCR, WB, immunofluorescence and immunohistochemistry. In vitro cell assays, in vivo nude mice model was used to assess the effect of TC2N ectopic expression on tumor metastasis and stemness of breast cancer cells. The downstream signaling pathway or target molecule of TC2N was mined using a combination of transcriptomics, proteomics and lipidomics, and the underlying mechanism was explored by WB and co-IP assays. RESULTS: Here, we found that the expression of TC2N remarkedly silenced in metastatic and poorly differentiated tumors. Function-wide, TC2N strongly inhibits tumor metastasis and stem-like properties of BC via inhibition of fatty acid synthesis. Mechanism-wise, TC2N blocks neddylated PTEN-mediated FASN stabilization by a dual mechanism. The C2B domain is crucial for nuclear localization of TC2N, further consolidating the TRIM21-mediated ubiquitylation and degradation of FASN by competing with neddylated PTEN for binding to FASN in nucleus. On the other hand, cytoplasmic TC2N interacts with import proteins, thereby restraining nuclear import of PTEN to decrease neddylated PTEN level. CONCLUSIONS: Altogether, we demonstrate a previously unidentified role and mechanism of TC2N in regulation of lipid metabolism and PTEN neddylation, providing a potential therapeutic target for anti-cancer.

Gender differences in symptom burden among people living with HIV/AIDS receiving antiretroviral therapy in Yunnan, China.

ABSTRACTLittle is known about gender differences in the symptom burden of people living with HIV/AIDS (PLWHA) on antiretroviral therapy in China. This study was conducted based on a biopsychosocial-medical model to describe gender differences in symptom burden among 1035 PLWHA in Yunnan Province, China. After propensity score matching, 798 PLWHA were included in this analysis. Feeling stressed, poor sleep, and memory loss were the most burdensome symptoms among men, while feeling stressed, memory loss, and dizziness were the most burdensome symptoms among women. Among men PLWHA, factors associated with symptom burden were being of the ethnic minority, CD4 count ≥ 500 cells/mm3, physical functioning, and social support. Among women PLWHA, factors associated with symptom burden were being an inpatient, physical functioning, psychological functioning, and social support. Our findings suggest that healthcare providers need to take into account gender differences when developing optimal prevention, treatment, and care programs that provide individualized care to reduce patients' symptom burden.

First Report of Diaporthe hongkongensis Causing Leaf Blight on Macadamia in China.

Macadamia (Macadamia ternifolia Maiden and Betche) belongs to the Proteaceae family (Li et al. 2022). In the hilly areas of Guangxi (southern China), macadamia trees are an important source of revenue. The planting area in Guangxi has increased in recent years, exceeding 53,333 hectares by the end of 2022, but this increase is also associated with emergency of, macadamia diseases. Leaf blight symptoms were observed in 37/241 macadamia trees (15% incidence) in a plantation in Nanning, Guangxi province in China, during June, 2022. Disease severity on infected trees ranged from 5% to 60%. The disease developed from the tips or margins of leaves, causing the leaves to turn brown, and later gradually withered (Fig. 1 A). Ten leaves with lesions were collected from five macadamia trees (two leaves per tree. Thereafter, small segments (3 to 4 mm²) excised from the margins of ten lesions were surface sterilized in 75% ethanol for 30 s and 1% hypochlorite for 90 s and Page 1 of 6 2 rinsed in sterile water, before plating onto potato dextrose agar (PDA) medium. Plates were incubated under lighting during the daytime, and darkness at night-time for 5 days at 25℃. Twenty-two purified colonies were generated by subculturing hyphal tips, of which eight exhibited similar morphology and were further characterized. The colonies on PDA were gray with a white outer ring and flat lawn on the surface (Fig. 1 B). The pycnidia were superficial to semi-immersed on PDA, solitary to aggregated, globose to sub-globose, brown to black and oozed yellow mucilaginous masses (Fig.1 C). The α-conidia were unicellular, hyaline elliptical or fusiform, and measuring 4-8 × 1.9-4 µm (n=30) ， whereas the ß-conidia were hyaline, long, straight or curved, measuring 20-23 × 0.9-2 µm (n=30) (Fig. 1 D-E). The morphological features were similar to Diaporthe hongkongensis (Dissanayake et al. 2015). The eight morphologically similar isolates were identified as D. hongkongensis using the internal transcribed spacer (ITS) region, but only one isolate, JG11, was selected for further molecular identification. Five target genes, including the ITS region, translation elongation factor 1 alpha (EF1-α), beta-tubulin genes (TUB2), calmodulin (CAL), and histone H3 (HIS) were amplified and sequenced using primers ITS1/ITS4, EF1-728F/EF1-986R, Bt2a/Bt2b, CAL-228F/CAL-737R, and CYLH3F/H3-1b, respectively (Carbone and Kohn 1999). The sequences were deposited in GenBank under accession numbers OQ932790 (ITS) and OR147955-58 for EF1-α, TUB, CAL and HIS genes, respectively. BLAST search of GenBank showed that ITS, EF1-α, TUB, CAL, and HIS sequences of JG11 were similar to Page 2 of 6 3 those of D. hongkongensis NR111848 (99.22% identity), KY433566 (99.72%), MW208603 (99.42%), MW221740 (99.80%), and MW221661 (99.79%), respectively. Phylogenetic analysis of concatenated sequences was performed with IQ-TREE software. JG11 was grouped in the same clade as other Diaporthe hongkongensis isolates (Fig. 2). Pathogenicity experiments were carried out on healthy macadamia trees in a greenhouse. Three macadamia trees were used as negative controls where five uninjured leaves per tree were sprayed with sterile distilled water. Uninjured five leaves per tree of three other macadamia trees were sprayed with conidia suspension of the isolate JG11 at a concentration of 1×106. Each treatment was repeated 3 times independently, with 5 leaves per tree (Liu et al. 2023; Havill et al. 2023; Zhang et al. 2022). Plastic bags were placed over all inoculated leaves. The average daily temperature and relative humidity in the greenhouse were 32°C and 65%, respectively. Two days later, browning appeared on the leaves inoculated with the spore suspension and expanded outward. After 5 days, all macadamia leaves inoculated with the fungal spores began to wither, while controls remained asymptomatic (Fig. 1 H-I). D. hongkongensis was consistently re-isolated and purified from inoculated leaves and the identity was confirmed by morphological identification and molecular analysis, completed Koch's postulates. D. hongkongensis has been reported on peach (Zhang et al. 2021), grapevine trunk (Dissanayake et al. 2015) and Cunninghamia lanceolata (Liao et al. 2022). To our knowledge, this is the first report of D. hongkongensis causing leaf blight on macadamia in China. These findings provide a foundation for future research on the epidemiology and control of this newly emerging disease of macadamia.

[Metabolomics of quality formation of different cultivars of Peucedanum praeruptorum].

This study aims to reveal the quality formation of different cultivars of Peucedanum praeruptorum based on the metabolic differences and provide a theoretical basis for the development and utilization of this medicinal herb. The non-target metabonomics analysis based on ultra-high performance liquid chromatography tandem mass spectrometry(UHPLC-MS/MS) was conducted for six cultivars(YS, H, LZ, LY, LX, and Z) of P. praeruptorum of the same origin and at the same development stage. The principal component analysis, orthogonal partial least squares discriminant analysis, and univariate statistical analysis were carried out to screen the differential metabolites of different cultivars. The potential biomarkers associated with quality formation were predicted based on the mass-to-charge ratio, Kyoto Encyclopedia of Genes and Genomes pathway enrichment, information of relevant literature, and correlation analysis. The results showed that metabolites differed significantly among the six cultivars, and 571 and 465 differential metabolites were obtained in the positive and negative ion modes, respectively. From the differential metabolites, 22 potential biomarkers related to quality formation were predicted, which involved 9 metabolic pathways, including phenylalanine, tyrosine and tryptophan biosynthesis, biosynthesis of phenylpropanoids, and biosynthesis of plant hormones. Compared with the YS cultivar, other cultivars showed decreased concentrations of psoralen, imperatorin, and luvangetin and increased concentrations of 7-hydroxycoumarine, esculetin, columbianetin, and jasmonic acid, which were involved in the biosynthesis of phenylpropanoids. The concentrations of 2-succinylbenzoate, heraclenol, and L-tyrosine involved in other metabolic pathways decreased, especially in the Z and H cultivars. Therefore, regulating the biosynthesis of phenylpropanoids is one of the key mechanisms for improving the cultivar quality of P. praeruptorum. The Z and H cultivars have better quality and metabolic processes than other cultivars and thus can be used for the screening and breeding of high-quality germplasm.

High-resolution mapping of the global silicate weathering carbon sink and its long-term changes.

Climatic and non-climatic factors affect the chemical weathering of silicate rocks, which in turn affects the CO2 concentration in the atmosphere on a long-term scale. However, the coupling effects of these factors prevent us from clearly understanding of the global weathering carbon sink of silicate rocks. Here, using the improved first-order model with correlated factors and non-parametric methods, we produced spatiotemporal data sets (0.25° × 0.25°) of the global silicate weathering carbon-sink flux (SCSFα ) under different scenarios (SSPs) in present (1950-2014) and future (2015-2100) periods based on the Global River Chemistry Database and CMIP6 data sets. Then, we analyzed and identified the key regions in space where climatic and non-climatic factors affect the SCSFα . We found that the total SCSFα was 155.80 ± 90 Tg C yr-1 in present period, which was expected to increase by 18.90 ± 11 Tg C yr-1 (12.13%) by the end of this century. Although the SCSFα in more than half of the world was showing an upward trend, about 43% of the regions were still showing a clear downward trend, especially under the SSP2-4.5 scenario. Among the main factors related to this, the relative contribution rate of runoff to the global SCSFα was close to 1/3 (32.11%), and the main control regions of runoff and precipitation factors in space accounted for about 49% of the area. There was a significant negative partial correlation between leaf area index and silicate weathering carbon sink flux due to the difference between the vegetation types. We have emphasized quantitative analysis the sensitivity of SCSFα to critical factors on a spatial grid scale, which is valuable for understanding the role of silicate chemical weathering in the global carbon cycle.

Design, Synthesis, and Biological Activity of Chalcone Analogs Containing 4-Phenylquinolin and Benzohydrazide.

A series of chalcone derivatives (3a-3m) containing 4-phenylquinoline and benzohydrazide were designed and synthesized, and their anti-inflammatory, analgesic, and antidepressant activities were evaluated. Using the classic antidepressant model, except for compounds 3a and 3d, 11 compounds all showed certain antidepressant activity at a dose of 100 mg/kg, among which compounds 3f, 3h, and 3m showed good antidepressant activity (inhibition rate, respectively 63.0 %, 73.2 %, and 76.4 %), which was equivalent to the positive control fluoxetine (inhibition rate of 70.0 %). Secondly, the inhibitory activity of these compounds on mouse MAOA was evaluated. At 10 mM, compounds 3f and 3j showed a certain selective inhibitory effect on mouse MAOA , while compounds 3b, 3d, 3g, 3i, and 3m had a good inhibitory effect on mouse MAOA (inhibition rate is 42.3-71.4 %). The mouse ear edema model was used to evaluate the anti-inflammatory activity of compounds 3a-3m. At 30 mg/kg, compounds 3b, 3c, 3e, 3f, 3g, and 3m showed certain anti-inflammatory effects (inhibition rate of 51.5-99.9 %), which was equivalent to the positive control indomethacin (inhibition rate of 69.7 %). Results of the acetic acid-induced abdominal writhing test showed that, at 30 mg/kg, excepted for compounds 3a, 3b and 3d, all the other 10 compounds can show certain analgesic activity (inhibition rate 67-99.9 %). The use of Auto dock Vina (simina) to simulate molecular target docking shows that the development of quinoline and benzohydrazide groups is of great significance to MAOA inhibitors.

Postoperative Inflammatory Marker Surveillance in Colorectal Peritoneal Carcinomatosis.

BACKGROUND: The prognostic significance of inflammatory markers in solid cancers is well-established, albeit with considerable heterogeneity. This study sought to investigate the postoperative inflammatory marker trend in peritoneal carcinomatosis (PC), with a focus on colorectal PC (CPC), and to propose optimal surveillance periods and cutoffs. METHODS: Data were collected from a prospectively maintained database of PC patients treated at the authors' institution from April 2001 to March 2019. The platelet-lymphocyte ratio (PLR), the neutrophil-lymphocyte ratio (NLR), and the lymphocyte-monocyte ratio (LMR) were collected preoperatively and on postoperative days 0, 1 to 3, 4 to 7, 8 to 21, 22 to 56, and 57 to 90 as averages. Optimal surveillance periods and cutoffs for each marker were determined by maximally selected rank statistics. The Kaplan-Meier method and Cox proportional hazard regression models were used to investigate the association of inflammatory markers with 1-year overall survival (OS) and recurrence-free survival (RFS) using clinicopathologic parameters. RESULTS: The postoperative inflammatory marker trend and levels did not differ between the patients with and those without hyperthermic intraperitoneal chemotherapy (HIPEC). Low postoperative LMR (days 4-7), high postoperative NLR (days 8-21), and high postoperative PLR (days 22-56) were optimal for prognosticating poor 1-year OS, whereas high postoperative PLR and NLR (days 57-90) and low postoperative LMR (days 8-21) were associated with poor 1-year RFS. A composite score of these three markers was prognostic for OS in CPC. CONCLUSIONS: The reported cutoffs should be validated in a larger population of CPC patients. Future studies should account for the inflammatory response profile when selecting appropriate surveillance periods.

TGFß1-Smad Signaling Pathway Participates in Interleukin-33 Induced Epithelial-to-Mesenchymal Transition of A549 Cells.

BACKGROUNDS/AIMS: Epithelial-to-mesenchymal transition (EMT) has been proven to be involved in development and progression of pulmonary fibrosis. This study aims to investigate the role of transforming growth factor ß1 (TGFß1)-smad signaling pathway in the interleukin-33 (IL-33) induced EMT. METHODS: The human type II alveolar epithelial cell line, A549, and small airway epithelial cells (SAEC) were cultured and divided into 4 groups including Control, LY-2109761 (TGFß receptor inhibitor), IL-33 and IL-33+LY-2109761 group. Expression of TGFß1, E-cadherin (E-cad) and α-smooth muscle actin (α-SMA) were examined by using real-time PCR (RT-PCR) and western blot assay, respectively. The smad3 signaling pathway factors, including smad3 and phosphorylated smad3 (p-smad3), were also detected by using western blot assay. RESULTS: IL-33 significantly activated T1/ST2 expression in A549 cells (P< 0.05). TGFß1 receptor inhibitor significantly suppressed the IL-33 caused down-expression of E-cad compared to IL-33 alone (P< 0.05). IL-33 significantly increased the α-SMA levels compared to Control group (P< 0.05) and TGFß1 receptor inhibitor inhibited the other effects of IL-33. IL-33 significantly enhanced the levels of TGFß1 compared to Control group (P< 0.05). TGFß1 receptor inhibitor suppressed the IL-33 induced up-expression of p-smad3. CONCLUSION: The TGFß1-smad signaling pathway participates in the IL-33 induced epithelial-to-mesenchymal transition of A549 cells.

The Effects of Platelet-Rich Plasma and Adipose-Derived Stem Cells on Neovascularization and Fat Graft Survival.

BACKGROUND: Adipose-derived stem cell (ADSCs)-assisted and platelet-rich plasma (PRP)-assisted lipofilling aim to enhance angiogenesis and cell proliferation and are promising techniques for lipofilling. This study aimed to compare the outcomes of ADSCs-assisted and PRP-assisted lipofilling. METHODS: Adipose tissue and human venous blood were obtained from women with early breast cancer. Human ADSCs were isolated and amplified in vitro. PRP was extracted through double centrifugation. The effect of PRP on ADSCs proliferation was evaluated. In the in vivo study, 1 ml of adipose tissue with saline (control group), PRP (PRP group), or ADSCs (ADSCs group) was injected subcutaneously into the dorsum of nude mice. At 2, 4, 8, and 12 weeks after injection, tissues were assessed for volume retention and ultrasound abnormality. For histological assessment, hematoxylin and eosin staining were performed. RESULTS: Cytokines in PRP and blood were comparable. Regarding the in vitro assay, PRP significantly improved ADSCs proliferation, and the effect was dose-dependent. Concerning the in vivo study, for each time point, ADSCs-assisted lipofilling showed superior volume maintenance. Similarly, the PRP group showed improved angiogenesis and fat survival, as compared with the control group. The angiogenic effect of PRP was inferior to that of ADSCs at most time points. No significant difference was observed at 12 weeks after lipofilling. Complication rates were comparable between the PRP group and ADSCs group. CONCLUSIONS: PRP-assisted and ADSCs-assisted lipofilling can significantly improve the cosmetic results of grafted fat. PRP-assisted lipofilling, which is considered convenient and clinically available, is a promising technique to improve neovascularization and fat survival. NO LEVEL ASSIGNED: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

A Cost-Effective Relative Humidity Sensor Based on Side Coupling Induction Technology.

A intensity-modulated optical fiber relative humidity (RH) sensor based on the side coupling induction technology (SCIT) is presented and experimentally demonstrated. The agarose gel and the twisted macro-bend coupling structure are first combined for RH sensing applications. The refractive index (RI) of the agarose gel increases with the increase of the RH and is in linear proportion from 20 to 80%RH. The side coupling power, which changes directly with the RI of the agarose gel, can strip the source noise from the sensor signal and improve the signal to noise ratio substantially. The experiment results show that the sensitivity of the proposed sensor increases while the bend radius decreases. When the bend radius is 8 mm, the sensor has a linear response from 40% to 80% RH with the sensitivity of 4.23 nW/% and the limit of detection of 0.70%. A higher sensitivity of 12.49 nW/% is achieved when RH raises from 80% to 90% and the limit of detection decreases to 0.55%. Furthermore, the proposed sensor is a low-cost solution, offering advantages of good reversibility, fast response time, and compensable temperature dependence.

Calotropin from Asclepias curasavica induces cell cycle arrest and apoptosis in cisplatin-resistant lung cancer cells.

Calotropin (M11), an active compound isolated from Asclepias curasavica L., was found to exert strong inhibitory and pro-apoptotic activity specifically against cisplatin-induced resistant non-small cell lung cancer (NSCLC) cells (A549/CDDP). Molecular mechanism study revealed that M11 induced cell cycle arrest at the G2/M phase through down-regulating cyclins, CDK1, CDK2 and up-regulating p53 and p21. Furthermore, M11 accelerated apoptosis through the mitochondrial apoptotic pathway which was accompanied by increase Bax/Bcl-2 ratio, decrease in mitochondrial membrane potential, increase in reactive oxygen species production, activations of caspases 3 and 9 as well as cleavage of poly ADP-ribose polymerase (PARP). The activation and phosphorylation of JNK was also found to be involved in M11-induced apoptosis, and SP610025 (specific JNK inhibitor) partially prevented apoptosis induced by M11. In contrast, all of the effects that M11 induce cell cycle arrest and apoptosis in A549/CDDP cells were not significant in A549 cells. Drugs with higher sensitivity against resistant tumor cells than the parent cells are rather rare. Results of this study supported the potential application of M11 on the non-small lung cancer (NSCLC) with cisplatin resistance.

[Role of acetylcholine in gelsenicine-induced death in mice].

The aim of this study was to investigate the relationship between the acetylcholine concentration in the blood and gelsenicine-induced death in mice. Kunming mice were given intraperitoneal injections of normal saline, gelsenicine or different doses of acetylcholine chloride. Atropine was given to the mice which received gelsenicine or medium dose acetylcholine chloride injection. The blood was sampled immediately when the mice died or survived for 20 min after injection. The acetylcholine concentration and acetylcholinesterase activity in the blood were measured by the testing kits, and the mortality was calculated and analyzed. The results showed that half lethal dose of gelsenicine (0.15 mg/kg) reduced the acetylcholinesterase activity and increased the blood acetylcholine concentration. The blood acetylcholine concentration of the dead mice in the gelsenicine group was increased to 43.0 µg/mL (from 31.1 µg/mL in the control), which was lower than that (53.9 µg/mL) of the dead mice in the medium dose acetylcholine chloride group, but almost equal to that (42.7 µg/mL) of the survival mice in the medium dose acetylcholine chloride group. Atropine could successfully rescue the mice from acetylcholine poisoning, but its efficiency of rescuing the mice from gelsenicine intoxication was weak. These results suggest that gelsenicine can inhibit acetylcholinesterase activity and increase blood acetylcholine concentration, but the accumulation of acetylcholine may not be the only or main cause of the death induced by gelsenicine in mice.

Synthesis and anticancer activities of thieno[3,2-d]pyrimidines as novel HDAC inhibitors.

A series of thieno[3,2-d]pyrimidines bearing a hydroxamic acid moiety as novel HDAC inhibitors were designed and synthesized. The structures of the new synthesized compounds were confirmed using IR, (1)H, (13)C NMR spectrum. Compounds 11-13 showed potent inhibitory activities against HDACs with IC50 values at 0.38, 0.49 and 0.61 µM. Most of target compounds displayed strong anti-proliferative activity by a MTT assay on three human cancer cell lines including HCT-116, MCF-7 and HeLa. Compound 11, having potent inhibitory activities against HDACs, induced apoptosis and G2/M cell cycle arrest in HCT-116 cell line.

Genome-wide analysis of DNA 5-hmC in peripheral blood of uremia by hMeDIP-chip.

BACKGROUND: Treatment of uremia is now dominated by dialysis; in some cases, patients are treated with dialysis for decades, but overall outcomes are disappointing. A number of studies have confirmed the relevance of several experimental insights to the pathogenesis of uremia, but the specific biomarkers of uremia have not been fully elucidated. To date, our knowledge about the alterations in DNA 5-hydroxymethylcytosine (5-hmC) in uremia is unclear, to investigate the role of DNA 5-hmC in the onset of uremia, we performed hMeDIP-chip between the uremia patients and the normal controls from the experiment to identify differentially expressed 5-hmC in uremia-associated samples. METHODS: Extract genomic DNA, using hMeDIP-chip technology of Active Motif companies for the analysis of genome-wide DNA 5-hmC, and quantitative real-time PCR confirmation to identify differentially expressed 5-hmC level in uremia-associated samples. RESULTS: There were 1875 genes in gene Promoter, which displayed significant 5-hmC differences in uremia patients compared with normal controls. Among these genes, 960 genes displayed increased 5-hmC and 915 genes decreased 5-hmC. 4063 genes in CpG Islands displayed significant 5-hmC differences in uremia patients compared with normal controls. Among these genes, 1780 genes displayed increased 5-hmC and 2283 genes decreased 5-hmC. Three positive genes, HMGCR, THBD, and STAT3 were confirmed by quantitative real-time PCR. CONCLUSION: Our studies indicate the significant alterations of 5-hmC. There is a correlation of gene modification 5-hmC in uremia patients. Such novel findings show the significance of 5-hmC as a potential biomarker or promising target for epigenetic-based uremia therapies.

Meticulous catheter care and aseptic approach reduce catheter-related bloodstream infections significantly in hemodialysis patients: A 5-year single center study.

AIM: The use of central venous catheters as hemodialysis vascular access is a major contributor to high bloodstream infection rate. In our dialysis unit in Shenzhen Guangdong Province China, we have developed and used our own dialysis catheter care protocol since May 2013 with good results. In this study, we would like to share our experience with the other units. METHODS: We have undertaken a 5-year retrospective analysis to determine our tunneled dialysis catheter-related blood stream infection rate by adding the number of infections divided by total number of catheter days × 1000. The results were compared with another study carried out in Henan Province China. Demographic data were summarized using descriptive statistics. Continuous and categorical variables were compared using t-test and χ2 test respectively. RESULTS: Between 2017 and 2021, a total of 216 tunneled dialysis catheters were managed by following our own dialysis access pathway and catheter care protocol. The tunneled dialysis catheter-related bloodstream infection rate was 0.0229 per 1000 catheter days in the 5-year period. CONCLUSION: Comparing with other published studies in China, our unit has achieved a very low rate of tunneled dialysis catheter-related bloodstream infection which has been sustained over time. This paper explores how our protocol and implementation might have contributed to the results.

The immunomodulatory role of paracrine signalling factor VSIG4 in peritoneal metastases.

Peritoneal metastasis (PM), the regional progression of intra-abdominal malignancies, is a common sequelae of colorectal cancer (CRC). Immunotherapy is slated to be effective in generating long-lasting anti-tumour response as it utilizes the specificity and memory of the immune system. In the tumour microenvironment, tumour associated macrophages (TAMs) are posited to create an anti-inflammatory pro-tumorigenic environment. In this paper, we aimed to identify immunomodulatory factors associated with colorectal PM (CPM). A publicly available colorectal single cell database (GSE183916) was analysed to identify possible immunological markers that are associated with the activation of macrophages in cancers. Immunohistochemical analysis for V-set and immunoglobin containing domain 4 (VSIG4) expression was performed on tumour microarrays (TMAs) of tumours of colorectal origin (n = 211). Expression of VSIG4 in cell-free ascites obtained from CPM patients (n = 39) was determined using enzyme-linked immunosorbent assay (ELISA). CD163-positive TAMs cluster expression was extracted from a publicly available single cell database and evaluated for the top 100 genes. From these macrophage-expressed genes, VSIG4, a membrane protein produced by the M2 macrophages, mediates the up-regulation of anti-inflammatory and down-regulation of pro-inflammatory macrophages, contributing to an overall anti-inflammatory state. CRC TMA IHC staining showed that low expression of VSIG4 in stromal tissues of primary CRC are associated with poor prognosis (p = 0.0226). CPM ascites also contained varying concentrations of VSIG4, which points to a possible role of VSIG4 in the ascites. The contribution of VSIG4 to CPM development can be further evaluated for its potential as an immunotherapeutic agent.

Transcriptomic convergence despite genomic divergence drive field cancerization in synchronous squamous tumors.

Introduction: Field cancerization is suggested to arise from imbalanced differentiation in individual basal progenitor cells leading to clonal expansion of mutant cells that eventually replace the epithelium, although without evidence. Methods: We performed deep sequencing analyses to characterize the genomic and transcriptomic landscapes of field change in two patients with synchronous aerodigestive tract tumors. Results: Our data support the emergence of numerous genetic alterations in cancer-associated genes but refutes the hypothesis that founder mutation(s) underpin this phenomenon. Mutational signature analysis identified defective homologous recombination as a common underlying mutational process unique to synchronous tumors. Discussion: Our analyses suggest a common etiologic factor defined by mutational signatures and/or transcriptomic convergence, which could provide a therapeutic opportunity.

Knockdown of ECHS1 protein expression inhibits hepatocellular carcinoma cell proliferation via suppression of Akt activity.

Overexpression of ECHS1 occurs in different cancers, including hepatocellular carcinoma (HCC). ECHS1 is also reported to have an oncogenic activity in various human cancers. This study investigated the effect of ECHS1 knockdown on the regulation of HCC growth. ECHS1 shRNA suppressed the expression of ECHS1 protein in HepG2 cells compared to the negative control vector-transfected HCC cells. ECHS1 knockdown also reduced HCC cell viability and enhanced cisplatin-induced apoptosis in HCC cells. Akt activation and the expression of various cell cycle-related genes were inhibited following ECHS1 knockdown. ECHS1 shRNA suppressed hepatocellular carcinoma growth in tumor xenograft mice. These data demonstrate that ECHS1 may play a role in HCC progression, suggesting that inhibition of ECHS1 expression using ECHS1 shRNA should be further evaluated as a novel target for the control of HCC.