Upregulation of EFCAB7 after radiofrequency ablation promoting hepatocellular carcinoma metastasis and survival by regulating PARK7.

BACKGROUND: Radiofrequency ablation (RFA) is an established treatment for unresectable and early-stage hepatocellular carcinoma (HCC). However, in some cases, residual tumor cells undergo malignant transformation following RFA. The molecular mechanisms underlying this phenomenon remain poorly understood. EFCAB7, a member of the EF-hand structure family, is of particular interest due to its association with oncogenesis. Nevertheless, the role of EFCAB7 in oncogenesis remains unclear. METHODS: Gene expression level of EFCAB7 in HCC tissues before and after RFA was measured, while in vitro and in vivo experiments were proposed for exploring the roles of EFCAB7 in tumor cell proliferation and metastasis. Mass spectrometry and CO-IP were adopted to validate the interaction between PARK7 and EFCAB7. Finally, PARK7 in EFCAB7 silencing cells was overexpressed and different functions were measured in vitro to determine regulation between two genes. RESULTS: EFCAB7 showed increased expression after RFA in patient samples and EFCAB7 expression correlated with poor prognosis in HCC patients from the TCGA database. Then, EFCAB7 promoted HCC tumor cell proliferation and metastasis while inhibiting apoptosis. Furthermore, Mass spectrometry and Co-IP experiments revealed a direct interaction between EFCAB7 and PARK7. Finally, when we overexpressed PARK7 in EFCAB7 knockdown tumor cells, it rescued proliferation and metastasis, indicating a functional relationship between these two genes. CONCLUSIONS: EFCAB7 might be a core contributor to HCC cells' malignant transformation after RFA and could be a potential novel target to provide a therapeutic strategy for the prevention of recurrence after RFA in HCC.

Relationship between carotid-femoral pulse wave velocity and prognosis in maintenance hemodialysis patients.

Carotid-femoral pulse wave velocity (Cf-PWV) can well predict the prognosis of the general population. However, whether Cf-PWV can be used as a prognostic indicator in maintenance hemodialysis (MHD) patients remains mysterious. The present study endeavored to explore the prognostic value of Cf-PWV among the MHD population. Patients who received MHD and underwent Cf-PWV examination at the hemodialysis center of Zhejiang Provincial People's Hospital between March 1, 2017 and October 15, 2019 were enrolled. Relevant clinical data were collected from these patients, who were subsequently followed up for a minimum of 1 year. During the follow-up period, the occurrence of all-cause death was recorded as a prognostic indicator. Based on the predetermined inclusion and exclusion criteria 178 patients were included in the final analysis. These patients were categorized into 2 groups based on Cf-PWV values: group 1 (Cf-PWV < 13.8 m/s), and group 2 (Cf-PWV ≥ 13.8 m/s). Thirty-four patients succumbed to their conditions within a median follow-up period of 23.3 months. Kaplan-Meier survival analysis revealed that the median survival time of group 2 was significantly shorter than group 1 (log-rank test, χ2 = 12.413, P < .001). After adjusting for various factors, including age, cardiovascular disease, peripheral arterial diastolic pressure, central arterial diastolic pressure, albumin, blood urea nitrogen, serum creatinine, left ventricular ejection fraction, 25 hydroxyvitamin D3, C-reactive protein and serum phosphorus, it was found that Cf-PWV ≥ 13.8m/s was an independent risk factor for all-cause mortality in MHD patients (relative risk = 3.04, 95% confidence interval [CI] = 1.22-7.57; P = .017). A high level of Cf-PWV (≥13.8 m/s) is an independent risk factor for all-cause death in MHD patients.

[Electrophysiological technique for treatment of chronic prostatiti: Curative effect observation].

OBJECTIVE: To observe the clinical effect of electrophysiological technique in treating chronic prostatitis. METHODS: Choose 40 patients of chronic prostatitis/chronic pelvic pain syndrome (chronicprostatis/chronicpelvicpainsyndrome, CP/CPPS) in People's Hospital in Zhijin and People's hospital in Guizhou Province from January 2022 to April 2023, The patients were randomly divided into control group (n=20) and treatment group (n=20). The treatment group received low-frequency neuromuscular electrical stimulation combined with drug therapy, while the control group received drug therapy alone. The improvement of prostatitis symptom score (NIH-CPSI) and International Prostatitis Symptom score (IPSS) before and after treatment was compared and analyzed. RESULTS: A total of 37 patients were followed up (1 patient in the treatment group withdrew due to hypersensitivity to the electrode; 2 patients in the control group were lost to follow-up. )There was no significant difference in baseline data between the two groups (P > 0.05). The NIH-CPSI score and IPSS score before and after treatment were compared between the two groups, and the difference was statistically significant (P< 0.05). The IPSS score of the two groups after treatment was compared, the average reduction of the treatment group was 15.84±0.92 points, and that of the control group was 7.17±0.40 points, and the difference was statistically significant (t=4.792, P< 0.05). The NIH-CPSI score of the two groups after treatment was compared, and the average reduction was 17.47±0.92 points in the treatment group and 10.56±0.49 points in the control group. The difference between the two groups was statistically significant (t=6.654, P< 0.05). CONCLUSION: The effect of electrophysiological combined drug therapy is obviously better than that of simple drug therapy. Electrophysiological therapy for chronic prostatitis has definite clinical effect and is worth promoting and applying.

Light-activated hypoxia-sensitive biomimetic decoy efficiently cascading photodynamic-chemo therapy for breast cancer.

The hypoxic microenvironment within the tumor microenvironment of breast cancer imposes a challenge in overcoming chemotherapy resistance. In this investigation, we designed a novel strategy utilizing a light-controlled cascade targeting nanomedicine specifically tailored for enhanced immune therapy of breast cancer. Albumin nanoparticle was achieved by crosslinking, followed by loading TPZ and Ce6, and subsequent modification to enable selective binding with CD44 hyaluronic acid to form nanomedicine. Encouragingly, it was demonstrated the remarkable ability of the nanomedicine to effectively internalize into cellular entities, thereby inducing apoptosis in 4T1 cells efficiently in vitro when exposed to light irradiation. In vivo assessments showcased the exceptional aptitude of the nanomedicine not only for preferential accumulation within tumor tissues, but also for substantial suppression of tumor growth. Immune mechanisms have shown that nanomedicine treatment promoted the maturation of DCs in vivo, enhanced the proportion of CD8+ T cells in the spleen and tumor, and simultaneously upregulated the ratio of M1 macrophages favorable for anti-tumor effects. These outcomes collectively advance a fresh perspective for the clinical breast cancer therapy.

Novel Water-Splitting Electrolyzer Design Incorporating a Gas Diffusion Electrode and a Gel Membrane for Highly Efficient Hydrogen Production.

Advancements in cost-effective, high-performance alkaline water-splitting systems are crucial for the hydrogen industry. While the significance of electrode material design has been widely acknowledged, the practical implementation of these advancements remains challenging. In this study, we focused on the holistic design of the electrolysis system and successfully developed a novel alkaline water-splitting electrolyzer. The unique configuration of our electrolyzer allows the designed NiFe-LDH/carbon cloth gas diffusion anode to interact solely with the PVA-based gel membrane and air, enabling the direct discharge of oxygen into the gas phase. This innovative feature accelerates anode bubble overflow, reduces gas interference, and decreases the system impedance by minimizing electrode spacing. As a result, by utilizing the NiFeSn-alloy/nickel mesh cathode, our electrolyzer achieves a high current density of 308 mA cm-2 at a cell voltage of 2.0 V and demonstrates exceptional stability over 1000 h.

Associations of gallbladder and gallstone parameters with clinical outcomes in patients with cirrhosis.

Background: Morphologic changes in the gallbladder and gallstones are common in cirrhotic patients, but their associations with outcomes of cirrhotic patients are unclear. Methods: We retrospectively enrolled 206 cirrhotic patients and measured their gallbladder length and width, gallbladder wall thickness, presence of gallstones, and gallstones' length and width in axial contrast-enhanced computed tomography (CT) images. X-tile software was utilized to calculate the optimal cutoff values of these parameters for evaluating survival and hepatic decompensation events in the cirrhosis group. Their associations with survival were explored by Cox regression analyses and Kaplan-Meier curve analyses. Their associations with hepatic decompensation events were evaluated by competing risk analyses and Nelson-Aalen cumulative risk curve analyses where death was a competing event. Results: Cirrhotic patients with gallbladder length < 72 mm had a significantly higher cumulative survival rate than those with a length of ≥ 72 mm (P = 0.049 by log-rank test), but gallbladder width, gallbladder wall thickness, presence of gallstones, and gallstones' length and width were not significantly associated with survival (P = 0.10, P = 0.14, P = 0.97, P = 0.73, and P = 0.73 by log-rank tests, respectively). Cirrhotic patients with gallbladder wall thickness < 3.4 mm had a significantly lower cumulative rate of hepatic decompensation events than those with a wall thickness of ≥ 3.4 mm (P = 0.02 by Gray's test), but gallbladder length and width, presence of gallstones, and gallstones' length and width were not significantly associated with hepatic decompensation events (P = 0.15, P = 0.15, P = 0.54, P = 0.76, and P = 0.54 by Gray's tests, respectively). Conclusion: Changes in gallbladder length and gallbladder wall thickness, rather than gallstone parameters, may be in parallel with the long-term outcomes of cirrhotic patients.

Species sensitivity distribution for nonylphenol: Acute toxicity and ecological risk in Bohai Region.

Nonylphenol (NP), a main byproduct of nonylphenol polyethoxylates (NPEs) degradation, is prevalent across diverse environmental settings. Given its widespread presence, evaluating the ecological risks associated with NP in coastal waters and sediments is essential for the protection of the marine environment. This study evaluates the acute toxicity of NP on ten representative aquatic species from the Bohai Sea, determining the Aquatic Life Criteria (ALC) through two distinct methods. The Criteria Maximum Concentration (CMC) for NP in seawater was established at 12.0 µg/L, with a Predicted No-Effect Concentration (PNEC) for water at 15.2 µg/L and for sediment at 33.3 µg/kg. Additionally, a tiered ecological risk assessment (ERA) of both surface seawater and sediment in the Bohai Sea revealed significant ecological risks at various sediment sites. These results offer crucial insights for assessing the ecological risks to coastal ecosystem and provide foundational data necessary for informed environmental protection and management strategies.

Estrogen receptor knockdown suggests its role in gonadal development regulation in Manila clam Ruditapes philippinarum.

The estrogen receptor (ER), a ligand-dependent transcription factor, is critical for vertebrate reproduction. However, its role in bivalves is not well understood, with ongoing debates regarding its function in regulating reproduction similarly to vertebrates. To investigate ER's function, we conducted a 21-day RNA interference experiment focusing on its role in gonadal development in bivalves. Histological analyses revealed that ER inhibition significantly suppressed ovarian development in females and, conversely, promoted gonadal development in males. Additionally, levels of 17ß-estrogen (E2) were markedly reduced in the gonads of both sexes following ER suppression. Transcriptomic analysis from RNA-seq of testes and ovaries after ER interference showed changes in the expression of key genes such as Vtg, CYP17, 3ß-HSD, and 17ß-HSD. These genes are involved in the estrogen signaling pathway and steroid hormone biosynthesis. Furthermore, ER suppression significantly affected the expression of genes linked to gametogenesis and the reproductive cycle. Our findings highlight ER's crucial, yet complex and sex-specific roles in gonadal development in bivalves, emphasizing the need for further detailed studies.

Key factor screening in mouse NASH model using single-cell sequencing combined with machine learning.

Aims: To identify and analyze genes closely related to the progression of nonalcoholic steatohepatitis (NASH) by employing a combination of single-cell RNA sequencing and machine-learning algorithms. Main methods: Single-cell RNA sequencing (scRNA-seq) analysis was performed to find the cell population with the most significant differences between the Chow and NASH groups. This approach was used to validate the developmental trajectory of this cell population and investigate changes in cellular communication and important signaling pathways among these cells. Subsequently, high dimensional Weighted Gene Co-expression Network Analysis (hdWGCNA) was used to find the key modules in NASH. Machine learning analyses were performed to further identify core genes. Deep learning techniques were applied to elucidate the correlation between core genes and immune cells. The accuracy of this correlation was further confirmed using deep learning techniques, specifically Convolutional Neural Networks. Key findings: By comparing scRNA-seq data between the Chow and NASH groups, we have observed a notable distinction existing in the Kupffer cell population. Signaling interactions between hepatic macrophages and other cells were significantly heightened in the NASH group. Through subsequent analysis of macrophage subtypes and key modules, we identified 150 genes tightly associated with NASH. Finally, we highlighted the 16 most significant core genes using multiple iterations of machine learning. Furthermore, we pointed out the close relationship between core genes and immune cells. Significances: Using scRNA-seq analysis and machine learning, we can distinguish NASH-related genes from large genetic datasets, providing theoretical support in finding potential targets for the development of novel therapies.

Molecular Pathways Regulating Circadian Rhythm and Associated Diseases.

Circadian rhythms, the natural cycles of physical, mental, and behavioral changes that follow a roughly 24-hour cycle, are known to have a profound effect on the human body. Light plays an important role in the regulation of circadian rhythm in human body. When light from the outside enters the eyes, cones, rods, and specialized retinal ganglion cells receive the light signal and transmit it to the suprachiasmatic nucleus of the hypothalamus. The central rhythm oscillator of the suprachiasmatic nucleus regulates the rhythm oscillator of tissues all over the body. Circadian rhythms, the natural cycles of physical, mental, and behavioral changes that follow a roughly 24-hour cycle, are known to have a profound effect on the human body. As the largest organ in the human body, skin plays an important role in the peripheral circadian rhythm regulation system. Like photoreceptor cells in the retina, melanocytes express opsins. Studies show that melanocytes in the skin are also sensitive to light, allowing the skin to "see" light even without the eyes. Upon receiving light signals, melanocytes in the skin release hormones that maintain homeostasis. This process is called "photoneuroendocrinology", which supports the health effects of light exposure. However, inappropriate light exposure, such as prolonged work in dark environments or exposure to artificial light at night, can disrupt circadian rhythms. Such disruptions are linked to a variety of health issues, emphasizing the need for proper light management in daily life. Conversely, harnessing light's beneficial effects through phototherapy is gaining attention as an adjunctive treatment modality. Despite these advancements, the field of circadian rhythm research still faces several unresolved issues and emerging challenges. One of the most exciting prospects is the use of the skin's photosensitivity to treat diseases. This approach could revolutionize how we think about and manage various health conditions, leveraging the skin's unique ability to respond to light for therapeutic purposes. As research continues to unravel the complexities of circadian rhythms and their impact on health, the potential for innovative treatments and improved wellbeing is immense.

Application of the TaqMan ARMS-PCR Approach for Genotyping Drug-Induced Hearing Loss Using Dried Blood Samples.

A single nucleotide variant in mitochondrial DNA (mtDNA) 1555A>G is associated with drug-induced hearing loss. For the 1555A>G mutation site, 1555A wild-type and 1555G mutant-type plasmids were constructed, respectively. In this study, a PCR method based on the TaqMan amplification refractory mutation system was proposed to detect mtDNA 1555A>G. A common upstream primer, a common TaqMan probe, and two downstream allele-specific primers with mismatched bases were designed. One-step amplification and detection of the wild-type and mutant type at the 1555 site were realized for the deafness-related gene through two reactions. Based on this detection method, the minimum detection limit of the wild-type and mutant type detection systems for plasmids was 50 copies/µL. The minimum sensitivity for the detection of nucleic acids in real dried blood spot (DBS) samples was 0.1 ng/µL. In the normal DBS DNA sample, the detection limit of the mutation abundance reached 0.78%. The specificity of the detection method was 100%, and the coefficient of variation was less than 3.36%. This approach was validated using clinical DNA extracted from 113 DBS samples of newborns. Additionally, it showed 100% agreement with bi-directional Sanger sequencing. It can be used as an optional method for the clinical detection of deafness-related genes.

The integration of single-cell and bulk RNA-seq atlas reveals ERS-mediated acinar cell damage in acute pancreatitis.

BACKGROUND: Acute pancreatitis (AP) is a clinically common acute abdominal disease, whose pathogenesis remains unclear. The severe patients usually have multiple complications and lack specific drugs, leading to a high mortality and poor outcome. Acinar cells are recognized as the initial site of AP. However, there are no precise single-cell transcriptomic profiles to decipher the landscape of acinar cells during AP, which are the missing pieces of jigsaw we aimed to complete in this study. METHODS: A single-cell sequencing dataset was used to identify the cell types in pancreas of AP mice and to depict the transcriptomic maps in acinar cells. The pathways' activities were evaluated by gene sets enrichment analysis (GSEA) and single-cell gene sets variation analysis (GSVA). Pseudotime analysis was performed to describe the development trajectories of acinar cells. We also constructed the protein-protein interaction (PPI) network and identified the hub genes. Another independent single-cell sequencing dataset of pancreas samples from AP mice and a bulk RNA sequencing dataset of peripheral blood samples from AP patients were also analyzed. RESULTS: In this study, we identified genetic markers of each cell type in the pancreas of AP mice based on single-cell sequencing datasets and analyzed the transcription changes in acinar cells. We found that acinar cells featured acinar-ductal metaplasia (ADM), as well as increased endocytosis and vesicle transport activity during AP. Notably, the endoplasmic reticulum stress (ERS) and ER-associated degradation (ERAD) pathways activated by accumulation of unfolded/misfolded proteins in acinar cells could be pivotal for the development of AP. CONCLUSION: We deciphered the distinct roadmap of acinar cells in the early stage of AP at single-cell level. ERS and ERAD pathways are crucially important for acinar homeostasis and the pathogenesis of AP.

Effects of vitamin family members on insulin resistance and diabetes complications.

The following letter to the editor highlights the article "Effects of vitamin D supplementation on glucose and lipid metabolism in patients with type 2 diabetes mellitus and risk factors for insulin resistance" in World J Diabetes 2023 Oct 15; 14 (10): 1514-1523. It is necessary to explore the role of vitamin family members in insulin resistance and diabetes complications.

Exploring the mechanism of nonylphenol-induced ovarian developmental delay of manila clams, Ruditapes philippinarum: Applying RNAi to toxicological analysis.

Nonylphenol (NP) contamination in the coastal environment of China poses ecological risks to aquatic organisms. However, the endocrine disruptive impacts of NP on bivalves, particularly on ovarian development, remain poorly understood. In this study, Manila clams Ruditapes philippinarum at the developing stage of gonad were exposed to 1.0 µg/L NP for 21 days. Utilizing RNA interference (RNAi) to suppress ER gene expression, we observed a delay in ovarian development as evidenced by histological observations under both NP and NPRi (NP with ER-RNAi) treatment, with Vtg elevation exclusive to the NP group. Comprehensive analyses encompassing transcriptomics, real-time quantitative PCR, and steroid hormone measurement revealed significant alterations in aldosterone synthesis, estrogen signaling, and thyroid hormone synthesis. These pathways showed similar perturbations in both NP and NPRi groups compared to controls. Notably, the NPRi group exhibited distinct enrichment in PPAR and insulin signaling pathways, may implicating these in ER function suppression. Steroid hormone biosynthesis was notably reduced in both treatments, pointing to a profound impact on hormone synthesis. The contrast between in vivo and in vitro findings suggests that NP's detrimental effects on ovarian development may primarily involve neuroendocrine regulation of steroidogenesis. This investigation highlights the complex dynamics of NP-induced endocrine disruption in bivalves, emphasizing the pivotal role of ER and associated pathways.

lncRNA NORAD alleviates dysfunction of renal proximal tubular epithelial cells during the sepsis-associated acute kidney injury by modulating the miR-155-5p-PDK1 axis.

The sepsis-associated acute kidney injury (Sa-AKI) is closely related to high mortality rates worldwide. Injury to the renal proximal tubular epithelial cells (RPTECs), caused by pathological conditions, is a major cause of acute kidney injury (AKI). The lncRNA NORAD has been reported to be positively associated with kidney cancers. However, the biological roles and underlying mechanisms of NORAD in RPTECs during AKI are still unclear. In this study, we found that NORAD was significantly downregulated in RPTECs from AKI tissues. Overexpression of NORAD alleviated RPTECs injury induced by lipopolysaccharide (LPS). Additionally, glucose metabolism was significantly impaired during AKI, and LPS treatment inhibited glucose metabolism in RPTECs. We demonstrated that NORAD rescued the LPS-induced inhibition of glucose metabolism in RPTECs. Furthermore, miRNA-155-5p was significantly upregulated in RPTECs from AKI. Through bioinformatics analysis, RNA pull-down, RNA IP, and luciferase assays, we showed that NORAD directly associated with miR-155-5p to downregulate its expression. Moreover, overexpression of miR-155-5p inhibited glucose metabolism by directly targeting the 3'UTR of the glucose metabolism enzyme, pyruvate dehydrogenase kinase 1 (PDK1). Finally, rescue experiments validated that NORAD's protective effect on RPTECs injury was mediated through modulation of the miR-155-5p-PDK1-glucose metabolism pathway. In summary, these results reveal that lncRNA NORAD can alleviate RPTECs dysfunction by targeting the miR-155-5p-PDK1 axis, suggesting that NORAD has the potential to contribute to the development of therapeutic approaches against Sa-AKI.

Association of echocardiography-related parameters with the prognosis of decompensated cirrhosis: a retrospective cohort study.

BACKGROUND: Cardiac morphology and function, which are conventionally evaluated by echocardiography, are often abnormal in decompensated cirrhosis. We aimed to evaluate the association of echocardiography-related parameters with prognosis in cirrhosis. METHODS: This retrospective study included 104 decompensated cirrhotic patients, in whom cardiac structure and function were measured by echocardiography, including mitral inflow early diastolic velocity/mitral inflow late diastolic velocity (E/A), left atrium diameter, left ventricular end-diastolic dimension, interventricular septal thickness, left ventricular posterior wall thickness, right atrial transverse diameter, right atrial longitudinal diameter, right ventricular dimension (RVD), stroke volume, cardiac output, left ventricular ejection fraction, and fractional shortening. Cox regression and competing risk analyses and Kaplan-Meier and Nelson-Aalen cumulative risk curves were used to evaluate their associations with further decompensation and death in cirrhotic patients, if appropriate. RESULTS: Lower RVD was a predictor of further decompensation in Cox regression (adjusted by Child-Pugh score: p = 0.138; adjusted by MELD score: p = 0.034) and competing risk analyses (p = 0.003), and RVD ≤17 mm was significantly associated with higher cumulative incidence of further decompensation in Kaplan-Meier (p = 0.002) and Nelson-Aalen cumulative risk curves (p = 0.002). E/A ≤ 0.8 was a significant predictor of death in Cox regression (adjusted by Child-Pugh score: p = 0.041; adjusted by MELD score: p = 0.045) and competing risk analyses (p = 0.024), and E/A ≤ 0.8 was significantly associated with higher cumulative incidence of death in Kaplan-Meier (p = 0.023) and Nelson-Aalen cumulative risk curves (p = 0.024). Other echocardiography-related parameters were not significantly associated with further decompensation or death. CONCLUSION: RVD and E/A may be considered for the prognostic assessment of decompensated cirrhosis.

Comparative pharmacokinetics of polymyxin B in critically ill elderly patients with extensively drug-resistant gram-negative bacteria infections.

Introduction: Elderly patients are more prone to develop acute kidney injury during infections and polymyxin B (PMB)-associated nephrotoxicity than young patients. The differential response to PMB between the elderly and young critically ill patients is unknown. We aimed to assess PMB exposure in elderly patients compared with young critically ill patients, and to determine the covariates of PMB pharmacokinetics in critically ill patients. Methods: Seventeen elderly patients (age ≥ 65 years) and six young critically ill patients (age < 65 years) were enrolled. Six to eight blood samples were collected during the 12 h intervals after at least six doses of intravenous PMB in each patient. PMB plasma concentrations were quantified by high-performance liquid chromatography-tandem mass spectrometry. The primary outcome was PMB exposure as assessed by the area under the concentration-time curve over 24 h at steady state (AUCss, 0-24 h). Results and Discussion: The elderly group had lower total body weight (TBW) and higher Charlson comorbidity scores than young group. Neither AUCss, 0-24 h nor normalized AUCss, 0-24 h (adjusting AUC for the daily dose in mg/kg of TBW) was significantly different between the elderly group and young group. The half-life time was longer in the elderly patients than in young patients (11.21 vs 6.56 h respectively, p = 0.003). Age and TBW were the covariates of half-life time (r = 0.415, p = 0.049 and r = -0.489, p = 0.018, respectively). TBW was the covariate of clearance (r = 0.527, p = 0.010) and AUCss, 0-24 h (r = -0.414, p = 0.049). Patients with AUCss, 0-24 h ≥ 100 mg·h/L had higher baseline serum creatinine levels and lower TBW than patients with AUCss, 0-24 h < 50 mg·h/L or patients with AUCss, 0-24 h 50-100 mg·h/L. The PMB exposures were comparable in elderly and young critically ill patients. High baseline serum creatinine levels and low TBW was associated with PMB overdose. Trial registration: ChiCTR2300073896 retrospectively registered on 25 July 2023.

Citric acid promotes SPARC release in pancreatic cancer cells and inhibits the progression of pancreatic tumors in mice on a high-fat diet.

Over the years, pancreatic cancer has experienced a global surge in incidence and mortality rates, largely attributed to the influence of obesity and diabetes mellitus on disease initiation and progression. In this study, we investigated the pathogenesis of pancreatic cancer in mice subjected to a high-fat diet (HFD) and observed an increase in citric acid expenditure. Notably, citrate treatment demonstrates significant efficacy in promoting tumor cell apoptosis, suppressing cell proliferation, and inhibiting tumor growth in vivo. Our investigations revealed that citrate achieved these effects by releasing secreted protein acidic and rich in cysteine (SPARC) proteins, repolarizing M2 macrophages into M1 macrophages, and facilitating tumor cell apoptosis. Overall, our research highlights the critical role of citric acid as a pivotal metabolite in the intricate relationship between obesity and pancreatic cancer. Furthermore, we uncovered the significant metabolic and immune checkpoint function of SPARC in pancreatic cancer, suggesting its potential as both a biomarker and therapeutic target in treating this patient population.

PLOD3 facilitated T cell activation in the colorectal tumor microenvironment and liver metastasis by the TNF-α/ NF-κB pathway.

BACKGROUND: Colorectal cancer (CRC) has been the third most prevalent cancer worldwide. Liver metastasis is the critical factor for the poor prognosis of CRC. Here, we investigated the expression and role of PLOD3 in CRC. METHODS: Different liver metastasis models were established by injecting PLOD3 stable knockdown or overexpression CT26 or MC38 mouse CRC cells into the spleen of mice to verify the tumorigenicity and metastasis ability in vivo. RESULTS: We identified PLOD3 is significantly overexpressed in liver metastasis samples of CRC. High expression of PLOD3 was significantly associated with poor survival of CRC patients. The knockdown of PLOD3 exhibited remarkable inhibition of proliferation, migration, and invasion in CRC cells, while the opposite results could be found in different PLOD3-overexpressed CRC cells. Stable knockdown of PLOD3 also significantly inhibited liver metastasis of CRC cells in different xenografts models, while stable overexpression of PLOD3 promotes liver metastasis and tumor progression. Further studies showed that PLOD3 facilitated the T cell activation in the tumor microenvironment and affected the TNF-α/ NF-κB pathway. CONCLUSIONS: This study revealed the essential biological functions of PLOD3 in colon cancer progression and metastasis, suggesting that PLOD3 is a promising translational medicine target and bioengineering targeting PLOD3 overcomes CRC liver metastasis.