Mussel-Mimetic Hydrogel Coating with Anticoagulant and Antiinflammatory Properties on a Poly(lactic acid) Vascular Stent.

Biodegradable stents are the most promising alternatives for the treatment of cardiovascular disease nowadays, and the strategy of preparing functional coatings on the surface is highly anticipated for addressing adverse effects such as in-stent restenosis and stent thrombosis. Yet, inadequate mechanical stability and biomultifunctionality limit their clinical application. In this study, we developed a multicross-linking hydrogel on the polylactic acid substrates by dip coating that boasts impressive antithrombotic ability, antibacterial capability, mechanical stability, and self-healing ability. Gelatin methacryloyl, carboxymethyl chitosan, and oxidized sodium alginate construct a double-cross-linking hydrogel through the dynamic Schiff base chemical and in situ blue initiation reaction. Inspired by the adhesion mechanism employed by mussels, a triple-cross-linked hydrogel is formed with the addition of tannic acid to increase the adhesion and antibiofouling properties. The strength and hydrophilicity of hydrogel coating are regulated by changing the composition ratio and cross-linking degree. It has been demonstrated in tests in vitro that the hydrogel coating significantly reduces the adhesion of proteins, MC3T3-E1 cells, platelets, and bacteria by 85% and minimizes the formation of blood clots. The hydrogel coating also exhibits excellent antimicrobial in vitro and antiinflammatory properties in vivo, indicating its potential value in vascular intervention and other biomedical fields.

PTEN Deficiency Induces an Extrahepatic Cholangitis-Cholangiocarcinoma Continuum via Aurora kinase A in Mice.

BACKGROUND & AIMS: The PTEN-AKT pathway is frequently altered in extrahepatic cholangiocarcinoma (eCCA). We aim to evaluate the role of PTEN in the pathogenesis of eCCA and find novel therapies for this disease. METHODS: The Pten gene in the biliary epithelial cells were genetically deleted using the Cre-loxp system. The pathologies were evaluated both macroscopically and histologically. The characteristics were further analyzed by immunohistochemistry (IHC), RT-PCR, cell culture, and RNAseq. Some features were compared to those in human eCCA samples. Further mechanistic studies utilized the conditional knockout of Trp53 and Aurora kinase A (Aurka) genes. Experimental therapy was tested using an Aurka inhibitor. RESULTS: We observed that genetic deletion of the Pten gene in the extrahepatic biliary epithelium and peri-ductal glands initiated sclerosing cholangitis-like lesions in mice, resulting in enlarged and distorted extrahepatic bile ducts in mice as early as one month old. Histologically, these lesions exhibited increased epithelial proliferation, inflammatory cell infiltration, and fibrosis. With aging, the lesions progressed from low-grade dysplasia to invasive carcinoma. Trp53 inactivation further accelerated the disease progression, potentially through downregulating senescence. Further mechanistic studies showed that both human and mouse eCCA showed high expressions of AURKA. Notably, the genetic deletion of Aurka completely eliminated Pten deficiency-induced extrahepatic bile duct lesions. Furthermore, pharmacological inhibition of Aurka alleviated disease progression. CONCLUSIONS: Pten deficiency in extrahepatic cholangiocytes and peribiliary glands led to a cholangitis-to-cholangiocarcinoma continuum through an Aurka-dependent manner. These findings offer new insights into preventive and therapeutic interventions for extrahepatic CCA. IMPACT AND IMPLICATIONS: The aberrant PTEN-PI3K-AKT signaling pathway is commonly observed in human extrahepatic cholangiocarcinoma (eCCA), a disease with a poor prognosis. In our study, we developed a mouse model mimicking cholangitis to eCCA progression by conditionally deleting the Pten gene via Pdx1-Cre in epithelial cells and peribiliary glands of the extrahepatic biliary duct. The conditional Pten deletion in these cells led to cholangitis, which gradually advanced to dysplasia, ultimately resulting in eCCA. The loss of Pten heightened Akt signaling, cell proliferation, inflammation, fibrosis, DNA damage, epigenetic signaling, epithelial-mesenchymal transition (EMT), cell dysplasia, and cellular senescence. Genetic deletion or pharmacological inhibition of Aurka successfully halted the disease progression. This model shall be valuable for testing novel therapies and unraveling the mechanisms of eCCA tumorigenesis.

GJ Express: an improvement initiative to decrease sedation and anesthesia for gastrojejunostomy tube exchanges.

BACKGROUND: Overuse of sedation and anesthesia causes delays in gastrojejunostomy tube (GJ) exchanges, increased risk of complications, unnecessary use of resources, preventable hospital admissions, and an adverse impact on patient and family experience. Our hospital was over-utilizing sedation and anesthesia, and we aimed to decrease this use from 78% to 20% within two years. METHODS: An interdisciplinary quality improvement team comprehensively evaluated current processes for GJ tube exchanges through a retrospective chart review for baseline data with prospective time series analysis after improvement implementation. The primary outcome measure was the percentage of pediatric patients that utilized sedation or anesthesia for routine GJ tube exchanges. RESULTS: A statistical process control p-chart was used to calculate and show changes over time for patients (n = 45 patients average). The median percent of pediatric GJ tube exchanges performed with sedation or anesthesia decreased from 77.8% to 11.3%. Most patients (76%) were covered by Medicaid programs; with low reimbursement rates, decreased anesthesiologist billing revenue does not have a negative financial impact. CONCLUSIONS: An interprofessional improvement initiative that engaged patients and families, incorporated pediatric-specific staff services, and developed systematic weaning was associated with a significant decrease in the overuse of sedation and anesthesia for GJ tube exchanges. IMPACT: We believe that this work is highly relevant and impactful for medical centers caring for children who require gastrojejunostomy tubes, an increasingly common approach to management of children with feeding issues. There is very little literature available on the use of sedation or anesthesia for changing these tubes. While large children's medical centers in the USA usually do not utilize sedation or anesthesia, there are likely many serious outliers, especially when children receive care outside of a pediatric specific institution. This paper brings awareness to this serious issue and provides information about how we changed care to achieve higher patient safety and lower medical costs.

Research on the antipruritic active ingredients of Mikania micrantha.

Mikania micrantha is a perennial liana of the genus Mikania of the Asteraceae family. It is a commonly used medicine in South America for treating fever, malaria, dysentery, snake bites, etc. Because of its strong adaptability and ability to inhibit the growth of its associated plants, Mikania micrantha is considered an invasive species in China and is known as a plant killer. Preliminary studies have shown that Mikania micrantha has an antipruritic effect, but the antipruritic active substance is not yet clear. In this study, a 4-aminopyridine-induced itching model in mice was used to determine the antipruritic effects of petroleum ether, ethyl acetate, ethanol extraction site, and Mikania micrantha volatile oil. GC-MS was used to analyze the components of the antipruritic fractions, combined with mice itch-causing models to study the antipruritic effects of ß-caryophyllene and humulene. The safety of ß-caryophyllene was preliminarily evaluated through the acute toxicity test of mice skin. The ethyl acetate and volatile oil of Mikania micrantha have apparent antipruritic effects. Humulene and ß-caryophyllene have a quantitative-effective relationship to inhibit itching in mice. The acute toxicity test of mouse skin showed that ß-caryophyllene has no acute toxicity. This study indicated that the main antipruritic active ingredients of Mikania micrantha are ß-caryophyllene and humulene.

Prenatal diagnosis of congenital chloride diarrhea: A case report. / Diagnóstico prenatal de clorhidrorrea congénita: reporte de caso.

Congenital chloride diarrhea (CCD) is a rare but significant genetic disorder characterized by severe electrolyte imbalances resulting from impaired intestinal chloride absorption. Affected children experience persistent diarrhea, dehydration, and malnutrition, complicating medical and developmental care. The enhancement of prenatal detection is crucial for improved patient management, early interventions, and informed genetic counseling. However, despite advancements in medicine, the complex nature and rarity of CCD make prenatal detection challenging. In this study, we report a fetal case where prenatal magnetic resonance imaging (MRI) effectively identified the distinctive characteristics of CCD, providing insights into the complexities of diagnosis and suggesting avenues for enhanced early detection strategies.

La clorhidrorrea congénita es un trastorno genético infrecuente pero importante caracterizado por una alteración grave del balance hidroelectrolítico como resultado de un defecto en la absorción intestinal de cloruros. Los niños afectados presentan diarrea persistente, deshidratación y malnutrición; el control médico y del desarrollo son complejos. Mejorar la detección prenatal es esencial para facilitar la atención del paciente, las intervenciones tempranas y el asesoramiento genético informado. Sin embargo, a pesar de los avances de la medicina, la naturaleza compleja y la escasa frecuencia de esta entidad, constituyen un desafío para la detección prenatal. En este estudio, se reporta el caso de una embarazada donde los estudios por imágenes de resonancia magnética fetales identificaron en forma efectiva las características típicas de la clorhidrorrea congénita. Se proveen conocimientos sobre las complejidades del diagnóstico y se sugieren caminos para las estrategias de detección temprana de esta enfermedad.

Recycling Waste Glyceroborate to Aqueous Lubricant for Tribological Applications.

The present study attempts to explore the direct recyclability of glyceroborate from medicine pharmaceutical production wastewater into an aqueous lubricant instead of conventional waste processing methods from the tribological view. In order to determine the tribological feasibility, the physicochemical properties of crude pharmaceutical wastewater are investigated and compared with those of pure glycerol to access their potential lubrication properties. The results demonstrated that the crude pharmaceutical wastewater has better friction-reducing and antiwear properties under the same working conditions. Besides outstanding lubricating properties, the friction-induced formation of borate tribo-film and intermediate FeOOH compound favors lowering of the shear stress between the rubbing surfaces. This finding better provides an alternative to transform glyceroborate from medicine pharmaceutical production wastewater after simple distillation processing to a potential aqueous lubricant.

A Novel Strategy for Whole-Cell Biotransformation Enabling Simultaneous l-Phenyllactic Acid Production and Coenzyme Regeneration.

l-Phenyllactic acid (l-PLA) is a small molecular organic acid that exhibits a powerful capacity for inhibition against foodborne pathogens. In this work, we developed a new cost-effective and environmentally friendly process for the biosynthesis of l-PLA. This strategy designed a novel whole-cell biotransformation system employing two heterologous enzymes, namely, phenylalanine dehydrogenase (PheDH) and l-hydroxyisocaproate dehydrogenase (l-HicDH). The novelty of this strategy lies in the first-time utilization of these two enzymes, which not only enables cascade catalysis for the production of l-PLA but also facilitates the regeneration of the coenzymes (NAD+/NADH) using only two enzymes rather than introducing more heterologous enzymes to the system. Consequently, this strategy can effectively simplify the biosynthesis process of l-PLA and minimize production costs. The initial l-PLA yield using this process achieved 2.53 ± 0.07 g/L. Furthermore, through meticulous optimization of the parameters for inducible enzyme expression and l-PLA biosynthesis, the l-PLA yield was successfully increased to 4.68 ± 0.04 g/L with a yield rate of 64.54 ± 0.29%. Moreover, this novel strategy is versatile in the biosynthesis of other organic acids, which can be achieved by easily modulating the combinations of substrates and enzymes.

Facile construction of drugs loaded lipid-coated calcium carbonate as a promising pH-Dependent drug delivery system for thyroid cancer treatment.

To develop innovative drug delivery carriers for controllable release and cancer-targeted delivery of therapeutic agents to accomplish efficient cancer chemotherapy. Herein we effectively fabricated CaCO3 primarily loaded biotin (BT) and directly the self-assembly of oxaliplatin (Pt (IV)) prodrugs form in liposomes. The acquired BT-Pt (IV)@PEG/CaCO3 with outstanding biological stability displays rapid pH-mediated degradations, thus allowing the effective pH-responsive delivery of BT. In vitro, anticancer assays proved that BT-Pt (IV)@PEG/CaCO3 effectively kills the thyroid cancer cells (B-CPAP and FTC-133). The biochemical staining assays investigated the morphological changes of thyroid cancer after treatment with nanoparticles. The DNA fragmentation of the cells was assessed by utilizing the comet assay. BT-Pt (IV)@PEG/CaCO3 increased ROS levels and caused mitochondrial membrane potential and DNA damage, which resulted in apoptosis. Due to its versatile drug-loading capability, this research demonstrates that CaCO3 liposomal formulation is a biocompatible and reliable substrate for establishing pH-mediated drug delivery methods and promising for possible therapeutic application.

Development and validation of novel immune-inflammation-based clinical predictive nomograms in HER2-negative advanced gastric cancer.

Purpose: To explore the predictive value of multiple immune-inflammatory biomarkers including serum VEGFA and systemic immune-inflammation index (SII) in HER2-negative advanced gastric cancer (AGC) and establish nomograms for predicting the first-line chemotherapeutic efficacy, progression-free survival (PFS) and overall survival (OS) of patients with this fatal disease. Methods: From November 2017 to April 2022, 102 and 34 patients with a diagnosis of HER2-negative AGC at the First Affiliated Hospital of Bengbu Medical College were enrolled as development and validation cohorts, respectively. Univariate and multivariate analyses were performed to evaluate the clinical value of the candidate indicators. The variables were screened using LASSO regression analysis. Predictive models were developed using significant predictors and are displayed as nomograms. Results: Baseline VEGFA expression was significantly higher in HER2-negative AGC patients than in nonneoplastic patients and was associated with malignant serous effusion and therapeutic efficacy (all p<0.001). Multivariate analysis indicated that VEGFA was an independent predictor for first-line therapeutic efficacy and PFS (both p<0.01) and SII was an independent predictor for first-line PFS and OS (both p<0.05) in HER2-negative AGC patients. The therapeutic efficacy model had an R2 of 0.37, a Brier score of 0.15, and a Harrell's C-index of 0.82 in the development cohort and 0.90 in the validation cohort. The decision curve analysis indicated that the model added more net benefits than VEGFA assessment alone. The PFS/OS models had Harrell's C-indexes of 0.71/0.69 in the development cohort and 0.71/0.62 in the validation cohort. Conclusion: The established nomograms integrating serum VEGFA/SII and commonly available baseline characteristics provided satisfactory performance in predicting the therapeutic efficacy and prognosis of HER2-negative AGC patients.

Antitumor activity of a whey peptide-based enteral diet in C26 colon tumor-bearing mice.

The antitumor effects of a whey peptide-based enteral diet, whose main components are whey peptides and yogurt fermented by Lactobacillus delbureckii subsp. bulgaricus 2038 and Streptococcus thermophilus 1131, were investigated in mice. Our results indicated that the tumor weight in C26 carcinoma-transplanted mice was significantly smaller at day 16 post-implantation in the whey peptide-based enteral diet group (1.36 ± 0.54 g) than in the control group (1.83 ± 0.89 g) (p < 0.05). The whey peptide-based enteral diet group exhibited higher tumor cell apoptosis, lower cell proliferation, and inactive angiogenesis indicating by higher degree of TUNEL, lower positive rates of Ki-67, VEGF, and CD34 than control group. It also attenuated inflammatory cell infiltration of spleen and liver as indicated by the decreased spleen index (10.89 ± 2.06 vs. 12.85 ± 2.92, p < 0.05) and increased liver index (58.09 ± 11.37 vs. 53.19 ± 6.67, p < 0.05) in the whey peptide-based enteral diet group than the control diet group. These results proved the inhibitory effect of the whey peptide-based enteral diet on tumor growth, which might be attributed to the whey peptides component. PRACTICAL APPLICATION: A whey peptide-based enteral diet (MEIN® ), containing cheese whey and multiple nutrients, was selected to verify the anti-tumor effect by animal experiments. The tumor weight growth, tumor cell proliferation, inflammatory cell infiltration of spleen and liver in tumor model mice was significantly attenuated by the whey peptide-based enteral diet, that might be attributed to its whey peptides component. These results provided an additive direction for cancer therapy and need a further study including clinical trials.

Changes in process and outcome for ST elevation myocardial infarction in central China from 2011 to 2018.

BACKGROUND: Limited data are available on the changes in the quality of care for ST elevation myocardial infarction (STEMI) during China's health system reform from 2009 to 2020. This study aimed to assess the changes in care processes and outcome for STEMI patients in Henan province of central China between 2011 and 2018. METHODS: We compared the data from the Henan STEMI survey conducted in 2011-2012 ( n = 1548, a cross-sectional study) and the Henan STEMI registry in 2016-2018 ( n = 4748, a multicenter, prospective observational study). Changes in care processes and in-hospital mortality were determined. Process of care measures included reperfusion therapies, aspirin, P2Y12 antagonists, ß-blockers, angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, and statins. Therapy use was analyzed among patients who were considered ideal candidates for treatment. RESULTS: STEMI patients in 2016-2018 were younger (median age: 63.1 vs . 63.8 years) with a lower proportion of women (24.4% [1156/4748] vs . 28.2% [437/1548]) than in 2011-2012. The composite use rate for guideline-recommended treatments increased significantly from 2011 to 2018 (60.9% [5424/8901] vs . 82.7% [22,439/27,129], P <0.001). The proportion of patients treated by reperfusion within 12 h increased from 44.1% (546/1237) to 78.4% (2698/3440) ( P <0.001) with a prolonged median onset-to-first medical contact time (from 144 min to 210 min, P <0.001). The use of antiplatelet agents, statins, and ß-blockers increased significantly. The risk of in-hospital mortality significantly decreased over time (6.1% [95/1548] vs . 4.2% [198/4748], odds ratio [OR]: 0.67, 95% confidence interval [CI]: 0.50-0.88, P = 0.005) after adjustment. CONCLUSIONS: Gradual implementation of the guideline-recommended treatments in STEMI patients from 2011 to 2018 has been associated with decreased in-hospital mortality. However, gaps persist between clinical practice and guideline recommendation. Public awareness, reperfusion strategies, and construction of chest pain centers need to be further underscored in central China.

Fluoxetine partially alleviates inflammation in the kidney of socially stressed male C57 BL/6 mice.

Stress-related illnesses are linked to the onset and progression of renal diseases and depressive disorders. To investigate stress-induced changes in the renal transcriptome associated with the development of depressive behaviors, we generated here a chronic social defeat stress (CSDS) model of C57 BL/6 male mice and then performed RNA sequencing of the kidneys to obtain an inflammation-related transcriptome. Administration of the antidepressant drug fluoxetine (10 mg·kg-1 ·day-1 ) during CSDS induction could partially alleviate renal inflammation and reverse CSDS-induced depression-like behaviors. Moreover, fluoxetine also modulated gene expression of stress-related hormone receptors, including prolactin and melanin-concentrating hormone. These results suggest that CSDS can induce gene expression changes associated with inflammation in the kidney of C57 BL/6 male mice, and this inflammation can be treated effectively by fluoxetine.

Triglyceride-glucose index as a marker of adverse cardiovascular prognosis in patients with coronary heart disease and hypertension.

BACKGROUND: The triglyceride-glucose (TyG) index has been proposed as a potential predictor of adverse prognosis of cardiovascular diseases (CVDs). However, its prognostic value in patients with coronary heart disease (CHD) and hypertension remains unclear. METHODS: A total of 1467 hospitalized patients with CHD and hypertension from January 2021 to December 2021 were included in this prospective and observational clinical study. The TyG index was calculated as Ln [fasting triglyceride level (mg/dL) × fasting plasma glucose level (mg/dL)/2]. Patients were divided into tertiles according to TyG index values. The primary endpoint was a compound endpoint, defined as the first occurrence of all-cause mortality or total nonfatal CVDs events within one-year follow up. The secondary endpoint was atherosclerotic CVD (ASCVD) events, including non-fatal stroke/transient ischemic attack (TIA) and recurrent CHD events. We used restricted cubic spline analysis and multivariate adjusted Cox proportional hazard models to investigate the associations of the TyG index with primary endpoint events. RESULTS: During the one-year follow-up period, 154 (10.5%) primary endpoint events were recorded, including 129 (8.8%) ASCVD events. After adjusting for confounding variables, for per standard deviation (SD) increase in the TyG index, the risk of incident primary endpoint events increased by 28% [hazard ratio (HR) = 1.28, 95% confidence interval (CI) 1.04-1.59]. Compared with subjects in the lowest tertile (T1), the fully adjusted HR for primary endpoint events was 1.43 (95% CI 0.90-2.26) in the middle (T2) and 1.73 (95% CI 1.06-2.82) in highest tertile (T3) (P for trend = 0.018). Similar results were observed in ASCVD events. Restricted cubic spline analysis also showed that the cumulative risk of primary endpoint events increased as TyG index increased. CONCLUSIONS: The elevated TyG index was a potential marker of adverse prognosis in patients with CHD and hypertension.

[Methylselenocysteine Promotes Etoposide Cytotoxicity by Enhancing Homotypic Gap Junctions Composed of Connexin 26].

Objective: To investigate the effect of methylselenocysteine (MSC) on the function of homotypic gap junction (GJ) composed of connexin (Cx) 26 and its regulation of chemotherapeutic drug cytotoxicity. Methods: The Tet-on HeLa cells transfected with and stably expressing Cx26 were used as the tool cells. Effects of MSC on cell growth, GJ function, and Cx26 protein expression were examined by MTT method, parachute assay, and Western blot analysis, respectively. The cytotoxicity of chemotherapeutic drugs was determined by standard colony-forming assay, and the relationship between MSC's effect on cytotoxicity of these chemotherapeutic drugs and its regulation of GJ was further analyzed. Results: In Tet-on HeLa cells, doxycycline (Dox) can induce the expression of Cx26, which could then form functional GJs. Within a concentration range of 50 µmol/L, MSC had no significant effect on HeLa cell growth. Non-toxic concentrations of MSC can enhance GJs in a concentration-dependent manner and exert its effect at the nanomolar level. This effect was associated with an induction of Cx26 protein expression by MSC. Among the three common chemotherapeutic agents with different mechanisms of action, etoposide (Eto) presented cytotoxicity differences between HeLa cells cultured at low density (nonconfluent, no GJ formed) and high density (confluent, GJ formed). What's more, the inhibitory effect of Eto combined with MSC on HeLa cell colony formation was stronger than that of Eto alone, and this effect occurred only in HeLa cells with GJ formation. Conclusion: MSC can potentiate the cytotoxicity of Eto by enhancing the GJs composed of Cx26, indicating that combined strategy of selenide and chemotherapy shows potential value in the treatment of malignant tumors.

Broad-Spectrum Detection of Tetracyclines by Riboswitch-Based Cell-Free Expression Biosensing.

We describe a sensitive and selective method for the determination of tetracycline content in foods using a riboswitch sensor. The sensor is based on a cell-free expression system that can be lyophilized to produce paper-based sensors or tube-based sensors for long-term storage. The riboswitch constructed using artificially screened tetracycline RNA aptamers was cloned into the pET-28a(+) vector of Escherichia coli TOP 10. The expression of the green fluorescent protein was positively correlated with the concentration of tetracyclines. The binding of tetracyclines to the aptamer domain results in a conformational change in the riboswitch secondary structure, resulting in the exposure of the ribosome binding site thereby promoting expression. The detection limits of the prepared sensor for the detection of tetracycline, oxytetracycline, chlortetracycline, and doxycycline were 0.47, 0.079, 0.084, and 0.43 µM, respectively. Moreover, the 1 µM tetracyclines allow for qualitative detection in milk samples by the naked eye. The work provides a proof-of-principle for riboswitch design to address global health and food safety.

Elevated MPP6 expression correlates with an unfavorable prognosis, angiogenesis and immune evasion in hepatocellular carcinoma.

Background: Membrane palmitoylated proteins (MPPs) are engaged in various biological processes, such as cell adhesion and cell polarity. Dysregulated MPP members have different effects on hepatocellular carcinoma (HCC) development. However, the role of MPP6 in HCC has been unknown. Method: HCC transcriptome and clinical data from different public databases were downloaded and analyzed, and the results were further validated by qRT-PCR, Western blotting and immunohistochemistry (IHC) using HCC cell lines and tissues. The association between MPP6 and prognosis, potential pathogenic mechanisms, angiogenesis, immune evasion, tumor mutation burden (TMB) and treatment response in HCC patients was analyzed by bioinformatics and IHC staining. Results: MPP6 was significantly overexpressed in HCC, and its expression was related to T stage, pathologic stage, histologic grade and adverse prognosis in HCC patients. Gene set enrichment analysis revealed that differentially expressed genes were mainly enriched in the synthesis of genetic materials and the WNT signaling pathway. GEPIA database analysis and IHC staining suggested that MPP6 expression had a positive correlation with angiogenesis. Single-cell dataset analysis indicated that MPP6 was associated with features of the tumor microenvironment. Additional analyses discovered that MPP6 expression was inversely related to immune cell infiltration and was involved in tumor immune evasion. MPP6 expression was positively associated with TMB, and patients with high TMB had an adverse prognosis. Immunotherapy was more effective in HCC patients with low MPP6 expression, whereas those with high MPP6 expression responded better to sorafenib, gemcitabine, 5-FU, and doxorubicin. Conclusions: Elevated MPP6 expression is associated with an unfavorable prognosis, angiogenesis and immune evasion in HCC. Moreover, MPP6 has the potential to be used to assess TMB and treatment response. Therefore, MPP6 might serve as a novel prognostic biomarker and therapeutic target for HCC.

Clinical characteristics and outcomes of Chinese patients with coronary heart disease and resistant hypertension.

There is currently few research on clinical characteristics and outcomes of coronary heart disease (CHD) with resistant hypertension in central region of China. This study aimed to assess the risk factors and outcomes of CHD and resistant hypertension in population of central region of China. A total of 1467 CHD patients with hypertension were included and considered to three groups according to blood pressure control: controlled group (blood pressure < 140/90 mmHg on three or less antihypertensive drugs); uncontrolled group (blood pressure ≥ 140/90 mmHg on two or less antihypertensive drugs); or resistant group (blood pressure ≥ 140/90 mmHg on three antihypertensive drugs or < 140/90 mmHg on at least four antihypertensive drugs including diuretic). The authors evaluated the clinical outcomes of three groups at 1-year follow-up. The prevalence of resistant hypertension was 21.8%. Significant adjusted associated factors of resistant hypertension included per unit changes body mass index (BMI, OR 1.12), and four categorical variable diagnosis by yes or no: heart failure (HF, OR 2.62), left ventricular hypertrophy (LVH, OR 2.83), diabetes (OR 1.55), and chronic kidney disease (CKD, OR 1.63). In multiple adjusted Cox regression analysis, patients in resistant group had a higher risk of the primary outcome (HR, 2.14 [95% CI, 1.47-3.11]; p < .001). Moreover, the risk of atherosclerotic cardiovascular disease (ASCVD) in patients with resistant hypertension is also significantly increased (HR, 2.11 [95% CI, 1.39-3.20]; p < .001). In conclusion, resistant hypertension was a quite common and high proportion finding in patients with CHD and hypertension in central region of China, and these patients have a worse clinical prognosis.

Research progress and therapeutic prospect of PHF5A acting as a new target for malignant tumors.

PHD-finger domain protein 5A (PHF5A) is a member of the PHD-finger like protein superfamily and widely expressed in the nucleus of eukaryotes. The PHD-finger like domain is a protein-DNA or protein-protein interaction region. In addition to regulate alternative splicing of target genes as a spliceosome protein subunit, PHF5A is also involved in pluripotency maintenance of embryonic stem cells, chromatin remodeling, DNA damage repair, embryogenesis and histomorphological development. Recently, increasing studies have focused on exploring spliceosome-related and non-spliceosome-related functions of PHF5A and its relationship with the tumorigenesis, development and patient prognosis of various malignant tumors, such as breast cancer, lung cancer and colorectal cancer. The underlying mechanisms of PHF5A may include mediating aberrant alternative splicing of target genes, activating downstream signaling pathways as an oncogene/protein, and regulating abnormal gene transcription as a nuclear transcription factor or cofactor. Besides, PHF5A was also found to be involved in the growth regulation of cancer stem cells. In this review, we aimed to delineate the structural and functional characteristics of PHF5A, to summarize its role in the occurrence and development of malignant tumors hitherto described, and to provide potential targets for anti-tumor therapy.

Real-World Outcome and Prognostic Factors Among HER2-Positive Metastatic Breast Cancer Patients Receiving Pyrotinib-Based Therapy: A Multicenter Retrospective Analysis.

Purpose: To explore the efficacy, safety, and potential factors influencing efficacy and outcome of pyrotinib-based therapy in human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC) in complex clinical practice. Methods: Real-world data for HER2-positive MBC patients treated with pyrotinib-based regimens from 6 hospitals in Northern Anhui, China, from September 2018 to February 2022, were retrospectively collected, and clinicopathological features, efficacy, prognosis, and safety were analyzed. Potential influencing factors including baseline serum vascular endothelial growth factor-A (VEGF-A) for evaluating pyrotinib's treatment response and outcome were also explored. Results: A total of 169 patients with HER2-positive MBC were enrolled. The objective response rate (ORR), disease control rate (DCR), and median progression-free survival (mPFS) of the overall cohort were 65.1%, 87.6%, and 12.4 months, respectively. Pyrotinib is highly beneficial as different treatment lines and appears to be a feasible strategy both in combination with chemotherapeutic drugs and alone. The mPFS values were 16.5 months, 12.4 months, and 9.3 months in the first, second, and third-or-higher lines of anti-HER2 therapy, respectively (P=0.027). The most common adverse event (AE) was diarrhea (88.2%), and patients with < grade 3 diarrhea achieved a longer mPFS than patients with ≥ grade 3 diarrhea (13.3 months vs 6.9 months, P=0.007). Among the patients with available baseline VEGF-A data, the ORR was 43.5% in patients with a high level of VEGF-A, compared to 81.5% in patients with a low level of VEGF-A (P=0.005). Moreover, patients in the VEGF-A-high group exhibited a shorter mPFS time than those in the VEGF-A-low group (7.8 months vs 19.1 months, P=0.004). Further analysis demonstrated AE of diarrhea and VEGF-A at baseline to be independent prognostic factors for PFS. Conclusion: Pyrotinib-based regimens showed promising efficacy, with manageable tolerance, and AE occurrence of severe diarrhea and baseline level of serum VEGF-A are helpful in predicting the treatment outcome of pyrotinib in HER2-positive MBC.

Identification of hematopoietic stem cells residing in the meninges of adult mice at steady state.

Steady-state extramedullary hematopoiesis during adulthood is an emerging field of great interest. The meninges contain both innate and adaptive immune cells, which provide immunosurveillance of the central nervous system (CNS). Hematopoietic progenitors that give rise to meningeal immune cells remain elusive. Here, we report that steady-state meninges of adult mice host hematopoietic stem cells (HSCs), as defined by long-term, efficient, multi-lineage reconstitution and self-renewal capacity in the meninges, blood, spleen, and bone marrow of sublethally irradiated adult recipients. HSCs lodge in the meninges after birth with local expression of pro-hematopoietic niche factors. Meningeal HSCs are locally maintained in homeostasis and get replenished from the blood only when the resident pool is reduced. With a tissue-specific expression profile, meningeal HSCs can provide the CNS with a constant supply of leukocytes more adapted to local microenvironment.