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Objective To explore the relationship between monocyte/high-density lipoprotein cholesterol ratio （MHR） and the progression and prognosis of type 2 diabetic kidney disease （DKD）. Methods From January 1， 2017 to December 31， 2022， 269 type 2 DKD patients were selected as DKD group while 269 healthy medical check-ups during the same period as healthy group. And the differences in MHR levels of two groups were compared. According to median MHR， DKD group were assigned into low-level MHR and high-level MHR sub-groups. General profiles， clinical data， the incidence rate of endpoint events and cumulative renal survival were compared two groups. Cox regression analysis was performed for exploring the independent risk factors for poor renal prognosis in DKD patients and drawing receiver operator characteristic curve （ROC） for exploring the diagnostic efficacy of MHR for poor prognosis of DKD. Results MHR level was higher in DKD group than that in healthy group [0.4918（0.3788，0.6818）×109/mmol vs 0.2984（0.1867，0.4112）×109/mmol] （P＜0.05）； high-level MHR group had higher levels of white blood cells （WBC） [7.70（6.40， 8.70）×109/L vs 6.50（5.40， 8.00）×109/L]， neutrophils （Ne） [4.60（3.60， 5.53）×109/L vs 3.99（3.18， 5.19）×109/L] and monocyte （Mono） [0.69（0.60， 0.70）×109/L vs 0.50（0.40， 0.60）×109/L]， urinary albumin to creatinine ratio （UACR） [1214.59（373.48， 3410.02）mg/g vs 1050.96（180.26， 3341.06） mg/g]， 24 h urine protein （24 hUP） [3.21（1.42， 5.51）g vs 2.66 （0.58， 4.56） g]， low-density lipoprotein cholesterol （LDL-C） [2.72（2.06， 3.40）mmol/L vs 2.23（1.63， 2.80）mmol/L]， serum creatinine （Scr） [152.10（95.20， 221.60）μmol/L vs 126.00（92.48， 186.55）μmol/L] than those in low-level MHR group； lymphocyte （Lym） [1.60（1.27， 2.20）×109/L vs 1.82（1.30， 2.40）×109/L]， high-density lipoprotein cholesterol （HDL-C） [0.94（0.83， 1.07）mmol/L vs 1.39（1.15， 1.65）mmol/L] and estimated glomerular filtration rate （eGFR） [39.69（25.19， 65.10）mL·min−1·（1.73 m²）−1 vs 47.12（28.86， 73.60）mL·min−1·（1.73 m²）−1] were lower than those in low-level MHR group； high-level MHR group had a cumulative kidney survival time and it was shorter than that in low level MHR group [63（39， 72）month vs 72（46， 72）month] （P＜0.05）； MHR was correlated positively with WBC， Ne， Mono， UACR， 24h UP， Scr and LDL-C （P＜0.05） and negatively with Lym， HDL-C， eGFR and cumulative renal survival time （P＜0.05）； the incidence of endpoint events was higher in high-level MHR group than that in low-level MHR group （52.59% vs 38.06%）（P＜0.05）； baseline MHR [0.5492（0.4030， 0.7235）×109/mmol vs 0.4255（0.3117， 0.5134）×109/mmol]， UACR [2062.65（752.80， 4234.80）mg/g vs 608.56（88.63. 1912.44）mg/g]， 24 hUP [3.79（2.54， 5.53）g vs 1.58（0.39， 4.85）g] and Scr [178.40（134.00， 234.23）μmol/L vs 100.95（74.25， 152.10）μmol/L] were higher than those in DKD patients without endpoint events； eGFR was lower than that in DKD patients without endpoint events [33.45（23.33， 46.41）mL·min−1·（1.73 m²）−1 vs 61.59（38.57， 95.98）mL·min−1·（1.73 m²）−1]（P＜0.05）. The results of Cox regression analysis indicated that MHR was an independent risk factor for a poor prognosis of DKD； The results of ROC curve showed that the area under the curve of MHR was 0.747 with a sensitivity of 0.820 and a specificity of 0.605. Conclusion DKD patients tend to have higher levels of MHR as compared with healthy individuals. As an independent risk for the progression of renal function in DKD patients， MHR has some diagnostic value for a poor prognosis of DKD. However， its specificity is not high.

Abstract Due to the large number of genes and mutations that result in inherited retinal degenerations (IRD), there has been a paucity of therapeutic options for these patients. There is a large unmet need for therapeutic approaches targeting shared pathophysiologic pathways in a mutation-independent manner. The Fas receptor is a major activator and regulator of retinal cell death and inflammation in a variety of ocular diseases. We previously reported the activation of Fas-mediated photoreceptor (PR) cell death in two different IRD mouse models, rd10 and P23H, and demonstrated the protective effect of genetic Fas inhibition. The purpose of this study was to examine the effects of pharmacologic inhibition of Fas in these two models by intravitreal injection with a small peptide inhibitor of the Fas receptor, ONL1204. A single intravitreal injection of ONL1204 was given to one eye of rd10 mice at P14. Two intravitreal injections of ONL1204 were given to the P23H mice, once at P14 and again at 2-months of age. The fellow eyes were injected with vehicle alone. Fas activation, rate of PR cell death, retinal function, and the activation of immune cells in the retina were evaluated. In both rd10 and P23H mice, ONL1204 treatment resulted in decreased number of TUNEL (+) PRs, decreased caspase 8 activity, enhanced photoreceptor cell counts, and improved visual function compared with vehicle treated fellow eyes. Treatment with ONL1204 also reduced immune cell activation in the retinas of both rd10 and P23H mice. The protective effect of pharmacologic inhibition of Fas by ONL1204 in two distinct mouse models of retinal degeneration suggests that targeting this common pathophysiologic mechanism of cell death and inflammation represents a potential therapeutic approach to preserve the retina in patients with IRD, regardless of the genetic underpinning.

Abstract Background This study was designed to evaluate the effect of progesterone receptor (PR) status on the prognosis of advanced estrogen receptor (ER)-high human epidermal growth factor receptor 2 (HER2)-negative breast cancer patients receiving CDK4/6 inhibitor combined with endocrine as first-line therapy. Methods Advanced ER-high HER2-negative breast cancer patients who were admitted to Harbin Medical University Cancer Hospital and received cyclin-dependent kinase (CDK)4/6 inhibitor combined with endocrine as first-line therapy were included for analysis. Patients were divided into PR-high group (11-100%), PR-low group (1-10%), and PR-negative group (

Accurate wheel-rail force data serves as the cornerstone for analyzing the wheel-rail relationship. However, achieving continuous and precise measurement of this force remains a significant challenge in the field. This article introduces a calibration algorithm for the wheel-rail force that leverages graph neural networks and long short-term memory networks. Initially, a comprehensive wheel-rail force detection system for trains was constructed, encompassing two key components: an instrumented wheelset and a ground wheel-rail force measuring system. Subsequently, utilizing this system, two distinct datasets were acquired from the track inspection vehicle: instrumented wheelset data and ground wheel-rail force data, a feedforward neural network was employed to calibrate the instrumented wheelset data, referencing the ground wheel-rail force data. Furthermore, ground wheel-rail force data for the locomotive was obtained for the corresponding road section. This data was then integrated with the calibrated instrumented wheelset data from the track inspection vehicle. Leveraging the GNN-LSTM network, the article establishes a mapping relationship model between the wheel-rail force of the track inspection vehicle and the locomotive wheel-rail force. This model facilitates continuous measurement of locomotive wheel-rail forces across three typical scenarios: straight sections, long and steep downhill sections, and small curve radius sections.

Mpox is a zoonotic infectious disease caused by the mpox virus (MPXV). Historically, the majority of mpox cases have been documented in Central Africa. However, since May 2022, there has been a notable rise in reported cases from regions beyond Africa. Currently, over 110 countries spanning Europe, North America, South America, Asia, and other territories have reported mpox infections. This report details a case involving a patient who identifies as a man who has sex with men (MSM) and is concurrently infected with MPXV, human immunodeficiency virus type 1 (HIV-1), Pneumocystis jiroveci, as well as extensively drug-resistant tuberculosis (XDR-TB). This patient had also received a vaccination for smallpox in the past. Additionally, we provide photographic documentation charting the progression of dermatological manifestations associated with mpox. This case highlights the significance of sexual intercourse as a crucial mode of transmission for mpox. The rapid and widespread dissemination of the MPXV across various regions, especially among MSM communities, underscores the importance of enhancing preventive education efforts targeted at high-risk populations.

Background: Female vulvar lichen sclerosus (VLS) is a chronic inflammatory skin disease of the vulva and its etiology is unknown. The main clinical symptoms are itching, burning and dyspareunia, and there is a lack of effective treatment. Methods: Clinical and follow-up data of women with VLS who underwent 5-Aminolevulinic acid photodynamic therapy (ALA-PDT) from January 2023 to December 2023 in the department of obstetrics and gynecology, Qilu Hospital of Shandong University, were retrospectively analyzed. According to the inclusion and exclusion criteria, 36 patients with VLS who received ineffective conventional treatment (intractable VLS) were enrolled. Objective signs and subjective symptoms of vulvar lesions were recorded before treatment and 6 months after the end of treatment according to corresponding scoring criteria. Quality of life was evaluated using the Dermatology Life Quality Index (DLQI). Results: All patients received six sessions of ALA-PDT treatment and follow-up visits. After ALA-PDT treatment, 24 of 36 (66.67 %) patients' itching symptoms completely disappeared, 10 of 36 (27.78 %) patients' itching symptoms were relieved from severe to mild, and only 2 of 36 (5.56 %) patients' symptoms were not significantly relieved. 16 of 36 (44.4 %) patients' itching symptoms completely disappeared, 9 of 36 (25 %) patients' itching symptoms were relieved from severe to mild, and only 2 of 36 (5.56 %) patients still had severe pain. Compared to 22 patients with dyspareunia before treatment, only 9 patients still had dyspareunia with varying degrees of dyspareunia relief after treatment. Clinical signs improved significantly in the patients after ALA-PDT treatment. The total scores of clinical signs were (5.31 ± 1.67 vs 3.67 ± 1.71) before and after treatment. All patients showed improvement in DLQI after treatment. The main side effects of ALA-PDT were pain, erythema and swelling which were transient and tolerable. All patients were “satisfied” or “very satisfied” with the results of the treatment. Conclusions: ALA-PDT is a safe and effective treatment for women with intractable vulva lichen sclerosus.

Abstract Irradiation (IR) induces immunogenic cell death (ICD) in tumors, but it rarely leads to the abscopal effect (AE); even combining IR with immune checkpoint inhibitors has shown only anecdotal success in inducing AEs. In this study, we aimed to enhance the IR-induced immune response and generate reproducible AEs using the anti-alcoholism drug, disulfiram (DSF), complexed with copper (DSF/Cu) to induce tumor ICD. We measured ICD in vitro and in vivo. In mouse tumor models, DSF/Cu was injected intratumorally followed by localized tumor IR, creating an in situ cancer vaccine. We determined the anticancer response by primary tumor rejection and assessed systemic immune responses by tumor rechallenge and the occurrence of AEs relative to spontaneous lung metastasis. In addition, we analyzed immune cell subsets and quantified proinflammatory and immunosuppressive chemokines/cytokines in the tumor microenvironment (TME) and blood of the vaccinated mice. Immune cell depletion was investigated for its effects on the vaccine-induced anticancer response. The results showed that DSF/Cu and IR induced more potent ICD under hypoxia than normoxia in vitro. Low-dose intratumoral (i.t.) injection of DSF/Cu and IR(12Gy) demonstrated strong anti-primary and -rechallenged tumor effects and robust AEs in mouse models. These vaccinations also increased CD8+ and CD4+ cell numbers while decreasing Tregs and myeloid-derived suppressor cells in the 4T1 model, and increased CD8+, dendritic cells (DC), and decreased Treg cell numbers in the MCa-M3C model. Depleting both CD8+ and CD4+ cells abolished the vaccine’s anticancer response. Moreover, vaccinated tumor-bearing mice exhibited increased TNFα levels and reduced levels of immunosuppressive chemokines/cytokines. In conclusion, our novel approach generated an anticancer immune response that results in a lack of or low tumor incidence post-rechallenge and robust AEs, i.e., absence of or decreased spontaneous lung metastasis in tumor-bearing mice. This approach is readily translatable to clinical settings and may increase IR-induced AEs in cancer patients.

Identifying travel modes is essential for modern urban transportation planning and management. Recent advancements in data collection, especially those involving Global Positioning System (GPS) technology, offer promising opportunities for rapidly and accurately inferring users' travel modes. This study presents an innovative method for inferring travel modes from GPS trajectory data. The method utilizes multi-scale convolutional techniques to capture and analyze both temporal and spatial information of the data, thereby revealing the underlying spatiotemporal relationships inherent in user movement and behavior patterns. In addition, an attention mechanism is integrated into the model to enable autonomous learning. This mechanism enhances the model's capacity to identify and emphasize key information across different time periods and spatial locations, thus improving the accuracy of travel mode inference. Evaluation on the open-source GPS trajectory dataset, GeoLife, demonstrates that the proposed method attained an accuracy of 83.3%. This result highlights the effectiveness of the method, demonstrating that the model can more accurately understand and predict user travel modes through the integration of multi-scale convolutional technologies and attention mechanisms.

BackgroundThe aim of this study was to classify distinct subgroups of adolescents based on the severity levels of their mobile phone addiction and to investigate how these groups differed in terms of their psychosocial characteristics. We surveyed a total of 2,230 adolescents using three different questionnaires to assess the severity of their mobile phone addiction, stress, anxiety, depression, psychological resilience, and personality. Latent class analysis was employed to identify the subgroups, and we utilized Receiver Operating Characteristic (ROC) curves and multinomial logistic regression for statistical analysis. All data analyses were conducted using SPSS 26.0 and Mplus 8.5.MethodsWe classified the subjects into subgroups based on their mobile phone addiction severity, and the results revealed a clear pattern with a three-class model based on the likelihood level of mobile phone addiction (p 14, which corresponded to the maximum Youden index (Youden index = 0.751).ResultsThe latent classification process in this research confirmed the existence of three distinct mobile phone user groups. We also examined the psychosocial characteristics that varied in relation to the severity levels of addiction.ConclusionThis study provides valuable insights into the categorization of adolescents based on the severity of mobile phone addiction and sheds light on the psychosocial characteristics associated with different addiction levels. These findings are expected to enhance our understanding of mobile phone addiction traits and stimulate further research in this area.

Electrochemical mass spectrometry is an important technique for studying the mechanism of electrochemical reactions. Mass spectrometry has the advantages of high detection sensitivity, high detection throughput and high specificity, which enables simultaneous acquisition of qualitative and quantitative informations for multiple components, making it highly valuable in the monitoring of electrochemical reaction products and the identification of intermediates. In general, electrolyte is necessary for electrochemical reaction. However, these electrolyte salts are detrimental to mass spectrometry analysis as they not only cause condensation in the mass spectrometry inlet, leading to blockage, but also impede the signal of the target analyte or form adduct ions with target analyte, resulting in a complex mass spectrum and increased analytical challenges. It is of great significance to develop a mass spectrometry method to real-time obtain trace organic components in high concentration buffer salt solutions. Therefore, a novel atmospheric pressure chemical ionization mass spectrometry (APCI-MS) method was developed for online analysis of trace organic components in high concentration buffer salt solutions, and a small volume flow electrolytic cell, stable performance, and simple structure were fabricated for on-line electrochemical reaction, which employed Pt, Pt and Ag/AgCl as working electrode, counter electrode and reference electrode, respectively. After combination of the APCI-MS and flow electrolytic cell, an electrochemical mass spectrometry device and method for on-line analysis of the electrochemical process in high concentration buffer salt solutions were constructed. As a proof of concept application, the device and method were used to on-line and real-time study the electrochemical oxidation process of dopamine in phosphate buffer salt solutions. The experimental results showed that the APCI-MS method can efficiently remove the inorganic salts in solutions on-line by on-line thermal deposition, while the organic components can be ionized by APCI for mass spectrometry detection. The results of dopamine electrochemical oxidation analysis showed that dopamine was not oxidized under the oxidation potential at 0 V, and only the protonated dopamine m/z 154 [M+H]+ was obtained. When the oxidation potential was +0.3 V, in addition to the protonated dopamine, the protonated peak m/z 150 [M+H]+ of dopachrome was generated by losing 4e- from dopamine, and the protonated peak m/z 303 [M+H]+ of the adduct dopachrome and dopamine formed by the intermolecular hydrogen bonding were also obtained. When the oxidation potential increased to +0.6 V, the contents of oxidation products m/z 150 and m/z 303 were further increased. The results demonstrated that this method has great application potential in studying the electrochemical reaction.

The rich blood supply of the bone marrow provides favorable conditions for tumor cell proliferation and growth. In the disease’s early stages, circulating tumor cells can escape to the bone marrow and form imperceptible micro metastases. These tumor cells may be reactivated to regain the ability to grow aggressively and eventually develop into visible metastases. Symptomatic bone marrow metastases with abnormal hematopoiesis solid tumor metastases are rare and have poor prognoses. Treatment options are carefully chosen because of the suppression of bone marrow function. In this review, we summarized the mechanisms involved in developing bone marrow metastases from tumor cells and the clinical features, treatment options, and prognosis of patients with symptomatic bone marrow metastases from different solid tumors reported in the literature.

BackgroundThymus mandschuricus is an aromatic and medicinal plant with notable antibacterial and antioxidant properties. However, traditional breeding methods rely on phenotypic selection due to a lack of molecular resources. A high-quality reference genome is crucial for marker-assisted breeding, genome editing, and molecular genetics.ResultsWe utilized PacBio and Hi-C technologies to generate a high-quality chromosome-level reference genome for T. mandschuricus, with a size of 587.05 Mb and an N50 contig size of 8.41 Mb. The assembled genome contained 29,343 predicted protein-coding genes, and evidence of two distinct whole-genome duplications in T. mandschuricus was discovered. Comparative genomic analysis revealed rapid evolution of genes involved in phenylpropanoid biosynthesis and the CYP450 gene family in T. mandschuricus. Additionally, we reconstructed the gene families of terpenoid biosynthesis structural genes, such as TPS, BAHD, and CYP, and identified regulatory networks controlling the expression of aroma-synthesis genes by integrating transcriptome data from various organs and developmental stages. We discovered that hormones and transcription factors may collaborate in controlling aroma-synthesis gene expression.ConclusionThis study provides the first high-quality genome sequence and gene annotation for T. mandschuricus, an indigenous thyme species unique to China. The genome assembly and the comprehension of the genetic basis of fragrance synthesis acquired from this research could potentially serve as targets for future breeding programs and functional studies.

Abstract Background and aims Secreted frizzled-related protein 5 (SFRP5) is a member of the SFRP family that is known for its potent anti-inflammatory properties. Nevertheless, little is known regarding the relevance of SFRP5 in coronary artery disease (CAD). The current study examined the correlation between serum levels of SFRP5 and the triglyceride-glucose (TyG) index in patients who underwent coronary angiography (CAG) as a component of cardiovascular assessment and for the purpose of prognosis evaluation. Methods A total of 310 hospitalized patients were enrolled in this study between May 2021 and March 2022 and were divided into three groups based on their CAG results and SYNTAX (synergy between PCI with TAXUS drug-eluting stent and cardiac surgery) scores: the control group, mild lesion group, and moderate-severe lesion group. Univariate and multivariate analyses were employed to investigate the relationships between changes in patients and clinical variables. To investigate the impact of the TyG index and serum SFRP5 levels on the occurrence of major adverse cardiovascular events (MACEs), Kaplan‒Meier curves were plotted. Serum SFRP5 levels were measured utilizing an enzyme-linked immunosorbent assay (ELISA) kit. Results The serum SFRP5 levels significantly decreased with the increasing severity and complexity of CAD, while the TyG index significantly increased (P 115.58 pg/mL was the best predictive value for CAD (OR:0.87, P 115.58 pg/mL and a TyG index

Abstract Background Protein supplements have been widely used among those who are struggling with sarcopenic obesity among older adults. However, despite their popularity, there is still a lack of concrete evidence on both the potential benefits and side effects of protein supplementation and exercise on sarcopenic obesity (SO). Objective Thus, we aimed to determine the impacts of protein supplementation and exercise in older adults with sarcopenic obesity. Method A systematic database search was conducted for randomised controlled trials, quasi experimental study and pre-post study design addressing the effects of protein supplementation in improving sarcopenic obesity among older adults. This scoping review was conducted based on PRISMA-Scr guidelines across PubMed, Embase, Web of Science and Cochrane Library databases. To assess record eligibility, two independent reviewers performed a rigorous systematic screening process. Results Of the 1,811 citations identified, 7 papers met the inclusion criteria. Six studies were randomised controlled trials and one study was a pre-post test study design. The majority of studies discussed the use of both protein supplements and exercise training. The included studies prescribed protein intake ranging from 1.0 to 1.8 g/kg/BW/day for the intervention group, while the duration of exercise performed ranged from 2 to 3 times per week, with each session lasting for 1 hour. Whey protein supplementation has been shown to be effective in improving sarcopenic conditions and weight status in SO individuals. The combination of exercise training especially resistance training and the used of protein supplement provided additional benefits in terms of lean muscle mass as well as biomarkers. The study also revealed a lack of consistency in exercise design among interventions for sarcopenic obesity. Conclusion Overall, it appears to be a promising option for SO individuals to improve their sarcopenic condition and weight status through the combination of resistance exercise and whey protein supplementation. However, it also highlights the need for caution when it comes to high amounts of protein intake prescription. Future research is warranted to investigate the optimal exercise design for this population, given the limited research conducted in this specific area.

Abstract Some studies have shown that lyophilization significantly improves the stability of mRNA-LNPs and enables long-term storage at 2–8 °C. However, there is little research on the lyophilization process of mRNA-lipid nanoparticles (LNPs). Most previous studies have used empirical lyophilization with only a single lyoprotectant, resulting in low lyophilization efficiency, often requiring 40–100 h. In the present study, an efficient lyophilization method suitable for mRNA-LNPs was designed and optimized, shortening the total length of the lyophilization process to 8–18 h, which significantly reduced energy consumption and production costs. When the mixed lyoprotectant composed of sucrose, trehalose, and mannitol was added to mRNA-LNPs, the eutectic point and collapse temperature of the system were increased. The lyophilized product had a ginger root-shaped rigid structure with large porosity, which tolerated rapid temperature increases and efficiently removed water. In addition, the lyophilized mRNA-LNPs rapidly rehydrated and had good particle size distribution, encapsulation rate, and mRNA integrity. The lyophilized mRNA-LNPs were stable at 2–8 °C, and they did not reduce immunogenicity in vivo or in vitro. Molecular dynamics simulation was used to compare the phospholipid molecular layer with the lyoprotectant in aqueous and anhydrous environments to elucidate the mechanism of lyophilization to improve the stability of mRNA-LNPs. This efficient lyophilization platform significantly improves the accessibility of mRNA-LNPs.

Abstract The poor efficacy of chimeric antigen receptor T-cell therapy (CAR T) for solid tumors is due to insufficient CAR T cell tumor infiltration, in vivo expansion, persistence, and effector function, as well as exhaustion, intrinsic target antigen heterogeneity or antigen loss of target cancer cells, and immunosuppressive tumor microenvironment (TME). Here we describe a broadly applicable nongenetic approach that simultaneously addresses the multiple challenges of CAR T as a therapy for solid tumors. The approach reprograms CAR T cells by exposing them to stressed target cancer cells which have been exposed to the cell stress inducer disulfiram (DSF) and copper (Cu)(DSF/Cu) plus ionizing irradiation (IR). The reprogrammed CAR T cells acquire early memory-like characteristics, potent cytotoxicity, enhanced in vivo expansion, persistence, and decreased exhaustion. Tumors stressed by DSF/Cu and IR also reprogram and reverse the immunosuppressive TME in humanized mice. The reprogrammed CAR T cells, derived from peripheral blood mononuclear cells of healthy donors or metastatic female breast cancer patients, induce robust, sustained memory and curative anti-solid tumor responses in multiple xenograft mouse models, establishing proof of concept for empowering CAR T by stressing tumor as a promising therapy for solid tumors.

Any system for evaluating the safety service performance of heavy-haul railway lines must effectively reflect the real-time service status of the line. The working conditions of heavy-load lines are complex and diverse, particularly on uphill sections. Existing evaluation systems struggle to accurately reflect the service conditions of long and steep uphill sections bearing heavy loads, posing a significant threat to the safe operation of these lines. To address this problem, we propose a new method for evaluating the safety service performance of long and steep uphill sections of heavy-haul railway lines by establishing a scoring system based on the Analytic Hierarchy Process (AHP). First, damage indicators for heavy-haul lines are categorized into three groups: track geometry status indicators, track structure status indicators, and track traffic status indicators. Using data from existing heavy-haul lines and maintenance experiences, we determine a score deduction standard, classifying lines into four levels based on their safety service quality. Next, we establish a coefficient table for the service performance of long and steep uphill sections after the corresponding scores are deducted. Using data for the length and elevation grade of the actual uphill section, we adjust the deducted scores of the track structure status indicators, enhancing the evaluation system’s accuracy in describing the working conditions. Finally, we verify the stability of the entire system by conducting a sensitivity analysis of the indicator evaluation results using the One-At-a-Time (OAT) method. This method fills a critical gap in the safe operation and maintenance of heavy-haul railways and provides a safety guarantee for the operation of long uphill sections of heavy-haul railways.

Objective: This study aimed to establish the methods for determining the content of sodium hyaluronate in solid drinks by reversed-phase high performance liquid chromatography. Methods: With sodium hyaluronate content as evaluation index, after the sample extract was precipitated by ethanol, hyaluronase was used to hydrolyze the precipitate. The optimal enzymolysis conditions obtained by single factor test and orthogonal test were as follows: enzymolysis, at 34 ℃ and pH 6.5, for 120 min. The determination was performed on Uliumate C18 (4.6 mm×250 mm,5 μm) column with mobile phase: acetonitrile 10 mmol/L sodium octane sulfonate solution (Vacetonitrile∶Voctane sulfonate =10∶90) at flow rate of 0.6 mL/min. The detection wavelength was 232 nm and quantified by external standard method. Results: The correlation coefficient of sodium hyaluronate was 0.999 9. The recoveries of samples were between 96.1%~101%, and the relative standard deviation was 3.16%. The determination of limit was 0.062 g/kg. Conclusion: Ethanol precipitation combined with enzymolysis-reversed phase chromatography has strong specificity, high accuracy, good repeatability and less interference, which is suitable for the determination of sodium hyaluronate in solid drinks.

Abstract Background and aims Lipoprotein (a) [Lp(a)] is a genetically regulated lipoprotein particle that is an independent risk factor for coronary atherosclerotic heart disease. However, the correlation between Lp(a) and left ventricular ejection fraction (LVEF) in patients with myocardial infarction (MI) has been poorly studied. The present study investigated the correlation between Lp(a) and LVEF, as well as the impact of Lp(a) on long-term mortality in patients with MI. Methods Patients who underwent coronary angiography resulting in MI diagnosis between May 2018 and March 2020 at the First Affiliated Hospital of Anhui Medical University were included in this study. The patients were divided into groups based on the Lp(a) concentration and LVEF (reduced ejection fraction group: 455 mg/L was the best predictive value for reduced ejection fraction (AUC: 0.7694, P

BackgroundAn estimated 301 million people worldwide suffer from anxiety disorders. People living with HIV/AIDS (PLWHA) are particularly prone to anxiety disorders that could interfere with the important developmental process in an individual’s development and ultimately result in a wide range of negative mental, physical, and psychosocial consequences, as well as poor quality of life in those population groups. Early intervention for anxiety disorders can reverse some of the physical damage caused by anxiety. However, based on systematic reviews and meta-analyses, the specific prevalence of anxiety disorders in PLWHA remains unknown.MethodWe conducted a literature search on PubMed, Embase, and Web of Science up to 22 October 2022. A random-effects meta-analysis was used to pool prevalence rates from the included studies. Sensitivity and subgroup analyses were performed to identify the possible sources of heterogeneity and to compare the prevalence estimates across groups. The Joanna Briggs Institute’s Quality Assessment Checklist was used to assess the quality of the included studies. Cochran’s Q and I2 tests were used to assess the between-study heterogeneity.ResultsTen studies with a total of 238,570 cases were included for the final analysis. Results showed that 15.5% of HIV/AIDS patients had anxiety disorders. The prevalence was higher in females (20.8%) than males (20.7%). The mean age of PLWHA with anxiety disorders was 46.58 ± 11.15 years in these included studies. The subgroup analyses showed significant higher prevalence in non-heterosexual (32.1%).ConclusionWe attempted to quantify literature that could allow for stronger inferences to be made regarding the significantly higher prevalence of anxiety disorders in PLWHA, a finding that suggests the imperativeness of intervention strategies to alleviate suffering and reduce the probable negative ramifications.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42023442219, identifier CRD42023442219.

ObjectiveThe Toll-like receptor (TLR) 4-mediated nuclear factor kappa B (NF-κB) signaling pathway regulates the production of inflammatory factors and plays a key role in the pathogenesis of gouty arthritis. The aim of the present study was to investigate the link among TLR4 gene polymorphisms at various loci, protein expression, and gouty arthritis susceptibility.MethodsBetween 2016 and 2021, a case-control study was used to collect a total of 1207 study subjects, including 317 male patients with gouty arthritis (gout group) and 890 healthy males (control group). The association between gout susceptibility and different genetic models was analyzed by typing three loci of the TLR4 gene (rs2149356, rs2737191, and rs10759932) using a multiplex point mutation rapid assay, and the association between protein expression and gout was confirmed by measuring TLR4 protein concentrations using enzyme-linked immunosorbent assays (ELISAs).ResultsIn a codominant models AA and AG, the rs2737191 polymorphism in the gout group increased the risk of gout compared to the AA genotype (OR = 2.249, 95%CI 1.010~5.008), and the risk of gout was higher for those carrying the G allele compared to the A allele (OR = 2.227, 95%CI 1.006~4.932). TLR4 protein expression was different between the two groups with different locus genotypes. The differences in TLR4 protein expression between the gout group and control group were statistically significant between the following genotypes: the GG and GT genotypes of the rs2149356 polymorphism; the AA and AG genotypes of the rs2737191 polymorphism; and the TT and TC genotypes of the rs10759932 polymorphism(PConclusionThe AG genotype of the TLR4 gene rs2737191 polymorphism may be correlated with the development of gouty arthritis. The level of TLR4 protein expression is significantly higher in patients with gouty arthritis than in controls, and there is a correlation between high TLR4 protein expression and the development of gouty arthritis.

ObjectiveThe surgical treatment of the primary site has been a subject of controversy in patients with de novo metastatic breast cancer. In recent years, studies using large databases and retrospective analyses have provided evidence of the survival benefits of localized surgery for these patients. However, due to the improved prognosis associated with novel antitumor agents and the widespread use of anti-HER2 therapy, it is important to investigate the role of primary site surgery in the context of new drug treatments for stage IV HER2-positive breast cancer.MethodsThis retrospective analysis included patients with metastatic breast cancer at diagnosis who were consulted at the First Hospital of Jilin University between 2016 and 2022. We compared the patients’ clinical and pathological characteristics, treatment regimens, and prognosis between the surgery and non-surgery groups.ResultsA total of 96 patients with stage IV HER2-positive breast cancer were included in the study, with 24 patients (25%) undergoing surgery for the primary lesion. Patients with lower Eastern Cooperative Oncology Group (ECOG) scores, earlier T-stage, metastases confined to one organ/site, and fewer metastases were more likely to undergo surgery. Patients in the surgical group had longer progression-free survival (median 25.7 vs. 15.9 months, p=0.073) and overall survival (median 79.1 vs. 48 months, p=0.073) compared to patients in the non-surgical group, however, there was no statistical difference. Univariate and multivariate Cox regression analysis suggested that the choice of first-line targeted therapy regimens rather than surgical treatment influenced the patients’ prognoses. In the subgroup of patients receiving first-line targeted therapy with trastuzumab plus pertuzumab, the decision to undergo surgery on the primary site did not have a statistically significant effect on prognosis.ConclusionPrimary site surgery does not improve the prognosis of de novo stage IV HER2-positive breast cancer. In the era of anti-HER2 therapy, primary surgery is not recommended, except in exceptional circumstances.

PurposeOngoing Monkeypox (MPX) outbreaks in countries outside Africa have unique characteristics. However, data on cohorts of confirmed cases in China is limited. The study provides important epidemiological, diagnostic, and clinical information about this disease in China.MethodsWe report a series of Chinese individuals with confirmed MPX infections identified at Beijing Youan Hospital (China) from June 10 to July 15, 2023. Samples were taken from the skin, anus, throat, and blood. An epidemiological questionnaire was used to collect demographic and clinical data. Further, we compared the MPX viral (MPXV) loads across different anatomical sites.Results66 samples were collected from 20 patients, all of whom were cisgender men. Median patient age was 29 years. Notably, 19 (95%) patients reported unprotected sexual encounters with men in the preceding month, and 13 (65%) were human immunodeficiency virus (HIV)-positive. Among those with HIV, 12 (92%) were receiving antiretroviral therapy, and 11 (85%) had well-controlled infections (HIV viral load

Abstract Lung cancer is the leading cause of death among all cancers. A persistent chronic inflammatory microenvironment is highly correlated with lung cancer. However, there are no anti‐inflammatory agents effective against lung cancer. Cytochrome P450 2E1 (CYP2E1) plays an important role in the inflammatory response. Here, it is found that CYP2E1 is significantly higher in the peritumoral tissue of non‐small cell lung cancer (NSCLC) patients and lung tumor growth is significantly impeded in Cyp2e1−/− mice. The novel CYP2E1 inhibitor Q11, 1‐(4‐methyl‐5‐thialzolyl) ethenone, is effective in the treatment of lung cancer in mice, which can inhibit cancer cells by changing macrophage polarization rather than directly act on the cancer cells. It is also clarify that the benefit of Q11 may associated with the IL‐6/STAT3 and MAPK/ERK pathways. The data demonstrate that CYP2E1 may be a novel inflammatory target and that Q11 is effective on lung cancer by regulation of the inflammatory microenvironment. These findings provide a molecular basis for targeting CYP2E1 and illustrate the potential druggability of the CYP2E1 inhibitor Q11.

Cyclic air braking is a key factor affecting the safe operation of trains on long downhill sections. However, a train’s cycle braking strategy is constrained by multiple factors such as driving environment, speed, and air-refilling time. A Q-learning algorithm-based cyclic braking strategy for a heavy haul train on long downhill sections is proposed to address this challenge. First, the operating environment of a heavy haul train on long downhill sections is designed, considering various constraint parameters, such as the characteristics of special operating routes, allowable operating speeds, and train tube air-refilling time. Second, the operating status and braking operation of a heavy haul train on long downhill sections are discretized in order to establish a Q-table based on state–action pairs. The training of algorithm performance is achieved by continuously updating Q-tables. Finally, taking the heavy haul train formation as the study object, actual line data from the Shuozhou–Huanghua Railway are used for experimental simulation, and different hyperparameters and entry speed conditions are considered. The results show that the safe and stable cyclic braking of a heavy haul train on long downhill sections is achieved. The effectiveness of the Q-learning control strategy is verified.

Cyclic air braking is a key element for ensuring safe train operation when running on a long and steep downhill railway section. In reality, the cyclic braking performance of a train is affected by its operating environment, speed and air-refilling time. Existing optimization algorithms have the problem of low learning efficiency. To solve this problem, an intelligent control method based on the deep Q-network (DQN) algorithm for heavy-haul trains running on long and steep downhill railway sections is proposed. Firstly, the environment of heavy-haul train operation is designed by considering the line characteristics, speed limits and constraints of the train pipe’s air-refilling time. Secondly, the control process of heavy-haul trains running on long and steep downhill sections is described as the reinforcement learning (RL) of a Markov decision process. By designing the critical elements of RL, a cyclic braking strategy for heavy-haul trains is established based on the reinforcement learning algorithm. Thirdly, the deep neural network and Q-learning are combined to design a neural network for approximating the action value function so that the algorithm can achieve the optimal action value function faster. Finally, simulation experiments are conducted on the actual track data pertaining to the Shuozhou–Huanghua line in China to compare the performance of the Q-learning algorithm against the DQN algorithm. Our findings revealed that the DQN-based intelligent control strategy decreased the air braking distance by 2.1% and enhanced the overall average speed by more than 7%. These experiments unequivocally demonstrate the efficacy and superiority of the DQN-based intelligent control strategy.

ObjectiveStudies have shown that the exercise-induced cytokine Irisin functions were as a dimer, so tandem Irisin-Irisin mock dimers were designed to explore the similarities and differences between recombinant Irisin-Irisin expressed by Escherichia coli and commercial Irisin in activity and function on tumor cells.MethodsEscherichia coli strain BL21 (DE3) and pET-30a expression vectors were selected to obtain recombinant Irisin-Irisin by isopropyl β-D-1-thiogalactopyranoside (IPTG) induction. High purity recombinant Irisin-Irisin was obtained by Ni Sepharose excel. C2C12 skeletal muscle cells were treated with recombinant Irisin-Irisin and monomeric Irisin respectively, and the expressions of mitochondrial related gene UCP-1 were observed to test the activity. The functions were verified in gastric cancer, colorectal cancer and other gastrointestinal tumors, and the activity and function of recombinant Irisin-Irisin and monomeric Irisin on tumor cells were compared.Results(1) Expression and purification of recombinant Irisin-Irisin: compared with the non-induced samples, the recombinant Irisin-Irisin was significantly expressed after IPTG induction; high purity recombinant Irisin-Irisin with a molecular weight of about 27 kDa was obtained by Ni Sepharose excel. (2) Detection of recombinant Irisin-Irisin activity: compared with the blank control group, both the recombinant Irisin-Irisin group and the Irisin group could up-regulate the expression of UCP-1 in C2C12 cells (PPPPEscherichia coli has activity, and the activity is higher than that of the monomeric Irisin; recombinant Irisin-Irisin has an effect on the migration of gastric cancer cells and colorectal cancer cells, and the effect was better than that of the monomeric Irisin.

Abstract At present, the clinicopathological features, optimal treatment patterns, and prognosis of breast metaplastic squamous cell carcinoma (SCC) are not fully understood and are still controversial. Here, we report a 56‐year‐old female patient with breast infiltrating ductal carcinoma with axillary lymph node metastasis of metaplastic SCC admitted to our hospital. Their homology was clarified by comparing the gene mutation results of the two lesions, that is, the axillary lymph node lesion was a metastasis of breast metaplastic SCC. We treated the patient with Poly ADP‐ribose Polymerase (PARP) inhibitors in combination with immune checkpoint inhibitors (ICIs) and found that she could achieve clinical benefit from the combination regimen. We reported a successful diagnosis and treatment of this rare refractory disease and reviewed the literature on the characteristics, pathogenesis, and advances in the diagnosis and treatment of breast metaplastic SCC.

BackgroundThe significance of uric acid (UA) and high-density lipoprotein cholesterol (HDL-C) in the prognosis of acute myocardial infarction (AMI) remains controversial. This study investigated the effect of the interaction between UA and HDL-C on the prognosis of patients with AMI.MethodsIn total, 480 patients with AMI were included in this study. Baseline and follow-up data were collected, and the primary endpoint was major adverse cardiovascular events (MACE). The secondary endpoint was all-cause death. Both additive and multiplicative interactions were calculated to evaluate their interaction with prognosis. Then, the impact of UA and HDL-C ratio (UHR) on prognosis was assessed.ResultsOver a median follow-up period of 41 (30,46) months, 136 (28.3%) MACEs, and 44 (9.2%) deaths were recorded. There was a positive additive interaction between UA and HDL-C for MACEs. The attributable proportion (AP) showed that 46% of the estimated effect (MACE in patients) was attributable to this interaction. The synergy index (SI) was 2.04 (1.07,3.88) for MACE, indicating that the risk for patients presenting with both risk factors was greater than the sum of the risk factors alone. Multivariate Cox regression analysis revealed that UHR independently predicted MACEs and mortality. Kaplan–Meier survival curves according to tertiles of UHR showed statistically significant differences in MACE (log-rank test, P

Excess ketogenesis can lead to ketoacidosis, a serious complication in patients with diabetes. Here the authors report an insulin independent pathway, the hepatic nonparenchymal S100A9-TLR4-mTORC1 axis, that is able to normalize diabetic ketogenesis and pre-clinical data to suggest potential for development of S100A9 based adjunctive therapy to insulin.

We report a 30-year-old man involving gastrointestinal symptoms, vitreous opacity, and multiple cranial neuropathies. Transthyretin-related hereditary amyloidosis genetic testing revealed a rare c.251T > C variant p.(Phe84Ser). Only four cases with this variant have been reported before.

This study examines the impact of energy poverty on internal immigration based on the current situation in which reducing energy poverty is a necessary condition for ensuring sustainable development. The threshold effects model is applied to verify the significance of energy poverty in the prediction of internal immigration. The main results suggest that energy poverty significantly and negatively affects internal immigration. A heterogeneity analysis between coastal and non-coastal regions shows that the effects are more pronounced in non-coastal regions than in coastal regions. Further analysis reveals that there exists a kink in the threshold effects. The results remain robust using the specification of the kink threshold effects model. The policy implication is that a balanced development of energy infrastructure in different regions is required to achieve better social welfare for migrants.

Glaucomatous optic neuropathy (GON) can be diagnosed and monitored using fundus photography, a widely available and low-cost approach already adopted for automated screening of ophthalmic diseases such as diabetic retinopathy. Despite this, the lack of validated early screening approaches remains a major obstacle in the prevention of glaucoma-related blindness. Deep learning models have gained significant interest as potential solutions, as these models offer objective and high-throughput methods for processing image-based medical data. While convolutional neural networks (CNN) have been widely utilized for these purposes, more recent advances in the application of Transformer architectures have led to new models, including Vision Transformer (ViT,) that have shown promise in many domains of image analysis. However, previous comparisons of these two architectures have not sufficiently compared models side-by-side with more than a single dataset, making it unclear which model is more generalizable or performs better in different clinical contexts. Our purpose is to investigate comparable ViT and CNN models tasked with GON detection from fundus photos and highlight their respective strengths and weaknesses. We train CNN and ViT models on six unrelated, publicly available databases and compare their performance using well-established statistics including AUC, sensitivity, and specificity. Our results indicate that ViT models often show superior performance when compared with a similarly trained CNN model, particularly when non-glaucomatous images are over-represented in a given dataset. We discuss the clinical implications of these findings and suggest that ViT can further the development of accurate and scalable GON detection for this leading cause of irreversible blindness worldwide.

In view of the large difference between the elastic modulus of human bone structure and metal materials and the difficulty of control, the goal is to reduce or eliminate the “stress shielding” effect in a wide span, introduce a negative Poisson’s ratio metamaterial with an unconventional deformation mechanism, carry out the design and experimental research of porous microstructure with wide span and low elastic modulus. Based on the negative Poisson’s ratio auxetic structure unit, the three-dimensional cellular porous microstructures with different control parameters and porosity were designed.Experimental samples were prepared by selective laser melting. The variation rules between mechanical properties and structural parameters such as strength and elastic modulus were revealed through compression tests, and the matching degree of negative Poisson’s ratio microstructure and human bone was evaluated. The experimental results show that the auxetic structure has good manufacturability, and the forming quality is correlated with the concave angle and porosity.The mechanical properties of negative Poisson’s ratio auxetic structure are highly dependent on the geometric structure and porosity of the cell.Compared with the positive Poisson’s ratio structure, the auxetic structure with negative Poisson’s ratio has lower elastic modulus and similar yield strength under the same porosity, and can control the 316 L stainless steel bone material with wide span elastic modulus by 0.47 GPa～1.75 GPa.Therefore, the negative Poisson’s ratio auxetic microstructure has potential advantages in the application of human bone structure.

As one of common malignancies, prostate adenocarcinoma (PRAD) has been a growing health problem and a leading cause of cancer-related death. To obtain expression and functional relevant RNAs, we firstly screened candidate hub mRNAs and characterized their associations with cancer. Eight deregulated genes were identified and used to build a risk model (AUC was 0.972 at 10 years) that may be a specific biomarker for cancer prognosis. Then, relevant miRNAs and lncRNAs were screened, and the constructed primarily interaction networks showed the potential cross-talks among diverse RNAs. IsomiR landscapes were surveyed to understand the detailed isomiRs in relevant homologous miRNA loci, which largely enriched RNA interaction network due to diversities of sequence and expression. We finally characterized TK1, miR-222-3p and SNHG3 as crucial RNAs, and the abnormal expression patterns of them were correlated with poor survival outcomes. TK1 was found synthetic lethal interactions with other genes, implicating potential therapeutic target in precision medicine. LncRNA SNHG3 can sponge miR-222-3p to perturb RNA regulatory network and TK1 expression. These results demonstrate that TK1:miR-222-3p:SNHG3 axis may be a potential prognostic biomarker, which will contribute to further understanding cancer pathophysiology and providing potential therapeutic targets in precision medicine.

Abstract Background Cryptococcal meningitis (CM) has a high morbidity and mortality due to the low detection of Cryptococcus in cerebrospinal fluid (CSF) during the early stage of the disease with traditional methods. Case presentation In addition to the traditional methods of India ink staining and cryptococcal antigen (CrAg), we used nanopore sequencing and next-generation sequencing (NGS) to detect pathogenic DNA in CSF samples of three patients with CM. The CSF samples of all three patients were positive by India ink staining and CrAg. NGS also detected Cryptococcus in all three CSF samples. Nanopore sequencing detected Cryptococcus in two CSF samples. Conclusion Nanopore sequencing may be useful in assisting with the clinical diagnosis of CM. Further research is needed to determine the sensitivity and specificity of nanopore sequencing of CSF.

Abstract Objective To investigate the prognostic value of derived neutrophil to lymphocyte ratio (dNLR) and lactate dehydrogenase (LDH) in patients with advanced HER2 positive breast cancer treated with trastuzumab emtansine. Methods Fifty one patients with advanced HER2 positive breast cancer who received T-DM1 treatment in Harbin Medical University Cancer Hospital were selected. The clinical data and blood test indexes were collected, and the ROC curve determined the optimal cut-off value. Kaplan-Meier survival curve and Cox regression model was used to analyze the effect of different levels of dNLR,LDH,LNI (dNLR combined with LDH index) before and after T-DM1 treatment on the survival of patients. Results The median PFS and OS of the patients with advanced HER2 positive breast cancer who received T-DM1 treatment were 6.9 months and 22.2 months, respectively. The optimal cut-off value of LDH and dNLR before T-DM1 treatment was 244 U / L (P = 0.003) and 1.985 (P = 0.013), respectively. Higher LDH and dNLR were significantly correlated with shorter median PFS and OS (P 244 U / L, dNLR > 1.985, LNI > 0, ECOG ≥1 and HER-2 (IHC2 +, FISH+) before the T-DM1 treatment were the poor prognostic factors. LDH uptrend after the T-DM1 treatment also predicted poor prognosis. Conclusion Serum LDH > 244 U / L and dNLR > 1.985 before the T-DM1 treatment were prognostic risk factors for patients with advanced HER2 positive breast cancer receiving T-DM1 treatment. The higher LNI score was significantly associated with shorter PFS and OS. LDH uptrend after T-DM1 treatment was also related to the poor prognosis.

PurposeThe lungs are a common metastatic organ in breast cancer, mainly due to blood metastasis. On imaging, most metastatic lesions show a peripheral round mass in the lung, occasionally with a hilar mass as the primary manifestation, showing burr and lobulation signs. This study aimed to investigate breast cancer patient's clinical characteristics and prognosis with two different metastatic sites in the lung.MethodsWe retrospectively analyzed patients admitted to the First Hospital of Jilin University between 2016 and 2021 diagnosed with breast cancer lung metastases. Forty breast cancer patients with hilar metastases (HM) and 40 patients with peripheral lung metastases (PLM) were matched 1:1 using a pairing method. To analyze the patient's prognosis, the clinical characteristics of patients with two different metastatic sites were compared using the chi-square test, Kaplan–Meier curve, and Cox proportional hazards model.ResultsThe median follow-up time was 38 months (2–91 months). The median age of patients with HM was 56 years (25–75 years), and that of patients with PLM was 59 years (44–82 years). The median overall survival (mOS) was 27 months in the HM group and 42 months in the PLM group (p = 0.001). The results of the Cox proportional hazards model showed that the histological grade (hazard ratio = 2.741, 95% confidence interval 1.442–5.208, p = 0.002) was a prognostic factor in the HM group.ConclusionThe number of young patients in the HM group was higher than that in the PLM group, with higher Ki-67 indexes and histological grades. Most patients had mediastinal lymph node metastasis, with shorter DFI and OS and poor prognosis.

ABSTRACT Umifenovir, a broad-spectrum nonnucleoside antiviral drug, has a promising efficacy against coxsackievirus B4 (CVB4) infection, but its mechanism remains unclear. CVB4 is a common human single-stranded RNA virus that belongs to the Picornaviridae family and the Enterovirus genus. Enterovirus can cause severe diseases, such as meningitis, myocarditis, pancreatitis, insulin-dependent diabetes, and several other diseases, in both adults and children. We have previously demonstrated the critical role of interleukin 10 (IL-10) in promoting CVB4 infection and the downregulation of IL-10 by umifenovir. To further explore the underlying mechanisms of umifenovir, we characterized the epigenetic regulation of IL-10 in IL-10 knockout RAW264.7 cells and a BALB/c mouse splenocyte model. Mechanistically, we found that umifenovir inhibited CVB4-activated IL-10 by enhancing the methylation level of the repressive histones H3K9me3 and H3K27me3 while reducing the acetylation level of the activating histone H3K9ac in the promoter region of the IL-10 gene. Furthermore, using a chromosome conformation capture approach, we discovered that CVB4 infection activated the IL-10 gene by forming an intrachromosomal interaction between the IL-10 gene promoter and an intronic enhancer of the downstream MK2 (mitogen-activated protein kinase [MAPK]-activated protein kinase 2 [MAPKAPK2]) gene, a critical component of the p38-MAPK signaling pathway, which is required for IL-10 gene expression. However, umifenovir treatment abolished this spatial conformation and chromatin interaction, thus reducing the continuous expression of IL-10 and subsequent CVB4 replication. In conclusion, this study reveals a novel epigenetic mechanism by which umifenovir controls CVB4 infections, thus laying a theoretical foundation for therapeutic use of umifenovir. IMPORTANCE Viral infections are major threats to human health because of their strong association with a variety of inflammation-related diseases, especially cancer. Many antiviral drugs are performing poorly in treating viral infections. This is probably due to the immunosuppressive effect of highly expressed IL-10, which is caused by viral infection. Umifenovir is a broad-spectrum antiviral drug. Our recent studies showed that umifenovir has a significant inhibitory effect on CVB4 infection and can reduce IL-10 expression caused by CVB4. However, another antiviral drug, rupintrivir, showed good antiviral activity but had no effect on the expression of IL-10. This suggests that the regulation of IL-10 expression is a key part of the antiviral mechanism of umifenovir. Therefore, due to the dual function of the inhibition of CVB4 replication and the regulation of immune antiviral pathway, the mechanism of umifenovir is of great value to study.

Purpose Dovitinib is a receptor tyrosine kinase inhibitor of VEGFR1-3, PDGFR, FGFR1/3, c-KIT, FLT3 and topoisomerase 1 and 2. The drug response predictor (DRP) biomarker algorithm or DRP-Dovitinib is being developed as a companion diagnostic to dovitinib and was applied retrospectively. Patients and methods Archival tumor samples were obtained from consenting patients in a phase 3 trial comparing dovitinib to sorafenib in renal cell carcinoma patients and the DRP-Dovitinib was applied. The biomarker algorithm combines the expression of 58 messenger RNAs relevant to the in vitro sensitivity or resistance to dovitinib, including genes associated with FGFR, PDGF, VEGF, PI3K/Akt/mTOR and topoisomerase pathways as well as ABC drug transport, and provides a likelihood score between 0–100%. Results The DRP-Dovitinib divided the dovitinib treated RCC patients into two groups, sensitive (n = 49, DRP score >50%) or resistant (n = 86, DRP score ≤ 50%) to dovitinib. The DRP sensitive population was compared to the unselected sorafenib arm (n = 286). Median progression-free survival (PFS) was 3.8 months in the DRP sensitive dovitinib arm and 3.6 months in the sorafenib arm (hazard ratio 0.71, 95% CI 0.51–1.01). Median overall survival (OS) was 15.0 months in the DRP sensitive dovitinib arm and 11.2 months in the sorafenib arm (hazard ratio 0.69, 95% CI 0.48–0.99). The observed clinical benefit increased with increasing DRP score. At a cutoff of 67% the median OS was 20.6 months and the median PFS was 5.7 months in the dovitinib arm. The results were confirmed in five smaller phase II trials of dovitinib which showed a similar trend. Conclusion The DRP-Dovitinib shows promise as a potential biomarker for identifying advanced RCC patients most likely to experience clinical benefit from dovitinib treatment, subject to confirmation in an independent prospective trial of dovitinib in RCC patients.

BackgroundThe presence of lymph node metastasis leads to a poor prognosis for prostate cancer (Pca). Recently, many studies have indicated that gene signatures may be able to predict the status of lymph nodes. The purpose of this study is to probe and validate a new tool to predict lymph node metastasis (LNM) based on alternative splicing (AS).MethodsGene expression profiles and clinical information of prostate adenocarcinoma cohort were retrieved from The Cancer Genome Atlas (TCGA) database, and the corresponding RNA-seq splicing events profiles were obtained from the TCGA SpliceSeq. Limma package was used to identify the differentially expressed alternative splicing (DEAS) events between LNM and non-LNM groups. Eight machine learning classifiers were built to train with stratified five-fold cross-validation. SHAP values was used to explain the model.Results333 differentially expressed alternative splicing (DEAS) events were identified. Using correlation filter and the least absolute shrinkage and selection operator (LASSO) method, a 96 AS signature was identified that had favorable discrimination in the training set and validated in the validation set. The linear discriminant analysis (LDA) was the best classifier after 100 iterations of training. The LDA classifier was able to distinguish between LNM and non-LNM with an area under the receiver operating curve of 0.962 ± 0.026 in the training set (D1 = 351) and 0.953 in the validation set (D2 = 62). The decision curve analysis plot proved the clinical application of the AS-based model.ConclusionMachine learning combined with AS data could robustly distinguish between LNM and non-LNM in Pca.

ObjectiveBreast cancer symptomatic bone marrow metastasis (BMM) is rare and has a poor prognosis. Chemotherapy is usually the primary treatment, but it has limited efficacy, resulting in dose reduction and a decrease in quality of life due to the adverse effects of the agent. Other than chemotherapy, there are no other treatment studies for BMM. This study aimed to explore the clinicopathological characteristics of BMM patients with breast cancer, the prognosis using different treatment modalities, and the risk factors that affect the prognosis.MethodsThis retrospective study included patients diagnosed with breast cancer BMM from January 2018 to January 2022 in the Cancer Center of the First Hospital of Jilin University. The analysis focused on the characteristics of the patients, the treatment regimen, and the prognosis.ResultsOf 733 patients with advanced breast cancer, 33 patients were identified with BMM. All patients showed a hemoglobin decrease, and 25 (75.75%) presented with a fever of unknown origin. As for the metastasis breast cancer subtype, 25 (75.75%) were hormone receptor (HR) positive/human epidermal growth factor receptor 2 (HER2) negative, three (9.09%) had HER2 overexpression, and five (15.15%) were triple negative. The BMM patients had a median progression-free survival (PFS) of 7 months (1–21 months) and a median overall survival (OS) of 18 months (2–108 months). Among 25 HR+/HER2− BMM patients treated with different modalities, the median OS of the endocrine therapy (ET) group was 23 months, compared with 5 months in the chemotherapy group. Cox proportional hazards models suggested that higher Eastern Cooperative Oncology Group (ECOG) scores and old age were associated with shorter survival.ConclusionWhen breast cancer patients present with anemia and fever of unknown origin, BMM should be considered. For HR+/HER2− patients with good physical status and can receive active treatment, CDK4/6 inhibitors combined with ET can be used to control disease progression, improve quality of life, and prolong survival.

Background Breast cancer (BC) poses a serious threat to women worldwide. This research was designed to explore the association between the rs4784227 polymorphism of cancer susceptibility candidate gene 16 (CASC16) and BC susceptibility and prognosis, aiming to provide further information for the early detection of BC and to accelerate comprehensive cancer management. Methods A total of 1,733 subjects were recruited for this case-control study, of which 828 are BC patients and 905 are healthy individuals. The relevance between SNP rs4784227 and BC risk in diverse genetic models was analyzed by using the SNPStats analysis program and was assessed by odds ratios (ORs) and 95% confidence intervals (CIs) using the binary logistic regression model. Pearson’s χ2 test was used to determine the correlation between the polymorphism and clinical characteristics of BC patients. Additionally, univariate survival analysis was performed by the Kaplan-Meier method and log-rank test, and multivariate survival analysis was performed by Cox regression. Results SNP rs4784227 was significantly associated with susceptibility to BC in the dominant model (CT/TT versus CC, OR = 1.237, 95% CI = 1.012–1.513, P = 0.038). The minor allele of SNP rs4784227 was significantly linked to an increased risk of BC (OR = 1.197, 95% CI = 1.022–1.401, P = 0.026). In addition, the rs4784227 polymorphism of CASC16 was associated with perineural invasion (P = 0.030), menstrual status (P = 0.016) and histological grade (P = 0.001, P = 0.003, P = 0.025; respectively) of BC patients. There was no significant association between the genotypes of rs4784227 and disease-free survival (DFS) or overall survival (OS) of breast cancer patients (P > 0.05). Conclusions The rs4784227 polymorphism of CASC16 may affect susceptibility to breast cancer and is associated with perineural invasion, menstrual status and histological grade in BC patients. Additionally, our results could not confirm that this polymorphism was related to breast cancer prognosis.

This pilot study (NCT03958097; https://www.clinicaltrials.gov/ct2/show/NCT03958097) was aimed to evaluate the efficacy and safety of PD-1 antibody combined autologous NK cells in the treatment of patients with stage IIIB/IIIC or IV non-small-cell lung cancer (NSCLC) who failed the first-line platinum-based chemotherapy. All patients received both sintilimab 200mg and 3×109 NK cells every 3 weeks. 20 patients were enrolled, median follow up time was 22.6 months. The median PFS was 11.6 months, ORR was 45%. Median OS was 17.7 months, 6-month OS rate and 12-month OS rate was 95.0% and 80.0%. Unexpected adverse events were not observed. 2 patients reported grade 3 adverse events (hypertriglyceridemia, neutropenia and increased creatine kinase). The autologous NK cells did not add extra adverse events to the ICI treatment. Autologous NK plus sintilimab showed promising antitumor activity and an acceptable safety profile in advanced driven-mutation negative NSCLC who failed on the first line treatment.

Abstract Background For a patient presenting with fever, multiple lymphadenopathy and splenomegaly, pathogen infection should be preferentially considered, followed by lymphoid malignancies. When traditional laboratory and pathological detection cannot find the pathogenic microorganism, metagenomic sequencing (MGS) which targets the person’s genome for exceptional genetic disorders may detect a rare pathogen. Case presentation Here, we introduced the diagnostic clue of a case of multicentric Castleman disease (MCD) with hemophagocytic syndrome which was elicited from the detection of human herpesvirus-8 in the blood of a HIV-1 infected person by MGS technology during pathogen inspection. This case highlights the need to increase the awareness of MCD among clinicians and pathologists. Conclusions MGS technology may play a pivotal role in providing diagnostic clues during pathogen inspection, especially when pathogens are not detectable by conventional methods.