Efficacy and Safety of Crisugabalin (HSK16149) in Adults with Postherpetic Neuralgia: A Phase 3 Randomized Clinical Trial.

Importance: China carries a heavy burden of postherpetic neuralgia, with an unmet need for novel drugs with greater efficacy and less prominent neurotoxic effects than existing calcium channel ligands. Objective: To investigate the efficacy and safety of crisugabalin, an oral calcium channel α2δ-1 subunit ligand, for postherpetic neuralgia. Design, Setting, and Participants: This randomized clinical trial, carried out between November 9, 2021, and January 5, 2023, at 48 tertiary care centers across China had 2 parts. Part 1 was a phase 3, multicenter, randomized, double-blind, placebo-controlled, parallel-group study consisting of a 2-week screening period, a 7-day run-in period, and a 12-week double-blind treatment period. Part 2 was a 14-week open-label extension study. Investigators, statisticians, trial clinicians, and patients were blinded to trial group assignments. Participants included adults with postherpetic neuralgia with an average daily pain score (ADPS) of at least 4 on the 11-point Numeric Pain Rating Scale over the preceding week, with the exclusion of patients with pain not controlled by prior therapy with pregabalin (≥300 mg/d) or gabapentin (≥1200 mg/d). Interventions: Patients were randomized 1:1:1 to receive crisugabalin, 20 mg twice daily (ie, 40 mg/d), and crisugabalin, 40 mg twice daily (ie, 80 mg/d), or placebo for 12 weeks. Eligible patients received crisugabalin, 40 mg, twice daily during extension. Main Outcome and Measure: The primary efficacy end point was the change from baseline in ADPS at week 12. Results: The study enrolled 366 patients (121 patients receiving crisugabalin, 40 mg/d; 121 patients receiving crisugabalin, 80 mg/d; 124 patients receiving placebo; median [IQR] age, 63.0 [56.0-69.0] years; 193 men [52.7%]). At week 12, the least squares mean (SD) change from baseline in ADPS was -2.2 (0.2) for crisugabalin, 40 mg/d, and -2.6 (0.2) for crisugabalin, 80 mg/d, vs -1.1 (0.2) for placebo, with a least squares mean difference of -1.1 (95% CI, -1.6 to -0.7; P < .001) and -1.5 (-95% CI, -2.0 to -1.0; P < .001) vs placebo, respectively. No new safety concerns emerged. Conclusions and Relevance: Crisugabalin, 40 mg/d, or crisugabalin, 80 mg/d, was well tolerated and demonstrated a statistically significant improvement in ADPS over placebo. Trial Registration: ClinicalTrials.gov Identifier: NCT05140863.

Machine learning identifies the risk of complications after laparoscopic radical gastrectomy for gastric cancer.

BACKGROUND: Laparoscopic radical gastrectomy is widely used, and perioperative complications have become a highly concerned issue. AIM: To develop a predictive model for complications in laparoscopic radical gastrectomy for gastric cancer to better predict the likelihood of complications in gastric cancer patients within 30 days after surgery, guide perioperative treatment strategies for gastric cancer patients, and prevent serious complications. METHODS: In total, 998 patients who underwent laparoscopic radical gastrectomy for gastric cancer at 16 Chinese medical centers were included in the training group for the complication model, and 398 patients were included in the validation group. The clinicopathological data and 30-d postoperative complications of gastric cancer patients were collected. Three machine learning methods, lasso regression, random forest, and artificial neural networks, were used to construct postoperative complication prediction models for laparoscopic distal gastrectomy and laparoscopic total gastrectomy, and their prediction efficacy and accuracy were evaluated. RESULTS: The constructed complication model, particularly the random forest model, could better predict serious complications in gastric cancer patients undergoing laparoscopic radical gastrectomy. It exhibited stable performance in external validation and is worthy of further promotion in more centers. CONCLUSION: Using the risk factors identified in multicenter datasets, highly sensitive risk prediction models for complications following laparoscopic radical gastrectomy were established. We hope to facilitate the diagnosis and treatment of preoperative and postoperative decision-making by using these models.

Mechanism of action and treatment of type I interferon in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) caused by HBV, HCV infection, and other factors is one of the most common malignancies in the world. Although, percutaneous treatments such as surgery, ethanol injection, radiofrequency ablation, and transcatheter treatments such as arterial chemoembolization are useful for local tumor control, they are not sufficient to improve the prognosis of patients with HCC. External interferon agents that induce interferon-related genes or type I interferon in combination with other drugs can reduce the recurrence rate and improve survival in HCC patients after surgery. Therefore, in this review, we focus on recent advances in the mechanism of action of type I interferons, emerging therapies, and potential therapeutic strategies for the treatment of HCC using IFNs.

Stability and optimal control of a cytokine-enhanced general HIV infection model with antibody immune response and CTLs immune response.

In this article, a cytokine-enhanced viral infection model with cytotoxic T lymphocytes (CTLs) immune response and antibody immune response is proposed and analyzed. The model contains six compartments: uninfected CD4+T cells, infected CD4+T cells, inflammatory cytokines, viruses, CTLs and antibodies. Different from the previous works, this model not only considers virus-to-cell transmission and cell-to-cell transmission, but also includes a new infection mode, namely cytokine-enhanced viral infection. The incidence rates of the healthy CD4+T cells with viruses, infected cells and inflammatory cytokines are given by general functions. Moreover, the production/proliferation and removal/death rates of all compartments are represented by general functions. Firstly, we prove that all the solutions of the model are nonnegative and uniformly bounded. Then, five key parameters with strong biological significance, namely the virus basic reproduction number R0, CTLs immune response reproduction number R1, antibody immune response reproductive number R2, CTLs immune competitive reproductive number R3 and antibody immune competitive reproductive number R4 are derived. Then, by using Lyapunov's method and LaSalle's invariance principle, we have shown the global stability of each equilibrium. In addition, the numerical simulation results also show that the theoretical results are correct. Finally, we formulate an optimal control problem and solve it using Pontryagins Maximum Principle and an efficient iterative numerical methods. The results of our numerical simulation show that it is very important to control the infection between viruses and cells and between cells and inflammatory cytokines for controlling HIV.

Joint Particle Swarm Optimization of Power and Phase Shift for IRS-Aided D2D Underlaying Cellular Systems.

Device-to-device (D2D) communication is a promising wireless communication technology which can effectively reduce the traffic load of the base station and improve the spectral efficiency. The application of intelligent reflective surfaces (IRS) in D2D communication systems can further improve the throughput, but the problem of interference suppression becomes more complex and challenging due to the introduction of new links. Therefore, how to perform effective and low-complexity optimal radio resource allocation is still a problem to be solved in IRS-assisted D2D communication systems. To this end, a low-complexity power and phase shift joint optimization algorithm based on particle swarm optimization is proposed in this paper. First, a multivariable joint optimization problem for the uplink cellular network with IRS-assisted D2D communication is established, where multiple DUEs are allowed to share a CUE's sub-channel. However, the proposed problem considering the joint optimization of power and phase shift, with the objective of maximizing the system sum rate and the constraints of the minimum user signal-to-interference-plus-noise ratio (SINR), is a non-convex non-linear model and is hard to solve. Different from the existing work, instead of decomposing this optimization problem into two sub-problems and optimizing the two variables separately, we jointly optimize them based on Particle Swarm Optimization (PSO). Then, a fitness function with a penalty term is established, and a penalty value priority update scheme is designed for discrete phase shift optimization variables and continuous power optimization variables. Finally, the performance analysis and simulation results show that the proposed algorithm is close to the iterative algorithm in terms of sum rate, but lower in power consumption. In particular, when the number of D2D users is four, the power consumption is reduced by 20%. In addition, compared with PSO and distributed PSO, the sum rate of the proposed algorithm increases by about 10.2% and 38.3%, respectively, when the number of D2D users is four.

TIPE2 deficiency prolongs mouse heart allograft survival by facilitating immature DCs-induced Treg generation.

It has been reported that deletion of tumor necrosis factor-α-induced protein-8 like 2 (TNFAIP8L2, TIPE2) facilitates the activation of T-cell receptors. However, the role of TIPE2 in T-cell-mediated acute transplant rejection remains unclear. To illustrate the underlying cellular mechanisms, we transplanted BALB/c hearts into C57BL/6 wild-type (WT) or C57BL/6 mice deficient for TIPE2 (TIPE2-/-) and found that TIPE2-/- recipient mice showed significantly prolonged survival of heart allografts and suppressed maturation of CD11c+ dendritic cells (DCs), which largely abolished the activation and proliferation of alloreactive T cells and their cytotoxic activity. TIPE2-/- DCs increased CD4+CD25+Foxp3+CD127- regulatory T cells (Tregs)generation, likely by inhibiting DCs maturation and CD80 and CD86 expression. Administration of anti-CD25 abolished the allograft survival induced by TIPE2 deficiency. Moreover, TIPE2 deficiency increased IL-10 production in T cells and in recipient serum and allografts. Mechanistic studies revealed that TIPE2-/- restrained the maturation of DCs via inhibition of PI3K/AKT phosphorylation during alloantigen stimulation. Taken together, TIPE2 deficiency in recipient mice inhibited acute rejection by increasing Tregs generated by immature DCs. Thus, TIPE2 could be a therapeutic target for suppressing rejection in organ transplantation.

EGFR-TKI Combined with Pemetrexed versus EGFR-TKI Monotherapy in Advanced EGFR-mutated NSCLC: A Prospective, Randomized, Exploratory Study.

PURPOSE: We aimed to evaluate whether the addition of pemetrexed is effective in improving progression-free survival (PFS) in epidermal growth factor receptor (EGFR)-mutated patients with or without concomitant alterations. Materials and Methods: This multicenter clinical trial was conducted in China from June 15, 2018, to May 31, 2019. A total of 92 non-small cell lung cancer (NSCLC) patients harboring EGFR-sensitive mutations were included and divided into concomitant and non-concomitant groups. Patients in each group were randomly treated with EGFR-tyrosine kinase inhibitor (TKI) monotherapy or EGFR-TKI combined with pemetrexed in a ratio of 1:1. PFS was recorded as the primary endpoint. RESULTS: The overall median PFS of this cohort was 10.1 months. There were no significant differences in PFS between patients with and without concomitant and between patients received TKI monotherapy and TKI combined with pemetrexed (p=0.210 and p=0.085, respectively). Stratification analysis indicated that patients received TKI monotherapy had a significantly longer PFS in non-concomitant group than that in concomitant group (p=0.002). In concomitant group, patients received TKI combined with pemetrexed had a significantly longer PFS than patients received TKI monotherapy (p=0.013). Molecular dynamic analysis showed rapidly emerging EGFR T790M in patients received TKI monotherapy. EGFR mutation abundance decreased in patients received TKI combined chemotherapy, which supports better efficacy for a TKI combined chemotherapy as compared to TKI monotherapy. A good correlation between therapeutic efficacy and a change in circulating tumor DNA (ctDNA) status was found in 66% of patients, supporting the guiding role of ctDNA minimal residual disease (MRD) in NSCLC treatment. CONCLUSION: EGFR-TKI monotherapy is applicable to EGFR-sensitive patients without concomitant alterations, while a TKI combined chemotherapy is applicable to EGFR-sensitive patients with concomitant alterations. CtDNA MRD may be a potential biomarker for predicting therapeutic efficacy.

Distribution and clinical significance of circulating CD8+CD28- regulatory T cells in the peripheral blood of patients with pulmonary tuberculosis.

BACKGROUND: Regulatory T cells (Treg cells) in the peripheral blood of patients with pulmonary tuberculosis (PTB) may be closely related to the progression of PTB. In this study, the distribution characteristics and clinical importance of CD8+CD28- Treg cells in patients with tuberculosis were systematically analyzed, and the role and importance of CD8+CD28- Treg cells in influencing the immune response and progression of tuberculosis were discussed, which will provide immunological indices and reference values for the clinical diagnosis of tuberculosis. METHODS: Flow cytometry, sputum smears and computed tomography imaging were used to analyze the distribution characteristics of CD8+CD28- Treg cells in the peripheral blood of patients with PTB and the correlation between CD8+CD28-Treg cells and clinical and immune indices. RESULTS: The percentages of CD4+CD25high and CD8+CD28- Treg cells in the peripheral blood of patients with PTB were significantly higher than those in the healthy control (HC) group. Further analysis showed that the percentage of CD4+CD25highTreg cells in the Stage II group was significantly higher than that in the HC group. The percentages of CD4+CD25high and CD8+CD28- Treg cells increased significantly in patients in the Stage II group. The proportion of CD8+CD28- Treg cells was directly proportional to the degree of positivity in sputum smears, while CD4+CD25highTreg cells did not exhibit this trend. The correlations between the percentage of CD4+CD25high and CD8+CD28- Treg cells and the percentage of lymphocyte subsets were examined. The percentage of CD8+CD28- Treg cells was negatively correlated with the percentage of CD4+T cells and positively correlated with the CD8+T cell percentage in the HC and PTB groups. The percentage of CD4 + CD25highTreg cells was positively correlated with the percentage of CD4+T cells only in the PTB group. CONCLUSIONS: This study was the first to show that the proportion of CD8+CD28- Treg cells in the peripheral blood of patients with PTB was significantly increased, and the increase in CD8+CD28- Treg cells was related to the progression of PTB, which may affect the proportion of immune cell subsets by inhibiting the immune response, resulting in the progression of PTB.

Autologous Cytokine-Induced Killer Cell Immunotherapy Enhances Chemotherapy Efficacy against Multidrug-Resistant Tuberculosis.

Objective: Multidrug-resistant tuberculosis (MDR-TB) causes persistent infection and challenges tuberculosis control worldwide. T cell-mediated immunity plays a critical role in controlling Mycobacterium tuberculosis (Mtb) infection, and therefore, enhancing Mtb-specific T cell immune responses represents a promising therapeutic strategy against TB. Cytokine-induced killer (CIK) immunotherapy is based on autologous infusion of in vitro expanded bulk T cells, which include both pathogen-specific and nonspecific T cells from patient peripheral blood mononuclear cells (PBMC) into TB patients. Preclinical mouse studies have shown that the adoptive T cell therapy inhibited Mtb infection. However, the efficacy of CIK immunotherapy in the treatment of MDR-TB infection has not been evaluated in clinical trials. Methods: We performed a retrospective study of MDR-TB patients who received CIK immunotherapy in combination with anti-TB chemotherapy and those who had standard chemotherapy. Results: Our results showed that CIK immunotherapy in combination with anti-TB chemotherapy treatment increased the conversion rate of sputum smear and Mtb culture, alleviated symptoms, improved lesion absorption, and increased recovery. The kinetics of serology and immunology index monitoring data showed good safety profiles for the CIK treatment. Conclusion: Our study has provided strong evidence that CIK immunotherapy in combination with anti-TB chemotherapy is beneficial for MDR-TB patients. A multicenter clinical trial is warranted to evaluate CIK as a new immune therapy for MDR-TB.

PAK3 promotes the metastasis of hepatocellular carcinoma by regulating EMT process.

Purpose: Hepatocellular carcinoma (HCC) is one of the most common malignant tumors. The malignant biological behavior of HCC is closely related to epithelial-mesenchymal transition (EMT), and EMT plays an important role in the progression, migration and metastasis of HCC. P21-activated kinase 3 (PAK3) is a serine/threonine protein kinase, and PAK3 affects the EMT, proliferation, metastasis and invasion of HCC. Methods: In this study, the relationship between PAK3 and HCC was first analyzed by bioinformatics, and then, the expression of PAK3 in clinical samples was detected by immunohistochemistry (IHC), quantitative real-time PCR (qRT-PCR) and Western blotting. Subsequently, the expression of PAK3 was further confirmed in HCC cells. In addition, after the overexpression or knockdown of PAK3 in cells, the proliferation, migration and invasion abilities of these cells were assessed by Cell Counting Kit-8 (CCK-8), wound healing and Transwell assays, and the results were confirmed in vivo experiments in mice. In addition, we also verified that PAK3 affected the EMT and EMT-related pathway of HCC through qRT-PCR, Western blotting and immunofluorescence experiments. Results: Through database analysis, we found that PAK3 was highly expressed in HCC patients and was positively correlated with tumor stage and grade, suggesting that PAK3 expression was closely related to HCC occurrence and development. We subsequently confirmed that PAK3 was overexpressed in HCC clinical samples and HCC cell lines and that PAK3 promoted the proliferation, migration and invasion of HCC cells in vitro. Finally, we found that PAK3 regulated EMT-related molecule expression and EMT-related TGF-ß/smad signaling pathway. Conclusion: High expression of PAK3 enhances the invasion of HCC and regulates EMT, suggesting that PAK3 may be a potential target for the treatment of HCC.

Identification of crucial genes of pyrimidine metabolism as biomarkers for gastric cancer prognosis.

BACKGROUND: Metabolic reprogramming has been reported in various kinds of cancers and is related to clinical prognosis, but the prognostic role of pyrimidine metabolism in gastric cancer (GC) remains unclear. METHODS: Here, we employed DEG analysis to detect the differentially expressed genes (DEGs) in pyrimidine metabolic signaling pathway and used univariate Cox analysis, Lasso-penalizes Cox regression analysis, Kaplan-Meier survival analysis, univariate and multivariate Cox regression analysis to explore their prognostic roles in GC. The DEGs were experimentally validated in GC cells and clinical samples by quantitative real-time PCR. RESULTS: Through DEG analysis, we found NT5E, DPYS and UPP1 these three genes are highly expressed in GC. This conclusion has also been verified in GC cells and clinical samples. A prognostic risk model was established according to these three DEGs by Univariate Cox analysis and Lasso-penalizes Cox regression analysis. Kaplan-Meier survival analysis suggested that patient cohorts with high risk score undertook a lower overall survival rate than those with low risk score. Stratified survival analysis, Univariate and multivariate Cox regression analysis of this model confirmed that it is a reliable and independent clinical factor. Therefore, we made nomograms to visually depict the survival rate of GC patients according to some important clinical factors including our risk model. CONCLUSION: In a word, our research found that pyrimidine metabolism is dysregulated in GC and established a prognostic model of GC based on genes differentially expressed in pyrimidine metabolism.

Upregulation of PD-1 expression on circulating CD8+ but not CD4+ T cells is associated with tuberculosis infection in health care workers.

BACKGROUND: Health care workers (HCWs) are at risk for occupationally acquired Mycobacterium tuberculosis infection and tuberculosis (TB) disease due to repeated exposure to workplace tubercle bacilli. To determine whether continual mycobacterial stimulation correlates with increased expression of inhibitory T cell receptors, here we compared PD-1 receptor expression on surfaces of circulating T cells between naïve (uninfected) HCWs and HCWs with latent TB infection (LTBI). RESULT: Data collected from 133 medical workers who met study selection criteria were included in the final analysis. QuantiFERON-TB Gold In-​Tube (QFT-GIT) testing yielded positive results for 32 HCWs, for an overall LTBI rate of 24.1%. Multivariate analysis identified HCW length of service > 15 years as an independent risk factor for a positive QFT-GIT result. In addition, comparisons of blood T cell subgroup profiles between QFT- and QFT+ groups indicated QFT+ subjects possessed greater proportions of mature (TM), transitional memory (TTM) and effector memory (TEM) CD4+ T cell subgroups and lower proportions of naïve T cells (TN). Moreover, the QFT+ group percentage of CD8+ T cells with detectable surface PD-1 was significantly higher than the corresponding percentage for the QFT- group. Meanwhile, no statistical intergroup difference was observed in percentages of CD4+ T cells with detectible surface PD-1. CONCLUSIONS: Our data demonstrated that upregulated PD-1 expression on circulating CD8+, but not CD4+ T cells, was associated with latent TB infection of HCWs. As compared to other hospitals, occupational TB infection risk in our hospital was substantially mitigated by implementation of multitiered infection control measures.

Repurposing of camptothecin: An esterase-activatable prodrug delivered by a self-emulsifying formulation that improves efficacy in colorectal cancer.

The global burden of colorectal cancer (CRC), the third most commonly diagnosed malignancy, continues to rise. Therefore, more effective and less toxic therapies are needed for CRC. CPT-11 (also called irinotecan), the standard-of-care treatment for CRC, has only had limited effects on survival outcomes. In vivo, CPT-11 must be converted to an active metabolite, SN38, to exert antitumor activity in the presence of carboxylesterases, but the conversion rate is extremely low (usually less than 8%). To fully harness the active SN38 compound, we showed here that esterification of SN38 using α-linolenic acid (LNA) generated a prodrug (termed LSN38), which can be formulated in pharmaceutically acceptable surfactants, such as polysorbate 80. Upon blending with an aqueous ethanolic solution, the mixture of LSN38/polysorbate 80 formed self-emulsifying nanomicelles (termed LSN38 NMs), enabling systemic injection. Unlike the insufficient release of active SN38 from CPT-11, drug activation from the LSN38 prodrug was quantitative and relied on esterase, which is abundant in cancerous cells. Pharmacokinetics studies revealed that polysorbate 80-based nanomicelles stably constrained the prodrug in the reservoir and prolonged blood circulation compared to CPT-11. Furthermore, LSN38 NMs showed superior therapeutic efficacy against a colorectal xenograft-bearing mouse model that failed to be treated with clinically approved CPT-11. Overall, these studies highlight the feasibility of converting a chemotherapeutic agent that is not miscible or compatible with pharmaceutical surfactants into an injectable self-emulsifying formulation. This approach could be applied to rescue other drugs or drug candidates that are abandoned in the preclinical stages due to pharmaceutical challenges.

Supramolecular nanoparticles self-assembled from reduction-responsive cabazitaxel prodrugs for effective cancer therapy.

Using hydrophobic cabazitaxel as a target anticancer drug, we show that the conjugation of oligo(ethylene glycol)-oligolactide (OEG-OLA) via a self-immolative linkage induces the self-assembly of the resulting prodrug into injectable nanoparticles. The nanoparticles release chemically unmodified cabazitaxel after endocytosis in cancer cells. With the optimal conjugate, the nanotherapy not only potently induces tumor regression but also has a higher safety margin in animals than the free drug administered in its clinical formulation. Our studies highlight the design rationale that attaching a short amphiphilic oligomer to a toxic drug can convert it to a self-deliverable and safe nanotherapy.

Microbial Community Profiling Distinguishes Left-Sided and Right-Sided Colon Cancer.

The difference between left- and right-sided colon cancer has become the focus of global attention, and researchers have found differences in the morbidity, molecular biological characteristics, and response to targeted drug therapy between left- and right-sided colon cancer. Therefore, the identification of more effective predictive indicators is critical for providing guidance to future clinical work. We collected samples from different colon sites and regions and analyzed the identities and distributions of differentially expressed species in the microbiota in the left and right sides of the colon to better explore the pathogenesis of colon cancer and provided a basis for individualized drug therapy. We collected samples from different regions in the body of 40 patients with colon cancer, including stool and tissues. The Subjects were classified into four groups, and this classification was mainly based on the colon cancer distribution. The microbiota composition of the left-sided and right-sided colon samples was assessed by specifically amplifying the V3-V4 region of the 16S rDNA gene from DNA extracts from the samples. These amplicons were examined by Illumina HiSeq 2500 sequencing. The microbial taxa in the left-sided colon samples are more abundant than those in the right-sided colon samples. The flora in the left-sided colon samples, such as Clostridium perfringens and Fusobacterium nucleatum, might be associated with VEGF expression and are more likely to promote colon cancer. The microbiota distribution in the right-sided colon samples is less invasive and harmful and particularly rich in Bifidobacterium dentium. In addition, Streptococcus, which is the target of EGFR, was found to be expressed in both the left- and right-sided colon samples but was found at a higher level in the left-sided colon samples. Additionally, the differential pathways involved in the left-sided colon samples mainly mediate DNA damage, methylation, and histone modifications, whereas those in the right-sided colon samples are dominated by DNA synthesis. The comparison of only the geographical differences revealed a significant difference in the distribution of the microbial population. The adherent microbiota composition and structural changes between the left- and right-sided colon samples might contribute to the development of colon cancer, lead to different morbidities, and further affect the prognosis of patients and their sensitivity to targeted drugs. Therefore, the identification of the differential flora in the colon could be used as an indicator for predicting the occurrence and development of colon cancer, which is also beneficial for future individualized drug therapy.

Clinical characteristics and laboratory indicator analysis of 67 COVID-19 pneumonia patients in Suzhou, China.

BACKGROUND: Sudden exacerbations and respiratory failure are major causes of death in patients with severe coronavirus disease 2019(COVID-19) pneumonia, but indicators for the prediction and treatment of severe patients are still lacking. METHODS: A retrospective analysis of 67 collected cases was conducted and included approximately 67 patients with COVID-19 pneumonia who were admitted to the Suzhou Fifth People's Hospital from January 1, 2020 to February 8, 2020. The epidemiological, clinical and imaging characteristics as well as laboratory data of the 67 patients were analyzed. RESULTS: The study found that fibrinogen (FIB) was increased in 45 (65.2%) patients, and when FIB reached a critical value of 4.805 g/L, the sensitivity and specificity、DA, helping to distinguish general and severe cases, were 100 and 14%、92.9%, respectively, which were significantly better than those for lymphocyte count and myoglobin. Chest CT images indicated that the cumulative number of lung lobes with lesions in severe patients was significantly higher than that in general patients (P < 0.05), and the cumulative number of lung lobes with lesions was negatively correlated with lymphocyte count and positively correlated with myoglobin and FIB. Our study also found that there was no obvious effect of hormone therapy in patients with severe COVID-19. CONCLUSIONS: Based on the retrospective analysis, FIB was found to be increased in severe patients and was better than lymphocyte count and myoglobin in distinguishing general and severe patients. The study also suggested that hormone treatment has no significant effect on COVID-19.

Clinical metagenomic sequencing for diagnosis of pulmonary tuberculosis.

OBJECTIVES: The aim of this study is to investigate the clinical usefulness of metagenomic Next-generation sequencing (mNGS) on bronchoalveolar lavage fluid (BALF) samples to discriminate pulmonary tuberculosis (PTB) from Non-TB community-acquired pneumonia (CAP) in PTB suspects. METHODS: We investigate the performance of mNGS on BALF samples from 110 PTB suspects, in comparison with conventional microbiological testing (solid media culture, acid-fast bacilli staining (AFS), Xpert) of BALF or sputum samples and final clinical diagnosis. RESULTS: We finally clinically diagnosed 48 cases of pulmonary tuberculosis patients and 62 cases of non-tuberculosis patients. Comparing to the final clinical diagnosis, mNGS produced a sensitivity of 47.92%, which was similar to that of Xpert (45.83%) and culture (46.81%), but much higher than that of AFS (29.17%) for TB diagnosis in BALF samples. Apart from detecting Mycobacterium tuberculosis, mNGS also identified mixed infections in PTB patients, including 3 fungal cases and 1 bacteria case. Meanwhile, mNGS efficiently identified 14 of 22 (63.63%) cases of non-tuberculous mycobacteria (NTM), 7 cases of fungi, 1 case of viral infection, and other common bacterial pathogens in Non-PTB group. Finally, mNGS identified 67.23% infection cases within 3 days, while the conventional methods identified 49.58% infection cases for over 90 days. CONCLUSION: Our data show that mNGS of BALF represents a potentially effective tool for the rapid diagnosis of PTB suspects.

Niacin-ligated platinum(iv)-ruthenium(ii) chimeric complexes synergistically suppress tumor metastasis and growth with potentially reduced toxicity in vivo.

Niacin-ligated platinum(iv)-ruthenium(ii) chimeric complexes (PtRu 1-4) have been synthesized and evaluated for their antitumor performance. Using the optimal complex, PtRu-1, we show that this water-soluble chimeric prodrug not only potently inhibits the metastasis and proliferation of tumor cells but also has an unexpectedly higher safety margin in animals compared with the traditionally-used, clinically approved drug cisplatin.

A Method Framework for Automatic Airspace Reconfiguration-Monte Carlo Method for Eliminating Irregular Sector Shapes Generated by Region Growth Method.

With the growth of air traffic demand in busy airspace, there is an urgent need for airspace sectorization to increase air traffic throughput and ease the pressure on controllers. The purpose of this paper is to develop a method framework that can perform airspace sectorization automatically, reasonably, which can be used as an advisory tool for controllers as an automatic system, especially for eliminating irregular sector shapes generated by simulated annealing algorithm (SAA) based on the region growth method. The two graph cutting method, dynamic Monte Carlo method by changing location of flexible vertices (MC-CLFV) and Monte Carlo method by radius changing (MC-RC) were developed to eliminate irregular sector shapes generated by SAA in post-processing. The experimental results show that the proposed method framework of airspace sectorization (AS) can automatically and reasonably generate sector design schemes that meet the design criteria. Our methodology framework and software can provide assistant design and analysis tools for airspace planners to design airspace, improve the reliability and efficiency of airspace design, and reduce the burden of airspace planners. In addition, this lays the foundation for reconstructing airspace with the more intelligent method.

Dual-Specificity Tyrosine Phosphorylation-Regulated Kinase 3 Loss Activates Purine Metabolism and Promotes Hepatocellular Carcinoma Progression.

Cancer cells metabolize different energy sources to generate biomass rapidly. The purine biosynthetic pathway was recently identified as an important source of metabolic intermediates for these processes. However, very little was known about the regulatory mechanisms of purine metabolism in hepatocellular carcinoma (HCC). We explored the role of dual-specificity tyrosine (Y) phosphorylation-regulated kinase 3 (Dyrk3) in HCC metabolism. Dyrk3 was significantly down-regulated in HCC compared with normal controls. Its introduction in HCC cells markedly suppressed tumor growth and metastasis in xenograft tumor models. Mass spectrometric analysis of metabolites suggests that the effect of Dyrk3 on HCC occurred at least partially through down-regulating purine metabolism, as evidenced by the fact that inhibiting purine synthesis reverted the HCC progression mediated by the loss of Dyrk3. We further provide evidence that this action of Dyrk3 knockdown requires nuclear receptor coactivator 3 (NCOA3), which has been shown to be a coactivator of activating transcription factor 4 (ATF4) to target purine pathway genes for transcriptional activation. Mechanistically, Dyrk3 directly phosphorylated NCOA3 at Ser-1330, disrupting its binding to ATF4 and thereby causing the inhibition of ATF4 transcriptional activity. However, the phosphorylation-resistant NCOA3-S1330A mutant has the opposite effect. Interestingly, the promoter activity of Dyrk3 was negatively regulated by ATF4, indicating a double-negative feedback loop. Importantly, levels of Dyrk3 and phospho-NCOA3-S1330 inversely correlate with the expression of ATF4 in human HCC specimens. Conclusion: Our findings not only illustrate a function of Dyrk3 in reprograming HCC metabolism by negatively regulating NCOA3/ATF4 transcription factor complex but also identify NCOA3 as a phosphorylation substrate of Dyrk3, suggesting the Dyrk3/NCOA3/ATF4 axis as a potential candidate for HCC therapy.