Expert Consensus on the Application of Stem Cells in Psoriasis Research and Clinical Trials.

Psoriasis is an immune-mediated, chronic, relapsing, inflammatory, systemic disease induced by individual-environmental interactions, and is often lifelong because of the difficulty of treatment. In recent years, a variety of targeted therapies, including biologics, have improved the lesions and quality of life of most psoriasis patients, but they still do not address the problem of relapse and may be associated with decreased efficacy or adverse events such as infections over time. Therefore, there is an urgent need for breakthroughs in psoriasis treatment and in relapse-delaying and non-pharmacologic strategies, and stem cell therapy for psoriasis has emerged. In recent years, research on stem cell therapy for psoriasis has received a lot of attention, however, there is no reference standard as well as consensus in this field of research. Therefore, according to the latest consensus and guidelines, combined with relevant literature reports, clinical practice experience and the results of discussions with experts, this consensus specifies the types of stem cells commonly used in the treatment of psoriasis, the methods, dosages, and routes of stem cell therapy for psoriasis, as well as the clinical evaluations (efficacy and safety) of stem cell therapy for psoriasis. In addition, this consensus also provides normative standards for the processes of collection, preparation, preservation and quality control of stem cells and their related products, as well as recommendations for the management of stem cells during infusion for the treatment of psoriasis. This consensus provides the latest specific reference standards and practice guidelines for the field of stem cell therapy for psoriasis.

Role of rs873601 Polymorphisms in Prognosis of Lung Cancer Patients Treated with Platinum-Based Chemotherapy.

BACKGROUND: Lung cancer is still the most lethal malignancy in the world, according to the report of Cancer Statistics in 2021. Platinum-based chemotherapy combined with immunotherapy is the first-line treatment in lung cancer patients. However, the 5-year survival rate is always affected by the adverse reactions and drug resistance caused by platinum-based chemotherapy. DNA damage and repair system is one of the important mechanisms that can affect the response to chemotherapy and clinical outcomes in lung cancer patients. OBJECTIVE: The objective of this study is to find the relationship between the polymorphisms of DNA repair genes with the prognosis of platinum-based chemotherapy in lung cancer patients. PATIENTS AND METHODS: We performed genotyping in 17 single nucleotide polymorphisms (SNPs) of Excision Repair Cross-Complementation group (ERCC) genes and X-ray Repair Cross-Complementing (XRCC) genes of 345 lung cancer patients via Sequenom MassARRAY. We used Cox proportional hazard models, state, and plink to analyze the associations between SNPs and the prognosis of lung cancer patients. RESULTS: We found that the ERCC5 rs873601 was associated with the overall survival time in lung cancer patients treated with platinum-based chemotherapy (p = 0.031). There were some polymorphisms that were related to the prognosis in specific subgroups of lung cancer. Rs873601 showed a great influence on the prognosis of patients more than 55 years, Small Cell Lung Cancer (SCLC), and smoking patients. Rs2444933 was associated with prognosis in age less than 55 years, SCLC, metastasis, and stage III/IV/ED patients. Rs3740051 played an important role in the prognosis of SCLC and metastasis patients. Rs1869641 was involved in the prognosis of SCLC patients. Rs1051685 was related to the prognosis in non-metastasis patients. CONCLUSION: The ERCC5 rs873601 (G>A) was a valuable biomarker for predicting the prognosis in lung cancer patients treated with platinum-based chemotherapy.

Safety, tolerability, pharmacokinetics and effects of diet on AD16, a novel neuroinflammatory inhibitor for Alzheimer's disease: a randomized phase 1 study.

BACKGROUND: AD16 is a Class 1.1 new drug candidate for Alzheimer's disease (AD), which has demonstrated potential benefits in AD by reducing neuroinflammation in preclinical studies. Herein, the pharmacokinetics (PK), safety, and tolerability of single and multiple-dose AD16 and the effect of food were assessed in healthy Chinese adults. METHODS: Single-center, randomized, placebo-controlled, double-blind studies were conducted for single and multiple ascending doses. A total of 62 subjects were enrolled in single-dose groups; 10 each in 5, 10, 20, 30, and 40 mg groups, and 6 each in 60 and 80 mg dose groups. Twenty subjects were divided equally into 30 and 40 mg groups for the multiple-dose study. To determine the effect of a high-fat diet on AD16, 16 subjects were administered a single 20 mg dose of AD16 under the fasted and fed condition in a single-center, randomized, open-label, two-cycle, two-crossover study. Moreover, safety and PK parameters were also assessed. RESULTS: Plasma exposure to a single oral dose of AD16 increased at an approximate dose-increasing rate. The pharmacodynamic dose of the AD16 can be maintained through the accumulation effect of the drug within the safety window. Compared to fasting, ingesting a high-fat meal decelerated the rate of AD16 absorption, albeit without effect on its overall absorption. No dose-related toxicities were seen in any of the studies, all treatment-emergent adverse events were grade I/II, and no serious adverse event occurred. CONCLUSIONS: The present study exhibited favorable safety, tolerability, and PK profile of AD16, supporting its further research as a potential drug treatment for AD. TRIAL REGISTRATION: ClinicalTrials.gov; NCT05787028, NCT05787041, NCT05806177. The SAD and FE studies were retrospectively registered on 28 March 2023. The MAD study was retrospectively registered on 10 April 2023.

The prevention and treatment of COVID-19 in patients treated with hemodialysis.

Patients treated with hemodialysis are often immunocompromised due to concomitant disease. As a result, this population is at high risk of infection and mortality from COVID-19. In addition to symptomatic treatment, a series of antiviral drugs targeting COVID-19 are now emerging. However, these antivirals are used mainly in mild or moderate patients with high-risk factors for progression to severe disease and are not available as pre- or post-exposure prophylaxis for COVID-19. There is a lack of clinical data on the use of anti-COVID-19 drugs, especially in patients treated with hemodialysis, therefore, vaccination remains the main measure to prevent SARS-CoV-2 infection in these patients. Here, we review the clinical features and prognosis of patients on hemodialysis infected with SARS-CoV-2, the main anti-COVID-19 drugs currently available for clinical use, and the safety and efficacy of anti-COVID-19 drugs or COVID-19 vaccination in patients treated with hemodialysis. This information will provide a reference for the treatment and vaccination of COVID-19 in patients treated with hemodialysis and maximize the health benefits of these patients during the outbreak.

Multiple doses of SHR-1222, a sclerostin monoclonal antibody, in postmenopausal women with osteoporosis: A randomized, double-blind, placebo-controlled, dose-escalation phase 1 trial.

SHR-1222, a novel humanized monoclonal antibody targeting sclerostin, has been shown to induce bone formation and decrease bone resorption at a single dose ranging 50-400 mg in our previous phase 1 trial. This study was a randomized, double-blind, placebo-controlled, dose-escalation phase 1 trial, which further investigated the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity of multiple ascending doses of SHR-1222 in women with postmenopausal osteoporosis (POP). A total of 105 women with POP were enrolled and randomly assigned. Twenty-one received placebo and eighty-four received SHR-1222 sequentially (100 mg QM, n=4; 200 or 300 mg QM, n=20; and 400 or 600 mg Q2M, n=20). The most common adverse events included increased blood parathyroid hormone, increased low-density lipoprotein, increased blood alkaline phosphatase, increased blood cholesterol, back pain, and arthralgia, the majority of which were mild in severity without noticeable safety concerns. Serum SHR-1222 exposure (Cmax,ss and AUC0-tau,ss) increased in a greater than dose-proportional manner. Following multiple doses of SHR-1222, the bone formation markers (terminal propeptide of type I procollagen, bone-specific alkaline phosphatase, and osteocalcin) increased in a dose-dependent manner, whereas the bone resorption marker (ß-C-telopeptide) was downregulated. Accordingly, BMD gains in the lumbar spine, total hip, and femoral neck were observed. The maximum BMD increase from baseline at the lumbar spine was detected in the 300 mg QM cohort (14.6% vs. 0.6% in the placebo group on day 169). Six (6/83; 7.2%) subjects developed anti-SHR-1222 antibodies with no discernible effects on PKs, PDs, and safety. Thus, multiple doses of SHR-1222 showed an acceptable safety profile and dose-dependent plasma exposure in women with POP, and could improve their BMD rapidly and prominently by promoting bone formation and inhibiting bone resorption. These findings further support SHR-1222 as a potential alternative agent for the treatment of POP.

Integrated Microbiome and Metabolomic Analysis Reveal Responses of Rhizosphere Bacterial Communities and Root exudate Composition to Drought and Genotype in Rice (Oryza sativa L.).

BACKGROUND: As climate change events become more frequent, drought is an increasing threat to agricultural production and food security. Crop rhizosphere microbiome and root exudates are critical regulators for drought adaptation, yet our understanding on the rhizosphere bacterial communities and root exudate composition as affected by drought stress is far from complete. In this study, we performed 16S rRNA gene amplicon sequencing and widely targeted metabolomic analysis of rhizosphere soil and root exudates from two contrasting rice genotypes (Nipponbare and Luodao 998) exposed to drought stress. RESULTS: A reduction in plant phenotypes was observed under drought, and the inhibition was greater for roots than for shoots. Additionally, drought exerted a negligible effect on the alpha diversity of rhizosphere bacterial communities, but obviously altered their composition. In particular, drought led to a significant enrichment of Actinobacteria but a decrease in Firmicutes. We also found that abscisic acid in root exudates was clearly higher under drought, whereas lower jasmonic acid and L-cystine concentrations. As for plant genotypes, variations in plant traits of the drought-tolerant genotype Luodao 998 after drought were smaller than those of Nipponbare. Interestingly, drought triggered an increase in Bacillus, as well as an upregulation of most organic acids and a downregulation of all amino acids in Luodao 998. Notably, both Procrustes analysis and Mantel test demonstrated that rhizosphere microbiome and root exudate metabolomic profiles were highly correlated. A number of differentially abundant genera responded to drought and genotype, including Streptomyces, Bacillus and some members of Actinobacteria, were significantly associated with organic acid and amino acid contents in root exudates. Further soil incubation experiments showed that Streptomyces was regulated by abscisic acid and jasmonic acid under drought. CONCLUSIONS: Our results reveal that both drought and genotype drive changes in the compositions of rice rhizosphere bacterial communities and root exudates under the greenhouse condition, and that organic acid exudation and suppression of amino acid exudation to select specific rhizosphere bacterial communities may be an important strategy for rice to cope with drought. These findings have important implications for improving the adaptability of rice to drought from the perspective of plant-microbe interactions.

Pharmacokinetics, bioequivalence and safety of two formulations of ticagrelor in healthy Chinese subjects: Effects of food.

Ticagrelor is the first reversible ADP P2Y12 receptor antagonist approved to treat acute coronary syndrome. To investigate the effects of food on the pharmacokinetics (PK), bioequivalence and safety of ticagrelor tablets in healthy Chinese volunteers, 32 healthy subjects were randomly assigned to an open-labelled, single-centre, two-preparation, two-sequence, two-cycle, double-crossover trial under fasting and fed conditions, with a washout period of 7 days. Plasma concentrations of ticagrelor and AR-C124910XX were determined using LC-MS/MS. The Cmax , AUC0-t and AUC0-∞ of the reference and test tablets were determined using ANOVA and the USFDA bioequivalence statistical criterion of 90% CI for the 80%-125% range (p ≤ 0.05) of the geometric mean ratios. Adverse events (AEs) were observed and recorded. Food consumption increased the AUC0-t and AUC0-∞ (p < 0.01) of ticagrelor, lowered the Cmax (p < 0.01) and prolonged the t12z (p < 0.05) of AR-C124910XX. The effects of food on the reference preparations were comparable. Formulation, time and sequence had no significant effects on the PK parameters (p â‰§ 0.05). The test formulation was bioequivalent to the reference formulation as the geometric mean ratios under fasting and fed conditions were within equivalence limits (80%-125%). No serious AEs were reported. Thus, test and reference ticagrelor are bioequivalent in Chinese subjects under fasting and fed conditions.

Safety and efficacy of compound methyl salicylate liniment for topical pain: A multicenter real-world study in China.

Compound methyl salicylate liniment (Ammeltz) is composed of various components, such as methyl salicylate, menthol, camphor, chlorpheniramine maleate, and thymol. It was approved for listing in China in 2011. The purpose of this phase Ⅳ clinical trial was to evaluate the safety and efficacy of Ammeltz in a real-life environment in China. Adverse events and adverse drug reactions were used to assess the safety of the monitored drugs. Visual analog scale (VAS) scores were evaluated to assess the severity of pain and the pain relief rate was used to evaluate the efficacy of the study drug. Of 3,600 subjects enrolled, 3,515 (97.64%) subjects completed the study and 85 (2.36%) terminated the study prematurely. A total of 277 adverse events occurred in 258 subjects (7.28%). The most common adverse events included upper respiratory infections (130 cases, 3.67%), local pruritus (17 cases, 0.48%), and diarrhea (12 cases, 0.34%). A total of 50 (1.41%) subjects experienced 58 adverse drug reactions. The most common adverse drug reactions included local pruritus (17 cases, 0.48%), a burning sensation at the application site (10 cases, 0.28%), and irritation at the application site (local) (7 cases, 0.2%). No adverse reactions were identified as new adverse drug reactions. The majority of adverse drug reactions were mild (48 cases, 1.36%), and no severe adverse drug reactions occurred. The subjects experienced significant pain relief after using Ammeltz (mean VAS scores: 5.34 vs. 2.79; Day 7 ± 1 vs. Baseline; p < 0.0001). The pain relief rate was 47.11% ± 23.13%, and in 2,769 cases (78.31%) the drug was effective in pain relief. After excluding subjects who used drugs that could affect the efficacy of the study drug, the subgroups of subjects experienced significant pain relief after using Ammeltz (mean VAS scores: 5.31 vs 2.77; Day 7 ± 1 vs Baseline; p < 0.0001). The pain relief rate was 47.34% ± 23.00%, and 2,612 subjects (78.75%) experienced effective pain relief. In conclusion, Ammeltz is safe and effective in real-life use. It can significantly relieve soft tissue pain caused by shoulder and neck pain, back pain, or muscle pain. No new adverse drug reactions were found in our multicenter real-world study. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT05489939?cond=Safety+and+efficacy+of+compound+methyl+salicylate+liniment+for+topical+pain%3A+A+multicenter+real-world+study+in+China&draw=2&rank=1, identifier NCT05489939.

Trastuzumab deruxtecan versus chemotherapy for patients with HER2-low advanced breast cancer: A US-based cost-effectiveness analysis.

Background: In recent years, the rise of antibody-drug conjugates (ADCs) has changed the treatment paradigm for patients with HER2-low advanced breast cancer (ABC). DESTINY-Breast04 (NCT03734029) has demonstrated the antitumor activity of trastuzumab deruxtecan (T-DXd). However, the balance between the efficacy and cost of T-DXd remains undefined. Consequently, there is a great need to assess the cost-effectiveness of T-DXd for patients with HER2-low ABC when compared with chemotherapy. Methods: A Markov decision-analytic model with a time horizon of 15 years was employed to estimate the costs and clinical efficacy of trials with the administration of T-DXd in contrast to chemotherapy alone as a later-line therapy in a group of patients with hormone receptor-positive (HR+) or negative (HR-) HER2-low ABC. The US payer perspective was taken into account when factors such as medical lifetime expenditure, incremental cost-effectiveness ratios (ICERs), and quality-adjusted life years (QALYs) were calculated. Sensitivity analyses were used to determine the model's stability. A subgroup analysis was also conducted on the HR+/HER2-low cohort. Results: T-DXd was associated with an improvement of 0.543, 0.558, and 0.789 QALYs when compared with treatment with chemotherapy for overall, HR+, and HR- HER2-low patients, respectively. However, incorporating T-DXd into later-line therapy led to increased costs ($161,406, $177,907, and $155,757), which causes the ICER for T-DXd to be $296,873, $318,944, and $197,355 per QALY. The cost of T-DXd and the patient's weight were the most influential factors for ICER. T-DXd being the dominant strategy is about 1.5%, 0.5%, and 28.0% in overall, HR+, and HR- HER2-low ABC patients, respectively. In addition, the T-DXd regimen was not cost-effective in all subgroups. Conclusion: Compared with chemotherapy, T-DXd was not cost-effective for patients with HER2-low ABC in the United States. However, it can provide more health benefits to patients with HR+/HER2-low ABC.

Survey on status quo and development needs of research and innovation capabilities of young researchers at university-affiliated hospitals in China: a cross-sectional survey.

Background: Researches in China on the innovation ability and development needs of young scientific research talents is not enough. The survey is aimed to shed light on the status quo, problems, and development needs of research and innovation capabilities among young researchers in terms of orientation, innovation atmosphere, platform support, training mechanisms, and training measures. Methods: From January to March 2022, a randomly-selected method was used to conduct a web-based self-made questionnaire survey on young talents in 6 university affiliated hospitals in 5 provinces in China. Intergroup comparisons were based on the chi-square test or Fisher' exact test. Results: Overall, 586 usable responses had been collected, including 233 from full-time researchers and 353 from part-time researchers. 182 (31.06%) researchers believe that they have the ability to master innovative theories, tools and methods, 136 (23.21%) researchers choose "working alone". Compared with part-time research talents, the proportion of full-time research talents self-assessed as "very good" in scientific research innovation ability is higher (χ2=17.048, P<0.001). Full-time researchers had less knowledge about the relevant policies at their affiliation (χ2=3.190, P=0.074), were more likely to believe that the "talent management system" had a greater impact (χ2=4.906, P=0.027), and had higher expectations of "multiple incentive mechanisms" (χ2=10.312, P=0.001). In contrast, the proportion of part-time researchers who hoped that their affiliation would take measures such as "increasing financial investment" (χ2=9.049, P=0.003) and "strengthening external supports" (χ2=8.383, P=0.004) was significantly higher. Conclusions: Full-time and part-time scientific researchers have different requirements for capital investment, support for scientific research platforms, leadership demonstrations by senior peers, and a good atmosphere for scientific and technological innovation. Thus, it is important to promote innovation capacity-building among young researchers at university-affiliated hospitals (UAHs) by enhancing both talent training and introduction in a hierarchical, classified, multidimensional, and stepwise manner.

Human umbilical cord mesenchymal stem cells for psoriasis: a phase 1/2a, single-arm study.

Psoriasis is a common, chronic immune-mediated systemic disease that had no effective and durable treatment. Mesenchymal stem cells (MSCs) have immunomodulatory properties. Therefore, we performed a phase 1/2a, single-arm clinical trial to evaluate the safety and efficacy of human umbilical cord-derived MSCs (UMSCs) in the treatment of psoriasis and to preliminarily explore the possible mechanisms. Seventeen patients with psoriasis were enrolled and received UMSC infusions. Adverse events, laboratory parameters, PASI, and PGA were analyzed. We did not observe obvious side effects during the treatment and 6-month follow-up. A total of 47.1% (8/17) of the psoriasis patients had at least 40% improvement in the PASI score, and 17.6% (3/17) had no sign of disease or minimal disease based on the PGA score. And the efficiency was 25% (2/8) for males and 66.7% (6/9) for females. After UMSC transplantation (UMSCT), the frequencies of Tregs and CD4+ memory T cells were significantly increased, and the frequencies of T helper (Th) 17 and CD4+ naive T cells were significantly decreased in peripheral blood (PB) of psoriasis patients. And all responders showed significant increases in Tregs and CD4+ memory T cells, and significant decreases in Th17 cells and serum IL-17 level after UMSCT. And baseline level of Tregs in responders were significantly lower than those in nonresponders. In conclusion, allogeneic UMSCT is safe and partially effective in psoriasis patients, and level of Tregs may be used as a potent biomarker to predict the clinical efficacy of UMSCT. Trial registration Clinical Trials NCT03765957.

Influencing factors of and multiple paths to high performance in multidisciplinary scientific research cooperation in colleges in China: a fuzzy-set qualitative comparative analysis.

Background: In the context of globalization of science and technology, multidisciplinary cooperation plays an important role in enhancing national scientific research strength. Many countries issue policies and reports to promote the implementation of interdisciplinary research. Colleges play a central role in knowledge generation and scientific inquiry and thus frequently contain a variety of scientific research organizations. With rapid advances in science, large-scale scientific research cooperation across disciplines and institutions is increasingly common. Many factors can affect the performance of research collaboration, and the implementation paths of some key factors remain unclear. In addition, no standardized collaboration system has been established in relevant research. Further studies on interdisciplinary scientific research cooperation will be particularly valuable for improving the efficiency of resource allocation and increasing the level of academic research. Here we explored the "joint effect" of various influencing factors on interdisciplinary collaborative research in colleges and the "interactions" among these factors. Methods: With stratified-cluster random sampling, 358 researchers from 181 research teams at 6 colleges across China were surveyed using a self-administered questionnaire. We used fuzzy-set qualitative comparative analysis (fsQCA) to analyze data to obtain more insight into the status quo of interdisciplinary cooperation among colleges. Results: The results showed that initiation and organization by an institution was a necessary condition for achieving high-performance scientific research collaboration. The performance incentive method of high-tech collaboration could be divided into four main paths: configuration organized by an institution; configuration organized by an institution, with high policy-based guarantees (PG); configuration organized by an institution, with high cooperation willingness (CW) and high cooperation ability (CA); and configuration organized by an institution, with high CW, abilities, and outputs. The drive mechanism of high performance in scientific cooperation could be divided into two types: organization-led and ability/willingness-driven. Conclusions: Only the integration of internal changes with the support of the external environment can ensure the stable development of multidisciplinary scientific research cooperation among colleges.

Serplulimab plus chemotherapy as first-line treatment for extensive-stage small-cell lung cancer: A cost-effectiveness analysis.

Introduction: The ASTRUM-005 trial (NCT04063163) revealed that combination serplulimab plus chemotherapy (etoposide and carboplatin [EC]) treatment was associated with survival advantages relative to chemotherapy alone in patients diagnosed with extensive-stage small-cell lung cancer (ES-SCLC). As these immuno-chemotherapeutic regimens are extremely expensive, however, it is critical that the relative cost-effectiveness of combination serplulimab and chemotherapy treatment as a first-line treatment for ES-SCLC patients be examined in detail. Methods: The cost-effectiveness of combined serplulimab plus chemotherapeutic treatment was examined using a comprehensive Markov model with a 10-year boundary, enabling the calculation of overall cost, life years (LYs), quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio (ICER). Model instability was interrogated through one-way and probabilistic sensitivity analyses. Results: Serplulimab plus chemotherapy or chemotherapy alone respectively yielded 1.217 QALYs (2.243 LYs) and 0.885 QALYs (1.661 LYs) with corresponding total costs of $11,202 and $7,194, with an ICER of $12,077 per QALY ($6,883 per LY). This model was most strongly influenced by the utility of progression-free survival. Probabilistic sensitivity analysis showed that serplulimab plus chemotherapy had a 91.6% probability of being cost-effective at a willingness-to-pay (WTP) of $37,653 per QALY (3 × capita gross domestic product of China in 2021). In subgroup analyses, this combination treatment regimen was found to be most cost-effective in patients who were former smokers, had an ECOG performance status of 0, and were diagnosed with brain metastases. Conclusion: From a payer perspective in China, combination serplulimab plus chemotherapy treatment represents a cost-effective first-line intervention for ES-SCLC patients.

Clinical Activity and Safety of Penpulimab (Anti-PD-1) With Anlotinib as First-Line Therapy for Unresectable Hepatocellular Carcinoma: An Open-Label, Multicenter, Phase Ib/II Trial (AK105-203).

OBJECTIVE: This study aims to assess the efficacy and safety of penpulimab (a humanized anti-PD-1 IgG1 antibody) with anlotinib in the first-line treatment of Chinese patients with uHCC. METHODS: In this open-label multicenter phase Ib/II trial, patients with histologically or cytologically confirmed uHCC, without previous systemic treatment, aged 18-75 years old, classified as BCLC stage B (not amenable for locoregional therapy) or C, with Child-Pugh score ≤7 and ECOG performance status ≤1 were enrolled. Patients received penpulimab [200 mg intravenous (i.v.) Q3W] and oral anlotinib (8 mg/day, 2 weeks on/1 week off). The primary endpoint was objective response rate (ORR). Secondary endpoints included safety, disease control rate (DCR), progression-free survival (PFS), time to progression (TTP), duration of response (DoR), and overall survival (OS). This trial is registered with ClinicalTrials.gov (NCT04172571). RESULTS: At the data cutoff (December 30, 2020), 31 eligible patients had been enrolled and treated with a median follow-up of 14.7 months (range, 1.4-22.1). The ORR was 31.0% (95% CI, 15.3-50.8%), and the DCR was 82.8% (95% CI, 64.2-94.2%). The median PFS and TTP for 31 patients were 8.8 months (95% CI, 4.0-12.3) and 8.8 months (95% CI, 4.0-12.9) respectively. The median OS was not reached; the 12-month OS rate was 69.0% (95% CI, 48.9-82.5%). Only 19.4% (6/31) of patients had grade 3/4 treatment-related adverse events (TRAEs). CONCLUSION: Penpulimab plus anlotinib showed promising anti-tumor activity and a favorable safety profile as first-line treatment of patients with uHCC.

Neferine in the Lotus Plumule Potentiates the Antitumor Effect of Imatinib in Primary Chronic Myeloid Leukemia Cells In Vitro.

Imatinib, the prototype BCR-ABL tyrosine kinase inhibitor (TKI), is the first-line treatment for Philadelphia chromosome-positive chronic myeloid leukemia (CML) in the chronic phase. However, a subgroup of patients exhibit poor response or experience relapse. This issue may be overcome by combination therapy using natural compounds. Neferine, a major bisbenzylisoquinoline alkaloid extracted from "lotus plumule" (seed embryo of lotus) commonly used in traditional Chinese medicine and tea, was used herein in the combination treatment of CML. The MTT assay showed that neferine exerted cytotoxicity in primary CML cells in a dose-dependent manner. Moreover, low concentrations of neferine (4 and 8 µM) sensitized primary CML cells to imatinib (CI < 1), and significantly decreased its IC50 from 0.70 ± 0.10 to 0.32 ± 0.06 µM and 0.16 ± 0.02 µM, respectively. Cotreatment of neferine and imatinib significantly decreased the expression of BCR-ABL protein and its molecular chaperone heat shock protein 90 (Hsp90) mRNA and protein levels, and further decreased phospho-extracellular regulated protein kinase 1/2 (p-Erk1/2) and myeloid cell leukemia (Mcl-1) expression. These results suggest that neferine might be a potential imatinib sensitizer in CML treatment. PRACTICAL APPLICATION: In China, Lotus plumule, the green embryo of lotus, is used as a tea and as a source of herbal medicine in the treatment of anxiety, insomnia, spermatorrhea, and thirst. Additional, neferine, a bisbenzylisoquinoline alkaloid extracted from lotus plumule has been shown to have antitumor potential. Herein, the effect of neferine and imatinib cotreatment on primary CML cells obtained from CML patients was assessed, with a synergistic effect being observed between the two compounds. Therefore, neferine might be a promising natural compound to potentiate imatinib in CML patients.

Creating novel translation inhibitors to target pro-survival proteins in chronic lymphocytic leukemia.

The viability of chronic lymphocytic leukemia (CLL) is critically dependent upon staving off death by apoptosis, a hallmark of CLL pathophysiology. The recognition that Mcl-1, a major component of the anti-apoptotic response, is intrinsically short-lived and must be continually resynthesized suggested a novel therapeutic approach. Pateamine A (PatA), a macrolide marine natural product, inhibits cap-dependent translation by binding to the initiation factor eIF4A. In this study, we demonstrated that a synthetic derivative of PatA, des-methyl des-amino PatA (DMDAPatA), blocked mRNA translation, reduced Mcl-1 protein and initiated apoptosis in CLL cells. This action was synergistic with the Bcl-2 antagonist ABT-199. However, avid binding to human plasma proteins limited DMDAPatA potency, precluding further development. To address this, we synthesized a new series of PatA analogs and identified three new leads with potent inhibition of translation. They exhibited less plasma protein binding and increased cytotoxic potency toward CLL cells than DMDAPatA, with greater selectivity towards CLL cells over normal lymphocytes. Computer modeling analysis correlated their structure-activity relationships and suggested that these compounds may act by stabilizing the closed conformation of eIF4A. Thus, these novel PatA analogs hold promise for application to cancers within the appropriate biological context, such as CLL.

Genetic polymorphism predicting Methotrexate efficacy in Chinese patients with psoriasis vulgaris.

BACKGROUND: Methotrexate is the first systemic therapeutics of psoriasis. It is reported that 40% of the patients achieved a PASI75 after 12 weeks with a small dose of methotrexate (15mg / w) treatment. So far there is not any large-scale exome sequencing been used to predict the efficacy of methotrexate in the treatment of psoriasis vulgaris. OBJECTIVE: To analyze the genetic polymorphism to predict methotrexate efficacy in Chinese patients with psoriasis vulgaris. METHODS: In this study, we used the whole exon high-throughput sequencing technology to detect the DNA sequence of 22 psoriasis vulgaris patients (11 responders, 11 non-responders) treated with methotrexate and captured approximately 236 variants with statistically significant in the whole exon sequencing, then in accordance with statistical differences and clinical relevance, we further selected 36 SNPs and 14 SNPs that have been reported in articles associated with the response of methotrexate. We used MassARRAY method to verify the 50 SNPs in 100 psoriatic patients treated with methotrexate. RESULTS: We found 3 SNPs, rs216195T>C in SMG6, rs1050301G>A in IMMT, rs2285421T>C in UPK1A which might associate with the drug response of methotrexate. CONCLUSION: We have searched 3 new SNPs that could predict the efficacy of methotrexate in psoriasis vulgaris to some extent, providing a theoretical basis for precision medicine of methotrexate in future.

Combination of magnetic resonance imaging and targeted contrast agent for the diagnosis of myocardial infarction.

Myocardial infarction is one of the most common human cerebrovascular conditions and frequently leads to ischemic stroke. Evidence has indicated that magnetic resonance imaging (MRI) is a potential method for the diagnosis of patients with cardiovascular injury. However, the efficacy of MRI in diagnosing patients with myocardial infarction requires to be improved. In the present study, a novel nano-size contrast agent, a chitosan/Fe3O4-enclosed albumin (CFEA), was introduced that was used to quantify blood volume and permeability in the infarcted myocardium. A total of 68 patients with suspected myocardial infarction were recruited to analyze the efficacy of MRI combined with CFEA (MRI-CFEA). All patients received diagnosis by MRI and MRI-CFEA. It was revealed that MRI-CFEA provided a higher signal intensity than MRI in the same patients. It was demonstrated that the diagnostic efficacy of MRI-CFEA for patients with myocardial infarction was higher than that of MRI (P<0.05). By MRI-CFEA, 50/68 of cases with myocardial infarction were diagnosed, providing a significantly higher diagnostic rate compared with the 38/68 of cases diagnosed by contrast-enhanced MRI (P<0.01). MRI-CFEA successfully discriminated the infarcted regions based on a decreased fractional blood volume and increased permeability-surface (PS) area product in the infarcted myocardium. A pharmacodynamics analysis indicated that CFEA was eliminated within 24 h in all individuals. In conclusion, the present study provided a novel method to diagnose infarcted myocardium for patients with myocardial infarction, providing an imaging biomarker for the assessment of endothelial dysfunction in the clinic.

Graphene oxide composites for magnetic solid-phase extraction of trace cytokinins in plant samples followed by liquid chromatography-tandem mass spectrometry.

In this work, an easy, effective, and sensitive method based on graphene oxide@silica@magnetite composites as adsorbent of magnetic solid-phase extraction combined with liquid chromatography and tandem mass spectrometry, was established and validated for the trace analysis of cytokinins in different plants. The prepared magnetic composite was characterized by infrared spectroscopy, transmission electron microscopy, Brunauer-Emmett-Teller analysis, and magnetic hysteresis. Under the optimized conditions, good linearities in the range of 0.5-100 ng/mL were obtained with the corresponding linear correlation coefficient >0.9989 for the investigated four cytokinins, and good sensitivity levels were achieved with low detection limits ranging from 93 to 120 pg/mL. The established magnetic solid-phase extraction with liquid chromatography and tandem mass spectrometry method has been validated in the separation and analysis of four cytokinins in plant samples with good recoveries between 78.9 and 97.3% for four cytokinins with the relative standard deviations lower than 13.5%.

Topical Sunitinib ointment alleviates Psoriasis-like inflammation by inhibiting the proliferation and apoptosis of keratinocytes.

Psoriasis is a chronic auto-immune inflammation disease with skin lesions and abnormal keratinocyte proliferation. Sunitinib, a multi-targeted tyrosine kinase inhibitor, is known to selectively inhibit several growth factor receptors, including vascular endothelial growth factor receptor, platelet-derived growth factor receptor and stem cell factor. It was reported that a patient with renal cell carcinoma (RCC) whose psoriatic lesion was resolved dramatically during treatment with Sunitinib, however, the mechanism is still unclear. We applied Sunitinib ointment to treat imiquimod-induced mouse model of psoriasis and found that Sunitinib ointment could alleviate imiquimod-induced psoriasis-like inflammation and reduce the Ki67 expression, while Sunitinib ointment couldn't reduce imiquimod-induced splenomegaly of the mouse model, then we concentrated on studying the effect of Sunitinib on the proliferation and apoptosis of keratinocytes, we cultivated HaCaT cells with epidermal growth factor (HaCaT/E cells) to represent as a state of highly proliferative psoriatic keratinocytes. We found that Sunitinib could inhibit the proliferation of Hacat/E cell in a time and concentration dependent manner by influencing the expression level of cell cycle protein D1, cycle protein E1, in addition, Sunitinib could induce the apoptosis of Hacat/E cell and up-regulate the expression of poly ADP-ribose polymerase (PARP). Sunitinib down-regulated the expression of phosphorylated signal transduction and activator of transcription 3 (p-Stat3) of Hacat/E cells significantly. We conclude that Sunitinib alleviates imiquimod-induced psoriasis-like inflammation by regulating the proliferation and apoptosis of HaCaT cells through inhibiting the expression of p-Stat3.