Castleman Disease Presenting in the Neck: A Report of 3 Cases and a Literature Review.

BACKGROUND Castleman's disease (CD) is a reactive lymph node hyperplasia initially identified by Castleman in 1956. CD predominantly affects individuals 20-50 years of age, with low incidence in children. This case report describes 3 cases of CD treated in our hospital and reviews the relevant literature. The purpose of this case report was to enhance clinical understanding and treatment of CD in the head and neck in children. CASE REPORT To enhance clinical understanding and improve treatment of CD in the head and neck region in children, we present the cases of 3 patients who were admitted to the hospital, primarily presenting with a neck mass. Preoperatively, the patients collectively exhibited non-specific findings. Surgical interventions were performed with Cases 1 and 3 undergoing left functional (radical) neck lymph node dissection, in contrast to Case 2, in which bilateral functional (radical) neck lymph node dissection was executed. Pathological examination confirmed the diagnosis of CD in each of the 3 patients. Following surgery, a follow-up period ranging from 3 months to 1 year revealed that all patients had successfully recovered, with no recurrence. CONCLUSIONS Castleman disease is a rare disease in children and difficult clinical diagnosis. Some patients with unicentric Castleman disease (UCD) can be treated with surgery, and those with multicentric Castleman disease (MCD) need chemotherapy, but at present there is no widely accepted treatment plan.

6-month consequences of COVID-19 in patients discharged from hospital: a cohort study.

BACKGROUND: The long-term health consequences of COVID-19 remain largely unclear. The aim of this study was to describe the long-term health consequences of patients with COVID-19 who have been discharged from hospital and investigate the associated risk factors, in particular disease severity. METHODS: We did an ambidirectional cohort study of patients with confirmed COVID-19 who had been discharged from Jin Yin-tan Hospital (Wuhan, China) between Jan 7 and May 29, 2020. Patients who died before follow-up; patients for whom follow-up would be difficult because of psychotic disorders, dementia, or readmission to hospital; those who were unable to move freely due to concomitant osteoarthropathy or immobile before or after discharge due to diseases such as stroke or pulmonary embolism; those who declined to participate; those who could not be contacted; and those living outside of Wuhan or in nursing or welfare homes were all excluded. All patients were interviewed with a series of questionnaires for evaluation of symptoms and health-related quality of life, underwent physical examinations and a 6-min walking test, and received blood tests. A stratified sampling procedure was used to sample patients according to their highest seven-category scale during their hospital stay as 3, 4, and 5-6, to receive pulmonary function test, high resolution CT of the chest, and ultrasonography. Enrolled patients who had participated in the Lopinavir Trial for Suppression of SARS-CoV-2 in China received SARS-CoV-2 antibody tests. Multivariable adjusted linear or logistic regression models were used to evaluate the association between disease severity and long-term health consequences. FINDINGS: In total, 1733 of 2469 discharged patients with COVID-19 were enrolled after 736 were excluded. Patients had a median age of 57·0 years (IQR 47·0-65·0) and 897 (52%) were male and 836 (48%) were female. The follow-up study was done from June 16 to Sept 3, 2020, and the median follow-up time after symptom onset was 186·0 days (175·0-199·0). Fatigue or muscle weakness (52%, 855 of 1654) and sleep difficulties (26%, 437 of 1655) were the most common symptoms. Anxiety or depression was reported among 23% (367 of 1616) of patients. The proportions of 6-min walking distance less than the lower limit of the normal range were 17% for those at severity scale 3, 13% for severity scale 4, and 28% for severity scale 5-6. The corresponding proportions of patients with diffusion impairment were 22% for severity scale 3, 29% for scale 4, and 56% for scale 5-6, and median CT scores were 3·0 (IQR 2·0-5·0) for severity scale 3, 4·0 (3·0-5·0) for scale 4, and 5·0 (4·0-6·0) for scale 5-6. After multivariable adjustment, patients showed an odds ratio (OR) of 1·61 (95% CI 0·80-3·25) for scale 4 versus scale 3 and 4·60 (1·85-11·48) for scale 5-6 versus scale 3 for diffusion impairment; OR 0·88 (0·66-1·17) for scale 4 versus scale 3 and OR 1·76 (1·05-2·96) for scale 5-6 versus scale 3 for anxiety or depression, and OR 0·87 (0·68-1·11) for scale 4 versus scale 3 and 2·75 (1·61-4·69) for scale 5-6 versus scale 3 for fatigue or muscle weakness. Of 94 patients with blood antibodies tested at follow-up, the seropositivity (96·2% vs 58·5%) and median titres (19·0 vs 10·0) of the neutralising antibodies were significantly lower compared with at the acute phase. 107 of 822 participants without acute kidney injury and with an estimated glomerular filtration rate (eGFR) of 90 mL/min per 1·73 m2 or more at acute phase had eGFR less than 90 mL/min per 1·73 m2 at follow-up. INTERPRETATION: At 6 months after acute infection, COVID-19 survivors were mainly troubled with fatigue or muscle weakness, sleep difficulties, and anxiety or depression. Patients who were more severely ill during their hospital stay had more severe impaired pulmonary diffusion capacities and abnormal chest imaging manifestations, and are the main target population for intervention of long-term recovery. FUNDING: National Natural Science Foundation of China, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, National Key Research and Development Program of China, Major Projects of National Science and Technology on New Drug Creation and Development of Pulmonary Tuberculosis, and Peking Union Medical College Foundation.

Efficacy and safety of TCMs with anti-inflammatory effect in patients with rheumatoid arthritis: A network meta-analysis.

Background: Traditional Chinese medicines (TCMs), such as Tripterygium wilfordii Hook F (TwHF), Glycyrrhiza uralensis, Caulis sinomenii and others have anti-inflammatory effects. They are widely used in China to treat rheumatoid arthritis (RA), but proof of their use as an evidence-based medicine is little. The aim of this network meta-analysis (NMA) was to evaluate the efficacy and safety of TCMs. Methods: By searching online databases and using a manual retrieval method, randomized controlled trials (RCTs) that met specific selection criteria were included in the meta-analysis. The search included papers that were published between the establishment of the databases and November 10, 2022. Analyses were performed using Stata software (version 14) and Review Manager (version 5.3). Results: 61 papers with 6316 subjects were included in the current NMA. For ACR20, MTX plus SIN therapy (94.30%) may be a significant choice. For ACR50 and ACR70, MTX plus IGU therapy (95.10%, 75.90% respectively) performed better than other therapies. IGU plus SIN therapy (94.80%) may be the most promising way to reduce DAS-28, followed by MTX plus IGU therapy (92.80%) and TwHF plus IGU therapy (83.80%). In the analysis of the incidence of adverse events, MTX plus XF therapy (92.50%) had the least potential, while LEF therapy (22.10%) may cause more adverse events. At the same time, TwHF therapy, KX therapy, XF therapy and ZQFTN therapy were not inferior to MTX therapy. Conclusions: TCMs with anti-inflammatory effect were not inferior to MTX therapy in the treatment of RA patients. Combining with TCMs can improve the clinic efficacy and reduce the possibility of adverse events of DMARDs, which may be a promising regimen. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022313569.

SNHG15 enhances cisplatin resistance in lung adenocarcinoma by affecting the DNA repair capacity of cancer cells.

BACKGROUND: Lung adenocarcinoma (LUAD) is a prevalent malignancy. SNHG15 has been demonstrated to be oncogenic in many kinds of cancers, however the mechanism of SNHG15 in LUAD cisplatin (DDP) resistance remains unclear. In this study, we demonstrated the effect of SNHG15 on DDP resistance in LUAD and its related mechanism. METHODS: Bioinformatics analysis was adopted to assess SNHG15 expression in LUAD tissues and predict the downstream genes of SNHG15. The binding relationship between SNHG15 and downstream regulatory genes was proved through RNA immunoprecipitation, chromatin immunoprecipitation and dual-luciferase reporter assays. Cell counting kit-8 assay was adopted to evaluate LUAD cell viability, and gene expression was determined by Western blot and quantitative real-time polymerase chain reaction. We then performed comet assay to assess DNA damage. Cell apoptosis was detected by Tunnel assay. Xenograft animal models were created to test the function of SNHG15 in vivo. RESULTS: SNHG15 was up-regulated in LUAD cells. Moreover, SNHG15 was also highly expressed in drug-resistant LUAD cells. Down-regulated SNHG15 strengthened the sensitivity of LUAD cells to DDP and induced DNA damage. SNHG15 could elevate ECE2 expression through binding with E2F1, and it could induce DDP resistance by modulating the E2F1/ECE2 axis. In vivo experiments verified that the SNHG15 could enhance DDP resistance in LUAD tissue. CONCLUSION: The results suggested that SNHG15 could up-regulate ECE2 expression by recruiting E2F1, thereby enhancing the DDP resistance of LUAD.

Identification and validation of a hypoxia-immune signature for overall survival prediction in lung adenocarcinoma.

Objective: The interaction between immunity and hypoxia in tumor microenvironment (TME) has clinical significance, and this study aims to explore immune-hypoxia related biomarkers in LUAD to guide accurate prognosis of patients. Methods: The LUAD gene expression dataset was downloaded from GEO and TCGA databases. The immune-related genes and hypoxia-related genes were acquired from ImmPort and MSigDB databases, respectively. Genes related to immune and hypoxia in LUAD were obtained by intersection. The significantly prognostic genes in LUAD were obtained by LASSO and Cox regression analyses and a prognostic model was constructed. Kaplan-Meier and receiver operating characteristic curves were generated to evaluate and validate model reliability. Single-sample gene set enrichment analysis (ssGSEA) and gene set variation analysis (GSVA) were employed to analyze immune cell infiltration and pathway differences between high- and low-risk groups. Nomogram and calibration curves for survival curve and clinical features were drawn to measure prognostic value of the model. Results: The prognosis model of LUAD was constructed based on seven immune-hypoxia related genes: S100P, S100A16, PGK1, TNFSF11, ARRB1, NCR3, and TSLP. Survival analysis revealed a poor prognosis in high-risk group. ssGSEA result suggested that activities of immune cells in high-risk group was remarkably lower than in low-risk group, and GSVA result showed that immune-related pathway was notably activated in low-risk group. Conclusion: Immune-hypoxia related genes were found to be prognostic biomarkers for LUAD patients, based on which a 7-immune-hypoxia related gene-signature was constructed. This model can assess immune status of LUAD patients, and provide clinical reference for individualized prognosis, treatment and follow-up of LUAD patients.

PAR2 promotes tumor-associated angiogenesis in lung adenocarcinoma through activating EGFR pathway.

BACKGROUND: Metastasis of advanced lung adenocarcinoma (LUAD) is a key cause of cancer-related death, and angiogenesis is the main feature of tumor growth and metastasis. METHODS: The expression level of F2R like trypsin receptor 1(F2RL1) which encodes protease-activated receptor 2 (PAR2) protein in LUAD tissues was analyzed by bioinformatics. The effects of F2RL1 overexpression/silencing on cell proliferation and sphere-forming were analyzed by Cell Counting Kit-8 and colony formation assays, stem cell sphere-forming assay, and angiogenesis assay, respectively. The F2RL1 mRNA expression level and the PAR2 protein expression level, vascular endothelial growth factor A (VEGFA), and epidermal growth factor receptor (EGFR) in lung cancer cell lines were evaluated by real-time quantitative polymerase chain reaction and western blot. The level of VEGFA secreted by lung cancer cells was analyzed by Enzyme-linked immunosorbent assay (ELISA). The effect of F2RL1-mediated EGFR signaling on angiogenesis was further explored by EGFR inhibitor AG1478. RESULTS: F2RL1 was substantially up-regulated in LUAD tissues and cells, and overexpression of F2RL1 could promote proliferation and stem cell sphere-forming of lung cancer cell lines, as well as formation of blood vessels and branch points of human umbilical vein endothelial cells (HUVECs). Meanwhile, overexpression of F2RL1 significantly upregulated VEGFA expression and promoted EGFR phosphorylation. EGFR inhibitor AG1478 treatment significantly down-regulated pEGFR, and AG1478 treatment reversed the promoting effect of cancer cell cultured medium (oe-F2RL1) on HUVEC angiogenesis. SIGNIFICANCE: In summary, this study revealed the molecular mechanism of PAR2 promoting LUAD angiogenesis by activating EGFR signaling pathway, which further improves our understanding of LUAD angiogenesis, and provides a potential therapeutic strategy for LUAD treatment.

Effect of Baihe Gujin decoction combined with Shengmai powder on the expression of IL-1ß and IL-1Ra in peripheral blood CD14+ monocytes from patients with pulmonary tuberculosis.

This experiment was conducted to investigate the effect of taking Baihe Gujin decoction combined with Shengmai powder on IL-1ß and IL-1Ra expression in peripheral blood CD14+ monocytes from patients with pulmonary tuberculosis. For this purpose, one hundred adult patients with primary pulmonary tuberculosis were selected for the study. The age of the enrolled cases ranged from 18 to 60 years old, with a controlled male to the female sex ratio of about 1:1. The Chinese medical evidence was considered to be a qi-yin deficiency type of pulmonary consumption. The patients were randomly divided into experimental and control groups, 50 cases each. In addition, 50 cases of healthy people were selected as a healthy control group, totaling 150 cases. In the experimental group, patients were given Baihe gujin decoction and Shengmai powder based on conventional western medicine, 1 dose for 1 day, 150mL/time for 2 times. The control group was treated with conventional Western medicine. 2 mL of fasting elbow venous blood from the subjects was taken in the morning. Peripheral blood mononuclear cells were isolated by density centrifugation. Monocytes were obtained after incubation with 5 µL of CD14+ immune magnetic beads at 4°C. The relative expression of IL1ß and IL1R genes were measured using real-time quantitative PCR (RT-PCR), respectively. Results showed that the relative expression of IL1ß and IL1R genes was significantly lower in the experimental group after 3 months compared with the control group, and the statistical difference was highly significant (p<0.01). It was concluded that the administration of Baihe gujin decoction and Shengmai powder was closely related to the relative expression of IL1ß and IL1R genes in patients' serum, indicating that Baihe gujin decoction and Shengmai powder have an important role in improving the clinical symptoms of pulmonary tuberculosis.

Identification of Genetic Loci for Sugarcane Leaf Angle at Different Developmental Stages by Genome-Wide Association Study.

Sugarcane (Saccharum spp.) is an efficient crop mainly used for sugar and bioethanol production. High yield and high sucrose of sugarcane are always the fundamental demands in sugarcane growth worldwide. Leaf angle and size of sugarcane can be attributed to planting density, which was associated with yield. In this study, we performed genome-wide association studies (GWAS) with a panel of 216 sugarcane core parents and their derived lines (natural population) to determine the genetic basis of leaf angle and key candidate genes with +2, +3, and +4 leaf at the seedling, elongation, and mature stages. A total of 288 significantly associated loci of sugarcane leaf angle at different developmental stages (eight phenotypes) were identified by GWAS with 4,027,298 high-quality SNP markers. Among them, one key locus and 11 loci were identified in all three stages and two stages, respectively. An InDel marker (SNP Ss6A_102766953) linked to narrow leaf angle was obtained. Overall, 4,089 genes were located in the confidence interval of significant loci, among which 3,892 genes were functionally annotated. Finally, 13 core parents and their derivatives tagged with SNPs were selected for marker-assisted selection (MAS). These candidate genes are mainly related to MYB transcription factors, auxin response factors, serine/threonine protein kinases, etc. They are directly or indirectly associated with leaf angle in sugarcane. This research provided a large number of novel genetic resources for the improvement of leaf angles and simultaneously to high yield and high bioethanol production.

Drug Repurposing of Quisinostat to Discover Novel Plasmodium falciparum HDAC1 Inhibitors with Enhanced Triple-Stage Antimalarial Activity and Improved Safety.

Our previous work found that the clinical histone deacetylase (HDAC) inhibitor quisinostat exhibited a significant antimalarial effect but with severe toxicity. In this work, 35 novel derivatives were designed and synthesized based on quisinostat as the lead compound, and their in vitro antimalarial activities and cytotoxicities were systematically evaluated. Among them, JX35 showed potent inhibition against both wild-type and multidrug-resistant parasite strains and displayed a significant in vivo killing effect against all life cycles of parasites, including the blood stage, liver stage, and gametocyte stage, indicating its potential for the simultaneous treatment, chemoprevention, and blockage of malaria transmission. Compared with quisinostat, JX35 exhibited stronger antimalarial efficacy, more adequate safety, and good pharmacokinetic properties. Additionally, mechanistic studies via molecular docking studies, induced PfHDAC1/2 knockdown assays, and PfHDAC1 enzyme inhibition assays jointly indicated that the antimalarial target of JX35 was PfHDAC1. In summary, we discovered the promising candidate PfHDAC1 inhibitor JX35, which showed stronger triple-stage antimalarial effects and lower toxicity than quisinostat.

Genome survey sequencing and characterization of simple sequence repeat (SSR) markers in Platostoma palustre (Blume) A.J.Paton (Chinese mesona).

Platostoma palustre (Blume) A.J.Paton is an annual herbaceous persistent plant of the Labiatae family. However, there is a lack of genomic data for this plant, which severely restricts its genetic improvement. In this study, we performed genome survey sequencing of P. palustre and developed simple sequence repeat (SSR) markers based on the resulting sequence. K-mer analysis revealed that the assembled genome size was approximately 1.21 Gb. A total of 15,498 SSR motifs were identified and characterized in this study; among them, dinucleotide, and hexanucleotide repeats had the highest and lowest, respectively. Among the dinucleotide repeat motifs, AT/TA repeat motifs were the most abundant, and GC/CG repeat motifs were rather rare, accounting for 44.28% and 0.63%, respectively. Genetic similarity coefficient analysis by the UPMGA methods clustered 12 clones, of P. palustre and related species into two subgroups. These results provide helpful information for further research on P. palustre resources and variety improvements.

Methylprednisolone accelerate chest computed tomography absorption in COVID-19: A three-centered retrospective case control study from China.

BACKGROUND: Based on the results of some large randomized controlled trials (RCTs) confirmed the efficacy of corticosteroids in coronavirus disease 2019 (COVID-19), corticosteroids have been included in World Health Organization guidelines, but remain controversial. AIM: To investigate the efficacy and safety of low-to-moderate dose (30 to 40 mg/d) short-term methylprednisolone for COVID-19 patients. METHODS: The clinical data of 70 patients diagnosed with COVID-19 who received antiviral therapy with Arbidol for 7-10 d before admission but had no obvious absorption on chest computed tomography (CT) imaging were retrospectively analyzed. Arbidol (as the control group) and methylprednisolone (as the corticosteroid group) were given respectively after admission. After treatment, chest CT was reexamined to evaluate the absorption of pulmonary lesions. Additionally, we evaluated and compared the lymphocyte count, erythrocyte sedimentation rate (ESR), interleukin-6(IL-6), serum ferritin, lactate dehydrogenase (LDH), creatine kinase-MB (CK-MB), hypersensitive C-reactive protein (hs-CRP) and D-dimer levels, and also analyzed the incidence of toxic and side effects. RESULTS: All patients in the corticosteroid group had varying degrees of CT absorption, which was significantly better than that in the control group (CT obvious absorption rate: 89.47% vs 12.5%, P < 0.05). The average daily dose and course of methylprednisolone in the patients with significant improvement on chest CT was (38.55 ± 13.17) mg and (6.44 ± 1.86) d respectively. During the treatment, the lymphocyte count, ESR, IL-6, serum ferritin, LDH, CK-MB, hs-CRP and D-dimer levels all improved gradually, indicating that both Arbidol and methylprednisolone therapy were contributed to improving the condition of COVID-19 patients. The corticosteroid regimen did not prolong the clearance time of severe acute respiratory syndrome coronavirus 2. There were no severe adverse reactions such as gastrointestinal bleeding, secondary severe infection, hypertension, diabetic ketoacidosis, mental disorders or electrolyte disorders during the whole corticosteroid treatment process. CONCLUSION: Low-to-moderate dose short-term methylprednisolone can accelerate the chest CT imaging absorption of COVID-19 so as to improve symptoms and alleviate the condition in a short term, reduce the hospital stay, meanwhile avoid severe COVID-19 phases. The protocol has been proven to be effective and safe in clinical use.

Structure and function encoding of a bidirectional activatable synergetic DNA machine for speeded and ultrasensitive determination of microRNAs.

This work describes the unique design of a bidirectional activatable synergetic DNA machine (BAS-DNA machine) for speeded and ultrasensitive determination of microRNA-21 (miR-21), a well-known biomarker for biomedical research and early diagnosis of lung cancer. The BAS-DNA machine is composed by a pair of track strands (Track 1 and Track 2) encoding with two regions in the opposite direction for miR-21 recognition. Introduction of miR-21 can hybridize either with Track 1 or with Track 2 to activate the BAS-DNA machine with a synergistic effect for speeded amplifying the fluorescence signal. Moreover, compared with common DNA machine with only one switch for exogenous target recognition, the BAS-DNA machine with two switches for miR-21 binding allows the speeded and strong operation of the autonomous strand scission, replication, and displacement on Track 1 and Track 2 simultaneously. This behavior makes the BAS-DNA machine powerful for ultrasensitive, specific, and fast screening of miR-21 even from real biological samples, and the fluorescence signal was found to be linear from 1 pM to 10 nM with a detection limit of 703.6 fM. We envision this BAS-DNA machine with its superior assay performance will provide a new avenue for simple, sensitive, and affordable biomedical assays.

Successful treatment of gastrointestinal infection-induced septic shock using the oXiris® hemofilter: A case report.

BACKGROUND: Septic shock leads to multiple organ failure, and bacterial endotoxins and endogenous cytokines play essential roles in the pathogenesis. The oXiris® hemofilter can efficiently adsorb endotoxins and cytokines. CASE SUMMARY: We admitted a critically ill 59 year-old male patient with gastrointestinal septic shock due to infection by a Gram-negative bacterium and septic acute kidney injury (AKI). Prior to intensive care unit admission, the patient reported intermittent diarrhea and decreased urine output. His blood pressure was 70/40 mmHg, necessitating fluid resuscitation and large doses of noradrenaline. Based on the results of a blood culture and the presence of hypotension, oliguria, and hypoxemia, we diagnosed septic shock, AKI, and multiple organ dysfunction. We administered continuous renal replacement therapy (CRRT) with an oXiris® hemofilter for 72 h with intermittent continuous veno-venous hemodiafiltration (CVVHDF), and changed the filter every 12 h. After his hemodynamic parameters were stable, we used a traditional filter (AN69 hemofilter) with intermittent CVVHDF. The 72 h CRRT with the oXiris® hemofilter led to stabilization of his vital signs, marked reductions in disease severity scores, and decreased levels of procalcitonin, endotoxin, and inflammatory factors. After 8 d of CRRT, his kidney function had completely recovered. CONCLUSION: We conclude that the oXiris® hemofilter combined with appropriate antibacterial therapy was an effective treatment for this patient with gastrointestinal septic shock.

Cellulose based hyper-crosslinked polymer for efficiently recovering valuable materials from PO/SM wastewater.

Herein, a TEMPO-oxidized cellulose-grafted-polystyrene hypercrosslinked polymer (TOC-PS-HCP) was synthesized facilely by TEMPO oxidation, grafting copolymerization and post crosslinking route. Based on the structural characterization, it was confirmed that TOC-PS-HCP mainly consisted of polystyrene chain on cellulose and rigid crosslinked bridge. Additionally, the as-prepared TOC-PS-HCP displayed appropriate hydrophobicity (water contact angle = 102.44°) and high specific surface area (SBET = 601.20 m2·g--1), which could efficiently recover ethylbenzene and styrene from PO/SM wastewater. The adsorption experiment was conducted to study the recovery performance for ethylbenzene and styrene in the aqueous phase. The results showed that TOC-PS-HCP could recover ethylbenzene and styrene quickly by adsorption process, and maintain a stable recovery rate both in different aqueous conditions and recycle experiments. The adsorption experiment in the simulated wastewater solution showed that TOC-PS-HCP exhibited the greater affinity for ethylbenzene and styrene than other substrates. Furthermore, a possible mechanism for the efficient recovery of ethylbenzene and styrene was suggested on the basis of experimental and theoretical results, which may be associated with van der Waals force and π-π stacking.

Design, synthesis, and biological evaluation of multiple targeting antimalarials.

Malaria still threatens global health seriously today. While the current discoveries of antimalarials are almost totally focused on single mode-of-action inhibitors, multi-targeting inhibitors are highly desired to overcome the increasingly serious drug resistance. Here, we performed a structure-based drug design on mitochondrial respiratory chain of Plasmodium falciparum and identified an extremely potent molecule, RYL-581, which binds to multiple protein binding sites of P. falciparum simultaneously (allosteric site of type II NADH dehydrogenase, Qo and Qi sites of cytochrome bc 1). Antimalarials with such multiple targeting mechanism of action have never been reported before. RYL-581 kills various drug-resistant strains in vitro and shows good solubility as well as in vivo activity. This structure-based strategy for designing RYL-581 from starting compound may be helpful for other medicinal chemistry projects in the future, especially for drug discovery on membrane-associated targets.

A natural symbiotic bacterium drives mosquito refractoriness to Plasmodium infection via secretion of an antimalarial lipase.

The stalling global progress in the fight against malaria prompts the urgent need to develop new intervention strategies. Whilst engineered symbiotic bacteria have been shown to confer mosquito resistance to parasite infection, a major challenge for field implementation is to address regulatory concerns. Here, we report the identification of a Plasmodium-blocking symbiotic bacterium, Serratia ureilytica Su_YN1, isolated from the midgut of wild Anopheles sinensis in China that inhibits malaria parasites via secretion of an antimalarial lipase. Analysis of Plasmodium vivax epidemic data indicates that local malaria cases in Tengchong (Yunnan province, China) are significantly lower than imported cases and importantly, that the local vector A. sinensis is more resistant to infection by P. vivax than A. sinensis from other regions. Analysis of the gut symbiotic bacteria of mosquitoes from Yunnan province led to the identification of S. ureilytica Su_YN1. This bacterium renders mosquitoes resistant to infection by the human parasite Plasmodium falciparum or the rodent parasite Plasmodium berghei via secretion of a lipase that selectively kills parasites at various stages. Importantly, Su_YN1 rapidly disseminates through mosquito populations by vertical and horizontal transmission, providing a potential tool for blocking malaria transmission in the field.

Point-of-care test system for detection of immunoglobulin-G and -M against nucleocapsid protein and spike glycoprotein of SARS-CoV-2.

The coronavirus disease 2019 (COVID-19) epidemic continues to ravage the world. In epidemic control, dealing with a large number of samples is a huge challenge. In this study, a point-of-care test (POCT) system was successfully developed and applied for rapid and accurate detection of immunoglobulin-G and -M against nucleocapsid protein (anti-N IgG/IgM) and receptor-binding domain in spike glycoprotein (anti-S-RBD IgG/IgM) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Any one of the IgG/IgM found in a sample was identified as positive. The POCT system contains colloidal gold-based lateral flow immunoassay test strips, homemade portable reader, and certified reference materials, which detected anti-N and anti-S-RBD IgG/IgM objectively in serum within 15 min. Receiver operating characteristic curve analysis was used to determine the optimal cutoff values, sensitivity, and specificity. It exhibited equal to or better performances than four approved commercial kits. Results of the system and chemiluminescence immunoassay kit detecting 108 suspicious samples had high consistency with kappa coefficient at 0.804 (P < 0.001). Besides, the levels and alterations of the IgG/IgM in an inpatient were primarily investigated by the POCT system. Those results suggested the POCT system possess the potential to contribute to rapid and accurate serological diagnosis and epidemiological survey of COVID-19.

Discovery of Novel Plasmodium falciparum HDAC1 Inhibitors with Dual-Stage Antimalarial Potency and Improved Safety Based on the Clinical Anticancer Drug Candidate Quisinostat.

Previously, we identified the clinical anticancer drug candidate quisinostat as a novel and potent antimalarial lead compound. To further enhance the antimalarial effect and improve safety, 31 novel spirocyclic hydroxamic acid derivatives were synthesized based on the structure of quisinostat, and their antimalarial activities and cytotoxicity were evaluated. Among them, compound 11 displayed broad potency in vitro against several multiresistant malarial parasites, especially two artemisinin-resistant clinical isolates. Moreover, 11 could eliminate both liver and erythrocytic parasites in vivo, kill all morphological erythrocytic parasites with specific potency against schizonts, and show acceptable metabolic stability and pharmacokinetic properties. Western blot analysis, PfHDAC gene knockdown, and enzymatic inhibition experiments collectively confirmed that PfHDAC1 was the target of 11. In summary, 11 is a structurally novel PfHDAC1 inhibitor with the potential to prevent and cure malaria, overcome multidrug resistance, and provide a prospective prototype for antimalarial drug research.

miR-202-3p negatively regulates MMP-1 to inhibit the proliferation, migration and invasion of lung adenocarcinoma cells.

Lung adenocarcinoma (LUAD) is one of the common cancers. Studies show that MMP-1 is involved in tumor progression, yet relevant regulatory mechanism in LUAD remains to be further elucidated. Here, we demonstrated from bioinformatics analysis for GEO data that MMP-1 was differentially up-regulated in LUAD. miR-202-3p, identified as the upstream regulator of MMP-1 by both bioinformatics and dual-luciferase assays, was differentially down-regulated in LUAD and presented a negative correlation with MMP-1. Following cell biological experiments proved that knocking down the expression of MMP-1 inhibited the proliferation, migration and invasion of LUAD cells, while overexpressed miR-202-3p posed a similar suppressive effect on cancer progression. Additionally, rescue assay further identified that overexpression of MMP-1 attenuated the suppressive effect of up-regulated miR-202-3p on malignant progression of LUAD cells. In all, this research suggests a mechanism by which MMP-1 under the regulation of miR-202-3p modulates the proliferation, migration and invasion of LUAD cells, which may contribute to the development of new therapeutic strategies.

6-month consequences of COVID-19 in patients discharged from hospital: a cohort study.

BACKGROUND: The long-term health consequences of COVID-19 remain largely unclear. The aim of this study was to describe the long-term health consequences of patients with COVID-19 who have been discharged from hospital and investigate the associated risk factors, in particular disease severity. METHODS: We did an ambidirectional cohort study of patients with confirmed COVID-19 who had been discharged from Jin Yin-tan Hospital (Wuhan, China) between Jan 7, 2020, and May 29, 2020. Patients who died before follow-up, patients for whom follow-up would be difficult because of psychotic disorders, dementia, or re-admission to hospital, those who were unable to move freely due to concomitant osteoarthropathy or immobile before or after discharge due to diseases such as stroke or pulmonary embolism, those who declined to participate, those who could not be contacted, and those living outside of Wuhan or in nursing or welfare homes were all excluded. All patients were interviewed with a series of questionnaires for evaluation of symptoms and health-related quality of life, underwent physical examinations and a 6-min walking test, and received blood tests. A stratified sampling procedure was used to sample patients according to their highest seven-category scale during their hospital stay as 3, 4, and 5-6, to receive pulmonary function test, high resolution CT of the chest, and ultrasonography. Enrolled patients who had participated in the Lopinavir Trial for Suppression of SARS-CoV-2 in China received severe acute respiratory syndrome coronavirus 2 antibody tests. Multivariable adjusted linear or logistic regression models were used to evaluate the association between disease severity and long-term health consequences. FINDINGS: In total, 1733 of 2469 discharged patients with COVID-19 were enrolled after 736 were excluded. Patients had a median age of 57·0 (IQR 47·0-65·0) years and 897 (52%) were men. The follow-up study was done from June 16, to Sept 3, 2020, and the median follow-up time after symptom onset was 186·0 (175·0-199·0) days. Fatigue or muscle weakness (63%, 1038 of 1655) and sleep difficulties (26%, 437 of 1655) were the most common symptoms. Anxiety or depression was reported among 23% (367 of 1617) of patients. The proportions of median 6-min walking distance less than the lower limit of the normal range were 24% for those at severity scale 3, 22% for severity scale 4, and 29% for severity scale 5-6. The corresponding proportions of patients with diffusion impairment were 22% for severity scale 3, 29% for scale 4, and 56% for scale 5-6, and median CT scores were 3·0 (IQR 2·0-5·0) for severity scale 3, 4·0 (3·0-5·0) for scale 4, and 5·0 (4·0-6·0) for scale 5-6. After multivariable adjustment, patients showed an odds ratio (OR) 1·61 (95% CI 0·80-3·25) for scale 4 versus scale 3 and 4·60 (1·85-11·48) for scale 5-6 versus scale 3 for diffusion impairment; OR 0·88 (0·66-1·17) for scale 4 versus scale 3 and OR 1·77 (1·05-2·97) for scale 5-6 versus scale 3 for anxiety or depression, and OR 0·74 (0·58-0·96) for scale 4 versus scale 3 and 2·69 (1·46-4·96) for scale 5-6 versus scale 3 for fatigue or muscle weakness. Of 94 patients with blood antibodies tested at follow-up, the seropositivity (96·2% vs 58·5%) and median titres (19·0 vs 10·0) of the neutralising antibodies were significantly lower compared with at the acute phase. 107 of 822 participants without acute kidney injury and with estimated glomerular filtration rate (eGFR) 90 mL/min per 1·73 m2 or more at acute phase had eGFR less than 90 mL/min per 1·73 m2 at follow-up. INTERPRETATION: At 6 months after acute infection, COVID-19 survivors were mainly troubled with fatigue or muscle weakness, sleep difficulties, and anxiety or depression. Patients who were more severely ill during their hospital stay had more severe impaired pulmonary diffusion capacities and abnormal chest imaging manifestations, and are the main target population for intervention of long-term recovery. FUNDING: National Natural Science Foundation of China, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, National Key Research and Development Program of China, Major Projects of National Science and Technology on New Drug Creation and Development of Pulmonary Tuberculosis, and Peking Union Medical College Foundation.