Efficacy and safety of orelabrutinib in relapsed/refractory idiopathic multicentric Castleman disease: A single-centre, retrospective study.

Idiopathic multicentric Castleman disease (iMCD) is a rare and heterogeneous lymphoproliferative disorder that lacks standardised treatment options for patients with refractory or relapsed (r/r) disease. Blocking Bruton's tyrosine kinase (BTK) has emerged as a promising therapeutic approach for iMCD without depleting B cells. This single-centre, retrospective study enrolled 10 patients with r/r iMCD who were treated with orelabrutinib, a novel, next-generation BTK inhibitor. The median age at orelabrutinib initiation was 48 (range: 31-58) years. The overall response rate was 70% (7/10 patients, 95% CI: 34.8-93.3), with 20% (n = 2) achieving complete response and 50% (n = 5) achieving partial response. The median time to response was 9.8 (range: 5.9-20.5) months. Patients in the non-responder group also demonstrated a continuous improvement in haemoglobin (91-105 g/L) and albumin (32-38 g/L) levels at month 12 of treatment despite not fulfilling response criteria. No grade 3 or higher adverse events occurred during the median time to the next treatment of 29.0 (range: 15.0-36.2) months. No patient mortality was recorded during the median follow-up duration of 32.8 (range: 15.0-36.9) months. In conclusion, orelabrutinib is a safe and effective regimen for r/r iMCD.

Idiopathic multicentric Castleman disease (iMCD)-idiopathic plasmacytic lymphadenopathy: A distinct subtype of iMCD-not otherwise specified with different clinical features and better survival.

Idiopathic multicentric Castleman disease (iMCD) is subclassified into iMCD-thrombocytopenia, anasarca, reticulin fibrosis, renal dysfunction, organomegaly (TAFRO) and iMCD-not otherwise specified (NOS) according to the Castleman Disease Collaborative Network (CDCN) consensus criteria. With a deeper understanding of iMCD, a group of patients with iMCD-NOS characterised by polyclonal hypergammaglobulinaemia, plasmacytic/mixed-type lymph node histopathology and thrombocytosis has attracted attention. This group of patients has been previously described as having idiopathic plasmacytic lymphadenopathy (IPL). Whether these patients should be excluded from the current classification system lacks sufficient evidence. This retrospective analysis of 228 patients with iMCD-NOS identified 103 (45.2%) patients with iMCD-IPL. The clinical features and outcomes of patients with iMCD-IPL and iMCD-NOS without IPL were compared. Patients with iMCD-IPL showed a significantly higher inflammatory state but longer overall survival. No significant difference in overall survival was observed between severe and non-severe patients in the iMCD-IPL group according to the CDCN severity classification. Compared with lymphoma-like treatments, multiple myeloma-like and IL-6-blocking treatment approaches in the iMCD-IPL group resulted in significantly higher response rates and longer time to the next treatment. These findings highlight the particularities of iMCD-IPL and suggest that it should be considered a new subtype of iMCD-NOS.

Sirolimus is effective for refractory/relapsed idiopathic multicentric Castleman disease: A single-center, retrospective study.

Refractory/relapsed idiopathic multicentric Castleman disease (R/R iMCD) has limited treatment options. With studies showing increased mTOR activation in iMCD patients, sirolimus becomes an attractive and promising therapy for R/R iMCD. Here we report the results of a retrospective study involving 26 R/R iMCD patients treated with sirolimus-containing regimen. The median age at sirolimus initiation was 40.5 years (23-60), with a median prior treatment line of 2 (1-5). 18 patients (69.2%) achieved symptomatic and biochemical response, with a median time to at least overall partial remission of 1.9 months (0.5-14.6). The median follow-up time from sirolimus initiation was 11.7 months (1.6-50.7) and the median time to next treatment (TTNT) was 46.2 months. No patients died at the end of follow-up. Most of the patients in the cohort are in ongoing responses and continue sirolimus therapy. Sirolimus is well tolerated with minor adverse effects. In conclusion, sirolimus is effective for R/R iMCD patients with good tolerance.

A targeted extracellular vesicles loaded with montelukast in the treatment of demyelinating diseases.

The main pathological characteristics of demyelinating diseases are central nervous system (CNS) myelin damage, and the differentiation of oligodendrocyte precursor cells is the therapeutic target of myelin repair. Previous studies have found that a large number of platelet-derived growth factor receptor α(PDGFRα) positive oligodendrocyte progenitor cells (OPCs) accumulate in the lesion area of myelin injury, and differentiation is blocked. However, the therapeutic effects of drugs currently used clinically on OPCs differentiation and myelin repair are limited. The main reason is that it is difficult to reach the effective concentration of the drug in the lesion area. Therefore, efficiently delivering into the CNS lesion area is of great significance for the treatment of MS. Natural exosomes have good biocompatibility and are ideal drug carriers. The delivery of drugs to lesion areas can be achieved by giving the exosomes armed targeting ligand. Therefore, in this study, combining exosomes with PDGFA helps them accumulate in OPCs in vitro and in vivo. Further, load montelukast into exosomes to achieve targeted therapy for cuprizone-induced demyelination animal model. The implementation of this research will help provide effective treatments for demyelinating diseases and lay a theoretical foundation for its application in the clinical treatment of different demyelinating diseases.

Treatment with anacardic acid modulates dendritic cell activation and alleviates the disease development of autoimmune neuroinflammation in mice.

Anacardic acid (AA) is a phenolic acid extract found in a number of plants, crops, and fruits. It exhibits a wide range of biological activities. This study displayed that AA effectively alleviated EAE, a classical mouse model of multiple sclerosis. AA administered to the EAE greatly decreased inflammatory cell infiltration to the CNS and protected the myelin integrity in the white matter of the spinal cord. AA could block lipopolysaccharide-induced DC activation. inhibited the polarization of 2D2 mice-derived T cells by inhibiting the DCs activity. Immunoblot results indicated that the phosphorylation of NF-κB is significantly suppressed in AA-treated DCs. This work displayed that AA possessed a potential anti-inflammatory therapeutic effect for the treatment of autoimmune disease.

[Role of Imaging in Early Therapeutic Response Assessment for Neuroendocrine Neoplasm with Liver Metastasis:from Anatomical to Functional View].

Liver metastasis is not rare during the course of neuroendocrine neoplasms.The methods for treating neuroendocrine neoplasm with liver metastasis(NENLM)are diversifying,which exposes the limitations of the early therapeutic response assessment based on only morphological changes.The emerging imaging biomarkers can sensitively describe changes in response to treatment from the functional level,providing new ideas for the therapeutic response evaluation of NENLM.In this paper,we reviewed the status quo and the latest research progress of imaging assessment for early therapeutic response of NENLM,aiming to provide reference for assessing the response and further exploring the treatment-related biomarkers.

Composition of gut and oropharynx bacterial communities in Rattus norvegicus and Suncus murinus in China.

BACKGROUND: Rattus norvegicus and Suncus murinus are important reservoirs of zoonotic bacterial diseases. An understanding of the composition of gut and oropharynx bacteria in these animals is important for monitoring and preventing such diseases. We therefore examined gut and oropharynx bacterial composition in these animals in China. RESULTS: Proteobacteria, Firmicutes and Bacteroidetes were the most abundant phyla in faecal and throat swab samples of both animals. However, the composition of the bacterial community differed significantly between sample types and animal species. Firmicutes exhibited the highest relative abundance in throat swab samples of R. norvegicus, followed by Proteobacteria and Bacteroidetes. In throat swab specimens of S. murinus, Proteobacteria was the predominant phylum, followed by Firmicutes and Bacteroidetes. Firmicutes showed the highest relative abundance in faecal specimens of R. norvegicus, followed by Bacteroidetes and Proteobacteria. Firmicutes and Proteobacteria had almost equal abundance in faecal specimens of S. murinus, with Bacteroidetes accounting for only 3.07%. The family Streptococcaceae was most common in throat swab samples of R. norvegicus, while Prevotellaceae was most common in its faecal samples. Pseudomonadaceae was the predominant family in throat swab samples of S. murinus, while Enterobacteriaceae was most common in faecal samples. We annotated 33.28% sequences from faecal samples of S. murinus as potential human pathogenic bacteria, approximately 3.06-fold those in R. norvegicus. Potential pathogenic bacteria annotated in throat swab samples of S. murinus were 1.35-fold those in R. norvegicus. CONCLUSIONS: Bacterial composition of throat swabs and faecal samples from R. norvegicus differed from those of S. murinus. Both species carried various pathogenic bacteria, therefore both should be closely monitored in the future, especially for S. murinus.

Comfort level discussion for prosthetic sockets with different fabricating processing conditions.

BACKGROUND: In the past, manufacture of prosthetic socket by using traditional handmade method not only consumed research time but also required a special assembly approach. Recently, reverse engineering and rapid prototype technology have grown up explosively, and thus, provide a choice to fabricate prosthetic socket. METHODS: Application 3D computer aided design and manufacturing (computer-aided design/computer-aided engineering) tools approach the surface shape stump data is digitized and can be easily modified and reused. Collocation investigates gait parameters of prosthetic socket, and interface stress between stump and socket with different processing conditions. Meanwhile, questionnaire was utilized to survey satisfaction rating scale, comfort level, of subjects using this kind of artificial device. RESULTS: The main outcome of current research including gait parameters, stress interface and satisfaction rating scale those would be an informative reference for further studies in design and manufacture as well as clinical applications of prosthetic sockets. CONCLUSIONS: This study found that, regardless of the method used for socket fabrication, most stress was concentrated in tibia end pressure-relief area. This caused discomfort in the area of tibia end to the participant wearing prosthesis. This discomfort was most evident in case when the prosthetic socket was fabricated using RE and RP.

A prospective study of zanubrutinib, a Bruton tyrosine kinase inhibitor, in relapsed/refractory idiopathic multicentric Castleman disease.

Relapsed and refractory (R/R) idiopathic multicentric Castleman disease (iMCD) is a clinical challenge with no standard treatment. In this preliminary clinical trial, we investigated the efficacy and safety profiles of a Bruton tyrosine kinase inhibitor (BTKi), zanubrutinib, in patients with R/R iMCD. The primary endpoint was the overall response rate at Week 12 according to the Castleman Disease Collaborative Network (CDCN) response criteria. The trial was terminated early due to a lack of treatment response in the first enrolled 5 patients. Although 3 patients achieved symptomatic response, none of the 5 patients had an overall response by Week 12. One patient had progressive disease and the other 4 had stable disease. The study drug was well tolerated without grade 2 or higher adverse events. Our findings suggest that BTKi therapy is not effective for iMCD, and further attempts at single-agent therapy with zanubrutinib or other BTKis for iMCD should be considered with caution and probably avoided. This trial was registered at www.clinialtrials.gov as #NCT04743687.

Cholesterol metabolism: Towards a therapeutic approach for multiple sclerosis.

Growing evidence points to the importance of cholesterol in preserving brain homeostasis. Cholesterol makes up the main component of myelin in the brain, and myelin integrity is vital in demyelinating diseases such as multiple sclerosis. Because of the connection between myelin and cholesterol, the interest in cholesterol in the central nervous system increased during the last decade. In this review, we provide a detailed overview on brain cholesterol metabolism in multiple sclerosis and its role in promoting oligodendrocyte precursor cell differentiation and remyelination.

Drivers and mechanisms of spontaneous plant community succession in abandoned PbZn mining areas in Yunnan, China.

The drivers and mechanisms underlying succession and the spontaneous formation of plant communities in mining wasteland remain largely unknown. This study investigated the use of nature-based restoration to facilitate the recovery of viable plant communities in mining wasteland. It was found that scientific analyses of spontaneously formed plant communities in abandoned mining areas can provide insights for nature-based restoration. A chronosequence ("space for time") approach was used to establish sites representing three successional periods with six successional stages, and 90 quadrats were constructed to investigate changes in plant species and functional diversity during succession in abandoned PbZn mining areas. A total of 140 soil samples were collected to identify changes in soil properties, including plant nutrient and heavy metal concentrations. Then, this paper used structural equation models to analyze the mechanisms that drive succession. It was found that the functional diversity of plant communities fluctuated substantially during succession. Species had similar functional traits in early and mid-succession, but traits tended to diverge during late succession. Soil bulk density and soil organic matter gradually increased during succession. Total nitrogen (N), pH, and soil Zn concentrations first increased and then decreased during succession. Concentrations of Mn and Cd gradually decreased during succession. During early succession, soil organic matter was the key factor driving plant colonization and succession. During mid-succession, soil Zn functioned as an environmental filter factor limiting the rates of succession in mining wasteland communities. During late succession, soil bulk density and competition for nutrient resources contributed to more balanced differentiation among plant species. This thesis proposed that a nature-based strategy for the stabilization of abandoned mining lands could facilitate effective plant community restoration that promotes ecosystem services and functioning.

Targeting central nervous system extracellular vesicles enhanced triiodothyronine remyelination effect on experimental autoimmune encephalomyelitis.

The lack of targeted and high-efficiency drug delivery to the central nervous system (CNS) nidus is the main problem in the treatment of demyelinating disease. Extracellular vesicles (EVs) possess great promise as a drug delivery vector given their advanced features. However, clinical applications are limited because of their inadequate targeting ability and the "dilution effects" after systemic administration. Neural stem cells (NSCs) supply a plentiful source of EVs on account of their extraordinary capacity for self-renewal. Here, we have developed a novel therapeutic system using EVs from modified NSCs with high expressed ligand PDGF-A (EVPs) and achieve local delivery. It has been demonstrated that EVPs greatly enhance the target capability on oligodendrocyte lineage. Moreover, EVPs are used for embedding triiodothyronine (T3), a thyroid hormone that is critical for oligodendrocyte development but has serious side effects when systemically administered. Our results demonstrated that systemic injection of EVPs + T3, versus EVPs or T3 administration individually, markedly alleviated disease development, enhanced oligodendrocyte survival, inhibited myelin damage, and promoted myelin regeneration in the lesions of experimental autoimmune encephalomyelitis mice. Taken together, our findings showed that engineered EVPs possess a remarkable CNS lesion targeting potential that offers a potent therapeutic strategy for CNS demyelinating diseases as well as neuroinflammation.

Role of Plant-Derived Natural Compounds in Experimental Autoimmune Encephalomyelitis: A Review of the Treatment Potential and Development Strategy.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system that is mainly mediated by pathological T-cells. Experimental autoimmune encephalomyelitis (EAE) is a well-known animal model of MS that is used to study the underlying mechanism and offers a theoretical basis for developing a novel therapy for MS. Good therapeutic effects have been observed after the administration of natural compounds and their derivatives as treatments for EAE. However, there has been a severe lag in the research and development of drug mechanisms related to MS. This review examines natural products that have the potential to effectively treat MS. The relevant data were consulted in order to elucidate the regulated mechanisms acting upon EAE by the flavonoids, glycosides, and triterpenoids derived from natural products. In addition, novel technologies such as network pharmacology, molecular docking, and high-throughput screening have been gradually applied in natural product development. The information provided herein can help improve targeting and timeliness for determining the specific mechanisms involved in natural medicine treatment and lay a foundation for further study.

[Comparison of Plasma Components between Frozen Plasma and Fresh Frozen Plasma].

OBJECTIVE: To compare the plasma components of frozen plasma (FP) and fresh frozen plasma (FFP). METHODS: Twenty samples of FP and 20 samples of FFP from Beijing Red Cross Blood Center were randomly selected. Immediately after plasma melting, 12 plasma components including coagulation factor, fibrinolytic system and anticoagulation protein were detected, including activated partial thromboplastin time (APTT), prothrombin time (PT), coagulation factor Ⅷ (FⅧ) activity, coagulation factor Ⅴ (FⅤ) activity, fibrinogen(FIB) level, ADAMTS-13 activity, von Willebrand factor(vWF) activity, D-dimer (D-dimer, DD), fibrin degradation products (FDP), antithrombin (AT), protein C (PC), and protein S (PS). All these coagulation components between the two types of plasma were compared and analyzed. RESULTS: Compared with FFP, APTT in FP was significantly prolonged(t=3.428, P<0.01), and PT was also significantly prolonged(z=-2.140, P<0.05), and FⅧ activity was decreased (t=-3.372, P<0.01), but all in the reference range, and PS activity was decreased(t=-2.458，P＜0.05), there was no statistical difference in the other part between two types of plasma(P>0.05). CONCLUSION: FP can substitute FFP in the treatment of some diseases, although it is lack of some coagulation factors and anticoagulation protein.

Trends in burden of multidrug-resistant tuberculosis in countries, regions, and worldwide from 1990 to 2017: results from the Global Burden of Disease study.

BACKGROUND: Antituberculosis-drug resistance is an important public health issue, and its epidemiological patterns has dramatically changed in recent decades. This study aimed to estimate the trends of multidrug-resistant tuberculosis (MDR-TB), which can be used to inform health strategies. METHODS: Data were collected from the Global Burden of Disease study 2017. The estimated annual percentage changes (EAPCs) were calculated to assess the trends of MDR-TB burden at global, regional, and national level from 1990 to 2017 using the linear regression model. RESULTS: Globally, the age-standardized rate (ASR) of MDR-TB burden including incidence, prevalence, death and disability-adjusted life years (DALYs) had pronounced increasing trends from 1990 to 1999, with the EAPCs were 17.63 [95% confidence interval (CI): 10.77-24.92], 17.57 (95% CI 11.51-23.95), 21.21 (95% CI 15.96-26.69), and 21.90 (95% CI 16.55-27.50), respectively. Particularly, the largest increasing trends were seen in areas and countries with low and low-middle sociodemographic index (SDI). However, the trends in incidence, prevalence, death and DALYs of MDR-TB decreased globally from 2000 to 2017, with the respective EAPCs were - 1.37 (95% CI - 1.62 to - 1.12), - 1.32 (95% CI - 1.38 to - 1.26), - 3.30 (95% CI - 3.56 to - 3.04) and - 3.32 (95% CI - 3.59 to - 3.06). Decreasing trends of MDR-TB were observed in most regions and countries, particularly that of death and DALYs in Slovenia were - 18.96 (95% CI - 20.82 to - 17.06) and -19.35 (95% CI - 21.10 to - 17.55), respectively. Whereas the pronounced increasing trends of MDR-TB occurred in Papua New Guinea, Singapore, and Australia. CONCLUSIONS: The ASR of MDR-TB showed pronounced decreasing trends from 2000 to 2017. However, the MDR-TB burden remains a substantial challenge to the TB control globally, and requires effective control strategies and healthcare systems.

Draft Genome Sequence of Bacillus velezensis B6, a Rhizobacterium That Can Control Plant Diseases.

The draft genome of Bacillus velezensis strain B6, a rhizobacterium with good biocontrol performance isolated from soil in China, was sequenced. The assembly comprises 32 scaffolds with a total size of 3.88 Mb. Gene clusters coding either ribosomally encoded bacteriocins or nonribosomally encoded antimicrobial polyketides and lipopeptides in the genome may contribute to plant disease control.

[Spatial distribution pattern of soil nitrogen in Huanghuadianzi watershed and related affecting factors].

This research was conducted in Huanghuadianzi watershed in Aohan, Chifeng, Inner Mongolia. Geostatistic was used to study the spatial distribution of soil nitrogen and their affecting factors. The results showed that the soil nitrogen contents in all layers distributed as an island shape, and the high value areas were mainly distributed in the northwest of the watershed as an obvious fertile island shape, while the low value areas were mainly distributed in the south of the watershed. Nitrogen was mainly concentrated in the surface soil, and its content decreased with the increase of soil depth. The soil nitrogen content at first increased then decreased with the altitude, decreased with the slope, and showed the order of shady slope>semi-shady slope>semi-sunny slope> sunny slope in different aspects. The average soil nitrogen contents in different land use types ranked as cropland >woodland > grassland.

Rhizosphere Inhibition of Cucumber Fusarium Wilt by Different Surfactin- excreting Strains of Bacillus subtilis.

Bacillus subtilis B006 strain effectively suppresses the cucumber fusarium wilt caused by Fusarium oxysporum f. sp. cucumerinum (Foc). The population dynamics of Foc, strain B006 and its surfactin over-producing mutant B841 and surfactin-deficient mutant B1020, in the rhizosphere were determined under greenhouse conditions to elucidate the importance of the lipopeptides excreted by these strains in suppressing Foc. Results showed that B. subtilis strain B006 effectively suppressed the disease in natural soil by 42.9%, five weeks after transplanting, whereas B841 and B1020 suppressed the disease by only 22.6% and 7.1%, respectively. Quantitative PCR assays showed that effective colonization of strain B006 in the rhizosphere suppressed Foc propagation by more than 10 times both in nursery substrate and in field-infected soil. Reduction of Foc population at the cucumber stems in a range of 0.96 log10 ng/g to 2.39 log10 ng/g was attained at the third and the fifth weeks of B006 treatment in nursery substrate. In field-infected soil, all three treatments with B. subtilis suppressed Foc infection, indicated by the reduction of Foc population at a range of 2.91 log10 ng/g to 3.36 log10 ng/g at the stem base, one week after transplanting. This study reveals that the suppression of fusarium wilt disease is affected by the effective colonization of the surfactin-producing B. subtilis strain in the rhizosphere. These results improved our understanding of the biocontrol mechanism of the B. subtilis strain B006 in the natural soil and facilitate its application as biocontrol agent in the field.