Profiling dendritic cells subsets in renal tissue of patients with crescentic glomerulonephritis.

BACKGROUND: Dendritic cells (DCs) have been speculated to be involved in the pathogenesis of glomerular diseases. However, the numbers and distribution of DC subsets in the kidneys of patients with crescentic glomerulonephritis (CrGN) have not been clearly elucidated. METHODS: A total of 26 patients with biopsy-proven CrGN were enrolled. Indirect immunofluorescence staining was used to quantify DC subsets in renal specimens. Double staining of HLA with CD11C, BDCA2 and CD209 respectively was performed to detect DC subsets. The correlation between DC subsets infiltrated in the kidney and clinical and pathological parameters was investigated. RESULTS: DC subsets were predominantly present in the kidney interstitium, particularly in the peri-glomerular area. The numbers of CD11C+DCs, BDCA2+DCs and CD209+DCs increased in the patients with CrGN and varied among different types of CrGN. Though significant correlation between DC subsets and the percentage of crescents had not been identified, a notable increase in the number of CD11C+DCs were observed with the chronic development of crescents. Furthermore, patients with severe tubulointerstitial injury exhibited significantly more infiltrations of CD11C+DCs, BDCA2+DCs and CD209+DCs. Moreover, the numbers of CD11C+DCs and BDCA2+DCs were found to correlate with the level of serum C3. CONCLUSIONS: Patients with CrGN showed increased kidney infiltration of DC subsets, primarily localized in the renal interstitium and peri-glomerular region. The correlation between DC subsets and fibrosis of crescent and severe tubulointerstitial injury implied a potential involvement of DCs in the development of CrGN.

Depletion of donor dendritic cells ameliorates immunogenicity of both skin and hind limb transplants.

Acute cellular rejection remains a significant obstacle affecting successful outcomes of organ transplantation including vascularized composite tissue allografts (VCA). Donor antigen presenting cells (APCs), particularly dendritic cells (DCs), orchestrate early alloimmune responses by activating recipient effector T cells. Employing a targeted approach, we investigated the impact of donor-derived conventional DCs (cDCs) and APCs on the immunogenicity of skin and skin-containing VCA grafts, using mouse models of skin and hind limb transplantation. By post-transplantation day 6, skin grafts demonstrated severe rejections, characterized by predominance of recipient CD4 T cells. In contrast, hind limb grafts showed moderate rejection, primarily infiltrated by CD8 T cells. Notably, the skin component exhibited heightened immunogenicity when compared to the entire VCA, evidenced by increased frequencies of pan (CD11b-CD11c+), mature (CD11b-CD11c+MHCII+) and active (CD11b-CD11c+CD40+) DCs and cDC2 subset (CD11b+CD11c+ MHCII+) in the lymphoid tissues and the blood of skin transplant recipients. While donor depletion of cDC and APC reduced frequencies, maturation and activation of DCs in all analyzed tissues of skin transplant recipients, reduction in DC activities was only observed in the spleen of hind limb recipients. Donor cDC and APC depletion did not impact all lymphocyte compartments but significantly affected CD8 T cells and activated CD4 T in lymph nodes of skin recipients. Moreover, both donor APC and cDC depletion attenuated the Th17 immune response, evident by significantly reduced Th17 (CD4+IL-17+) cells in the spleen of skin recipients and reduced levels of IL-17E and lymphotoxin-α in the serum samples of both skin and hind limb recipients. In conclusion, our findings underscore the highly immunogenic nature of skin component in VCA. The depletion of donor APCs and cDCs mitigates the immunogenicity of skin grafts while exerting minimal impact on VCA.

Choledochal cyst as an incidental finding during acute cholecystitis: A case report.

Key Clinical Message: This case demonstrates an atypical presentation of choledochal cysts (CDCs) and elaborates on the diagnostic challenges encountered when presented with CDCs in adulthood, as it principally presents in children. Abstract: A choledochal cyst is a rare congenital anomaly characterized by cystic dilations in the extrahepatic and intrahepatic biliary trees. These cysts are classified according to their location and characteristics. This case study aims to demonstrate how nonspecific clinical features can pose a diagnostic dilemma when presented in adults. Additionally, the case report provides an overview of diagnostic methods and treatment options. In this case, we discuss a 50-year-old female who presented with a 2- to 3-day history of severe colicky pain in the right upper quadrant of her abdomen without any other symptoms or abnormal laboratory tests. In addition to ultrasonography evidence of CBD dilation and cholelithiasis, MRCP results confirmed the diagnosis. She underwent surgical intervention involving cyst excision, a Roux-en-Y hepatojejunostomy, and a cholecystectomy. The postoperative period was without significant complications. The case presented here illustrates the potential outcomes for individuals who present with choledochal cysts during adulthood. Often, these cases present with vague symptoms or as the underlying cause of a more severe condition. This case contributes to the existing knowledge of choledochal cysts by providing insight into the clinical presentation, diagnostic methods, and treatment options.

Isoproterenol pre-treatment improve the therapeutic efficacy of cardiosphere-derived cells transplantation for myocardial infarction.

Background: This study aimed to investigate the effect of isoproterenol pre-treatment on the therapeutic efficacy of cardiosphere-derived cells (CDCs) transplantation for myocardial infarction (MI). Methods: Thirty 8-week-old male Sprague-Dawley (SD) rat model of MI was generated by ligation of the left anterior descending artery. The MI rats were treated with PBS (MI group, n=8), CDCs (MI + CDC group, n=8) and isoproterenol pre-treated CDCs (MI + ISO-CDC group, n=8), respectively. In the MI + ISO-CDC group, CDCs were pre-treated by 10-6 M isoproterenol and the cultured for additional 72 h, then injected to the myocardial infraction area like other groups. At 3 weeks after the operation, echocardiographic, hemodynamic, histological assessments and Western blot were performed to compare the CDCs differentiation degree and therapeutic effect. Results: Isoproterenol treatment (10-6 M) simultaneously inhibited proliferation and induced apoptosis of CDCs, up-regulated proteins of vimentin, cTnT, α-sarcomeric actin and connexin 43, and down-regulated c-Kit proteins (all P<0.05). The echocardiographic and hemodynamic analysis demonstrated that the MI rats in the two CDCs transplantation groups had significantly better recovery of cardiac function than the MI group (all P<0.05). MI + ISO-CDC group had better recovery of cardiac function than the MI + CDC group, although the differences did not reach significant. Immunofluorescence staining showed that the MI + ISO-CDC group had more EdU-positive (proliferating) cells and cardiomyocytes in the infarct area than the MI + CDC group. MI + ISO-CDC group had significantly higher protein levels of c-Kit, CD31, cTnT, α-sarcomeric actin and α-SMA in the infarct area than the MI + CDC group. Conclusions: These results suggested that in CDCs transplantation, isoproterenol pre-treated CDCs can provide a better protective effect against MI than the untreated CDCs.

Transcriptional regulation of dendritic cell development and function.

Dendritic cells (DCs) are sentinel immune cells that form a critical bridge linking the innate and adaptive immune systems. Extensive research addressing the cellular origin and heterogeneity of the DC network has revealed the essential role played by the spatiotemporal activity of key transcription factors. In response to environmental signals DC mature but it is only following the sensing of environmental signals that DC can induce an antigen specific T cell response. Thus, whilst the coordinate action of transcription factors governs DC differentiation, sensing of environmental signals by DC is instrumental in shaping their functional properties. In this review, we provide an overview that focuses on recent advances in understanding the transcriptional networks that regulate the development of the reported DC subsets, shedding light on the function of different DC subsets. Specifically, we discuss the emerging knowledge on the heterogeneity of cDC2s, the ontogeny of pDCs, and the newly described DC subset, DC3. Additionally, we examine critical transcription factors such as IRF8, PU.1, and E2-2 and their regulatory mechanisms and downstream targets. We highlight the complex interplay between these transcription factors, which shape the DC transcriptome and influence their function in response to environmental stimuli. The information presented in this review provides essential insights into the regulation of DC development and function, which might have implications for developing novel therapeutic strategies for immune-related diseases.

Modified single-port versus multiport laparoscopic choledochal cysts excision and Roux-en-Y hepaticojejunostomy: a retrospective comparative cohort study.

Background: The feasibility, benefit, and safety of multiport laparoscopic choledochal cyst (CDC) excision and Roux-en-Y hepaticoenterostomy (MPCH) have been consistently confirmed. Single-port laparoscopic CDC excision and Roux-en-Y hepaticoenterostomy (SPCH) has advantages of less traumatic and more cosmetic beneficial, it has been reported in some case series, but it is technically challenging. We propose a modified technique to reduce technical difficulty in performing SPCH. The safety and feasibility of modified SPCH were compared with those of conventional multiport laparoscopic CDC excision. Methods: A total of 43 consecutive patients who diagnosed with CDC by preoperative magnetic resonance cholangiopancreatography (MRCP) and underwent SPCH (n=24) and MPCH (n=19) for choledochal cyst (CDC) by a single surgeon between January 1, 2018, and January 1, 2021, were enrolled. The baseline clinical characteristics, efficacy and safety outcomes of short-term were compared. Results: The baseline clinical characteristics of the MPCH and SPCH groups are comparable. Average postoperative length of hospital stay was shorter in the SPCH group than in the MPCH group, but the difference was not statistically significant (7.00 vs. 7.58 days; P>0.99). The operation time (281.75 vs. 277.3 min; P=0.58) and the amount of blood loss (9.33 vs. 16.68 mL; P=0.57) were similar in both groups. A significantly greater number of drainage tubes were placed in the MPCH group compared to the SPCH group (11 vs. 5; P=0.01). One patient suffered from hepaticoenterostomy anastomosis stricture in the SPCH group. Conclusions: The short-term outcome of modified SPCH is comparable with MPCH according to our study. It is easily adaptable treatment of CDC.

Neonatal Cri du chat syndrome with atypical facial appearance: A case report.

BACKGROUND: Cri du chat syndrome (CdCS), also known as 5p deletion syndrome (5p-) is a syndrome caused by partial deletion of the 5p chromosome in human beings. The incidence accounts for 1/50000 and the cause of CdCS is related to partial deletion of chromosome 5 short arm (p). CdCS is a sporadic event. Only one case of CdCS was detected by chromosome screening in 125 and 170 pregnant Iranian women[1]. The most prominent clinical manifestations of CdCS are typical high-pitched cat calls, severe mental retardation or mental retardation and is most harmful to both language and growth retardation[2]. CdCS is a chromosome mutation disease which occurs during embryonic development and the symptoms of some cases are extremely atypical. It is difficult to make an early diagnosis and screening in clinic. We can suspect the disease from its atypical manifestations in the weak crying of cats, and chromosome karyotype analysis can find some questionable gene deletion fragments to assist the clinical diagnosis and prognosis of CdCS. CASE SUMMARY: A 2-d-old male child who was admitted to our hospital with a poor postnatal reaction and poor milk intake. The baby's crying and sucking is weak, reaction and feeding time is poor and the baby has nausea and vomiting. Karyotype analysis showed that the chromosomes were 46, XY, deletion (5) p15. Whole genome microarray analysis (named ISCN2013) showed that the chromosomes of the child were male karyotypes and contained three chromosomal abnormalities. Among them, loss of 5p15.2pter (113576-13464559) was associated with cat call syndrome. After 3 mo of follow-up, the child still vomited repeatedly, had poor milk intake, did not return to normal growth, had developmental retardation and a poor directional response. CONCLUSION: Therefore, when cat crying and laryngeal sounds occur in the neonatal period, it should be considered that they are related to CdCS. Chromosome karyotype and genome analysis are helpful for the diagnosis of CdCS.

Strategies for Bottlenecks of rAAV-Mediated Expression in Skeletal and Cardiac Muscle of Duchenne Muscular Dystrophy.

Gene therapy using the adeno-associated virus (rAAV) to deliver mini/micro- dystrophin is the current promising strategy for Duchenne Muscular Dystrophy (DMD). However, the further transformation of this strategy still faces many "bottlenecks". Most gene therapies are only suitable for infants with strong muscle cell regeneration and immature immune system, and the treatment depends heavily on the high dose of rAAV. However, high-dose rAAV inevitably causes side effects such as immune response and acute liver toxicity. Therefore, how to reduce the degree of fibrosis and excessive immune response in older patients and uncouple the dependence association between therapeutic effect and high dose rAAV are crucial steps for the transformation of rAAV-based gene therapy. The article analyzes the latest research and finds that the application of utrophin, the homologous protein of dystrophin, could avoid the immune response associated with dystrophin, and the exploration of methods to improve the expression level of mini/micro-utrophin in striated muscle, combined with the novel MyoAAV with high efficiency and specific infection of striated muscle, is expected to achieve the same therapeutic efficacy under the condition of reducing the dose of rAAV. Furthermore, the delivery of allogeneic cardio sphere-derived cells (CDCs) with anti-inflammatory and anti-fibrotic characteristics combined with immune suppression can provide a continuous and appropriate "window period" for gene therapy. This strategy can expand the number of patients who could benefit from gene therapy.

Uncovering the molecular identity of cardiosphere-derived cells (CDCs) by single-cell RNA sequencing.

Cardiosphere-derived cells (CDCs) generated from human cardiac biopsies have been shown to have disease-modifying bioactivity in clinical trials. Paradoxically, CDCs' cellular origin in the heart remains elusive. We studied the molecular identity of CDCs using single-cell RNA sequencing (sc-RNAseq) in comparison to cardiac non-myocyte and non-hematopoietic cells (cardiac fibroblasts/CFs, smooth muscle cells/SMCs and endothelial cells/ECs). We identified CDCs as a distinct and mitochondria-rich cell type that shared biological similarities with non-myocyte cells but not with cardiac progenitor cells derived from human-induced pluripotent stem cells. CXCL6 emerged as a new specific marker for CDCs. By analysis of sc-RNAseq data from human right atrial biopsies in comparison with CDCs we uncovered transcriptomic similarities between CDCs and CFs. By direct comparison of infant and adult CDC sc-RNAseq data, infant CDCs revealed GO-terms associated with cardiac development. To analyze the beneficial effects of CDCs (pro-angiogenic, anti-fibrotic, anti-apoptotic), we performed functional in vitro assays with CDC-derived extracellular vesicles (EVs). CDC EVs augmented in vitro angiogenesis and did not stimulate scarring. They also reduced the expression of pro-apoptotic Bax in NRCMs. In conclusion, CDCs were disclosed as mitochondria-rich cells with unique properties but also with similarities to right atrial CFs. CDCs displayed highly proliferative, secretory and immunomodulatory properties, characteristics that can also be found in activated or inflammatory cell types. By special culture conditions, CDCs earn some bioactivities, including angiogenic potential, which might modify disease in certain disorders.

The thymic microenvironment gradually modulates the phenotype of thymus-homing peripheral conventional dendritic cells.

BACKGROUND & AIMS: Thymic conventional dendritic cells (t-DCs) are crucial for the development of T cells. A substantial fraction of t-DCs originates extrathymically and migrates to the thymus. Here, these cells contribute to key processes of central tolerance like the clonal deletion of self-reactive thymocytes and the generation of regulatory T (Treg) cells. So far, it is only incompletely understood which impact the thymic microenvironment has on thymus-homing conventional DCs (cDCs), which phenotypic changes occur after the entry of peripheral cDCs into the thymus and which functional properties these modulated cells acquire. MATERIALS & METHODS: In the present study, we mimicked the thymus-homing of peripheral cDCs by introducing ex vivo isolated splenic cDCs (sp-DCs) into reaggregated thymic organ cultures (RTOCs). RESULTS: Already after two days of culture, the transcriptomic profile of sp-DCs was modulated and had acquired certain key signatures of t-DCs. The regulated genes included immunomodulatory cytokines and chemokines as well as costimulatory molecules. After four days of culture, sp-DCs appeared to have at least partially acquired the peculiar Treg cell-inducing capacity characteristic of t-DCs. DISCUSSION & CONCLUSION: Taken together, our findings indicate that peripheral cDCs possess a high degree of plasticity enabling them to quickly adapt to the thymus-specific microenvironment. We further provide indirect evidence that thymus-specific properties such as the efficient induction of Treg cells under homeostatic conditions can be partially transferred to thymus-homing peripheral cDC subsets.

Intrapericardial Delivery of APA-Microcapsules as Promising Stem Cell Therapy Carriers in an Experimental Acute Myocardial Infarction Model.

The administration of cardiosphere-derived cells (CDCs) after acute myocardial infarction (AMI) is very promising. CDC encapsulation in alginate-poly-l-lysine-alginate (APA) could increase cell survival and adherence. The intrapericardial (IP) approach potentially achieves high concentrations of the therapeutic agent in the infarcted area. We aimed to evaluate IP therapy using a saline vehicle as a control (CON), a dose of 30 × 106 CDCs (CDCs) or APA microcapsules containing 30 × 106 CDCs (APA-CDCs) at 72 h in a porcine AMI model. Magnetic resonance imaging (MRI) was used to determine the left ventricular ejection fraction (LVEF), infarct size (IS), and indexed end diastolic and systolic volumes (EDVi; ESVi) pre- and 10 weeks post-injection. Programmed electrical stimulation (PES) was performed to test arrhythmia inducibility before euthanasia. Histopathological analysis was carried out afterwards. The IP infusion was successful in all animals. At 10 weeks, MRI revealed significantly higher LVEF in the APA-CDC group compared with CON. No significant differences were observed among groups in IS, EDVi, ESVi, PES and histopathological analyses. In conclusion, the IP injection of CDCs (microencapsulated or not) was feasible and safe 72 h post-AMI in the porcine model. Moreover, CDCs APA encapsulation could have a beneficial effect on cardiac function, reflected by a higher LVEF at 10 weeks.

The application of nanoparticles in cancer immunotherapy: Targeting tumor microenvironment.

The tumor development and metastasis are closely related to the structure and function of the tumor microenvironment (TME). Recently, TME modulation strategies have attracted much attention in cancer immunotherapy. Despite the preliminary success of immunotherapeutic agents, their therapeutic effects have been restricted by the limited retention time of drugs in TME. Compared with traditional delivery systems, nanoparticles with unique physical properties and elaborate design can efficiently penetrate TME and specifically deliver to the major components in TME. In this review, we briefly introduce the substitutes of TME including dendritic cells, macrophages, fibroblasts, tumor vasculature, tumor-draining lymph nodes and hypoxic state, then review various nanoparticles targeting these components and their applications in tumor therapy. In addition, nanoparticles could be combined with other therapies, including chemotherapy, radiotherapy, and photodynamic therapy, however, the nanoplatform delivery system may not be effective in all types of tumors due to the heterogeneity of different tumors and individuals. The changes of TME at various stages during tumor development are required to be further elucidated so that more individualized nanoplatforms could be designed.

The PDE4 Inhibitor Tanimilast Blunts Proinflammatory Dendritic Cell Activation by SARS-CoV-2 ssRNAs.

Phosphodiesterase 4 (PDE4) inhibitors are immunomodulatory drugs approved to treat diseases associated with chronic inflammatory conditions, such as COPD, psoriasis and atopic dermatitis. Tanimilast (international non-proprietary name of CHF6001) is a novel, potent and selective inhaled PDE4 inhibitor in advanced clinical development for the treatment of COPD. To begin testing its potential in limiting hyperinflammation and immune dysregulation associated to SARS-CoV-2 infection, we took advantage of an in vitro model of dendritic cell (DC) activation by SARS-CoV-2 genomic ssRNA (SCV2-RNA). In this context, Tanimilast decreased the release of pro-inflammatory cytokines (TNF-α and IL-6), chemokines (CCL3, CXCL9, and CXCL10) and of Th1-polarizing cytokines (IL-12, type I IFNs). In contrast to ß-methasone, a reference steroid anti-inflammatory drug, Tanimilast did not impair the acquisition of the maturation markers CD83, CD86 and MHC-II, nor that of the lymph node homing receptor CCR7. Consistent with this, Tanimilast did not reduce the capability of SCV2-RNA-stimulated DCs to activate CD4+ T cells but skewed their polarization towards a Th2 phenotype. Both Tanimilast and ß-methasone blocked the increase of MHC-I molecules in SCV2-RNA-activated DCs and restrained the proliferation and activation of cytotoxic CD8+ T cells. Our results indicate that Tanimilast can modulate the SCV2-RNA-induced pro-inflammatory and Th1-polarizing potential of DCs, crucial regulators of both the inflammatory and immune response. Given also the remarkable safety demonstrated by Tanimilast, up to now, in clinical studies, we propose this inhaled PDE4 inhibitor as a promising immunomodulatory drug in the scenario of COVID-19.

Epicardium-Derived Tbx18+ CDCs Transplantation Improve Heart Function in Infarcted Mice.

Cardiosphere-derived cells (CDCs) constitute a cardiac stem cell pool, a promising therapeutics in treating myocardial infarction (MI). However, the cell source of CDCs remains unclear. In this study, we isolated CDCs directly from adult mouse heart epicardium named primary epicardium-derived CDCs (pECDCs), which showed a different expression profile compared with primary epicardial cells (pEpiCs). Interestingly, pECDCs highly expressed T-box transcription factor 18 (Tbx18) and showed multipotent differentiation ability in vitro. Human telomerase reverse transcriptase (hTERT) transduction could inhibit aging-induced pECDCs apoptosis and differentiation, thus keeping a better proliferation capacity. Furthermore, immortalized epicardium CDCs (iECDCs) transplantation extensively promote cardiogenesis in the infracted mouse heart. This study demonstrated epicardium-derived CDCs that may derive from Tbx18+ EpiCs, which possess the therapeutic potential to be applied to cardiac repair and regeneration and suggest a new kind of CDCs with identified origination that may be followed in the developing and injured heart.

Comprehensive Phenotyping of Dendritic Cells in Cancer Patients by Flow Cytometry.

Dendritic cells (DCs) play a crucial role in the complex interplay between tumor cells and the immune system. During the elimination phase of cancer immunoediting, immunostimulatory DCs are critical for the control of tumor growth. During the escape phase, regulatory DCs sustain tumor tolerance and contribute to the development of the immunosuppressive tumor microenvironment that characterizes this phase. Moreover, increasing evidence indicates that DCs are also critical for the success of cancer immunotherapy. Hence, there is increasing need to fully characterize DC subsets and their activatory/inhibitory profile in cancer patients. In this review, we describe the role played by different DC subsets in the different phases of cancer immunoediting, the function exerted by different activatory and inhibitory molecules expressed on DC surface, and the cytokines produced by distinct DC subsets, in order to provide an overview on the DC features that may be useful to be assessed when dealing with the flow cytometric characterization of DCs in cancer patients. © 2020 International Society for Advancement of Cytometry.

Intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR): a randomized, placebo-controlled, double-blinded trial.

AIMS: Cardiosphere-derived cells (CDCs) are cardiac progenitor cells that exhibit disease-modifying bioactivity in various models of cardiomyopathy and in previous clinical studies of acute myocardial infarction (MI), dilated cardiomyopathy, and Duchenne muscular dystrophy. The aim of the study was to assess the safety and efficacy of intracoronary administration of allogeneic CDCs in the multicentre, randomized, double-blinded, placebo-controlled, intracoronary ALLogeneic heart STem cells to Achieve myocardial Regeneration (ALLSTAR) trial. METHODS AND RESULTS: We enrolled patients 4 weeks to 12 months after MI, with left ventricular ejection fraction (LVEF) ≤45% and LV scar size ≥15% of LV mass by magnetic resonance imaging (MRI). A pre-specified interim analysis was performed when 6-month MRI data were available. The trial was subsequently stopped due to the low probability of detecting a significant treatment effect of CDCs based on the primary endpoint. Patients were randomly allocated in a 2:1 ratio to receive CDCs or placebo in the infarct-related artery by stop-flow technique. The primary safety endpoint was the occurrence, during 1-month post-intracoronary infusion, of acute myocarditis attributable to allogeneic CDCs, ventricular tachycardia- or ventricular fibrillation-related death, sudden unexpected death, or a major adverse cardiac event (death or hospitalization for heart failure or non-fatal MI or need for left ventricular assist device or heart transplant). The primary efficacy endpoint was the relative percentage change in infarct size at 12 months post-infusion as assessed by contrast-enhanced cardiac MRI. We randomly allocated 142 eligible patients of whom 134 were treated (90 to the CDC group and 44 to the placebo group). The mean baseline LVEF was 40% and the mean scar size was 22% of LV mass. No primary safety endpoint events occurred. There was no difference in the percentage change from baseline in scar size (P = 0.51) between CDCs and placebo groups at 6 months. Compared with placebo, there were significant reductions in LV end-diastolic volume (P = 0.02), LV end-systolic volume (P = 0.02), and N-terminal pro b-type natriuretic peptide (NT-proBNP) (P = 0.02) at 6 months in CDC-treated patients. CONCLUSION: Intracoronary infusion of allogeneic CDCs in patients with post-MI LV dysfunction was safe but did not reduce scar size relative to placebo at 6 months. Nevertheless, the reductions in LV volumes and NT-proBNP reveal disease-modifying bioactivity of CDCs. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT01458405.

Examining Inequality in the Public Health Workforce Distribution in the Centers for Disease Control and Prevention (CDCs) System in China, 2008-2017.

OBJECTIVE: Allocation of human resources to address inequalities in the public health system has increasingly attracted societal and political attention. Using the Centers for Disease Control and Prevention (CDCs) system of China as an example, we evaluated inequality in the public health workforce distribution across different regions in China between 2008 and 2017, with the aim of providing information for policymakers to support resource allocation and address growing health inequities. METHODS: We used three standard public health workforce inequality indices - Gini coefficient, Theil L, and Theil T - and spatial autocorrelation analysis to explore spatial clusters of the workforce in different provinces, visualized with geographical tools. RESULTS: The aggregate workforce-to-population ratio decreased from 1.47 to 1.42 per 10,000 population from 2008 to 2017, and was consistently lower than the National Health Commission's (NHC) recommended critical shortage threshold of 1.75. The workforce distribution inequality indices varied by regional socioeconomic and health system development. Geographic clustering of CDCs workforce distribution was evident, with H-H and L-L clusters in western China and the Guangdong-Fujian region, respectively. CONCLUSIONS: Our study addressed key issues for government and policymakers in allocation of public health human resources. There is an urgent need for careful identification of analytic questions that will help carry out public health functions in the new era, alongside policy implications for an equitable distribution of the public health workforce focusing on the western region and low-low cluster areas.

Combination of Mycobacterium indicus pranii and Heat-Induced Promastigotes Cures Drug-Resistant Leishmania Infection: Critical Role of Interleukin-6-Producing Classical Dendritic Cells.

The major issues in available therapeutic modalities against leishmaniasis are cost, toxicity, and the emergence of drug resistance. The aim of this work was to develop a successful therapeutic adjuvant against drug-resistant Leishmania donovani infection by means of combining Mycobacterium indicus pranii with heat-induced promastigotes (HIP). One-month postinfected BALB/c mice were administered subcutaneously with M. indicus pranii (108 cells) and HIP (100 µg) for 5 days. Spleens were harvested for flow cytometric and reverse transcriptase PCR analysis. The antileishmanial effect of the combination strategy was associated with induction of a disease-resolving Th1 and Th17 response with simultaneous downregulation of CD4+ CD25+ Foxp3+ (nTreg) cells and CD4+ CD25- Foxp3- (Tr1) cells in the spleen. The significant expansion of CD4+ TCM (CD4+ CD44hi CD11ahi CD62Lhi) cells was a further interesting outcome of this therapeutic strategy in the context of long-term protection of hosts against secondary infection. Toll-like receptor 2 (TLR2) was also found instrumental in this antiparasitic therapy. Induced interleukin-6 (IL-6) production from expanded CD11c+ CD8α+ (cDC1) and CD11c+ CD11b+ (cDC2) dendritic cells (DCs) but not from the CD11b+ Ly6c+ inflammatory monocytes (iMOs), was found critical in the protective expansion of Th17 as evidenced by an in vivo IL-6 neutralization assay. It also promoted the hematopoietic conversion toward DC progenitors (pre-DCs) from common dendritic cell progenitors (CDPs), the immediate precursors, in bone marrow. This novel combinational strategy demonstrated that expansion of Th17 by IL-6 released from CD11c+ classical DCs is crucial, together with the conventional Th1 response, to control drug-resistant infection.

Infant cardiosphere-derived cells exhibit non-durable heart protection in dilated cardiomyopathy rats.

Stem cells provide a new strategy for the treatment of cardiac diseases; however, their effectiveness in dilated cardiomyopathy (DCM) has not been investigated. In this study, cardiosphere-derived cells (CDCs) were isolated from infants (≤ 24 months) and identified by the cell surface markers CD105, CD90, CD117 and CD45, which is consistent with a previous report, although increased CD34 expression was observed. The molecular expression profile of CDCs from infants was determined by RNA sequencing and compared with adult CDCs, showing that infant CDCs have almost completely altered gene expression patterns compared with adult CDCs. The upregulated genes in infant CDCs are mainly related to the biological processes of cell morphogenesis and differentiation. The molecular profile of infant CDCs was characterized by lower expression of inflammatory cytokines and higher expression of stem cell markers and growth factors compared to adult CDCs. After intramyocardial administration of infant CDCs in the heart of DCM rats, we found that infant CDCs remained in the heart of DCM rats for at least 7 days, improved DCM-induced cardiac function impairment and protected the myocardium by elevating the left ventricular ejection fraction and fraction shortening. However, the effectiveness of transplanted CDCs was reversed later, as increased fibrosis formation instead of angiogenesis was observed. We concluded that infant CDCs, with higher expression of stem cell markers and growth factors, exhibit non-durable heart protection due to limited residence time in the heart of DCM animals, suggesting that multiple administrations of the CDCs or post-regulation after transplantation may be the key for cell therapy in the future.