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On the other hand, thrombosis occurs in thrombocytopenia patients, such as HIT, TTP, ITP, and advanced liver diseases, andcritically ill patients with sepsis. Gene mutations related to platelet GPs, megakaryocytes, vWF, or ADAMTS13 can all lead to thrombocytopenia [[26], [28], [30]] and bleeding of different severities [[32]]. Primary immune thrombocytopenia (ITP) is the most common cause of thrombocytopenia in hematological diseases, in which multiple immune cells play roles in attacking platelets in peripheral blood and megakaryocytes in bone marrow. Major types of thrombocytopenia include primary immune thrombocytopenia, drug-induced thrombocytopenia, heparin-induced thrombocytopenia, thrombotic thrombocytopenia, disseminated intravascular coagulation, gestational thrombocytopenia, and inherited thrombocytopenia. [Extracted from the article]

• Compare advantages and disadvantages of 3C-based measurements. • Discuss about the optimization of various techniques. • Compare different analysis tools and computational system-based automatic analysis. Multiple dimensions of genome organization play critical roles in the regulation of non-coding regions in gene expression in cell/organ development and pathogenesis. Precise measurements of multi-dimensional genome structure ensure data quality and fully depend upon the study design. We here overview the number of methodologies used in the detection and analysis of genome structure and compare advantages and disadvantages of 3C-based, PCR amplification-based, and sequencing-based measurements. We discuss about the optimization of various techniques according to targeted genomic sites, the required resolution, and possible technique biases. Comparison of different analysis tools and computational system-based automatic analysis is evaluated to define more opportunities and challenges of data analysis in 3D genome research. The genome structure is visualized in levels of single genome organized by enhancer-promoter interactions, TAD, and intra-chromosomal and inter-chromosomal interactions between TADs. Thus, methodologies of genome organization multi-dimensions are not only critical in studies on 3D genome-regulated transcriptions, but also in the discovery of disease-specific biomarkers and targets for diagnosis and therapies. [ABSTRACT FROM AUTHOR]

Current methods for the detection of Mycobacterium tuberculosis (Mtb) are either time consuming or require expensive instruments and are thus are not suitable for point-of-care diagnosis. The design, synthesis, and evaluation of fluorogenic probes with high specificity for BlaC, a biomarker expressed by Mtb, are described. The fluorogenic probe CDG-3 is based on cephalosporin with substitutions at the 2 and 7 positions and it demonstrates over 120 000-fold selectivity for BlaC over TEM-1 Bla, the most common β-lactamase. CDG-3 can detect 10 colony-forming units of the attenuated Mycobacterium bovis strain BCG in human sputum in the presence of high levels of contaminating β-lactamases expressed by other clinically prevalent bacterial strains. In a trial with 50 clinical samples, CDG-3 detected tuberculosis with 90 % sensitivity and 73 % specificity relative to Mtb culture within one hour, thus demonstrating its potential as a low-cost point-of-care test for use in resource-limited areas. [ABSTRACT FROM AUTHOR]

Current methods for the detection of Mycobacterium tuberculosis (Mtb) are either time consuming or require expensive instruments and are thus are not suitable for point-of-care diagnosis. The design, synthesis, and evaluation of fluorogenic probes with high specificity for BlaC, a biomarker expressed by Mtb, are described. The fluorogenic probe CDG-3 is based on cephalosporin with substitutions at the 2 and 7 positions and it demonstrates over 120 000-fold selectivity for BlaC over TEM-1 Bla, the most common β-lactamase. CDG-3 can detect 10 colony-forming units of the attenuated Mycobacterium bovis strain BCG in human sputum in the presence of high levels of contaminating β-lactamases expressed by other clinically prevalent bacterial strains. In a trial with 50 clinical samples, CDG-3 detected tuberculosis with 90 % sensitivity and 73 % specificity relative to Mtb culture within one hour, thus demonstrating its potential as a low-cost point-of-care test for use in resource-limited areas. [ABSTRACT FROM AUTHOR]

Primary immune thrombocytopenia (ITP) is an acquired autoimmune disease with multiple immune cells take part in the pathogenesis. Macrophages play multiple roles in both innate and adaptive immune system. The report by Jiani Mo and colleagues identified new biomarkers and explore the role of mitophagy and ferroptosis in ITP pathogenesis. Commentary on: Mo et al. Comprehensive analysis and prediction model of mitophagy and ferroptosis in primary immune thrombocytopenia. Br J Haematol 2024;204:2429‐2442. [ABSTRACT FROM AUTHOR]

Reported herein is the design of fluorogenic probes specific for carbapenem-resistant Enterobacteriaceae (CRE) and they were designed based on stereochemically modified cephalosporin having a 6,7-trans configuration. Through experiments using recombinant b-lactamase enzymes and live bacterial species, these probes demonstrate the potential for use in the specific detection of carbapenemases, including metallob- lactamases in active bacterial pathogens. [ABSTRACT FROM AUTHOR]

Reported herein is the design of fluorogenic probes specific for carbapenem-resistant Enterobacteriaceae (CRE) and they were designed based on stereochemically modified cephalosporin having a 6,7-trans configuration. Through experiments using recombinant β-lactamase enzymes and live bacterial species, these probes demonstrate the potential for use in the specific detection of carbapenemases, including metallo-βlactamases in active bacterial pathogens. [ABSTRACT FROM AUTHOR]

Post-synthesis modification of DNA is an important way of functionalizing DNA molecules. Herein, we describe a method that first enzymatically incorporates a cyanobenzothiazole (CBT)-modified thymidine. The side-chain handle CBT can undergo a rapid and site-specific cyclization reaction with 1,2-aminothiols to afford DNA functionalization in aqueous solution. Another key advantage of this method is the formation of a single stereo/regioisomer in the process, which allows for precise control of DNA modification to yield a single component for aptamer selection work and other applications. [ABSTRACT FROM AUTHOR]

Background: Aplastic anemia (AA) is a kind of bone marrow failure (BMF) characterized by pancytopenia with hypoplasia/aplasia of bone marrow. Immunosuppressive therapy and bone marrow transplantation are effective methods to treat severe aplastic anemia. However, the efficacy is limited by complications and the availability of suitable donors. This study aimed to determine whether any circulating druggable protein levels may have causal effects on AA and provide potential novel drug targets for AA. Methods: Genetic variants strongly associated with circulating druggable protein levels to perform Mendelian randomization (MR) analyses were used. The effect of these druggable protein levels on AA risk was measured using the summary statistics from a large-scale proteomic genome-wide association study (GWAS) and FinnGen database (https://www.finngen.fi/en/access%5fresults). Multivariable MR analyses were performed to statistically adjust for potential confounders, including platelet counts, reticulocyte counts, neutrophil counts, and proportions of hematopoietic stem cells. Results: The data showed that higher level of circulating IFN-γ levels was causally associated with AA susceptibility. The causal effects of circulating IFN-γ levels on the AA were broadly consistent, when adjusted for platelet counts, reticulocyte counts, neutrophil counts and proportions of hematopoietic stem cells. Conclusions: High levels of circulating IFN-γ levels might increase the risk of AA and might provide a potential novel target for AA. Highlights: Genetic variants associated with circulating proteome to perform Mendelian randomization analyses in aplastic anemia. A higher level of circulating IFN-γ levels was causally associated with AA susceptibility. Mendelian randomization of circulating proteome provided large-scale epidemiological evidence and a potential drug target for AA. [ABSTRACT FROM AUTHOR]

Summary: Primary immune thrombocytopenia (ITP) is an acquired autoimmune disease. Cellular and systemic lipid metabolism plays a significant role in the regulation of immune cell activities. However, the role of lipoprotein lipids and apolipoproteins in ITP remains elusive. The automatic biochemistry analyser was used to measure the levels of serum total cholesterol (TC), triglyceride (TG), low‐density lipoprotein cholesterol (LDL‐C), high‐density lipoprotein cholesterol (HDL‐C), apolipoprotein A‐I (apoA‐I), apoB, apoE and lipoprotein a [LP(a)]. Genetic variants strongly associated with circulating lipoprotein lipids and apolipoproteins (LDL‐C, apoB, TG, HDL‐C and apoA‐I) were extracted to perform Mendelian randomization (MR) analyses. Finally, drug‐target MR and passive ITP mice model was used to investigate the potential druggable targets of ITP. Levels of HDL‐C, apoA‐I, decreased and LP(a) increased in ITP patients compared with healthy controls. Low HDL‐C was causally associated with ITP susceptibility. Through drug‐target MR and animal modelling, ABCA1 was identified as a potential target to design drugs for ITP. Our study found that lipid metabolism is related to ITP. The causative association between HDL‐C and the risk of ITP was also established. The study provided new evidence of the aetiology of ITP. ABCA1 might be a potential drug target for ITP. [ABSTRACT FROM AUTHOR]

The condensation reaction between 6‐hydroxy‐2‐cyanobenzothiazole (CBT) and cysteine has been shown for various applications such as site‐specific protein labelling and in vivo cancer imaging. This report further expands the substrate scope of this reaction by varying the substituents on aromatic nitriles and amino thiols and testing their reactivity and ability to form nanoparticles for cell imaging. The structure–activity relationship study leads to the identification of the minimum structural requirement for the macrocyclization and assembly process in forming nanoparticles. One of the scaffolds made of 2‐pyrimidinecarbonitrile and cysteine joined by a benzyl linker was applied to design fluorescent probes for imaging caspase‐3/7 and β‐galactosidase activity in live cells. These results demonstrate the generality of this system for imaging hydrolytic enzymes. [ABSTRACT FROM AUTHOR]

The condensation reaction between 6‐hydroxy‐2‐cyanobenzothiazole (CBT) and cysteine has been shown for various applications such as site‐specific protein labelling and in vivo cancer imaging. This report further expands the substrate scope of this reaction by varying the substituents on aromatic nitriles and amino thiols and testing their reactivity and ability to form nanoparticles for cell imaging. The structure–activity relationship study leads to the identification of the minimum structural requirement for the macrocyclization and assembly process in forming nanoparticles. One of the scaffolds made of 2‐pyrimidinecarbonitrile and cysteine joined by a benzyl linker was applied to design fluorescent probes for imaging caspase‐3/7 and β‐galactosidase activity in live cells. These results demonstrate the generality of this system for imaging hydrolytic enzymes. [ABSTRACT FROM AUTHOR]

Background: Cyclooxygenase (COX)-2 is a rate-limiting enzyme in the biosynthesis of prostanoids, which is mostly inducible by inflammatory cytokines. The participation of COX-2 in the maturation of megakaryocytes has been reported but barely studied in primary immune thrombocytopenia (ITP). Methods: The expressions of COX-2 and Caspase-1, Caspase-3 and Caspase-3 p17 subunit in platelets from ITP patients and healthy controls (HC), and the expressions of COX-2 and CD41 in bone marrow (BM) of ITP patients were measured and analyzed for correlations. The effects of COX-2 inhibitor on megakaryopoiesis and thrombopoiesis were assessed by in vitro culture of Meg01 cells and murine BM-derived megakaryocytes and in vivo experiments of passive ITP mice. Results: The expression of COX-2 was decreased and Caspase-1 and Caspase-3 p17 were increased in platelets from ITP patients compared to HC. In platelets from ITP patients, the COX-2 expression was positively correlated with platelet count and negatively correlated to the expression of Caspase-1. In ITP patients BM, the expression of CD41 was positively correlated with the expression of COX-2. COX-2 inhibitor inhibited the count of megakaryocytes and impaired the maturation and platelet production in Meg01 cells and bone marrow-derived megakaryocytes. COX-2 inhibitor aggravated thrombocytopenia and damaged megakaryopoiesis in ITP murine model. Conclusion: COX-2 plays a vital role in the physiologic and pathologic conditions of ITP by intervening the survival of platelets and impairing the megakaryopoiesis and thrombopoiesis of megakaryocytes. [ABSTRACT FROM AUTHOR]

The article describes the case of a 57-year-old woman diagnosed with T cell/histiocyte-rich large B cell lymphoma. The patient showed autoimmunity affecting multiple systems mimicking systemic lupus erythematosus (SLE). It discusses the link between tumors of lymphoid tissues with autoimmune disorders. The patient who suffered from invasive fungal infection died of respiratory failure four months after diagnosis.

Background: The first‐line therapy is effective for the treatment of primary immune thrombocytopenia (ITP); however, maintaining the long‐term responses remains challenging. Low‐dose decitabine (DAC) has been adopted to treat refractory ITP, while its role in macrophage polarization has not been fully understood. We aimed to investigate the mechanistic role of DAC in M2 macrophage polarization and evaluated its therapeutic effect in ITP. Methods: The M2 monocytes were identified by flow cytometry from peripheral blood mononuclear cells in healthy controls (HCs) and ITP patients. The expression of PPARγ, Arg‐1, DNMT3b and NLRP3, together with IL‐10 plasma levels was measured to examine its function. Bisulfite‐sequencing PCR was used to evaluate the methylation status of PPARγ promoter, and the binding affinity of KLF4 was measured by Cut&Tag. A sh‐PPARγ THP‐1 cell line was created to verify if low‐dose DAC‐modulated M2 macrophage polarization was PPARγ‐dependent. The passive ITP models were used to investigate the therapeutic effects of low‐dose DAC and its role in modulating polarization and immunomodulatory function of macrophages. NLRP3 inflammasome and reactive oxygen species were also tested to understand the downstream of PPARγ. Results: The M2 monocytes with impaired immunoregulation were observed in ITP. After high‐dose dexamethasone (HD‐DXM) treatment, M2 monocytes increased significantly with the elevated expression of PPARγ, Arg‐1 and IL‐10 in CR patients. Low‐dose DAC promoted M2 macrophage polarization in a PPARγ‐dependent way via demethylating the promoter of PPARγ, especially the KLF4 binding sites. Low‐dose DAC alleviated ITP mice by restoring the M1/M2 balance and fine‐tuning immunomodulatory function of macrophages. The downstream of the PPARγ modulation of M2 macrophage polarization might physiologically antagonize NLRP3 inflammasome. Conclusions: Low‐dose DAC promoted M2 macrophage polarization due to the demethylation within the promoter of PPARγ, thus enhanced the KLF4 binding affinity in ITP. [ABSTRACT FROM AUTHOR]

OPLS-DA score plots were used for the pairwise difference polar metabolites analysis among adult CRC, senior CRC and HC groups. The expression of 5-aminovaleric acid and d-allose in adult CRC patients was higher than that of HC and senior CRC patients (Figure 1J,L). Blood samples from CRC patients and healthy control (HC) groups were collected and identified by LC-MS and GC-MS and used for trans-omics analysis (A). Dear Editor, Colorectal cancer (CRC) is third most frequently diagnosed malignancy with the second highest mortality rate among all cancers.[[1], [3]] As CRC survival is highly dependent upon early diagnosis and treatment, novel sensitive and non-invasive detective approaches f are urgently required.[5] CRC is characterized by metabolic reprogramming.[[6]] In present study, using plasma metabolome analysis, a large scale trans-omic network was constructed by connecting polar metabolite data, lipid data, clinical phenoms and survival outcomes of CRC patients. [Extracted from the article]

Summary: Primary immune thrombocytopenia (ITP) is an autoimmune disorder characterized by isolated thrombocytopenia. This bibliometric analysis was applied to identify the characteristics of global scientific output, the hotspots, and frontiers of ITP over the past 10 years. We retrieved publications from 2011 to 2021 from the Web of Science Core Collection (WoSCC). Bibliometrix package, VOSviewer, and Citespace were used to analyse and visualize the trend, distribution, and hotspots of research on ITP. Altogether, there were 2084 papers, written by 9080 authors from 410 organizations in 70 countries/regions, published in 456 journals with 37 160 co‐cited references. In the last decades, the most productive journal was British Journal of Haematology, China was the most productive country. and the most cited journal was Blood. Shandong University was the most productive institution in the field of ITP. NEUNERT C, 2011, BLOOD, CHENG G, 2011, LANCET, and PATEL VL, 2012, BLOOD were the top three most cited documents. "Thrombopoietin receptor agonist", "regulatory T cell" and "sialic acid" were three hotspots of the last decade. And "immature platelet fraction", "Th17", and "fostamatinib" would be research frontiers in the feature. The present study provided a novel insight for future research directions and scientific decision‐making. [ABSTRACT FROM AUTHOR]

Clinical and translational medicine is an ongoing opportunity and challenge to transition science from bench to patient, from patient to bench, and from patient to policy for scientists and clinicians. Of the many objectives, the most important one is to improve the quality of life in patients, including living duration, dignity, emotional well‐being, psychiatric and physical health, as well as independency. Emphasis and redefining concepts has allowed clinical and translational medicine to experience exciting and productive developments. Further discoveries, innovations, validations, and developments in clinical and translational medicine are expected in 2020. The present editorial aims to present the top three most discussed topics with high expectations for translation from clinical investigations and trials into practice and application. [ABSTRACT FROM AUTHOR]

Background: Primary immune thrombocytopenia (ITP) is characterized for the skewed Th differentiation towards Th1 and Th17 cells as well as the impaired number and function of regulatory T cells (Tregs). Tregs are capable of co-expressing effector Th markers in different inflammatory milieu, which probably indicates Treg dysfunction and incompetence to counter over-activated immune responses. Methods: Ninety-two primary ITP patients from March 2013 to December 2018 were included, and proinflammatory plasticity in different Treg compartments, age groups, and TGFBR2 variant carrier status were investigated. Results: Patients were categorized into elderly (n = 44) and younger (n = 48) groups according to an age of 50 years at disease onset. The overall remission rate was 82.6% after first-line regimens, including 47.8% complete remission. TGFBR2 variants were found in 7 (7.6%) patients with three V216I and four T340M heterozygote carriers. ITP patients demonstrated elevated co-expression of IL-17 and decreased co-expression of both IFN-γ and IL-13 than health control (all p < 0.01). The elderly group demonstrated elevated prevalence of TGFBR2 variants (p = 0.037) and elevated co-expression of IL-17 (p = 0.017) in Tregs, while female predominance was found in the younger group (p = 0.037). In the elderly group, TGFBR2 variant carriers demonstrated further elevated co-expression of IL-17 (p = 0.023) and decreased co-expression of both IFN-γ (p = 0.039) and IL-13 (p = 0.046) in the aTreg compartment. Conclusions: Our findings revealed additional aberrations of Treg proinflammatory plasticity in elderly primary ITP patients, and highlighted the potential role of Treg dysfunction and senescence in the pathogenesis and management among these patients. [ABSTRACT FROM AUTHOR]

Review: 22 refs. [ABSTRACT FROM AUTHOR]

The drug resistance limits the optimal efficacy of drugs during target therapies for lung cancer and requires the development of precision medicine to identify and develop new highly selective drugs and more precise tailoring of medicine to the target population. Lung cancer heterogeneity as a potential cause of drug resistance to targeted therapy may foster tumor evolution and adaptation and fade personalized-medicine strategies. The present review elucidates the influence of tumor heterogeneity on drug efficacy and resistance, and discusses potential strategies to combat heterogeneity for cancer treatment. There is an urgent need to discover and develop disease- and biology-specific biomarkers for monitoring the existence and occurrence of lung cancer heterogeneity, testing targeted drugs in clinical trials, and implementing precision medicine for patients. Better understanding of lung cancer heterogeneity will strengthen therapeutic strategies and apply precision medicine to cure the disease. [ABSTRACT FROM AUTHOR]

Background: The role of high-dose dexamethasone in the treatment of immune thrombocytopenic purpura in adults is controversial. We assessed the effectiveness of high-dose dexamethasone as initial treatment in a series of consecutive adults with immune thrombocytopenic purpura. Methods: Consecutive patients with newly diagnosed immune thrombocytopenic purpura and a platelet count of less than 20,000 per cubic millimeter or a platelet count of less than 50,000 per cubic millimeter and clinically significant bleeding were enrolled between January 1997 and December 2000. Oral dexamethasone at a dose of 40 mg per day for four consecutive days was the initial treatment. A response was defined as an increase in the platelet count of at least 30,000 per cubic millimeter and a platelet count of more than 50,000 per cubic millimeter by day 10 after the initiation of treatment. A sustained response was defined as a platelet count of more than 50,000 per cubic millimeter six months after the initial treatment. Results: Of 157 consecutive patients, 125 were eligible. The mean (±SD) platelet count before treatment was 12,200±11,300 per cubic millimeter. A good initial response to high-dose dexamethasone occurred in 106 of the 125 patients (85 percent): the platelet count increased by at least 20,000 per cubic millimeter by the third day of treatment, and the mean platelet count was 101,400±53,200 per cubic millimeter (range, 50,000 to 260,000 per cubic millimeter) one week after the initiation of treatment. Among the 106 patients with a response, 53 (50 percent) had a sustained response; the other 53 (50 percent) had a relapse within six months, most of them (94 percent) within the first three months. A platelet count of less than 90,000 per cubic millimeter on day 10 was associated with a high risk of relapse. The treatment was well tolerated. Conclusions: A four-day course of high-dose dexamethasone is effective initial therapy for adults with immune thrombocytopenic purpura. N Engl J Med 2003;349:831-6. [ABSTRACT FROM AUTHOR]

The current asthma therapies are inadequate for many patients with severe asthma. Pyrroloquinoline quinone (PQQ) is a naturally-occurring redox cofactor and nutrient that can exert a multitude of physiological effects, including anti-inflammatory and antioxidative effects. We sought to explore the effects of PQQ on allergic airway inflammation and reveal the underlying mechanisms. In vitro, the effects of PQQ on the secretion of epithelial-derived cytokines by house dust mite- (HDM-) incubated 16-HBE cells and on the differentiation potential of CD4+ T cells were investigated. In vivo, PQQ was administered to mice with ovalbumin- (OVA-) induced asthma, and lung pathology and inflammatory cell infiltration were assessed. The changes in T cell subsets and signal transducers and activators of transcription (STATs) were evaluated by flow cytometry. Pretreatment with PQQ significantly decreased HDM-stimulated thymic stromal lymphopoietin (TSLP) production in a dose-dependent manner in 16-HBE cells and inhibited Th2 cell differentiation in vitro. Treatment with PQQ significantly reduced bronchoalveolar lavage fluid (BALF) inflammatory cell counts in the OVA-induced mouse model. PQQ administration also changed the secretion of IFN-γ and IL-4 as well as the percentages of Th1, Th2, Th17, and Treg cells in the peripheral blood and lung tissues, along with inhibition the phosphorylation of STAT1, STAT3, and STAT6 while promoting that of STAT4 in allergic airway inflammation model mice. PQQ can alleviate allergic airway inflammation in mice by improving the immune microenvironment and regulating the JAK-STAT signaling pathway. Our findings suggest that PQQ has great potential as a novel therapeutic agent for inflammatory diseases, including asthma. [ABSTRACT FROM AUTHOR]

Background: This study was conducted to investigate the short-term efficacy and safety of rhTPO for the management of severe ITP in the elderly as first-line treatment. Methods: A total of 54 elderly patients with severe ITP were studied, including 39 patients treated with a combination regimen of rhTPO plus standard treatment (glucocorticoid; rhTPO group) and 15 patients treated with glucocorticoid treatment alone (control group). The response rate, time to initial response, peak platelet counts, and time to peak platelet counts were compared, and clinical characteristics correlated with the efficacy of rhTPO were analyzed. The efficacy of rhTPO in the elderly is comparable to the non-elderly in terms of the OR, CR, time to initial response, and peak platelet counts. Results: There were no differences in the overall response (OR) and the complete response (CR) in the rhTPO group compared to the control group. The time to initial response in the rhTPO group was shorter than that in the control group (p = 0.032). In patients without intravenous immunoglobulin (IVIg) and platelet transfusion, the peak platelet counts in the rhTPO group were higher than those in the control group (p = 0.003). Conclusions: Standard glucocorticoid treatment plus rhTPO effectively shortens the time to response and increases platelet counts in the elderly with severe ITP. [ABSTRACT FROM AUTHOR]

Background: Primary immune thrombocytopenia (ITP) is an autoimmune disorder. The existence of autoreactive T cells has long been proposed in ITP. Yet the identification of autoreactive T cells has not been achieved, which is an important step to elucidate the pathogenesis of ITP. Methods: ITP patients' peripheral blood was collected prior to the treatment and one month after initiating dexamethasone treatment per related therapeutic guideline. Serum cytokines were profiled to examine T cell subtypes imbalance using a protein chip. TCR Vβ analysis in CD8+T cells of ITP patients, and TCR CDR3 DNA sequencing of CD4+T and CD8+T cells were performed to determine the autoreactive T cells' clones. Results: Cytokine profiling revealed imbalanced distribution of T cells subtypes, which was confirmed by CD4+T and CD8+T cells' oligoclonal expansion of TCR Vβ analysis and TCR CDR3 DNA sequencing. VDJ segments were found to be more frequently presented in ITP patients, when compared with health controls. There was an individualized CD4+T cell or CD8+T cell CDR3 sequence in each ITP patient. Conclusions: The present study revealed that T cell clones expanded in ITP patients' peripheral blood, and each clone had an individualized TCR CDR3 sequence. The expanded T cell clones preferred to use some specific VDJ segment. Further studies are warranted to get access to individualized treatment such as Car-T in patients with ITP. [ABSTRACT FROM AUTHOR]

Background: Primary immune thrombocytopenia (ITP) is an autoimmune disease. Some ITP patients are associated with pathogen infection undetected with conventional technologies. Investigating the changes of T cells and potential metabolic mechanism are important for better understanding of ITP. Methods: The study enrolled 75 newly diagnosed ITP patients. The pathogens of patients were detected by metagenomic next-generation sequencing (mNGS). Plasma lipids were measured by liquid chromatography-mass spectrometry (LC–MS). CD4 T cell and CD8 T cell were analyzed using flow cytometry. Mitochondrial reactive oxygen species (ROS) and mitochondrial membrane potential were measured by flow cytometry. Seahorse XF real-time ATP rate assay was used to investigate the change of cellular metabolism. Results: Positive plasma pathogens were detected in seven ITP patients. Of them, 5 (71.4%) positive pathogen-ITP patients were no response (NR) after first-line treatment with corticosteroids. Regulatory T cells (Tregs) increased significantly in positive pathogen-ITP patients compared to negative pathogen-ITP patients and healthy controls (HC). Mitochondrial membrane potential of Th17 and Tregs were decreased in positive pathogen-ITP and negative pathogen-ITP patients, compared to HC (all p < 0.05). The overall metabolism flux of positive pathogen-ITP patients was decreased, as compared to HC (p = 0.004), of them a higher proportion of glycolysis-derived ATP and a smaller proportion of oxidative phosphorylation (OXPHOS)-derived ATP were found in Tregs. The ATP rate index of Tregs was decreased significantly in positive pathogen-ITP patients compared to negative pathogen-ITP patients and HC (p < 0.05). Conclusions: Impaired mitochondria function of Tregs in positive pathogen-ITP patients caused a decrease of OXPHOS-derived ATP and overall metabolism flux that might be the cause of steroid resistance in ITP patients. [ABSTRACT FROM AUTHOR]

Background: Recent studies show that myeloid-derived suppressor cells (MDSCs) and M2-like macrophages are involved in the treatment of tumors; however, their therapeutic response role is rarely known in non-small cell lung cancer (NSCLC) during radiotherapy. We aim to explore the dynamic alteration of the circulating MDSCs and M2-like macrophages, to examine their relationship, and to evaluate their therapeutic response value for NSCLC patients in radiotherapy.Methods: Peripheral blood mononuclear cells from healthy controls and NSCLC patients with different radiotherapy phases were isolated to examine the circulating MDSCs and M2-like macrophages by flow cytometry. 40 plasma inflammatory cytokines were measured by multiplex ELISA.Results: In comparison with healthy controls, the percentages of MDSCs and CD68+CD163+M2-like macrophages of NSCLC patients were significantly elevated and were distinctly higher in radiotherapy than in preradiotherapy. MDSCs were correlated positively with CD68+CD163+M2-like macrophages in NSCLC patients in radiotherapy and postradiotherapy. Especially, we found that in comparison with those in the poor group, the percentages of two cells in the good response group were markedly increased during radiotherapy and they had a significantly positive correlation. During radiotherapy, the proportions of MDSCs were clearly increased in adenocarcinoma patients and the percentages of CD68+CD163+M2-like macrophages were markedly elevated in squamous carcinoma patients. We found that after radiotherapy, the expressions of eotaxin, MIP-1β, MCP-1, and BLC were significantly increased in NSCLC patients. Further results showed that the low levels of eotaxin and TNF RII expression before radiotherapy could predict a good therapeutic response. IL-1ra and MIP-1β had a positive relation with MDSCs or CD68+CD163+M2-like macrophages in NSCLC patients during radiotherapy, and eotaxin was correlated with CD68+CD163+M2-like macrophages but not MDSCs in NSCLC patients after radiotherapy.Conclusions: MDSCs and CD68+CD163+M2-like macrophages serve as therapeutic response biomarkers and are associated with the expressions of plasma inflammatory cytokines for NSCLC patients during radiotherapy. [ABSTRACT FROM AUTHOR]

Objectives: Immune thrombocytopenia (ITP) is an autoimmune disease characterised by impaired platelet production and increased platelet destruction. However, the involvement of neutrophils in ITP is yet to be explored. Methods: B‐cell activating factor (BAFF) expression and activation markers of neutrophils, as well as activation of platelets in ITP patients and healthy controls were measured. The interaction of CD62P on platelets and BAFF in neutrophils was analysed by correlation analysis and verified by co‐culture. The effects of neutrophils on apoptosis of acquired immune cells were evaluated in co‐culture systems with or without belimumab. Results: The BAFF expression and activation of neutrophils were increased in active ITP patients. BAFF levels in neutrophils were positively correlated with CD62P+ platelets and neutrophils produced increased BAFF by interfering with CD62P on platelets. Neutrophils inhibited the apoptosis of CD4+, CD8+ and CD19+ cells dependent on BAFF levels, and belimumab could interrupt the effects of neutrophils. Conclusions: Neutrophils were overactivated in ITP patients and participated in the progression of disease by producing excessive BAFF, which could be regulated by CD62P on platelets. Targeting BAFF by belimumab may be a novel potential therapy for ITP. [ABSTRACT FROM AUTHOR]

Background: During pregnancy, mother–child interactions trigger a variety of subtle changes in the maternal body, which may be reflected in the status of peripheral blood mononuclear cells (PBMCs). Although these cells are easy to access and monitor, a PBMC atlas for pregnant women has not yet been constructed. Methods: We applied single‐cell RNA sequencing (scRNA‐seq) to profile 198,356 PBMCs derived from 136 pregnant women (gestation weeks 6 to 40) and a control cohort. We also used scRNA‐seq data to establish a transcriptomic clock and thereby predicted the gestational age of normal pregnancy. Results: We identified reconfiguration of the peripheral immune cell phenotype during pregnancy, including interferon‐stimulated gene upregulation, activation of RNA splicing‐related pathways and immune activity of cell subpopulations. We also developed a cell‐type‐specific model to predict gestational age of normal pregnancy. Conclusions: We constructed a single‐cell atlas of PBMCs in pregnant women spanning the entire gestation period, which should help improve our understanding of PBMC composition turnover in pregnant women. [ABSTRACT FROM AUTHOR]

Spatial transcriptomics is considered as an important part of spatiotemporal molecular images to bridge molecular information with clinical images. Of those potentials and opportunities, the excellent quality of human sample preparation and handling will ensure the precise and reliable information generated from clinical spatial transcriptome. The present study aims at defining potential factors that might influence the quality of spatial transcriptomics in lung cancer, para‐cancer, or normal tissues, pathological images of sections and the RNA integrity before spatial transcriptome sequencing. We categorised potential influencing factors from clinical aspects, including patient selection, pathological definition, surgical types, sample harvest, temporary preservation conditions and solutions, frozen approaches, transport and storage conditions and duration. We emphasis on the relationship between the combination of histological scores with RNA integrity number (RIN) and the unique molecular identifier (UMI), which is determines the quality of of spatial transcriptomics; however, we did not find significantly relevance between them. Our results showed that isolated times and dry conditions of sample are critical for the UMI and the quality of spatial transcriptomic samples. Thus, clinical procedures of sample preparation should be furthermore optimised and standardised as new standards of operation performance for clinical spatial transcriptome. Our data suggested that the temporary preservation time and condition of samples at operation room should be within 30 min and in 'dry' status. The direct cryo‐preservation within OCT media for human lung sample is recommended. Thus, we believe that clinical spatial transcriptome will be a decisive approach and bridge in the development of spatiotemporal molecular images and provide new insights for understanding molecular mechanisms of diseases at multi‐orientations. [ABSTRACT FROM AUTHOR]

Abstract: Fluorescent boronic acids are very useful for the design and synthesis of carbohydrate sensors. In an earlier communication, we first described the effort of developing water soluble fluorescent α-amidoboronic acids, which change fluorescence upon sugar binding. In this report, we describe a general method of functionalizing such boronic acids and their applications in the preparation of bis-α-amidoboronic acids with significantly enhanced binding for oligosaccharides as compared to their monoboronic acid counterparts. The advantages of good water solubility, easy modification to generate diversity, and modularity in synthesis will make α-amidoboronic acids very useful building blocks for future synthesis of boronic acid-based fluorescent sensors. [Copyright &y& Elsevier]

Bicuspid aortic valve (BAV) is characterized by elevated risk of aortic dilatation and aneurysm. Although genetic susceptibility is suspected to influence on the development of BAV aortopathy, clinical application of genetic markers still needs validation in BAV entities with strictly defined phenotypic features. The 'root phenotype' represents a young, male predominant, and severely aortic regurgitant BAV population prone to aortic root dilatation. The present study launched a two-step genetic survey to evaluate the clinical significance of germline genetic markers in BAV patients. The whole-exome sequencing (WES) cohort consisted of 13 BAV patients with 'root phenotype' under the age of 40 years. We identified 28 different heterozygous missense mutations in 19 genes from the WES cohort, among which six variants (COL1A2 R882C, COL5A1 I1161F, ACVRL1 R218W, NOTCH1 P1227S, MYLK S243W, MYLK D717Y) were identified as pathogenic variants via unanimous agreement of in silico prediction tool analysis, and three variants (C1R I345L, TGFBR2 V216I, FBN2 G475V) were identified as recurrent variants. The panel of nine genetic markers was tested in an independent validation cohort of 154 BAV patients consecutively included from January to May 2018 in our institution. The validation cohort demonstrated 71.4% male predominance and the average age of 57 ± 13 years, among which 26.6% showed aortic root dilatation and 66.9% ascending aortic dilatation. Genetic markers were found in 32 patients, including 18 with C1R I345L, 11 with TGFBR2 V216I, 2 with FBN2 G475V, and 1 with both TGFBR2 V216I and MYLK D717Y. BAV patients carrying these genetic markers demonstrated younger age [(51 ± 12) vs. (58 ± 13) years, P = 0.014], more moderate to severe aortic regurgitation (56.2% vs. 33.6%, P = 0.019), elevated prevalence of mitral valve prolapse (9.4% vs. 0.8%, P = 0.028) and aortic root dilatation (62.5% vs. 17.2%, P < 0.001) but not ascending aortic dilatation than those without these markers. The early-onset 'root phenotype' entities displayed great value for BAV genetic surveys. As one of the promising complements of the current risk stratification system, recurrent germline mutations in TGFBR2, C1R, FBN2 genes could be identified and applied as genetic markers of elevated susceptibility for aortic root but not ascending aortic dilatation among BAV patients. [ABSTRACT FROM AUTHOR]

Fluoride has been found to protect boronic acids from copper(i)-mediated decomposition; such findings should be very useful for the preparation of boronic acid-based carbohydrate sensors and boronic acid conjugates using the copper(i)-mediated click reaction. [ABSTRACT FROM AUTHOR]

The intestinal microbiota is essential for the maintenance of the physiology of immune homeostasis. Dysbiosis has been described in some autoimmune diseases, however its role is still elusive in primary immune thrombocytopenia (ITP), which is one kind of autoimmune diseases. This study aimed to characterize the phylogenetic diversity of the fecal microbiota and its relationship with the platelet activation status in patients with ITP. The platelet activation status was assessed by 2 platelet markers, PAC-1 (antibody that recognizes the activated GPIIb/IIIa complex) and CD62p (Platelet surface P-selectin) by flow cytometry. Total DNA was extracted from fecal samples of ITP patients and healthy controls (HC). Sequencing the V4 hypervariable region of bacterial 16S rRNA genes was used to identify the changes in phylogenetic diversity and composition of the intestinal flora. The obtained sequencing reads were assigned to operational taxonomic units (OTUs, 97% sequence identity) and taxonomically classified to assess composition and diversity. The percentage of PAC-1+ platelets in ITP patients was higher than that in control group (p < 0.001), The percentage of CD62p+ and PAC-1+CD62p+ platelets in ITP patients both higher than those in control group (p < 0.001). At the phylum level, eight different phyla were identified in ITP individuals, with a majority of Bacteroidetes (45.96%) and Firmicutes (38.59%), followed by Proteobacteria (11.43%), Fusobacteria (1.29%), and Actinobacteria (1.22%). While in the Healthy volunteers, ten phyla were detected, with a predominance of Firmicutes (50.92%) and Bacteroidetes (34.26%), came before Proteobacteria (13.60%), and Actinobacteria (0.90%). The gut microbiota was skewed in ITP, with an increased proportion of Proteobacteria , Bacteroidetes and Bacteroidetes / Firmicutes ratio, a decreased proportion of Firmicutes compared with HC. Disease specific alterations in diversity was also identified, especially the potential markers (Anaerorhabdus , sutterella , Peptostreptococcaceae , Clostridium _ XI and carnobacteriaceae , p < 0.05) for ITP. The results suggested that the distinct microbiota dysbiosis in ITP characterized by alterations in biodiversity and composition, which could provide insights for diet therapy and fecal microbiota transplantation treatment to cure ITP. There might be somehow compensatory enhancement of platelet activation in ITP patients. And there is associate between platelet activation and intestinal microbiota in patients with ITP. • The microbiota dysbiosis in ITP by alterations in biodiversity and composition. • There might be somehow compensatory of platelet activation in ITP patients. • There is associate between platelet activation and intestinal microbiota in ITP. [ABSTRACT FROM AUTHOR]

Summary: Current first‐line treatments for immune thrombocytopenia (ITP) usually have transient effects and sustained platelet response off therapy remains low. We evaluated whether eltrombopag plus pulsed dexamethasone as first‐line therapy can increase the proportion of patients maintaining platelet counts >50 × 109/l for a prolonged period without further ITP therapy. Treatment consisted of eltrombopag 25–75 mg daily according to platelet response for 12 weeks plus dexamethasone, 40 mg daily for four consecutive days every four weeks for 1–3 courses. Primary endpoint was durable response off therapy defined as maintaining platelet counts >50 × 109/l for more than six months without further ITP therapy. Fifty ITP subjects were enrolled between November 2014 and March 2019. Out of 46 evaluable subjects, 26 (56·5%) had achieved the primary endpoint. The median platelet counts at six months off‐treatment follow‐up were 158 × 109/l. Only two out of 26 responders had relapsed at eight‐ and nine‐month follow‐up. The remaining 24 are still maintaining platelet counts >50 × 109/l, the longest over three years. All subjects tolerated treatment well and no Grade 3 or above adverse effects were reported. Eltrombopag plus pulsed dexamethasone as a first‐line therapy could result in durable response off therapy in a significant number of ITP subjects. [ABSTRACT FROM AUTHOR]

The application of precision medicine concept in clinical work needs a period of practice and experience accumulation. The present article introduced an example of functioning approach named "multidisciplinary therapy strategy of precision medicine" (MDTS‐PM), clinical practice and process, decision‐making, and therapies. The MDTS‐PM integrates multidisciplinary experts and develops real‐time therapeutic strategy based on clinical phenomes and gene sequencing of tissue DNA and circulating DNA. The strength of MDTS‐PM is the combination of dynamical clinical phenomes, genetic information, diagnosis, and treatment to make the therapy more targeted and specific. MDTS‐PM provides comprehensive, whole‐process, and personalized diagnosis and treatment services for patients with complex cancer or complex drug resistance progression; provides guidance for further adjustment of drug use; and establishes a multidisciplinary cooperative team, improves the quality of clinical diagnosis and treatment, and optimizes the process of medical services. [ABSTRACT FROM AUTHOR]

Primary immune thrombocytopenia (ITP) is an autoimmune heterogeneous disorder of which Treg cells are numerically or functionally deficient. It is known that human FoxP3+CD4+ T cells were composed of 3 phenotypically and functionally distinct subpopulations (resting Treg, rTreg; activated Treg, aTreg; and non-suppressive Treg, n-sTreg). The current study was aimed to determine whether these Treg subtypes are altered in ITP patients and the related potential clinical applications. Normal control volunteers and newly diagnosed ITP patients were enrolled in the study. The percentage of Treg cells' subtypes in peripheral blood was examined by flow cytometry before and after the glucocorticoid treatment. The IL-10 production by Treg subtypes was also examined. Treg cell subtypes of aTreg increased, rTreg decreased, and n-s Treg increased in newly diagnosed ITP patients' peripheral blood. The IL-10 production by respective Treg subtype didn't change after the treatment, and aTreg cells had the highest IL-10 yield. Patients who gained remission during follow-up had a higher aTreg cells' percentage than those who did not at the disease diagnosis. Tregs cell subtypes percentage was altered when ITP occurred. The increased aTreg cells at disease diagnosis might predict a better glucocorticoid treatment efficacy. • Our data suggested that Tregs cell subtypes (rTreg cells; aTreg cells; cytokine secreting Treg cells) percentage was altered when ITP occurred. • The increased aTreg cells at disease diagnosis might predict a better glucocorticoid treatment efficacy. • The change of Treg subtypes had prediction value for glucocorticoid treatment in newly diagnosed primary ITP patients. [ABSTRACT FROM AUTHOR]

Primary immune thrombocytopenia is an autoimmune disease, characterized with decreased platelet and increased risk of bleeding. Recent studies have shown the reduction and dysfunction of regulatory T (Treg) cells in ITP patients. CD39 is highly expressed on the surface of Treg cells. It degrades ATP to AMP and CD73 dephosphorylates AMP into adenosine. Then adenosine binds with adenosine receptor and suppresses immune response by activating Treg cells and inhibiting the release of inflammatory cytokines from effector T (Teff) cells. Adenosine receptor has several subtypes and adenosine A2A receptor (A2AR) plays a crucial role especially within lymphocytes. The CD39+ Treg cells and the expression of A2AR showed abnormality in some autoimmune disease. But knowledge of CD39+ Treg cells and A2AR which are crucial in the adenosine immunosuppressive pathway is still limited in ITP. Thirty-one adult patients with newly diagnosed ITP were enrolled in this study. CD39 and A2AR expression was measured by flow cytometry and RT-PCR. The function of CD39 was reflected by the change of ATP concentration detected by CellTiter-Glo Luminescent Cell Viability Assay. CD39 expression within CD4+CD25+ Treg cells in ITP patients was decreased compared to normal controls. After high-dose dexamethasone therapy, response (R) group showed increased CD39 expression within Treg cells while non-response (NR) group did not show any difference in contrast to those before treatment. The expression of A2AR in CD4+CD25− Teff and CD4+CD25+ Treg cells was both lower in ITP patients than that of normal controls. After therapy, CD4+CD25− Teff cells had higher A2AR expression while CD4+CD25+ Treg cells did not show any difference in comparison to that before treatment. The enzymatic activity of CD39 was damaged in ITP patients and improved after high-dose dexamethasone therapy. In ITP, there was not only numerical decrease but also impaired enzymatic activity in CD39+ Treg cells. After high-dose dexamethasone treatment, these two defects could be reversed. Our results also suggested that ITP patients had reduced A2AR expression in both CD4+CD25+ Treg cells and CD4+CD25− Teff cells. CD4+CD25− Teff cells had increased A2AR expression after treatment. [ABSTRACT FROM AUTHOR]

The venous thromboembolism, which may be caused by increased platelet activation, is a risk factor for tumor prognosis. We determined the platelet activation status for diagnosis and predicting postoperative prognosis of hepatocellular carcinoma. We conducted a prospective study of 191 patients diagnosed with HCC at Zhongshan Hospital from April 2016 to July 2016 as well as 99 healthy people. The platelet activation status was assessed by 2 platelet markers, PAC-1 and CD62p, using flow cytometry. The patients were treated with TACE or resection and monitored for ≥6 months. The diagnostic value of marker-positive platelets was determined by the receiver operating characteristic curve and the postoperative value were analyzed using the Kaplan-Meier method and COX regression model. All the 3 groups with high levels of marker-positive platelets were likely to be diagnosed with HCC and the PAC-1+ percentage had the best efficacy. The univariate analysis showed that the levels of PAC-1+ and CD62p+ platelets was risker factors for poor postoperative prognosis after both TACE and resection. Moreover, the multivariate analysis revealed that the level of PAC-1+ platelets was an independent risk factor for poor prognosis. The PAC-1+ percentage of platelets is a new indicator for diagnosis and predicting postoperative prognosis. • A new flow detection platform to assess platelet activation in peripheral blood from HCC patients. • Patients with HCC or poor prognosis had higher levels of PAC-1 and CD62p-positive platelets. • The PAC-1+ percentage of platelets had better efficacy to predict the outcome of HCC patients [ABSTRACT FROM AUTHOR]

Background. Th17/Treg balance skews towards Th17 in ITP patient. IRF4 has been highlighted for its close relationship to the immunosuppressive function of Treg cells and the IL-17 synthesis in CD4+ T cells. This study was aimed at examining the effects of IRF4 to the Th17/Treg cells in patients with ITP. Methods. Treg and Teff cells were isolated from PBMCs of newly diagnosed ITP patients. The percentages of CD4+CD25hiFoxp3+Treg cells and the CD3+CD4+IL-17+Th17 cells were detected by flow cytometry. After being cultured, the supernatants of Tregs were collected for IL-10 concentration test. The IRF4 levels of Tregs were measured. Teffs were cultured alone or with Tregs for 24 hours. Then the supernatants were collected for IL-17 concentration test. The binding intensity of IRF4 to the gene IL-10 in Treg cells was detected by ChIP-qPCR. Metabolic assays for Teffs and Tregs were performed with Agilent Seahorse XF96 Analyzer. Results. The secretion of IL-10 by Tregs was decreased in ITP patients. The intensity of IRF4 binding to IL-10 DNA of Tregs in patients was higher than that of normal controls and Teffs in ITP patients. The expressions of IRF4 of Tregs in ITP patients were remarkably lower than that of healthy controls. The percentage of Th17 cells in healthy controls was significantly increased after IRF4 mRNA silencing. Abnormal metabolism of Treg and Teff cells was found in ITP patients. Conclusion. The skewed ratio of Th17/Treg cells and dysfunction of Treg cells in newly diagnosed ITP patients was at least partly caused by IRF4 dysfunction. The underlying mechanism might be the impact of IRF4 on the metabolism of Treg and Teff cells. [ABSTRACT FROM AUTHOR]

Background: Allograft rejection and infection are the major sources of morbidity and mortality after heart transplant. Early differential diagnosis is clinically crucial but difficult. The aim of the study was to examine serum cytokine profiles associated with each entity and whether such profiles could help to differentiate between them.Methods: Heart allografts from Wistar rats were transplanted to Lewis rats as described by Yokoyama. Cardiac rejection and pulmonary bacterial infection were induced by Cyclosporine cessation and bacteria bronchus injection, and pathologically confirmed. Ninety serological cytokines profiles of the study objects were then simultaneously measured using a biotin label-based cytokine array. The fold change (FC) was used for relative cytokine concentration comparison analysis.Results: Four cytokines in cardiac rejection group were significantly dysregulated as compared to health controls (β -Catenin, 0.51 FC; E-Selectin, 0.62 FC; IFN-gamma, 1.87 FC; and IL-13, 0.60 FC, respectively). In pulmonary infection animals, 11 cytokines were remarkably dysregulated in comparison with the control group (CINC-3, 0.57 FC; CNTF R alpha, 0.59 FC; E-Selectin, 0.58 FC; FSL1,0.62 FC; Hepassocin, 0.64 FC; IL-2, 0.26 FC; IL-13, 0.49 FC; NGFR, 0.57 FC; RAGE, 0.50 FC; TIMP-1, 0.49 FC; and IFN-gamma, 1.77 FC, respectively). Eleven cytokines were significantly up-regulated in cardiac rejection group comparing to the pulmonary infection animals (FSL1, 2.32FC; Fractalkine, 1.65FC; GFR alpha-1, 1.64FC; IL-2, 2.72FC; IL-5, 1.60FC; MMP-2, 1.71FC; NGFR, 2.25FC; TGF-beta1, 1.58FC; TGF-beta3, 1.58FC; Thrombospondin, 1.64FC, and TIMP-1, 1.52FC, respectively).Conclusions: The current study illustrated the disease-specific serological cytokine profiles of allograft rejection and pulmonary bacterial infection after cardiac transplant. Such disease associated cytokine portraits might have the potential for early discrimination diagnosis. [ABSTRACT FROM AUTHOR]

The survival benefits of sorafenib treatment for patients with hepatocellular carcinoma (HCC) are limited due to drug resistance and side effects. Therefore, combinations of sorafenib with other low toxicity drugs, including arsenic trioxide (As2O3) require investigation. The present study aimed to evaluate the potency of apoptosis‑induction by As2O3/sorafenib treatment in HCC cell lines, Huh7, 97H and freshly‑isolated HCC cells, and also to elucidate the underlying mechanism. A total of 10 patients with HCC were enrolled in the present study. Freshly‑isolated HCC cells were purified from HCC tissues collected at surgery. HCC‑cell apoptosis was measured by flow cytometry using proprium iodide/Annexin‑V staining. The impacts of As2O3 and/or sorafenib on Huh7, 97H and fresh‑isolated HCC‑cell proliferation were evaluated by Cell Counting Kit‑8 assay. The expression of TNF‑related apoptosis‑inducing ligand (TRAIL) was determined by reverse transcription‑quantitative polymerase chain reaction and western blotting. The downregulation of TRAIL protein expression was achieved using small interfering RNA. The combination of As2O3 and sorafenib had anti‑proliferative and pro‑apoptotic effects in the liver cancer cell line, Huh7, via increased expression of TRAIL, but not in 97H cells. TRAIL‑knockdown increased the drug‑resistance of Huh7 cells. Freshly‑isolated HCC cells were more sensitive to the As2O3 and sorafenib combination than the single drug treatments. Overall, the combination of As2O3 and sorafenib demonstrated potent anti‑tumor activity in Huh7 and freshly‑isolated HCC cells via a TRAIL‑dependent pathway. This may be a potential therapeutic approach for advanced HCC treatment. [ABSTRACT FROM AUTHOR]

Abstract: In the era of intensity modulation radiation therapy (IMRT), no prospective randomized trial has evaluated the efficacy of adjuvant therapies such as adjuvant concurrent chemoradiotherapy (CCRT), adjuvant sequential chemotherapy and radiotherapy (CT‐RT), and adjuvant CT alone in resectable pancreatic adenocarcinoma (PA). Through propensity score matching, we designed a nationwide, population‐based, head‐to‐head cohort study to determine the effects of dissimilar adjuvant treatments on resectable PA. We minimized the confounding of various adjuvant treatment outcomes among the following resectable PA groups of patients from the Taiwan Cancer Registry database: group 1, adjuvant CCRT; group 2, adjuvant sequential CT‐RT; and group 3, adjuvant CT alone. All the studied techniques are IMRTs. The matching process yielded a final cohort of 588 patients (196, 196, and 196 patients in groups 1, 2, and 3, respectively). In both univariate and multivariate Cox regression analyses, adjusted hazard ratios (aHRs; 95% confidence interval [CI]) of death derived for the adjuvant CCRT and adjuvant sequential CT‐RT cohorts compared with the adjuvant CT alone cohort were 0.398 (0.314–0.504) and 0.307 (0.235–0.402), respectively. A combination of adjuvant IMRT and CT for resectable PA treatment improves survival to a greater extent than does adjuvant CT alone. [ABSTRACT FROM AUTHOR]

Phasor measurement units (PMUs) have been widely deployed in modern power grids, which provides a great opportunity for high-precision and real-time power system state estimation. If power networks are completely observable by PMUs, linear state estimation can be achieved with massive synchronous data. In this paper, the analysis of phasor error is presented and a complex number weighted least squares (CWLS) algorithm for state estimation is proposed, which shows high computational efficiency and stronger robustness to phasor errors. Meanwhile, self-adaptive weight and bad data identification techniques are developed to enhance the CWLS’s performance. Test results on various IEEE test systems and the realistic power grid validate the effectiveness and superiority of the proposed CWLS algorithm, outperforming the conventional weighted least squares (WLS) state estimation method as well as other existing industrial-grade approaches. [ABSTRACT FROM AUTHOR]

Single cell heterogeneity has already been highlighted in cancer classification, diagnosis, and treatment. Recent advanced technologies have gained more ability to reveal the heterogeneity on single cell level. In this review, we listed various detection targets applied in single cell study, including tumor tissue cells, circulating tumor cells (CTCs), disseminated tumor cells (DTCs), circulating tumor DNA (ctDNA), cell-free DNA (cfDNA), and cancer stem cells (CSCs). We further discussed and compared detection methods using these detection targets in different fields to reveal single cell heterogeneity in cancer. We focused not only on the methods that have already been established and validated, but also on newly developed methods. In morphology and phenotype, the methods mainly included cell imaging and immune-staining. In genomics and proteomics, the main methods were single cell sequencing and single cell western blotting. Collectively, from using these methods, we can have a better understanding of the single cell variation, as well as what kind of variation it is and how the variation works. Our observations imply that study on single cell heterogeneity in cancer is an important step to precision medicine. The development of technologies in detection of single cell heterogeneity will be sure to improve the diagnosis and treatment in cancer. [ABSTRACT FROM AUTHOR]

Background B cells play a critical role in the pathogenesis of immune thrombocytopenia (ITP), and toll-like receptor (TLR) signaling is essential for the activation of autoreactive B cells. The objective of this study was to investigate the expression profile of TLR signaling molecules in circulating and splenic CD19 + B cells isolated from ITP patients. Methods CD19 + B cells were magnetically isolated from peripheral blood and splenocytes. Human Toll-Like Receptor Signaling Pathway RT 2 Profiler™ PCR Array was used to determine the differences in mRNA expression of 84 TLR signaling pathway genes between ITP patients and controls. Flow cytometry was used to investigate intracellular expression of cytokines (IL-1β and IL-10). Results A total of 31 genes involving TLR signaling pathways were differentially transcribed in circulating CD19 + B cells, among which 27 were up-regulated in ITP. By comparison, differentially transcribed genes amounted to 39 in splenic B cells in ITP, among which only two were down-regulated. Up to 18 TLR signaling molecules exhibited up-regulated transcriptional levels both in splenic B cells and in circulating B cells in ITP. However, Only IL-10 and IL-1β were significantly upregulated in both the circulating and splenic B cells of patients with ITP. Intracellular staining of IL-10 and IL-1β confirmed the results of PCR Array. Conclusions The expression of TLRs and downstream cytokines, including IL-10 and IL-1β, is up-regulated in circulating and splenic B cells in ITP patients, suggesting that activated TLR signaling pathways in B cells may play dual roles in the pathophysiology of primary ITP. [ABSTRACT FROM AUTHOR]

Slow growth of Mycobacterium tuberculosis, the causative agent of tuberculosis, hinders advancement in all areas of research toward prevention and treatment. Real-time imaging with reporter enzyme fluorescence (REF) that uses custom fluorogenic substrates for bacterial enzymes allows rapid and specific detection of M. tuberculosis in live animals. We have synthesized a novel REF substrate, CNIR800, that carries a near-infrared (NIR) fluorochrome IRDye 800CW, with a quencher connected through the lactam ring that is hydrolyzed by the enzyme BlaC (β-lactamase) that is naturally expressed by M. tuberculosis. CNIR800 produces long-wavelength emission at 795 nm upon excitation (745 nm) and exhibits significantly improved signal to noise ratios for detection of M. tuberculosis. The detection threshold with CNIR800 is approximately 100 colony-forming units (CFU) in vitro and <1000 CFU in the lungs of mice. Additionally, fluorescence signal from cleaved CNIR800 reaches maximal levels 4-6 hours after administration in live animals, allowing accurate evaluation of antituberculous drug efficacy. Thus, CNIR800 represents an excellent substrate for accurate detection of M. tuberculosis rapidly and specifically in animals, facilitating research toward understanding pathogenic mechanisms, evaluation of therapeutic outcomes, and screening new vaccines. [ABSTRACT FROM AUTHOR]

Highlights: [•] Cytokines play important role in the pathogenesis and the progression of ITP. [•] Cytokines could be used as biomarkers for ITP diagnosis and treatment. [•] In particular, IL-5, IL-6, IL-13 and GRO might be used as markers of ITP relapse. [ABSTRACT FROM AUTHOR]

Background & Aims Thrombocytopaenia is a frequent feature in patients with HBV-related liver disease. Its underlying mechanism is not fully understood. Multiple factors might contribute to the development of thrombocytopaenia. In this study, we investigated the reticulated platelets ( RP), glycocalicin ( GC), serum thrombopoietin ( TPO) and platelet glycoprotein ( GP) in different stages of the disease. Methods One hundred and fourteen patients with HBV-related liver disease (30 with chronic hepatitis B ( CHB), 20 patients in Child A without thrombocytopaenia, 19 patients in Child A with thrombocytopaenia, 45 in Child B/C with thrombocytopaenia) and 25 normal controls ( NC) were enrolled. Liver cirrhosis ( LC) was classified according to modified Child-Turcotte-Pugh ( CTP) score. Serum TPO levels and GC were measured by ELISA. RP and platelet glycoprotein ( GP) expression were detected by flow cytometry. Results The TPO levels of patients with LC were significantly lower than that of controls, even in patients of Child A without thrombocytopaenia group. Serum TPO level was positively correlated ( r = 0.65, p < 0.01) with serum albumin in Child B/C group. Both the RP percentages and the glycocalicin index ( GCI) levels were significantly higher in patients groups including CHB and Child A without thrombocytopaenia than that of normal controls. A negative correlation existed in HBV DNA copies and the GPs% in patients with CHB and Child A without thrombocytopaenia. Conclusion Abnormal platelet production, destruction and platelet-specific glycoproteins levels were detected before the occurrence of thrombocytopaenia in HBV-related liver disease, indicating that multiple mechanisms might play roles in thrombocytopaenia in HBV-infected patients. [ABSTRACT FROM AUTHOR]

Primary immune thrombocytopenia (ITP) is an autoimmune heterogeneous disorder that is characterized by decreased platelet count. The interleukin-23 receptor (IL-23R) has been identified as a susceptibility gene for the development of multiple autoimmune diseases. To investigate the possible association of IL-23R gene single-nucleotide polymorphisms (SNPs) with ITP and the association with the clinical outcome of pulsed high-dose dexamethasone (HD-DXM) therapy, four SNPs in the IL-23R gene, rs10889677, rs1884444, rs7517847, and rs11209032, were tested in a cohort of 75 ITP subjects and 81 controls by direct sequencing. IL-23R rs1884444 GT/TT variant genotypes were observed to be associated with significantly increased risk of ITP as compared with controls (GT/TT vs. GG: odds ratio (OR) 2.776, 95 % confidence intervals (CI) 1.086-7.090, p = 0.028). However, other three SNPs revealed no statistically significant differences between patients and controls (rs10889677 CA/AA vs. CC: OR 2.200, 95 % CI 0.727-6.661, p = 0.155; rs11209032 GA/AA vs. GG: OR 0.747, 95 % CI 0.379-1.472, p = 0.399; rs7517847 TG/GG vs. TT: OR 1.031, 95 % CI 0.544-1.956, p = 0.925). Furthermore, IL-23R SNPs revealed no association with clinical outcome of HD-DXM therapy. This study suggests that polymorphism in the IL-23R gene, rs1884444, indicates a significant association with susceptibility to ITP in a recessive genetic model but does not have association with the clinical outcome of HD-DXM therapy. [ABSTRACT FROM AUTHOR]