Efficacy and safety of bispecific antibodies vs. immune checkpoint blockade combination therapy in cancer: a real-world comparison.

Emerging tumor immunotherapy methods encompass bispecific antibodies (BSABs), immune checkpoint inhibitors (ICIs), and adoptive cell immunotherapy. BSABs belong to the antibody family that can specifically recognize two different antigens or epitopes on the same antigen. These antibodies demonstrate superior clinical efficacy than monoclonal antibodies, indicating their role as a promising tumor immunotherapy option. Immune checkpoints are also important in tumor immunotherapy. Programmed cell death protein-1 (PD-1) is a widely acknowledged immune checkpoint target with effective anti-tumor activity. PD-1 inhibitors have demonstrated notable therapeutic efficacy in treating hematological and solid tumors; however, more than 50% of patients undergoing this treatment exhibit a poor response. However, ICI-based combination therapies (ICI combination therapies) have been demonstrated to synergistically increase anti-tumor effects and immune response rates. In this review, we compare the clinical efficacy and side effects of BSABs and ICI combination therapies in real-world tumor immunotherapy, aiming to provide evidence-based approaches for clinical research and personalized tumor diagnosis and treatment.

Dissecting T-cell heterogeneity in esophageal squamous cell carcinoma reveals the potential role of LAIR2 in antitumor immunity.

Esophageal squamous cell carcinoma (ESCC), one of the most commonly diagnosed and lethal malignant diseases, has a complex tumor ecosystem. An obvious requirement for T-cell-mediated tumor control is the infiltration of tumor-reactive T cells into the tumor. Here, we obtained detailed T-cell compositions in both ESCC tumors and matched peripheral blood mononuclear cells (PBMCs) at single-cell resolution. We demonstrated that T cells in tumors and PBMCs had different compositions and functional states. ESCC tumors were rich in Treg and exhausted T cells but poor in cytotoxic and naïve T cells compared with PBMCs. The exhausted T cells showed higher exhausted signature in tumors than in PBMCs, while the cytotoxic T cells exhibited higher cytotoxic signature in PBMCs than in tumors. Our data indicated an immunosuppressive status and a defect at the level of T-cell priming in the tumor microenvironment. Leukocyte-associated Ig-like receptor-2 (LAIR2), a soluble collagen receptor that prevents the binding of human leukocyte-associated Ig-like receptor-1 (LAIR1) to collagens, was predominantly expressed in proliferating CD8+ T and Treg cells in tumors but in cytotoxic cells in PBMCs. LAIR2 could inhibit tumor metastasis, invasion, and collagen deposition via suppressing transforming growth factor-ß signaling. These findings revealed differential T-cell populations in tumors and PBMCs and provided convincing evidence that LAIR2 acted as a tumor suppressor.

Robust binary fringe generation method with defocus adaptability.

Current binary defocus technology mainly focuses on fringe generation suitable for specific frequencies without considering fringe adaptability for defocus-degree variation, which decreases the measuring accuracy for this scenario. To achieve a high-quality measurement, we propose a robust binary fringe generation method to minimize the phase error caused by changes in defocus and the random error in measurement. In the method, we establish a complete phase error model and construct a novel objective function, to the best of our knowledge, to optimize the binarization threshold of each pixel. Through derivation of the threshold gradient calculation formula, we quickly obtain optimal binary fringes that can adapt to different fringe pitches and various degrees of defocus. The experimental results verify that the proposed method can generate robust binary fringes adaptive to different fringe pitches and defocus degree variation, and thus achieve high-quality 3D measurements.

MMP-7 affects peritoneal ultrafiltration associated with elevated aquaporin-1 expression via MAPK/ERK pathway in peritoneal mesothelial cells.

Peritoneal membrane dysfunction and the resulting ultrafiltration failure are the major disadvantages of long-term peritoneal dialysis (PD). It becomes increasingly clear that mesothelial cells play a vital role in the pathophysiological changes of the peritoneal membrane. Matrix metalloproteinases (MMPs) function in the extracellular environment of cells and mediate extracellular matrix turnover during peritoneal membrane homeostasis. We showed here that dialysate MMP-7 levels markedly increased in the patients with PD, and the elevated MMP-7 level was negatively associated with peritoneal ultrafiltration volume. Interestingly, MMP-7 could regulate the cell osmotic pressure and volume of human peritoneal mesothelial cells. Moreover, we provided the evidence that MMP-7 activated mitogen-activated protein kinases (MAPKs)-extracellular signal-regulated kinase 1/2 (ERK) pathway and subsequently promoted the expression of aquaporin-1 (AQP-1) resulting in the change of cell osmotic pressure. Using a specific inhibitor of ERK pathway abrogated the MMP-7-mediating AQP-1 up-regulation and cellular homeostasis. In summary, all the findings indicate that MMP-7 could modulate the activity of peritoneal cavity during PD, and dialysate MMP-7 might be a non-invasive biomarker and an alternative therapeutic target for PD patients with ultrafiltration failure.

High dynamic defocus response method for binary defocusing fringe projection profilometry.

The measurement accuracy of high-speed binary defocusing fringe projection profilometry depends on the fringe pitch and defocus degree. During the measurement process, the degree of defocus changes with the measurement depth of the scenes. This makes it difficult to obtain a suitable defocus degree and achieve high-precision measurement owing to dynamic changes in the measurement object or environment. To address this problem, we propose a highly dynamic defocus response method to adaptively adjust fringe pitches for binary defocusing fringe projection profilometry. As the defocus degree changes significantly, the proposed method can respond quickly and adjust the fringe pitches adaptively to the scenes. Therefore, a high-precision dynamic measurement can be achieved for the current measuring scene. In this study, considering the effect of random error and nonlinear error, we established a complete phase-error model and used it as an optimization function. Based on this function, we obtained the optimal fringe pitch expression with the defocus degree and harmonic response parameters as variables. With the proposed method, we can obtain the defocus degree and harmonic response parameters during the measurement process and calculate the optimal fringe pitches for the current scenes. Thus, the proposed method can dynamically adapt to the measuring depth change and achieve an accurate measurement without modifying any hardware parameters.

LINC00449 regulates the proliferation and invasion of acute monocytic leukemia and predicts favorable prognosis.

Acute myeloid leukemia (AML) is a highly aggressive disease that causes high mortality. Long noncoding RNA (lncRNA) have studied in recent years that could be a potential biomarker and therapeutic target. Therefore, it is urgently necessary to explore the novel lncRNAs in AML. Microarray analysis was performed to determine the differentially expressed lncRNAs between mononuclear cells of AML and normal samples. The biological function of lncRNA on cell proliferation and migration was measured in vitro. The predicted downstream target of lncRNA was validated by dual-luciferase reporter assay, RNA immunoprecipitation, RNA pull-down, and rescue experiments. The tumor formation and metastasis study were conducted in vivo. The expression of lncRNA in clinical samples was determined by a quantitative reverse transcription-polymerase chain reaction. LINC00449 was one of the most differentially expressed lncRNA which is mainly located in the cytoplasm. We found that overexpression of LINC00449 could inhibit the cell proliferation and invasion of AML cells in vitro and in vivo. Besides, miR-150 was identified as the downstream target gene that was negatively regulated by LINC00449 and FOXD3 was targeted by miR-150. The results were confirmed by dual-luciferase reporter assay, RNA immunoprecipitation, RNA pull-down, rescue experiments, and in vivo assays. Patients with AML with high expression of LINC0049 may characterize a favorable survival. All the above-mentioned findings indicated that the LINC00449/miR-150/FOXD3 signaling pathway might represent a novel prognostic biomarker or therapeutic target for the treatment of AML.

miR-183-5p Inhibits Occurrence and Progression of Acute Myeloid Leukemia via Targeting Erbin.

Erbin has been shown to have significant effects on the development of solid tumors. However, little is known about its function and regulatory mechanism in hematological malignancies. The biological function of Erbin on cell proliferation was measured in vitro and in vivo. The predicted target of Erbin was validated by dual-luciferase reporter assay and rescue experiment. We found that overexpression of Erbin could inhibit the cell proliferation and promote the cell differentiation of acute myeloid leukemia (AML) cells, whereas depletion of Erbin could enhance the cell proliferation and block the cell differentiation in AML cells in vitro and in vivo. Besides, miR-183-5p was identified as the upstream regulator that negatively regulated the Erbin expression. The results were confirmed by dual-luciferase reporter and RNA pull-down assay. Furthermore, we found that miR-183-5p negatively regulated Erbin, resulting in enhanced cell proliferation of AML cells via activation of RAS/RAF/MEK/ERK and PI3K/AKT/FoxO3a pathways. The activation of RAS/RAF/MEK/ERK and PI3K/AKT/FoxO3a pathways was mediated by Erbin interacting with Grb2. These results were also validated by rescue experiments in vitro and in vivo. All above-mentioned findings indicated that the miR-183-5p/Erbin signaling pathway might represent a novel prognostic biomarker or therapeutic target for treatment of AML.

A novel protein encoded by a circular RNA circPPP1R12A promotes tumor pathogenesis and metastasis of colon cancer via Hippo-YAP signaling.

BACKGROUND: It has been well established that circular RNAs (circRNAs) play an important regulatory role during tumor progression. Recent studies have indicated that even though circRNAs generally regulate gene expression through miRNA sponges, they may encode small peptides in tumor pathogenesis. However, it remains largely unexplored whether circRNAs are involved in the tumorigenesis of colon cancer (CC). METHODS: The expression profiles of circRNAs in CC tissues were assessed by circRNA microarray. Quantitative real-time PCR, RNase R digestion assay and tissue microarray were used to confirm the existence and expression pattern of circPPP1R12A. The subcellular distribution of circPPP1R12A was analyzed by nuclear mass separation assay and fluorescence in situ hybridization (FISH). SDS-PAGE and LC/MS were employed to evaluate the protein-coding ability of circPPP1R12A. CC cells were stably transfected with lentivirus approach, and cell proliferation, migration and invasion, as well as tumorigenesis and metastasis in nude mice were assessed to clarify the functional roles of circPPP1R12A and its encoded protein circPPP1R12A-73aa. RNA-sequencing and Western blotting analysis were furthered employed to identify the critical signaling pathway regulated by circPPP1R12A-73aa. RESULTS: We firstly screened the expression profiles of human circRNAs in CC tissues and found that the expression of hsa_circ_0000423 (termed as circPPP1R12A) was significantly increased in CC tissues. We also found that circPPP1R12A was mostly localized in the cytoplasm of CC cells. Kaplan-Meier analysis showed that patients with higher levels of circPPP1R12A had a significantly shorter overall survival. By gain- and loss-of-function approaches, the results suggested that circPPP1R12A played a critical role in proliferation, migration and invasion of CC cells. Furthermore, we showed that circPPP1R12A carried an open reading frame (ORF), which encoded a functional protein (termed as circPPP1R12A-73aa). Next, we found that PPP1R12A-C, not circPPP1R12A, promoted the proliferation, migration and invasion abilities of CC in vitro and in vivo. Finally, we identified that circPPP1R12A-73aa promoted the growth and metastasis of CC via activating Hippo-YAP signaling pathway. In addition, the YAP specific inhibitor Peptide 17 dramatically alleviated the promotive effect of circPPP1R12A-73aa on CC cells. CONCLUSIONS: In the present study, we illustrated the coding-potential of circRNA circPPP1R12A in the progression of CC. Moreover, we identified that circPPP1R12A-73aa promoted the tumor pathogenesis and metastasis of CC via activating Hippo-YAP signaling pathway. Our findings might provide valuable insights into the development of novel potential therapeutic targets for CC.

B7-H3 Overexpression Predicts Poor Survival of Cancer Patients: A Meta-Analysis.

BACKGROUND: B7-H3 exhibits altered expression in various cancers. However, the correlation between B7-H3 expression and prognosis of cancer patients remains controversial. Therefore, we elicit a meta-analysis to investigate the potential value of B7-H3 in the prognostic prediction in human cancers. MATERIALS AND METHODS: We searched PubMed (last update by June 15th, 2016) to identify studies assessing the effect of B7-H3 on survival of cancer patients. Hazard ratios (HRs) for overall survival (OS), recurrence free survival (RFS) and progression-free survival (PFS) from individual studies were calculated and pooled by using a random-effect or fix-effect model, and heterogeneity and publication bias analyses were also performed. RESULTS: Data from 24 observational studies consisting of 4141 patients were summarized. An elevated baseline B7-H3 was significantly correlated with poor OS (pooled HR = 2.09; 95% CI =1.60-2.74; P < 0.001). Differences across subgroups of tumor type (P = 0.324), year of publication (P = 0.431), ethnicity (P = 0.940), source of HR (P = 0.145), analysis type (P = 0.178) and sample size (P = 0.909) were not significant. Furthermore, high B7-H3 expression also predicted a significantly poor RFS (pooled HR = 1.39; 95% CI = 1.11-1.75; P = 0.004) but not PFS. CONCLUSIONS: This meta-analysis clarifies that elevated B7-H3 expression is significantly associated with poor survival in cancer patients.

Prognostic Significance of MiRNA in Patients with Diffuse Large B-Cell Lymphoma: a Meta-Analysis.

INTRODUCTION: This pooled analysis study aimed to reveal the prognostic relevance of microRNAs (miRNAs) in patients with diffuse large B-cell lymphoma (DLBCL). MATERIALS AND METHODS: We examined the impact of miRNAs on clinical outcome. Eligible studies were identified and quality assessed using multiple search strategies. Data were extracted from included studies which correlated survival with expression of miRNAs (serum or tissue). RESULTS: We pooled proper studies, and combined the hazard ratios with 95% confidence intervals to estimate strength of the correlations. There were 18 studies including 1950 patients with DLBCL eligible for pooled analysis. We found significant combined HRs for poor overall survival for high expression of miR-21 and low expression of miR-224 in tumor tissue, but for favorable relapse free survival for high expression of miR-21 in serum. Progression free survival was shortened in patients with low expression of miR-199a/b, miR-146b-5p, miR-224 and high expression of miR-222. CONCLUSION: MiRNAs may act as independent prognostic factors in patients with DLBCL, and useful in risk stratification.

Lower Bmi-1 Expression May Predict Longer Survival of Colon Cancer Patients.

BACKGROUND: This study aimed to investigate the Bmi-1 expression and the clinical significance in colon cancer (CC). PATIENTS AND METHODS: Bmi-1 expression in tumor tissue and the corresponding normal tissue was detected using immunohistological staining. The correlations between Bmi-1 expression and clinicopathological characteristics and the overall survival (OS) time were analyzed. RESULTS: The median H-scores of Bmi-1 in CC tissues and the corresponding tissues were 80.0 (0-270) and 5.0 (0-90), with no statistically significant difference (Z=-13.7, P<0.001). Bmi-1 expression in CC tissues was not statistically correlated with any characteristics. The median OS times for CC patients with high or low Bmi-1 expression were 53.7 months and 44.9 months, respectively, with no statistically significant difference (P = 0.123). The survival rates of patients with low Bmi-1 expression were higher than those of patients with high Bmi-1 expression but the differences were not statistically significant. CONCLUSION: Bmi-1 expression in CC tissue is significantly higher than that in corresponding normal tissue. While there may be a trend towards improved survival, this is not statistically significant.

Emerging immune checkpoints for cancer therapy.

BACKGROUND: Immunotherapy with immune checkpoint inhibitors has emerged as promising treatment modality for cancer based on the success of anti-CTLA-4 and -PD-1/PD-L1 antibodies. LAG-3 and TIM-3 are two new immune checkpoints. The aim of this work is to review the role and application of LAG-3 and TIM-3 for cancer immunotherapy. MATERIAL AND METHODS: Literatures were searched and collected in Medline/PubMed. RESULTS: LAG-3 is presented as a CD4 homolog type I transmembrane protein which binds MHC class II molecules. LAG-3 negatively regulates T cell proliferation, homeostasis and function. IMP321 is formed of an extracellular portion of human LAG-3 fused to the Fc fraction of human IgG1 and has shown increased T cell responses and tolerability in phase I studies on advanced renal cell cancer. When combined with paclitaxel, IMP321 has exerted immune enhancement and tumor inhibition with no significant IMP321-related adverse events. TIM-3 belongs to the TIM family and mainly negatively regulates Th1 immunity. The TIM-3/galectin-9 pathway contributes to the suppressive tumor microenvironment. TIM-3 overexpression is associated with poor prognosis in a variety of cancers. Both LAG-3 and TIM-3 are coexpressed with other immune checkpoints. The application of LAG-3 or TIM-3 does play an important role in anti-tumor responses, and maybe better when combing with anti-CTLA-4 and anti-PD-1/L1 antibodies. CONCLUSIONS: These two immune checkpoints play crucial roles in cancer development and may be used in future clinical practice of cancer therapy.

HERC2 promotes inflammation-driven cancer stemness and immune evasion in hepatocellular carcinoma by activating STAT3 pathway.

BACKGROUND: Hepatic inflammation is a common initiator of liver diseases and considered as the primary driver of hepatocellular carcinoma (HCC). However, the precise mechanism of inflammation-induced HCC development and immune evasion remains elusive and requires extensive investigation. This study sought to identify the new target that is involved in inflammation-related liver tumorigenesis. METHODS: RNA-sequencing (RNA-seq) analysis was performed to identify the differential gene expression signature in primary human hepatocytes treated with or without inflammatory stimulus. A giant E3 ubiquitin protein ligase, HECT domain and RCC1-like domain 2 (HERC2), was identified in the analysis. Prognostic performance in the TCGA validation dataset was illustrated by Kaplan-Meier plot. The functional role of HERC2 in HCC progression was determined by knocking out and over-expressing HERC2 in various HCC cells. The precise molecular mechanism and signaling pathway networks associated with HERC2 in HCC stemness and immune evasion were determined by quantitative real-time PCR, immunofluorescence, western blot, and transcriptomic profiling analyses. To investigate the role of HERC2 in the etiology of HCC in vivo, we applied the chemical carcinogen diethylnitrosamine (DEN) to hepatocyte-specific HERC2-knockout mice. Additionally, the orthotopic transplantation mouse model of HCC was established to determine the effect of HERC2 during HCC development. RESULTS: We found that increased HERC2 expression was correlated with poor prognosis in HCC patients. HERC2 enhanced the stemness and PD-L1-mediated immune evasion of HCC cells, which is associated with the activation of signal transducer and activator of transcription 3 (STAT3) pathway during the inflammation-cancer transition. Mechanically, HERC2 coupled with the endoplasmic reticulum (ER)-resident protein tyrosine phosphatase 1B (PTP1B) and limited PTP1B translocation from ER to ER-plasma membrane junction, which ameliorated the inhibitory role of PTP1B in Janus kinase 2 (JAK2) phosphorylation. Furthermore, HERC2 knockout in hepatocytes limited hepatic PD-L1 expression and ameliorated HCC progression in DEN-induced mouse liver carcinogenesis. In contrast, HERC2 overexpression promoted tumor development and progression in the orthotopic transplantation HCC model. CONCLUSION: Our data identified HERC2 functions as a previously unknown modulator of the JAK2/STAT3 pathway, thereby promoting inflammation-induced stemness and immune evasion in HCC.

[Drug resistance of extended-spectrum-ß-lactamases-producing bacteria in children with hematological malignancy after chemotherapy].

OBJECTIVE: To study the prevalence and drug resistance of extended-spectrum-ß-lactamases (ESBLs)-producing bacteria in blood culture isolated from children with hematological malignancy after chemotherapy. METHODS: Blood samples taken from 3264 children with hematological malignancy and severe infection following chemotherapy between 2002 and 2008 were cultured using the Bact/ALTER 3D blood culture system. VITEK 60 automicroscan was used to identify viral species and to conduct drug resistance tests. The results were indentified according to National Committee for Clinical Laboratory Standard guidelines. RESULTS: Fifty-eight strains of Escherichia coli and fifty-one strains of Klebsiella pneumoniae were isolated. Thirty-eight strains of Escherichia coli and nineteen strains of Klebsiella pneumoniae were ESBLs-producing and these ESBLs-producing strains were less susceptible than those that were non-ESBLs-producing to most antibiotics. Both ESBL- and non-ESBL-producing strains were susceptible to imipenem, piperacillin/tazobactam and amikacin. CONCLUSIONS: The prevalence of ESBLs-producing bacteria is high in childrn with hematological malignancy and infection following chemotherapy. ESBLs-producing bacteria are resistant to common antibiotics, suggesting that antibiotic treatment based on the result of antimicrobial susceptibility test is necessary in these children.

DesA Prognostic Risk Model of LncRNAs in Patients With Acute Myeloid Leukaemia Based on TCGA Data.

Purpose: This study aimed to combine the clinical data of acute myeloid leukaemia (AML) from The Cancer Genome Atlas (TCGA) database to obtain prognosis-related biomarkers, construct a prognostic risk model using long non-coding RNAs (lncRNAs) in AML and help patients with AML make clinical treatment decisions. Methods: We analysed the transcriptional group information of 151 patients with AML obtained from TCGA and extracted the expressions of lncRNAs. According to the mutation frequency, the patients were divided into the high mutation group (genomic unstable group, top 25% of mutation frequency) and low mutation group (genomic stable group, 25% after mutation frequency). The 'limma' R package was used to analyse the difference in lncRNA expressions between the two groups, and the "survival," "caret," and "glmnet" R packages were used to screen lncRNAs that are related to clinical prognosis. Subsequently, a prognosis-related risk model was constructed and verified through different methods. Results: According to the lncRNA expression data in TCGA, we found that seven lncRNAs (i.e. AL645608.6, LINC01436, AL645608.2, AC073534.2, LINC02593, AL512413.1, and AL645608.4) were highly correlated with the clinical prognosis of patients with AML, so we constructed a prognostic risk model of lncRNAs based on LINC01436, AC073534.2, and LINC02593. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway analyses of differentially expressed lncRNA-related target genes were performed, receiver operating characteristic (ROC) curves were created, the applicability of the model in children was assessed using the TARGET database and the model was externally verified using the GEO database. Furthermore, different expression patterns of lncRNAs were validated in various AML cell lines derived from Homo sapiens. Conclusions: We have established a lncRNA prognostic model that can predict the survival of patients with AML. The Kaplan-Meier analysis showed that this model distinguished survival differences between patients with high- and low-risk status. The ROC analysis confirmed this finding and showed that the model had high prediction accuracy. The Kaplan-Meier analysis of the clinical subgroups showed that this model can predict prognosis independent of clinicopathological factors. Therefore, the proposed prognostic lncRNA risk model can be used as an independent biomarker of AML.

Single-cell phenotypic profiling to identify a set of immune cell protein biomarkers for relapsed and refractory diffuse large B cell lymphoma: A single-center study.

Diffuse large B-cell lymphoma (DLBCL) is the most common invasive type of non-Hodgkin lymphoma. Cell-of-origin (COO) classification is related to patients' prognoses. Primary drug resistance in treatment for DLBCL has been observed. The specific serum biomarkers in these patients who suffer from relapsed and refractory (R/R)-DLBCL remains unclear. In the current study, using single-cell RNA sequencing (scRNA-seq) and mass cytometry (CyTOF), we determined and verified immune cell biomarkers at the mRNA and protein levels in single-cell resolution from 18 diagnostic PBMC specimens collected from patients with R/R DLBCL. As controls, 5 PBMC specimens from healthy volunteers were obtained. We identified a panel of 35 surface marker genes for the features of R/R DLBCL unique cell cluster by scRNA-seq of 8 R/R DLBCL patient samples and validated its efficiency in an external cohort consisting of 10 R/R DLBCL patients by CyTOF. The cell clustering and dimension reduction were compared among R/R DLBCL samples in CyTOF Space with COO as well as the C-MYC expression designation. Immune cells from each patient occupied unique regions in the 32-dimensional phenotypic space with no apparent clustering of samples into discrete subtypes. Significant heterogeneity observed in subgroups was mainly attributed to individual differences among samples and not to expression differences in a single, homogeneous immune cell subpopulation. The marker panel showed reliability in labeling R/R DLBCL without any influence from COO stratification and C-MYC expression designation. Furthermore, we compared all the markers between R/R DLBCL and normal samples. A total of 12 biomarkers were significantly overexpressed in R/R DLBCL relative to the normal samples. Therefore, we further optimized the diagnostic biomarker panel of R/R DLBCL comprising CD82, CD55, CD36, CD63, CD59, IKZF1, CD69, CD163, CD14, CD226, CD84, and CD31. In summary, we developed a novel set of biomarkers for the diagnoses of patients with R/R DLBCL. Detections procedures at single-cell resolution provide precise biomarkers, which may substantially overcome intertumoral and intratumoral heterogeneity among primary samples. The findings confirmed that each case was unique and may comprise multiple, genetically distinct subclones.

Secoisolariciresinol diglucoside-derived metabolite, enterolactone, attenuates atopic dermatitis by suppressing Th2 immune response.

Atopic dermatitis (AD) is a severe inflammatory skin disease caused by a combination of genetic, immune, and environmental factors. Intestinal microbiome disorders and changes in the immune microenvironment are associated with AD. We observed that gut bacterial metabolite enterolactone (ENL) was significantly reduced in AD model mice. Notably, patients with early childhood-onset AD exhibited decreased sera ENL level compared to the healthy controls, and the ENL level was negatively correlated with the SCORAD index. Secoisolariciresinol-diglycoside (SDG) is a natural dietary lignan of flaxseeds that can be converted by intestinal bacteria to ENL. Repeated applications of 2,4-dinitrochlorobenzene (DNCB) were performed on the ear and dorsal skin of mice to induce AD-like symptoms and skin lesions. Oral administration of SDG significantly decreased serum IgE levels and limited skin inflammation in the DNCB-induced AD mice. In addition, SDG treatment strongly limited the Th2 responses in AD mice. Moreover, we demonstrated that the IL-4 production was significantly suppressed by ENL under Th2 polarization conditions via the JAK-STAT6 signaling pathway in a concentration-dependent manner. We concluded that SDG and its derived metabolite ENL ameliorated AD development by reducing the Th2 immune response. These results suggested that SDG and ENL might be exploited as potential therapeutic candidates for AD treatment.

A novel treatment regimen of granulocyte colony-stimulating factor combined with ultra-low-dose decitabine and low-dose cytarabine in older patients with acute myeloid leukemia and myelodysplastic syndromes.

BACKGROUND: Older patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) unfit for intensive chemotherapy are emergent for suitable treatment strategies. Hypomethylating agents and low-dose cytarabine have generated relevant benefits in the hematological malignancies over recent decades. We evaluated the efficacy and safety of the novel treatment regimen consisting of ultra-low-dose decitabine and low-dose cytarabine, with granulocyte colony-stimulating factor (G-CSF) in this population of patients. METHODS AND MATERIALS: Patients aged more than 60 years with newly diagnosed AML/MDS were enrolled to receive therapy combined of 300 µg subcutaneously per day for priming, decitabine 5.15-7.62 mg/m2/d intravenously and cytarabine 15 mg/m2/d twice a day subcutaneously and G-CSF for consecutive 10 days every 28 days. The study enrolled 28 patients unfit for standard intensive chemotherapy. The median age of patients was 68 years (range 60-83 years) and 20 (71.4%) patients harbored AML. The primary outcome was to evaluate overall response rate. RESULTS: Overall, this novel ultra-low-dose treatment regimen was well tolerated, with 0% of both 4- and 8-week mortality occurrence. Objective response rate (CR + CRi + PR in AML and CR + mCR + PR in MDS) was 57.1% after the first treatment course. Responses of hematologic improvement (HI) aspect were achieved in 18 of 28 (64.3%) patients, 11 (39.3%), 12 (42.9%), and eight patients (28.6%) achieved HI-E, HI-P, HI-N, respectively. CONCLUSIONS: Untreated elderly with AML/MDS were well tolerated and benefited from this novel ultra-low-dose treatment regimen.

Mannan-binding lectin deficiency augments hepatic endoplasmic reticulum stress through IP3R-controlled calcium release.

The aberrant release of endoplasmic reticulum (ER) calcium leads to the disruption of intracellular calcium homeostasis, which is associated with the occurrence of ER stress and closely related to the pathogenesis of liver damage. Mannan-binding lectin (MBL) is a soluble calcium-dependent protein synthesized primarily in hepatocytes and is a pattern recognition molecule in the innate immune system. MBL deficiency is highly prevalent in the population and has been reported to be associated with susceptibility to several liver diseases. We here showed that genetic MBL ablation strongly sensitized mice to ER stress-induced liver injury. Mechanistic studies established that MBL directly interacted with ER-resident chaperone immunoglobulin heavy chain binding protein (BiP), and MBL deficiency accelerated the separation of PKR-like ER kinase (PERK) from BiP during hepatic ER stress. Moreover, MBL deficiency led to enhanced activation of the PERK-C/EBP-homologous protein (CHOP) pathway and initiates an inositol 1,4,5-trisphosphate receptor (IP3R)-mediated calcium release from the ER, thereby aggravating the hepatic ER stress response. Our results demonstrate an unexpected function of MBL in ER calcium homeostasis and ER stress response, thus providing new insight into the liver injury related to ER stress in patients with MBL deficiency.