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Cervical cancer (CC) is one of the leading causes of cancer‐related death in females worldwide. Genome‐wide association studies (GWASs) have identified CC‐related susceptibility loci in HLA regions. To investigate the associations between HLA genes and cervical intraepithelial neoplasia (CIN) or cervical cancer (CC), six loci of HLA class I (HLA‐A, ‐B, and ‐C) and II (HLA‐DRB1, ‐DPB1, and ‐DQB1) were selected for genotyping, and the associations between these alleles or their haplotypes with CIN or CC risk or protection from disease were evaluated. In total, 2193 participants, including 909 healthy individuals in the control group, 769 patients with CC, and 515 patients with CIN2+ (CIN II and III), were enrolled in the current study. HLA genes were genotyped using the NGSgo Illumina MiSeq workflow, and the associations between these loci and CIN2+ or CC at the allele and haplotype levels were analyzed. The allele frequencies of HLA‐A*33:03, B*58:01, C*03:02, DPB1*05:01, and DRB1*12:01 were lower in both the CC and CIN2+ groups than in the control group, whereas those of B*55:02, C*04:03, and DPB1*03:01 were higher in the CC group than in the control group. In the histologic CC type analysis, the differences in the frequencies of these alleles in squamous cell carcinoma (SCC) of the cervix and stage I CC showed a consistent trend. In the haplotype analysis, the frequency of A*33:03‐C*03:02‐B*58:01 was lower in the CC and CIN2+ groups than in the control group, and that of A*24:02‐C*04:03‐B*15:25 was higher in the CC group than in both the control and CIN2+ groups. These three different haplotype frequencies were also identified in the FIGO CC stage analysis. In addition, in human papilloma virus (HPV) genotype analyses, the frequencies of HLA‐C*03:02 and DPB1*05:01 were significantly lower in the CC and CIN2+ groups than in the control group, and in SCC subgroup, the frequencies of HLA‐DQB1*04:01 and DRB1*04:05 were higher in the HPV other genotype infection group than in the HPV16 infection group. In both HPV16 single infection and coinfection with other HPVs, the frequency of haplotype A*33:03‐C*03:02‐B*58:01 was lower in both CC and CIN2+ than in the control group, while the frequencies of A*11:01‐C*14:02‐B*51:01 and A*24:02‐C*03:04‐B*13:01 were higher in the CIN2+ than in CC and the control group. In the HPV16 and other HPV infection comparisons, the frequencies of DRB1*04:05‐DQB1*04:01‐DPB1*02:01 and DRB1*11:01‐DQB1*03:01‐DPB1*05:01 were lower in the HPV16 infection group than in the other HPV infection group. Our results suggest that the HLA class I and II genes may affect the risk of CIN and CC as well as the histologic CC types and FIGO stages of CC in the Han Chinese population. In addition, HLA genes were associated with HPV16 infection at both the allelic and haplotype levels. [ABSTRACT FROM AUTHOR]

Because of the growing problem of antibiotic resistance, the antibacterial activity of antimicrobial peptides (AMPs) has attracted attention. In this study, two PMAP-GI24 peptide analogs, PMAP-24WW and PMAP-24KK, were synthesized by extending the α-helix and increasing the positive charge of the parental peptide. The antibacterial activities of PMAP-GI24 and its analogs were detected in vitro and in vivo. The results showed that after modification, PMAP-24KK displayed an increased zone of inhibition against Escherichia coli ATCC25922 compared to that of PMAP-GI24. PMAP-24WW had inhibition zones against nine bacterial strains, among which, the antibacterial zones were larger than those of PMAP-GI24 against seven bacterial strains. Furthermore, PMAP-24KK had inhibition zones against ten bacterial strains, and the antibacterial zones were larger than those of PMAP-GI24 against seven bacterial strains. Moreover, in the in vivo efficacy assessment of mice infected with Salmonella enterica serovar choleraesuis C78-1 and Listeria monocytogenes CICC21533, the PMAP-GI24 analogs effectively reduced the number of bacterial and decreased the inflammatory damage in the mouse livers and lungs, thus effectively reducing mortality. This study provides reference data for the clinical design of effective antibiotic alternatives. [ABSTRACT FROM AUTHOR]

Quantitative monitoring of BCR-ABL1IS gene using reverse transcription quantitative-PCR (RT-qPCR) is an important method for evaluating the treatment effects in patients with chronic myeloid leukemia (CML). Digital-PCR (dPCR) can be applied to detect the BCR-ABL1 gene with high sensitivity. In the present study, the results of the Clarity™ dPCR system were compared with those of the RT-qPCR in order to determine whether dPCR can be applied in the clinical setting. A total of 83 patients were included in the present study, and they were divided into two groups according to the results of BCR-ABL1IS during ongoing monitoring. A total of 43 patients with undetectable BCR-ABL1IS where enrolled in group A. BCR-ABL1 testing was performed using the dPCR system on the same peripheral blood samples of patients from group A, and the association between dPCR results and relapse was analyzed. The RT-qPCR platform and dPCR system were used simultaneously to detect the BCR-ABL1 gene of another 40 patients who achieved either partial cytogenetic response (PCyR) or further response. Among patients with undetectable BCR-ABL1IS, patients with dPCR-positive disease (BCR-ABL1 >0.1%) were more likely to undergo molecular relapse (P=0.018). The results of dPCR detection of BCR-ABL1% were consistent with the RT-qPCR results (R2=0.9510) in patients who achieved PCyR or further response. For samples with BCR-ABL1IS <1.0%, the consistency of the dPCR and RT-qPCR results was better than that of BCR-ABL1IS >1.0% (R2=0.9488 vs. R2=0.9264 for BCR-ABL1IS). The detection results of the BCR-ABL1 gene in patients with CML using dPCR matched well with those from the RT-qPCR. To conclude, the results of the dPCR system can be applied as a supplement to the RT-qPCR platform, particularly for those with BCR-ABL1IS <1.0%. [ABSTRACT FROM AUTHOR]

The clinical value of the combined detection of miR-1202 and miR-195 in the early diagnosis of cervical cancer was studied. A retrospective analysis of 70 cervical cancer patients treated in the The Third Affiliated Hospital of Kunming Medical University and Yunnan Cancer Hospital from October 2015 to December 2017 was performed, and the lesion tissues were used as the experimental group. Normal cervical tissues from another 67 healthy females confirmed by physical examination at the same period were selected as the control group. The FIGO staging criteria were used for staging of the cervical cancer patients, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) method was used for the detection of the expression of miR-1202 and miR-195 in different tissues, and the receiver operating curve (ROC) was used for the analysis of the application values of miR-1202 and miR-195 diagnosis alone and their combined diagnosis in early cervical cancer patients. The levels of miR-1202 and miR-195 in the experimental group were lower than those in the control group (P<0.05). The differences were significant in the different stages of cervical cancer tissues (P<0.05). The later the staging of cervical cancer tissues were, the lower the levels of miR-1202 and miR-195 were. The sensitivities and area under the curve (AUC) values of miR-1202 and miR-195 in the combined diagnosis of early cervical cancer were significantly higher than those of miR-1202 and miR-195 alone. The expression levels of miR-1202 and miR-195 in the cervical cancer patients are different in different stages. Guiding clinical treatment and prognosis according to the results of combined detection is beneficial for the development of treatment for cervical cancer patients and for prognostic judgement, worthy of popularization and application. [ABSTRACT FROM AUTHOR]

Background: miR-21, miR-26b, miR-221/222 and miR-126 play crucial roles in cervical cancer development. Studies have shown that polymorphisms in miRNA genes can affect miRNA expression, which might be associated with cancer development.Methods: Ten single-nucleotide polymorphisms (SNPs) in the miR-21, miR-26b, miR-221/222 and miR-126 genes (rs1292037, rs13137 in miR-21; rs2227255, rs2227258 in miR-26b; rs2858061, rs34678647, rs2858060, rs2745709 in miR-221/222; rs2297537, rs2297538 in miR-126) were selected, and genotyped in a total of 2176 individuals, including 435 patients with cervical intraepithelial neoplasia (CIN), 743 patients with cervical cancer (CC) and 998 healthy persons using TaqMan assays, and their associations with CIN and CC were evaluated.Results: Our results showed significant differences for the rs2297538 genotypes between the CIN and CC groups (P = 0.001). In addition, our results also showed significant differences for the rs2297537 alleles between the CIN and CC groups (P = 0.003), and the C allele of rs2297537 might be associated with a decreased risk of CC (OR = 0.72, 95%CI: 0.58-0.90). At the inheritance analysis, between the CIN and control groups, the T/T-T/C genotype in rs1292037 and A/A-A/T genotype in rs13137 might be associated with an increased risk of CIN in the recessive model (OR = 1.61, 95% CI: 1.17-2.20 and OR = 1.58, 95% CI: 1.15-2.15). In addition, the C/C-T/T genotype of rs2745709 might be associated with a decreased risk of CIN in the overdominant model (OR = 0.66, 95% CI: 0.52-0.82). Between, CIN and CC group, the T/T-C/C genotype in rs1292037 and A/A-T/T genotype in rs13137 might be associated with an increased risk of CC in the overdominant model (OR = 1.43, 95% CI: 1.12-1.81 and OR = 1.42, 95% CI: 1.12-1.80). The rs2297538 G/G-A/G genotype might be associated with an increased risk of CC in the recessive model (OR = 2.83, 95% CI: 1.52-5.25). The rs2297537 2C/C + C/G genotype might be associated with a decreased risk of CC (OR = 0.71, 95% CI: 0.57-0.89) in the log-additive model. The rs2745709 T/T-C/C genotype might be associated with an increased risk of CC (OR = 1.44, 95% CI: 1.13-1.83) in the overdominant model.Conclusion: Our results indicate that rs2297538 and rs2297537 in miR-126, rs1292037 and rs13137 in miR-21, and rs2745709 in miR-221/222, may have important roles in the development of CIN or CC. [ABSTRACT FROM AUTHOR]

Few studies have reported the associations of granulocyte colony-stimulating factor (G-CSF) with cytokine release syndrome (CRS), neurotoxic events (NEs) and efficacy after chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). We present a retrospective study of 67 patients with R/R B-ALL who received anti-CD19 CAR T-cell therapy, 41 (61.2%) patients received G-CSF (G-CSF group), while 26 (38.8%) did not (non-G-CSF group). Patients had similar duration of grade 3–4 neutropenia between the two groups. The incidences of CRS and NEs were higher in G-CSF group, while no differences in severity were found. Further stratified analysis showed that the incidence and severity of CRS were not associated with G-CSF administration in patients with low bone marrow (BM) tumor burden. None of the patients with low BM tumor burden developed NEs. However, there was a significant increase in the incidence of CRS after G-CSF administration in patients with high BM tumor burden. The duration of CRS in patients who used G-CSF was longer. There were no significant differences in response rates at 1 and 3 months after CAR T-cell infusion, as well as overall survival (OS) between the two groups. In conclusion, our results showed that G-CSF administration was not associated with the incidence or severity of CRS in patients with low BM tumor burden, but the incidence of CRS was higher after G-CSF administration in patients with high BM tumor burden. The duration of CRS was prolonged in G-CSF group. G-CSF administration was not associated with the efficacy of CAR T-cell therapy. [ABSTRACT FROM AUTHOR]

Background: Cervical carcinoma is one of the most common malignant tumors of the female reproductive system. Lymph nodes metastasis, the most common metastasis, which can be detected even in small-size tumor patients, results in worse prognosis. Therefore, it is of great significance to explore novel lymph nodes metastasis associated biomarkers, which can predict the prognosis and provide a good reference for clinical decision making in cervical carcinoma patients. However, systematic and comprehensive studies related to the key molecules in lymph node metastasis in cervical carcinoma patients are still absent.Methods: Transcriptome and clinical data of 307 cervical carcinoma patients were obtained from The Cancer Genome Atlas (TCGA). Then, survival of patients with and without lymph node metastasis was analyzed by Kaplan-Meier (K-M) curves. Differential expressed genes (DEGs) were detected between tumor and control samples using limma package and defined as lymph node metastasis related genes. Univariate and multivariate Cox regression analyses were carried out to screen robust prognostic gene signature. The risk score model and nomogram for predicting survival were constructed based on prognostic gene signature. The performance of the risk score model was evaluated by operating characteristic (ROC) curves. Based on risk score, patients were divided into low- and high- risk groups. DEGs, functional enrichment analysis and tumor microenvironment (immune infiltration and expressions of immune checkpoints) were detected in low- and high-risk groups.Results: A total of 103 lymph node metastasis-associated genes were identified. Univariate and multivariate Cox regression analyses identified TEKT2, LPIN2, FABP4 and CXCL2 as prognostic gene signature. The risk score model was constructed and validated in cervical carcinoma patients. 345 DEGs identified between high- and low-risk groups were significantly enriched into immune-related biological processes. Furthermore, we found that the immune infiltration and expressions of immune checkpoints were significantly different between low- and high-risk groups.Conclusion: Our study revealed that lymph node metastasis played an important role in the prognosis of cervical carcinoma patients. Furthermore, we established a risk score model based on lymph node metastasis related genes, which could accurately predict the survival of cervical carcinoma patients. Besides, our findings in tumor microenvironments of low- and high-risk groups improved our understanding of the relationship between lymph node metastasis related genes and cervical carcinoma. [ABSTRACT FROM AUTHOR]

Bone marrow-derived CD34-positive (CD34+) endothelial progenitor cells (EPCs) has unique functions in the mechanism of compensatory lung growth (CLG). The content of this study is mainly to describe the effect of microRNA (miR)-155 in the mechanisms of EPCs and CLG. Our study found that transfection of miR-155 mimic could promote EPC proliferation, migration and tube formation, while transfection of miR-155 inhibitor had the opposite effect. It was also found that transfection of pc-JARID2 inhibited EPC proliferation, migration and tube formation, while transfection of si-JARID2 had the opposite effect. miR-155 can target and negatively regulate JARID2 expression. Overexpression of JARID2 weakened the promoting effects of miR-155 mimic on EPC proliferation, migration, and tubular formation, while silencing JARID2 weakened the inhibitory effects of miR-155 inhibitors on EPC proliferation, migration, and tubular formation. Transplantation of EPCs transfected with miR-155 mimic into the left lung model effectively increased lung volume, total alveolar number, diaphragm surface area, and lung endothelial cell number, while transplantation of EPCs co-transfected with miR-155 mimic and pc-JARID2 reversed this phenomenon. Overall, we found that miR-155 activates CD34+ EPC by targeting negative regulation of JARID2 and promotes CLG. [ABSTRACT FROM AUTHOR]

The host immune system plays an important role in infectious diseases and cancers. The heterodimer formed by transporter associated with antigen presenting (TAP)1 and TAP2 is responsible for intracellular peptide loading onto MHC‐I molecules. Studies have shown that single‐nucleotide polymorphisms (SNPs) in TAP genes might affect the expression and function of TAP and be associated with cancer risk. We aimed to investigate the association of SNPs in the TAP1 and TAP2 genes with cervical intraepithelial neoplasia (CIN) and cervical cancer (CC) in a Chinese Han population. Six SNPs in the TAP1 gene and seven in the TAP2 gene were selected. The 13 SNPs were genotyped in 1255 healthy individuals, 575 patients with CIN and 1034 patients with CC using the SNaPshot assay. The association between these SNPs and CIN and CC risk was analysed. The allelic and genotypic distributions of rs41549617 and rs1135216 showed significant differences between the control and CC groups (P < 0.0038). The T allele of rs41549617 was associated with a decreased risk of CC (OR = 0.476, 95%CI: 0.286–0.791). Moreover, the G allele of rs1135216 appears to be associated with a decreased risk of CC (OR = 0.746; 95%CI: 0.632–0.881). The allele and genotype distribution of rs241441 showed a significant difference between the control and CC groups (P < 0.0038), and the rs241441 G allele was associated with an increased risk of CC (OR = 1.232, 95%CI: 1.092–1.398). In addition, the results of the association between TAP alleles and CC showed that TAP1*020101 and TAP1*0301 have an association with CC (P = 0.001 and P = 0.002, respectively). Our results demonstrate that the TAP1 and TAP2 genes are associated with CC in the Chinese Han population. [ABSTRACT FROM AUTHOR]

Objectives: It is common of chronic phase chronic myeloid leukemia (CML-CP) patients coexisting anemia at diagnosis, but the role of anemia on the prognosis is not clear. This study aims to explore impact of anemia on outcomes of CML-CP patients in TKI era. Methods: In the retrospective study, 258 newly diagnosed CML patients treated with TKIs were enrolled. Patients with moderate anemia (Hb ≤ 90 g/L) and non-moderate anemia (Hb > 90 g/L) were compared. Results: The incidence of moderate anemia at the time of CML diagnosis was 34.8%. Compared with patients with non-moderate anemia, patients with moderate anemia had higher proportion of intermediate-high Sokal risks and more aggressive characteristics such as higher WBC counts, higher percent of myeloblasts and basophils. However, there were no statistical differences in terms of optimal response rates, 5-year PFS and OS between the two groups. Conclusion: Moderate anemia is a common concomitant symptom in CML-CP patients and is associated with high-risk CML, but its occurrence does not affect the survival of CML-CP patients in TKI era. [ABSTRACT FROM AUTHOR]

Proteasome subunit beta types 8 and 9 (PSMB8, PSMB9) play critical roles in the human leukocyte antigen class I (HLA I)-presenting system. Studies have suggested that polymorphisms in the PSMB8 and PSMB9 genes may influence the immune functions of PSMB8 and PSMB9, and thus be associated with various human cancers. We investigated associations involving single nucleotide polymorphisms (SNPs) rs2071543 in PSMB8 , rs1351383, rs17587 and rs2127675 in PSMB9 and risk of cervical intraepithelial neoplasia (CIN) and cervical cancer in a Chinese Han population. A total of 543 patients with CIN, 1008 patients with cervical cancer, and 1120 healthy individuals were enrolled. Agena MassArray was used for SNP genotyping of PSMB8 and PSMB9. Associations involving these SNPs and risk of CIN and cervical cancer were analysed. Our results showed that the PSMB8 T/T and T/G genotypes of rs2071543 may be associated with a higher risk of CIN (P = 0.011, OR = 1.35, 95% CI : 1.07–1.70) and cervical cancer (P = 0.006, OR = 1.31, 95% CI : 1.08–1.59). For rs17587, the A allele (P = 0.001, OR = 1.303, 95% CI : 1.115–1.522), and the A/A and A/G genotypes (P = 0.001, OR = 1.36, 95% CI : 1.13–1.63) may be risk factors for cervical cancer. These results indicated that PSMB8 rs2071543 might influence susceptibility to CIN and cervical cancer, and PSMB9 rs17587 might influence cervical cancer susceptibility in a Chinese Han population. [ABSTRACT FROM AUTHOR]

Background: Antigen-processing machinery molecules play crucial roles in infectious diseases and cancers. Studies have shown that polymorphisms in endoplasmic reticulum aminopeptidase (ERAP) genes can influence the enzymatic activity of ERAP proteins and are associated with the risk of diseases. In the current study, we evaluated the influence of ERAP gene (ERAP1 and ERAP2) polymorphisms on susceptibility to cervical intraepithelial neoplasia (CIN) and cervical cancer.Methods: Six single nucleotide polymorphisms (SNPs) in ERAP1 and 5 SNPs in ERAP2 were selected and genotyped in 556 CIN patients, 1072 cervical cancer patients, and 1262 healthy control individuals. Candidate SNPs were genotyped using SNaPshot assay. And the association of these SNPs with CIN and cervical cancer was analysed.Results: The results showed that allelic and genotypic frequencies of rs26653 in ERAP1 were significantly different between cervical cancer and control groups (P = 0.001 and 0.004). The allelic frequencies of rs27044 in ERAP1 and rs2287988 in ERAP2 were significantly different between control and cervical cancer groups (P = 0.003 and 0.004). Inheritance model analysis showed that genotypes of rs27044, rs26618, rs26653 and rs2287988 SNPs may be associated with the risk of cervical cancer (P = 0.003, 0.004, 0.001 and 0.002). Additionally, haplotype analysis results showed that the ERAP1 haplotype, rs27044C-rs30187T-rs26618T-rs26653G-rs3734016C, was associated with a lower risk of cervical cancer (P = 0.001). The ERAP2 haplotypes rs2549782G- rs2548538A-rs2248374A-rs2287988G-rs1056893T (P = 0.009 and 0.006) and rs2549782T-rs2548538T-rs2248374G-rs2287988A-rs1056893T (P = 0.003 and 0.009) might be associated with cervical cancer and the development from CIN to cervical cancer.Conclusion: Our results indicated that rs27044, rs26618 and rs26653 in ERAP1 and rs2287988 in ERAP2 influenced susceptibility to cervical cancer. [ABSTRACT FROM AUTHOR]

Background: C-C chemokine receptor 5 (CCR5) has attracted wide concern for its critical role in the progression of human immunodeficiency virus type 1 (HIV-1) infection. Several studies have demonstrated that CCR5 affects the processes of tumor cell migration, invasion, and metastasis. The aim of this study was to illustrate the association between the polymorphisms of the CCR5 promoter and the development of cervical cancer.Methods: 336 women with cervical intraepithelial neoplasia (CIN), 488 women with cervical cancer (CC), and 682 healthy controls were recruited to detect polymorphisms in the CCR5 promoter using a sequencing method.Results: Six loci with polymorphism were found in the CCR5 promoter; the frequencies of the minor alleles of rs1799987 was significantly higher in the CIN group than that in the control group (P = 0.007); and the genotypic frequencies of rs2734648, rs1799987, rs1799988 and rs1800023 were significantly different between the CIN group and the control group (P < 0.008). The inheritance model analysis showed that rs2734648, rs1799987, rs1799988 and rs1800023 significantly increased the susceptibility to CIN in a recessive genetic model (P < 0.008). The haplotype constructed by the major alleles of these 6 SNPs (rs2227010-rs1799987-rs1799988-rs2734648-rs1800023-rs1800024: A-G-A-C-A-T) was highly protective against CIN (OR = 0.731, 95%CI: 0.603-0.886, P = 5.68E-03). In addition, transcription prediction showed that mutation of these 6 SNPs might alternate the binding of particular transcription factors.Conclusion: The CCR5 promoter polymorphisms were significantly associated with cervical intraepithelial neoplasia by altering the expression of CCR5 on the cell surface in a Chinese Han population. [ABSTRACT FROM AUTHOR]

Abstract Human papillomavirus type 16 (HPV16) is considered to be the primary pathogen related to cervical cancer. The HPV16 E2 protein plays an important role in tumourigenicity of cervical carcinoma. In the current study, we enrolled 121 HPV16-positive cervical cancer patients in the case group and 130 HPV16-positive asymptomatic individuals in the control group, and we investigated the association between HPV16 E2 gene variations and cervical cancer. The HPV16 E2 DNA was amplified and sequenced. We identified two HPV variants (EUR and As) in the control group; the As variant was predominant (68.5%), followed by the EUR variant (31.5%). In the case group, three HPV variants (EUR, As and AA) were observed; the As variant was predominant (72.7%), followed by the EUR variant (22.3%) and the AA variant (5.0%). Our results showed a significant difference in the distribution of the HPV16 variants between the case and control groups ( P < 0.05). Moreover, in the HPV16 E2 gene variation analysis, the distribution of sixteen variations was significantly different between the case and control groups ( P < 0.05), and all of these variations were present in the AA variant. In the subgroup analysis, the frequency of the T3575G (S274A) variation in the EUR variant was significantly different between the case and control groups ( P = 0.029); however, there was no significant difference in the frequency of the variations in the As variant between the case and control groups. Our findings in the current study could provide a better understanding of the relationship between HPV16 variants, E2 gene variations and cervical cancer. Highlights • HPV16 AA variant plays an important role in the cervical cancer development. • Sixteen variations of HPV16 E2 are associated with the cervical cancer. • T3575G (S274A) variation in the EUR variant could influence the function of the HPV16 E2 protein. [ABSTRACT FROM AUTHOR]

Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) complicated by bone marrow necrosis (BMN) and acute renal insufficiency (ARI) is rare in clinical practice. The aim of the present study was to summarize the clinical characteristics and treatment methods of a case of Ph+ ALL complicated by BMN and ARI. A 23-year-old male patient presented with pyrexia and a 2-month history of bone pain, and was diagnosed with Ph+ ALL complicated with BMN and ARI on peripheral blood tests, blood biochemistry tests, BM smear and fluorescence in situ hybridization. The patient underwent repeated hemodialysis, imatinib combination and maintenance chemotherapy, followed by allogeneic hematopoietic stem-cell transplantation. Some of the clinical signs and symptoms were alleviated, whereas others disappeared, and renal function was restored to normal. BM aspiration confirmed absence of necrosis and null lymphoblasts. Therefore, timely accurate diagnosis and effective treatment are crucial for patients with Ph+ ALL exhibiting potentially fatal complications. [ABSTRACT FROM AUTHOR]

Few studies have reported the associations of granulocyte colony-stimulating factor (G-CSF) with cytokine release syndrome (CRS), neurotoxic events (NEs) and efficacy after chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory (R/R) multiple myeloma (MM). We present a retrospective study performed on 113 patients with R/R MM who received single anti-BCMA CAR T-cell, combined with anti-CD19 CAR T-cell or anti-CD138 CAR T-cell therapy. Eight patients were given G-CSF after successful management of CRS, and no CRS re-occurred thereafter. Of the remaining 105 patients that were finally analyzed, 72 (68.6%) received G-CSF (G-CSF group), and 33 (31.4%) did not (non G-CSF group). We mainly analyzed the incidence and severity of CRS or NEs in two groups of patients, as well as the associations of G-CSF timing, cumulative dose and cumulative time with CRS, NEs and efficacy of CAR T-cell therapy. Both groups of patients had similar duration of grade 3–4 neutropenia, and the incidence and severity of CRS or NEs.There were also no differences in the incidence and severity of CRS or NEs between patients with the timing of G-CSF administration ≤3 days and those >3 days after CAR T-cell infusion. The incidence of CRS was greater in patients receiving cumulative doses of G-CSF >1500 μg or cumulative time of G-CSF administration >5 days. Among patients with CRS, there was no difference in the severity of CRS between patients who used G-CSF and those who did not. The duration of CRS in anti-BCMA and anti-CD19 CAR T-cell–treated patients was prolonged after G-CSF administration. There were no significant differences in the overall response rate at 1 and 3 months between the G-CSF group and the non–G-CSF group. Our results showed that low-dose or short-time use of G-CSF was not associated with the incidence or severity of CRS or NEs, and G-CSF administration did not influence the antitumor activity of CAR T-cell therapy. [ABSTRACT FROM AUTHOR]

Chimeric antigen receptor (CAR) T-cell therapy is a new and effective method in relapsed or refractory (R/R) multiple myeloma (MM). This study was aimed to explore the risk factors of infection events. We retrospectively analyzed 68 patients with R/R MM who received CAR T-cell therapy at the Affiliated Hospital of Xuzhou Medical University from June 2017 to June 2021.35 patients received anti-CD19 combined with anti-BCMA CAR T-cell therapy and 33 patients received anti-BCMA CAR T-cell therapy alone. Infection events in patients who received ≥4 prior lines of treatment or with grade 3–5 cytokines released syndrome (CRS) mainly occurred within 4 months after CAR T-cell infusion(CTI). The duration of infection-free survival was positively correlated with progression-free survival of patients with R/R MM (R2 = 0.962, p < 0.001) and the first infection event was closely accompanied by the disease relapse or progression. Treatment lines (p = 0.05), duration of ANC<500 cells/mm3 after CTI (p = 0.036), CRS grade (p = 0.007) and treatment response (p < 0.001) were the independent risk factors associated with infection for a multivariable model. The infection incidence was higher in patients with dual CAR T-cell therapy than with mono CAR T-cell therapy18 months after CTI although no statistic differences were observed within 18 months. Infections after CTI were closely associated with more lines of prior treatment, longer duration of ANC<500 cells/mm3, higher grade CRS and poor treatment response. Infections tended to occur in the early stage after CTI in patients with more lines of prior treatment and higher grade CRS. [ABSTRACT FROM AUTHOR]

Objective: The NLRP3 inflammasome complex, an important regulatory factor of inflammation and cell apoptosis, has attracted considerable attention in the development of tumor. Here, we analyzed the expression and clinical significance of NLRP3 inflammasome complex and related cytokines in patients with multiple myeloma (MM). Methods: Peripheral blood and bone marrow of 38 newly diagnosed myeloma patients and 25 age- and gender-matched healthy people were studied. NLRP3 and caspase-1 were analyzed using quantitative real-time polymerase chain reaction and Western blot and IL-1beta, IL-18, RANKL, and OPG were evaluated by enzyme-linked immunosorbent assay. Results: We showed that aberrant NLRP3 and caspase-1 expression were observed in MM and down-regulated compared with the healthy people. We further demonstrated that NLRP3 mRNA was negatively correlated with beta2-microglobulin and plasma cell percentage in MM. The downstream cytokines IL-18 and sRANKL/OPG in MM patients were higher than that in control group. Moreover, the lower mRNA levels of NLRP3 and caspase-1 were shown to be positively correlated with IL-1beta in newly diagnosed MM patients. Conclusions: This study demonstrated that dysregulated expression of NLRP3–caspase-1–IL-1beta axis was observed in patients with MM, suggesting they might be involved in the pathogenesis of MM. [ABSTRACT FROM PUBLISHER]

Hertwig's epithelial root sheath (HERS) cells participate in cementum formation through epithelial-mesenchymal transition (EMT). Previous studies have shown that transforming growth factor beta 1 (TGF-β1) and fibroblast growth factor 2 (FGF2) are involved in inducing EMT. However, their involvement in HERS cell transition remains elusive. In this study, we confirmed that HERS cells underwent EMT during the formation of acellular cementum. We found that both TGF-β1 and FGF2 stimulated the EMT of HERS cells. The TGF-β1 regulated the differentiation of HERS cells into periodontal ligament fibroblast-like cells, and FGF2 directed the differentiation of HERS cells into cementoblast-like cells. Treatment with TGF-β1 or FGF2 inhibitor could effectively suppress HERS cells differential transition. Combined stimulation with both TGF-β1 and FGF-2 did not synergistically accelerate the EMT of HERS. Moreover, TGF-β1/FGF2-mediated EMT of HERS cells was reversed by the MEK1/2 inhibitor U0126. These results suggest that TGF-β1 and FGF2 induce the EMT of HERS through a MAPK/ERK-dependent signaling pathway. They also exert their different tendency of cellular differentiation during tooth root formation. This study further expands our knowledge of tooth root morphogenesis and provides more evidence for the use of alternative cell sources in clinical treatment of periodontal diseases. J. Cell. Physiol. 229: 1647-1659, 2014. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

We evaluated the potential relationship between miRNAs and Th17 cytokines in multiple myeloma (MM) patients. Twenty-seven newly diagnosed myeloma patients and eight normal donors were studied. We determined that the relative expression levels of miR-15a/16, miR-34a, miR-194 in MM patients were significantly lower than those in the healthy controls with exception for miR-181a/b, which showed significantly higher in MM patients ( P < 0.05). In contrast, the levels of IL-17, IL-21 and IL-27 were up-regulated in MM patients compared to healthy controls while IL-22 was down-regulated ( P < 0.05). The expression patterns of them were differentially present in various groups according to the International Staging System (ISS) criteria. Up-regulated IL-17, IL-21 and IL-27 may potentially down-regulate the expression of several miRNAs in MM patients. Establishment of the relationship may be useful for understanding the pathogenesis of MM and for clinical diagnosis of the disease. [ABSTRACT FROM AUTHOR]

Objective To elucidate the protective roles and the underlying mechanism of Tripterygium hypoglaucum Hutch (THH) in mice graft-versus-host disease (GVHD). Methods BALB/c (H-2kd) mice were firstly treated with total body irradiation and infused with a mixture of bone marrow and spleen cells from C57BL/6. Then the severity of acute GVHD (aGVHD), chimeras of donor cells, inflammatory cytokines (IFN-γ, IL-4, and IL-10) of plasma, and regulatory T cells were evaluated to elucidate the different drug combinations and concentrations of cyclosporin A (CsA) and THH in preventing aGVHD. Results The control group treated with phosphate buffer solution displayed more obvious ruffled hair, hunched posture, diarrhea, reduced weight and more lymphocytes infiltration into the spleen and intestine than these treated with CsA, THH or low-dosed CsA combined with THH, especially those treated with low-dosed CsA combined with THH. No significant differences were observed in the chimeras of donor cells and survival rate among the CsA, THH, or CsA combined with THH-treated groups. Further studies implied that THH might reduce the aGVHD by increasing IL-10, decreasing IL-4, activating Treg cell, and maintaining a relatively high Foxp3 mRNA level. Conclusion THH decreased the occurrence of mouse aGVHD and prolonged the survival time by increasing the levels of CD4+/CD25+ T cells, regulating the cytokine secretion and promoting the expression of Foxp3. [ABSTRACT FROM AUTHOR]

• A shuffle strategy regroups cell instances to create new relationship for modeling. • An approach enhances Transformers to be instance aware to eliminate perturbations. • The distribution, similarity and relationship are highlighted with training bags. • With natural and regrouped bags, the models can learn diverse relationships. The rapid on-site evaluation (ROSE) technique improves pancreatic cancer diagnosis by enabling immediate analysis of fast-stained cytopathological images. Automating ROSE classification could not only reduce the burden on pathologists but also broaden the application of this increasingly popular technique. However, this approach faces substantial challenges due to complex perturbations in color distribution, brightness, and contrast, which are influenced by various staining environments and devices. Additionally, the pronounced variability in cancerous patterns across samples further complicates classification, underscoring the difficulty in precisely identifying local cells and establishing their global relationships. To address these challenges, we propose an instance-aware approach that enhances the Vision Transformer with a novel shuffle instance strategy (SI-ViT). Our approach presents a shuffle step to generate bags of shuffled instances and corresponding bag-level soft-labels, allowing the model to understand relationships and distributions beyond the limited original distributions. Simultaneously, combined with an un-shuffle step, the traditional ViT can model the relationships corresponding to the sample labels. This dual-step approach helps the model to focus on inner-sample and cross-sample instance relationships, making it potent in extracting diverse image patterns and reducing complicated perturbations. Compared to state-of-the-art methods, significant improvements in ROSE classification have been achieved. Aiming for interpretability, equipped with instance shuffling, SI-ViT yields precise attention regions that identifying cancer and normal cells in various scenarios. Additionally, the approach shows excellent potential in pathological image analysis through generalization validation on other datasets. By proposing instance relationship modeling through shuffling, we introduce a new insight in pathological image analysis. The significant improvements in ROSE classification leads to protential AI-on-site applications in pancreatic cancer diagnosis. The code and results are publicly available at https://github.com/sagizty/MIL-SI. [ABSTRACT FROM AUTHOR]

Introduction: Anti‐CD19 chimeric antigen receptor (CAR) ‐T cells, which recognize and kill both B lymphoblasts and normal B cells, result in B cell aplasia and humoral immunodeficiency. However, there were only a few detailed reports on the profile of immune reconstitution after anti‐CD19 CAR‐T cell therapy. Methods: Thirty nine patients with relapsed or refractory (R/R) B cell acute lymphoblastic leukemia (ALL) receiving anti‐CD19 CAR‐T cell therapy were enrolled. Subjects died, relapsed, received other treatment, or lost to follow‐up within 60 days post‐infusion were excluded. 21 patients were finally selected. Laboratory and clinical data were collected for analysis of immune reconstitution. Results: CD8+ cells were the first to recover with a median time on day 21(7‐87), followed by CD16/CD56+ cells on day 28(14‐87), and finally CD4+ cells with only 5(23.81%) patients recovered within 60 days post‐infusion. CD4/CD8 ratio was inverted, sustaining for at least 1 year. B cell aplasia occurred in all patients and CD19+ cells returned to normal on a median time of day 79(41‐118). All patients developed hypogammaglobulinemia with a median onset time of 2 weeks post‐infusion. IgG recovered in 6 patients with a median time on day 184(89‐346). IgM recovered on days 212, 242, and 346 in 3 patients. IgA recovered most slowly and remained low >1 year postinfusion. A total of 9 infections occurred in 6(28.57%) patients. Conclusions: Our data showed prolonged reconstitution of immune function, especially humoral immunity, in R/R B cell ALL patients receiving anti‐CD19 CAR‐T cell therapy. [ABSTRACT FROM AUTHOR]

Prevention of acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is still to be explored. Statins are potent immunomodulatory agents that hold promise as novel and safe agents for aGVHD prophylaxis, yet the controversial effect and regulatory mechanism are incompletely understood. Here, in an MHC mismatched murine model, we found that Fluvastatin-pretreated donor cells could attenuate aGVHD severity by remission tissue pathological injury. Fluvastatin served to restrain effector T cells entry into aGVHD target organs from secondary lymphoid organs (SLOs). The potential mechanism of correcting the effector T cell biased distribution was that Fluvastatin elevated CD62L and CCR7 expression while decreased CXCR3 and CD44 levels, which were correlated with Kruppel-like factor 2 (KLF2) sustention in donor-derived cells. In addition, Fluvastatin was contributed to reducing cytokines IFN-γ, TNF-α, and granzyme-B production in allogeneic effector CD4+ and CD8+ T cells. Furthermore, evidence confirmed that Fluvastatin had a long-lasting effect to sustain KLF2 expression both in vitro and in vivo even under the stimulated circumstance. In conclusion, administration of Fluvastatin to donor mice showed protective effects against recipient aGVHD when compared to untreated mice due to the retention of effector T cells in lymphoid organs accompanying with reduction of nonlymphatic infiltration and related inflammatory cytokines. [ABSTRACT FROM AUTHOR]

Background: The problem of increasing resistance against conventional antibiotics has drawn people's attention. Therefore, the development of novel antibacterial agents with effective and safe therapeutic effects is imminent. Antimicrobial peptides (AMPs) are considered a promising class of antibacterial agents due to their broad antibacterial spectrum. Results: In this study, on the basis of our previously studied peptide PMAP-37(F34-R), a novel antimicrobial peptide Chol-37(F34-R) was developed by N-terminal cholesterol modification to increase hydrophobicity. We observed that the N-terminal cholesterol-modified Chol-37(F34-R) showed higher antimicrobial activity than PMAP-37(F34-R) in vitro. Chol-37(F34-R) also exhibited effective anti-biofilm activity and may kill bacteria by improving the permeability of their membranes. Chol-37(F34-R) exerted high stability in different pH, salt, serum, and boiling water environments. Chol-37(F34-R) also showed no hemolytic activity and substantially low toxicity. Furthermore, Chol-37(F34-R) exhibited good potency of bacteria eradication and promoted wound healing and abscess reduction in infected mice. Meanwhile, in S. aureus ATCC25923-infected peritonitis model, Chol-37(F34-R) exhibited an impressive therapeutic effect by reducing the decrease in systemic bacterial burden and alleviating organ damage. Conclusions: Our findings suggested that the N-terminal cholesterol modification of PMAP-37(F34-R) could improve antibacterial activity. Chol-37(F34-R) displayed excellent bactericidal efficacy and impressive therapeutic effect in vivo. Thus, Chol-37(F34-R) may be a candidate for antimicrobial agents against microbial infection in the clinic. [ABSTRACT FROM AUTHOR]

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by lower platelet count resulting from immune cells-mediated platelet clearance. Tacrolimus is an immunosuppressive agent which selectively inhibits T cell activation. Whether tacrolimus plays a role in ITP remains unclear. This study aimed to investigate the effect of tacrolimus on ITP in mice. An ITP mouse model was established by injection of rat anti-mouse integrin GPIIb/CD41 immunoglobulin and treated with tacrolimus followed by isolation of peripheral blood mononuclear cells and plasma. The mRNA expression of T-bet, GATA3, and Foxp3 was measured by RT-PCR, and level of IFN-γ, IL-12p70, IL-4, IL-13, and TGF-β in plasma was measured by ELISA. Tacrolimus inhibited antiplatelet antibody-mediated platelet clearance in ITP mouse model. Meanwhile, tacrolimus-treated ITP mice displayed a significant decrease in the mRNA expression of T-bet and plasma level of IFN-γ and IL-12p70 compared with ITP mice but without differences when compared with normal mice. Furthermore, the expression of GATA3, Foxp3, and plasma level of IL-4 and TGF-β were upregulated in tacrolimus-treated ITP mice without significant differences to normal mice (except TGF-β). Tacrolimus prevents antiplatelet antibody-mediated thrombocytopenia in ITP mice possibly through regulating T cell differentiations, suggesting it might be a novel approach for preventing ITP. [ABSTRACT FROM AUTHOR]

The article discusses the homogeneity and heterogeneity of biological characteristics in mesenchymal stem cells from human umbilical cords and exfoliated deciduous teeth. It mentions the role of Mesenchymal stem cells (MSCs) for cell-based therapy both in regenerative medicine and disease treatment.

• A high incidence of coagulation disorders was observed after chimeric antigen receptor (CAR)-T cell therapy infusion. • The changes of coagulation parameters were associated with cytokine release syndrome (CRS). • Disseminated intravascular coagulation was found in patients with severe CRS and indicated a poor prognosis. • Coagulation disorders are manageable in most patients after CAR-T cell infusion. Chimeric antigen receptor (CAR)-T cell therapy, a new immunotherapy for relapsed and refractory (R/R) hematologic malignancies, can be accompanied by adverse events, including coagulation disorders. Here, we performed a comprehensive analysis of coagulation parameters in 100 patients with R/R hematologic malignancies after receiving CAR-T cell therapy to illuminate the profiles of coagulation disorders and to facilitate the management of coagulation disorders. A high incidence of coagulation disorders was observed, including elevated D-dimer (50/100, 50%), increased fibrinogen degradation product (45/100, 45%), decreased fibrinogen (23/100, 23%), prolonged activated partial thromboplastin time (16/100, 16%), and prolonged prothrombin time (10/100, 10%). Coagulation disorders occurred mainly during day 6 to day 20 after CAR-T cell infusion. The changes in coagulation parameters were associated with high tumor burden in acute lymphoblastic leukemia, more lines of prior therapies, lower baseline platelet count, and especially cytokine release syndrome (CRS). Disseminated intravascular coagulation (DIC) was found in 7 patients with grade ≥3 CRS and indicated a poor prognosis. Our study suggests that coagulation disorders are manageable in most patients after CAR-T cell therapy. Coexistence of DIC and severe CRS is closely related to nonrelapsed deaths during the acute toxicity phase, and effective and timely treatment is the key to reduce nonrelapse mortality for patients with DIC and severe CRS. [ABSTRACT FROM AUTHOR]

Human papillomavirus type 16 (HPV16) is a high-risk HPV subtype and a potent carcinogen. The HPV16 E6 and E7 genes are considered oncogenes that play a core role in the development of cervical cancer. In the current study, we enrolled 97 HPV16-positive cervical cancer patients (case group) and 136 HPV16-positive asymptomatic individuals (control group) in a study to analyse the association between HPV16 E6 and E7 gene variations and cervical cancer. Our results showed that three HPV16 sub-lineages (A1-A3, A4 and D3) were present; the distribution of these variants between the case and control group was not significantly different (P = 0.178). When the distribution of the HPV16 E6 and E7 gene variations was compared, the distribution of only A131C (R10R) in the E6 gene showed a different trend between the case and control groups and C749T (S63F) in the E7 gene was significantly different between the case and control groups (P = 0.071 and P = 4.861 × 10−10, respectively). Regarding the sub-lineages, no variations in the E6 gene were significantly different between the case and control group for the A4 (As) and A1-A3 (EUR) sub-lineages. However, the distribution of C749T (S63F) in the E7 gene was significantly different between the case and control groups for the A4 (As) and A1-A3 (EUR) sub-lineages (P = 1.815 × 10−8 and P = 0.008). In the current study, we found that the C749T (S63F) variation in the HPV16 E7 gene was associated with cervical cancer not only in the A4 (As) sub-lineage but also in the A1-A3 (EUR) sub-lineage. Our study will provide a good reference for further functional studies of the relationship between cervical cancer carcinogenesis and the HPV16 E6 and E7 genes. • The distribution of HPV16 variants (A1-A3, A4 and D3) between the case and control group was not significantly different (P =.178). • The distribution of C749T (S63F) in the E7 gene of HPV16 was significantly different between the case and control groups (P = 4.861 × 10−10). • Regarding the sub-lineages, no variations in the E6 gene of HPV16 were significantly different between the case and control group for the HPV16 A4 (As) and A1-A3 (EUR) sub-lineages. • Regarding the sub-lineages, the distribution of C749T (S63F) in the E7 gene was significantly different between the case and control groups for the HPV16 A4 (As) and A1-A3 (EUR) sub-lineages (P = 1.815 × 10−8, P =.008). [ABSTRACT FROM AUTHOR]

Applying deformable transformer for dense video captioning has achieved great success recently. However, deformable transformer only explores local-perspective perception by attending to a small set of key sampling points, which will make the decoder short-sighted and generate semantically incoherent and contradictory dense captions for a long video. In this paper, we propose a novel Multi-Perspective Perception Network to improve this problem. We first introduce a hierarchical temporal-spatial summary method to generate global-perspective summary context for each decoder layer and avoid redundant information. Then our new designed multi-perspective attention encourages the model to selectively incorporate the multi-perspective perception feature. Finally, we propose a novel multi-perspective generator to perform both multi-perspective feature fusion and caption generation. Experiments show that our proposed model outperforms previously published methods and achieves a competitive performance on ActivityNet Captions and YouCook2. The design of our model also shows the universality of other visual tasks that we obtain comparable results by applying our model for Object Detection and Paragraph Video Captioning. [ABSTRACT FROM AUTHOR]

Bortezomib, an FDA approved drug in 2003 for newly diagnosed and relapsed/refractory MM, had showed great efficacy in different clinical settings. However, many patients still developed resistance to Bortezomib, and the mechanism of action remains unelucidated. Here, we showed that Bortezomib resistance can be partially overcome by targeting a different subunit of 20 S complex - PSMB6. PSMB6 knock down by shRNA increased sensitivity to Bortezomib in resistant and sensitive cell line. Interestingly, a STAT3 inhibitor, Stattic, is shown to selectively inhibit PSMB6 and induce apoptosis in Bortezomib resistant and sensitive MM cells, even with IL-6 induction. Therefore, PSMB6 is a novel target for Bortezomib resistance and Stattic may offer a potential therapeutic strategy. [ABSTRACT FROM AUTHOR]

Highlights • NLRP3 knockout mice were used as recipients in an allo-HCT model. • NLRP3 knockout reduced hepatic graft-versus-host-disease after allo-HCT. • NLRP3 knockout reduces IL-1β, TNF-α, adenosine triphosphate, and NLRP1a levels, which could protect the liver. Abstract NLRP3 is associated with multiple risks in graft-versus-host disease, though unifying principles for these findings remain largely unknown. To explore the effects and mechanisms of the absence of NLRP3 function on hepatic graft-versus-host-disease, we established an allogeneic hematopoietic cell transplantation mice model by infusing bone marrow mononuclear cells and spleno-T cells of the BALB/c mouse into either NLRP3 knockout (NLRP3−/−) or wild-type C57BL/6 mice. Elevated inflammatory cell infiltration, liver fibrosis, and secretions of alanine aminotransferase (ALT) and aspartate transaminase (AST), together with weight loss, were observed in C57BL/6 recipients after transplantation. However, moderate injury pathology was detected in the liver of NLRP3−/− recipients at day 14, which gradually improved over time. Likewise, proinflammatory cytokine IL-1β, a downstream effecter of NLRP3 inflammasome activation, showed significantly lower expression (P <.05) in the liver of NLRP3−/− recipients relative to C57BL/6 recipients at day 7 and day 21. Moreover, compared with C57BL/6 recipients, the expression of both TNF-α and IL-1β were decreased 3-fold and 4.7-fold, respectively, at day 21 in NLRP3−/− recipients. Interestingly, NLRP1a was expressed at a significantly reduced level in the liver of NLRP3−/− recipients (P <.001). Furthermore, systemic inflammation was analyzed by measuring the concentration of IL-1β and adenosine triphosphate (ATP) in serum. The concentration of IL-1β achieved a maximum at day 14, then decreased at day 21 and day 28 in NLRP3−/− recipients. In contrast, the concentration of IL-1β in C57BL/6 recipients gradually increased from day 7 to day 28. ATP levels reduced from day 7 to day 28 in NLRP3−/− recipients, but were extremely high in C57BL/6 recipients from day 14 to day 28 (P <.01). The decreased levels of P2X7R were connected to less ATP in NLRP3−/− recipients at day 21 and day 28. In conclusion, NLRP3 knockout in recipients could significantly relieve liver injury after transplantation and block the NLRP3 inflammasome pathway, thus providing a promising strategy for the treatment of graft-versus-host disease prophylaxis. [ABSTRACT FROM AUTHOR]

Immune thrombocytopenia (ITP) is an autoimmune disease, which is characterized by abnormal of T immunity. A disintegrin and metalloproteinase (ADAM) 10, a member of proteinase family, has been demonstrated to regulate T cell proliferation and effector function. Considering the closely association of dysregulation of T cell function with ITP, whether ADAM10 involves in the pathogenesis of ITP remains unclear. In this study, 54 active ITP patients, 18 ITP in remission and 24 age and gender matched healthy control were enrolled. Peripheral blood mononuclear cells (PBMCs) were isolated from patients and control for isolation of RNA and plasma which were used to measure mRNA level of ADAM10 and tissue inhibitor of metalloproteinase 3 (TIMP3) by quantitative real-time PCR and soluble level of FasL and lymphocyte activation gene-3 (LAG-3) in plasma by ELISA. Meanwhile, T cell activation was measured by flow cytometry. Our results showed significantly higher expression of ADAM10 and lower expression of TIMP3 in active ITP patients compared with control, which were all restored into normal level in remission patients. Consistent with the expression profile of ADAM10, increased soluble plasma level of FasL and LAG-3 were observed in active ITP patients and reduced to normal level in patients in remission. Furthermore, increased T cell activation as demonstrated by higher expression of HLA-DR and CD69 were found in active ITP patients. In conclusion, elevated expression of ADAM10 was associated with the pathogenesis and development of ITP and therapeutically targeting it might be a novel approach for the treatment of ITP. [ABSTRACT FROM AUTHOR]

Maternal gestational diabetes mellitus (GDM) has many adverse effects on the development of offspring. Aberrant DNA methylation is a potential mechanism associated with these effects. However, the effects of GDM on tooth development and the underlying mechanisms have not been thoroughly investigated. In the present study, a GDM rat model was established and incisor labial cervical loop tissue and dental epithelial stem cells (DESCs) were harvested from neonates of diabetic and control dams. GDM significantly suppressed incisor enamel formation and DESCs proliferation and self-renewal in offspring. Gene expression profiles showed that Apex1 was significantly downregulated in the offspring of diabetic dams. In vitro, gain and loss of function analyses showed that APEX1 was critical for DESCs proliferation and self-renewal and Oct4 and Nanog regulation via promoter methylation. In vivo, we confirmed that GDM resulted in significant downregulation of Oct4 and Nanog and hypermethylation of their promoters. Moreover, we found that APEX1 modulated DNA methylation by regulating DNMT1 expression through ERK and JNK signalling. In summary, our data suggest that GDM-induced APEX1 downregulation increased DNMT1 expression, thereby inhibiting Oct4 and Nanog expression, through promoter hypermethylation, resulting in suppression of DESCs proliferation and self-renewal, as well as enamel formation. [ABSTRACT FROM AUTHOR]

Graft versus host disease (GVHD) is a life threatening complication of bone marrow stem cell transplantation, in which considerable numbers of proinflammatory cytokines secreted by allo-reactive donor T cells are involved. We and other previous studies have found that interleukin-22 (IL-22) was able to aggravate the target organs damage of GVHD. However, the mechanism and the signal pathway of IL-22 in murine acute GVHD was not clear. Here, we observed that compared with GVHD group, more serious pathological damage and more CD3 + T cells infiltrated in GVHD target organs were detected in the mice injected with IL-22. Meanwhile, transcription factor T-bet, RORγt and AhR respectively associated with Th1, Th17 and Th22 cells changed in varying degrees in different GVHD target organs. Furthermore, the increased expression of IL-22R and its downstream protein P-STAT3 were detected in GVHD mice with IL-22 treated. These results suggested that the pathological role of IL-22 in GVHD target organs contribute to exogenous injected IL-22 as well as secreted IL-22 from the infiltrated allo-reactive effector T cells. In addition, the IL-22R-STAT3 pathway may play important role in GVHD tissue injury and target this way may yield new approaches for reduction of GVHD. [ABSTRACT FROM AUTHOR]

miRNAs have been reported to be involved in the pathogenesis of many cancers. In this article, we investigated the role and the mechanisms of miR-15a/16 in the pathogenesis of multiple myeloma (MM). We found that miR-15a/16 was down-regulated in bone marrow-derived mononuclear cells (BM-MNCs) of newly diagnosed patients with MM and the downregulation of miR-15a/16 was correlated with International Staging System (ISS) stage. We then demonstrated miR-15a/16 inhibited myeloma cells proliferation, and increased apoptosis rate of U266 cells by suppressing the expression of anti-apoptosis protein Bcl-2. We also found miR-15a/16 could decrease VEGF-A and IL-17 levels in the supernatant of myeloma cells. These results indicate that miR-15a/16 may function as a tumor suppressor in MM through multiple regulatory mechanisms and they may be potential targets for the therapy of MM. [ABSTRACT FROM AUTHOR]

Donor-derived CD4 + T lymphocytes are the major effector cells directly involved in the development of graft-versus-host disease (GVHD). As a negative regulator of immune cell differentiation and development, microRNA-150 (miR-150) induces immunological tolerance in CD4 + T cells after transplantation. However, the specific mechanisms have not been fully elucidated. In this study, we demonstrated that miR-150 is capable of not only inhibiting proliferation and activation of CD4 + T cells but also promoting apoptosis. Mechanistically, miR-150 targets v-akt murine thymoma viral oncogene homolog 3 (AKT3), and subsequently downregulates B-cell lymphoma 2 (Bcl-2) interacting mediator of cell death (BIM). We have also demonstrated that re-expression of AKT3 reversed miR-150-mediated inhibition of CD4 + T lymphocyte development. Therefore, we conclude that miR-150 negatively regulates CD4 + T cell function by inhibiting the AKT3/BIM signaling pathway. These findings also suggest that manipulating the levels of miRNA-150 could be a valuable strategy in prevention and/or treatment of acute graft-versus-host disease. [ABSTRACT FROM AUTHOR]

Conditioning regimens before hematopoietic stem cell transplantation (HSCT), cause damage to bone marrow and inflammation. Whether inflammasomes are involved in bone marrow inflammation remains unclear. The study aims to evaluate the role of inflammasomes in bone marrow inflammation after HSCT. On days 7, 14, 21 and 28 after HSCT, mice were sacrificed for analysis of bone marrow inflammation, pro-inflammatory cytokines secretion, inflammasomes expression and caspase-1 activation. Bone marrow inflammation with neutrophils and macrophages infiltration was observed after HSCT. Secretion of IL-1β, IL-18, TNF-α and IL-6 were elevated, with increased caspase-1 activation and inflammasomes expression. Caspase-1 inhibitor administration after HSCT significantly reduced infiltration of neutrophils and macrophages into bone marrow and increased the numbers of megakaryocytes and platelets. In conclusion, inflammasomes activation is involved in bone marrow inflammation after HSCT and caspase-1 inhibition attenuates bone marrow inflammation and promoted hematopoietic reconstitution, suggesting targeting caspase-1 might be beneficial for improving HSCT outcomes. [ABSTRACT FROM AUTHOR]

Constitutive NF-κB activation is required for survival of activated B cell-like subtype of diffuse large B cell lymphoma (ABC-DLBCL). However, current NF-κB targeting strategies lack cancer cell specificity. Here, we identified a novel inhibitor, piperlongumine, features direct binding to NF-κB p65 subunit and suppression of p65 nuclear import. This was accompanied by NF-κB reporter activity suppression and NF-κB target gene downregulation. Moreover, mutation of Cys 38 to Ser in p65 abolished this effect of piperlongumine on inhibition of p65 nuclear import. Furthermore, we show that piperlongumine selectively inhibited proliferation and induced apoptosis of ABC-DLBCL cells. Most notably, it has been reported that piperlongumine did not affect normal cells even at high doses and was nontoxic to animals. Hence, our current study provides new insight into piperlongumine's mechanism of action and novel approach to ABC-DLBCL target therapy. [ABSTRACT FROM AUTHOR]

Abstract: The development of periodontal ligament–cementum complex (PLCC) originates from the interaction between epithelial cells of Hertwig's epithelial root sheath (HERS) and mesenchymal cells of the dental follicle. While previous studies have suggested that the Wnt pathway is involved in osteogenic differentiation of dental follicle cells (DFCs) during tooth root development, its involvement in the interaction between DFCs and HERS cells (HERSCs) in tooth root mineralization remains unclear. Here, we investigated the hypothesis that HERSCs control osteogenic differentiation of DFCs via the Wnt pathway. We found that during co-culture with HERSCs, DFCs exhibited a greater tendency to form mineralized nodules. Moreover, under these conditions, DFCs expressed high levels of cementoblast/osteoblast differentiation-related markers, such as bone sialoprotein (BSP) and osteocalcin (OCN), the periodontal ligament phenotype-related gene type I collagen (COL1), and β-catenin (CTNNB1), a core player in the canonical Wnt pathway. In contrast, expression in DFCs of alkaline phosphatase (ALP) was greatly decreased in the presence of HERSCs. Expression of CTNNB1 in DFCs was stimulated by Wnt3a, a representative canonical member of the Wnt family of ligands, but suppressed by Dickkopf1 (DKK1), a Wnt/CTNNB1 signaling inhibitor. Furthermore, in the presence of treated dentin matrix (TDM), differentiation of DFCs was enhanced by Wnt3a when they were in direct contact with HERSCs, but was curtailed by DKK1. Taken together, these results indicate that during tooth root formation, HERSCs induce osteogenic differentiation of DFCs in a process involving the Wnt pathway and the dentin matrix. Our study not only contributes to our understanding of tooth root development and diseases of tooth root mineralization, but also proffers a novel potential strategy for controlling mineralization during tooth root regeneration. [Copyright &y& Elsevier]

Abstract: Mesenchymal stem cells (MSCs) possessing immunoregulatory activities have been evaluated in the treatment of graft-versus-host disease (GVHD). However, the immunomodulatory effects of MSCs are not always successfully achieved in some animal models, and this deficiency may be caused in part by poor homing of these cells to hematopoietic tissues. In this study, we assessed the immunsuppressive capacity of lentiviral vector transduced MSCs expressing CXCR4 in a major histocompatibility complex (MHC)-mismatched mouse model of bone marrow (BM) transplantation from C57BL/6 donors to BALB/c recipients. The survival, body weight and clinical score of GVHD in transplanted mice were monitored. Liver, intestine and skin from mice in each group were obtained for histological examination. Plasma concentrations of interleukin (IL)-2, IL-4, IL-6, IL-10, IFN-γ, TNF-α and IL-17A were also determined using a Cytometric Bead Array. CXCR4 over-expressing MSCs maintained their immunsuppressive capacity and showed enhanced migration capacity in vitro. In the mouse GVHD model, treatment with CXCR4 over-expressing MSCs decreased the mortality rate and attenuated clinical and pathological GVHD scores. Moreover, compared with control groups, the plasma IL-2, IL-6, IFN-γ and TNF-α levels in recipients infused with CXCR4 over-expressing MSCs were significantly decreased, while those of IL-4 and IL-10 were increased. In conclusion, our report reveals that CXCR4-transduced MSCs effectively controlled the occurrence of mouse GVHD following allogeneic BM transplantation. [Copyright &y& Elsevier]

The new HLA‐B*38:165N and HLA‐B*51:309 alleles in two Chinese cervical intraepithelial neoplasia patients. [ABSTRACT FROM AUTHOR]

Interleukin-22 (IL-22) promotes thymus recovery and improves T-cell recovery in preclinical allogeneic hematopoietic cell transplant models. However, the correlation between IL-22 and thymus recovery is unknown in human transplant. In this study, plasma IL-22 levels of transplanted humans were analyzed peri-transplant. Thymic output was assessed by detecting blood signal joint T-cell receptor excision circles (TRECs). Flow cytometry was applied to measure T-cell subsets. Plasma IL-22 level positively correlated with blood TRECs level at days 14 and 28 posttransplant. Multiple linear regression analysis showed plasma IL-22 level, occurrence of acute graft-versus-host disease (aGVHD) and age were significantly associated with blood TRECs level at day 28 after allotransplant. An increase of plasma IL-22 level during day 14 and day 28 correlated with faster recovery of blood TRECs and naïve T-cell levels in allotransplant recipients. Recipients with high TRECs levels at day 28 had lower incidence of aGVHD comparing with those who with low TRECs levels according to a median split of their TRECs levels, an effect also seen in the high IL-22 level and low IL-22 level cohorts. Other factors such as age and infection had impacts on plasma IL-22 level in allotransplants. Our findings suggest that dynamic change of plasma IL-22 level is an indicator of thymic output and occurrence of aGVHD. Monitoring plasma IL-22 level might help to assess recovery of thymus function in human allotransplants. • Blood IL-22 level positively correlated with TRECs level early posttransplant. • Increase of IL-22 level during d14 and d28 indicated faster thymic output recovery. • Patients with high IL-22 and TRECs levels at d28 showed less incidence of aGVHD. [ABSTRACT FROM AUTHOR]

Background: Platycodin D (PD) is one of the major bioactive components of the roots of Platycodon grandiflorum and possesses multiple biological and pharmacological properties, such as antiviral, anti-inflammatory, and anti-cancer activities. However, whether it affects platelet function remains unclear. This study aims to evaluate the role of PD in platelet function and thrombus formation.Methods: Platelets were treated with PD followed by measuring platelet aggregation, activation, spreading, clot retraction, expression of glycoprotein receptors. Moreover, mice platelets were treated with PD and infused into wild-type mice for analysis of in vivo hemostasis and arterial thrombosis.Results: Platycodin D treatment significantly inhibited platelet aggregation in response to collagen, ADP, arachidonic acid and epinephrine, reduced platelet P-selectin expression, integrin αIIbβ3 activation, spreading on fibrinogen as well as clot retraction, accompanied with decreased phosphorylation of Syk and PLCγ2 in collagen-related peptide or thrombin-stimulated platelets. Moreover, PD-treated mice platelets presented significantly impaired in vivo hemostasis and arterial thrombus formation. Interestingly, PD induced internalization of glycoprotein receptors αIIbβ3, GPIbα and GPVI. However, GM6001, cytochalasin D, BAPTA-AM and wortmannin did not prevent PD-induced internalization of receptors.Conclusions: Our study demonstrates that PD inhibits platelet aggregation, activation and impairs hemostasis and arterial thrombosis, suggesting it might be a potent anti-thrombotic drug. [ABSTRACT FROM AUTHOR]

Background: Acute myeloid leukemia (AML) is a highly heterogeneous disease. MicroRNAs function as important biomarkers in the clinical prognosis of AML.Methods: This study identified miR-425 as a prognostic factor in AML by screening the TCGA dataset. A total of 162 patients with AML were enrolled for the study and divided into chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT) groups.Results: In the chemotherapy group, patients with high miR-425 expression had significantly longer overall survival (OS) and event-free survival (EFS) compared with patients with low miR-425 expression. In multivariate analyses, high miR-425 expression remained independently predictive of a better OS (HR = 0.502, P = 0.005) and EFS (HR = 0.432, P = 0.001) compared with patients with low miR-425 expression. Then, all patients were divided into two groups based on the median expression levels of miR-425. Notably, the patients undergoing allo-HSCT had significantly better OS (HR = 0.302, P < 0.0001) and EFS (HR = 0.379, P < 0.0001) compared with patients treated with chemotherapy in the low-miR-425-expression group. Mechanistically, high miR-425 expression levels were associated with a profile significantly involved in regulating cellular metabolism. Among these genes, MAP3K5, SMAD2, and SMAD5 were predicted targets of miR-425.Conclusions: The expression of miR-425 may be useful in identifying patients in need of strategies to select the optimal therapy between chemotherapy and allo-HSCT treatment regimens. Patients with low miR-425 expression may consider early allo-HSCT. [ABSTRACT FROM AUTHOR]