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Acne is one of the most common skin diseases whose disfiguring results may cause psychological problems. Despite of the various choices in the treatment of acne, new therapy with fewer complications and lower relapse rate is still in need. In this study, we aim to evaluate the clinical efficacy of a new therapy using selective sebaceous gland electro-thermolysis and non-thermal plasma (NTP) in refractory acne patients. Treatments were given at a monthly interval for three times. The last visit was set at 3 months after the third treatment. Thirty-six moderate to very severe acne patients were enrolled. All the patients got more than 50% clearance after the third treatment. The excellent response rate was 44% at 1 month after the third treatment and 50% at 3 months after the third treatment. Porphyrin and erythema values were significantly reduced after the third treatment. No irreversible complication was reported. Selective sebaceous gland electro-thermolysis combined with NTP can be a safe and effective new option in the treatment of acne.

To examine the production time, type, and MFI of post-transplantation

Interleukin 27 (IL-27), a heterodimeric cytokine composed of Epstein-Barr virus-induced 3 and p28, is a pleiotropic cytokine with both pro-and anti-inflammatory properties. However, the precise role of IL-27 in acute graft-versus-host disease is not yet fully understood. In this study, utilizing mice with IL-27 p28 deficiency in dendritic cells (DCs), we demonstrated that IL-27 p28 deficiency resulted in impaired Treg cell function and enhanced effector T cell responses, corresponding to aggravated aGVHD in mice. In addition, using single-cell RNA sequencing, we found that loss of IL-27 p28 impaired Treg cell generation and promoted IL-1R2+TIGIT+ pathogenic CD4+ T cells in the thymus at a steady state. Mechanistically, IL-27 p28 deficiency promoted STAT1 phosphorylation and Th1 cell responses, leading to the inhibition of Treg cell differentiation and function. Finally, patients with high levels of IL-27 p28 in serum showed a substantially decreased occurrence of grade II-IV aGVHD and more favorable overall survival than those with low levels of IL-27 p28. Thus, our results suggest a protective role of DC-derived IL-27 p28 in the pathogenesis of aGVHD through modulation of the Treg/Teff cell balance during thymic development. IL-27 p28 may be a valuable marker for predicting aGVHD development after transplantation in humans.

Although defined as a lymphoid surface marker, CD7 is aberrantly expressed on a subtype of acute myeloid leukemia cells and appears to be associated with an inferior response to chemotherapy. Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative modality but no data has been reported in CD7-positive AML patients. We performed a retrospective analysis involving 141 AML patients who underwent allo-HCT in first morphological complete remission (CR1). The results showed that CD7-positive AML patients had a poor 2-year overall survival (64.5% vs 82.0%, P = 0.040), relapse-free survival (RFS) (56.5% vs 79.4%, P = 0.005), and higher cumulative incidence of relapse (27.0% vs 9.7%, P = 0.003) post-HCT. In addition, expression of CD7 was related to RAS and RUNX1 mutation, and high residual disease level pre-HCT. Multivariate analyses showed CD7 expression at diagnosis was an independent risk factor for RFS (P = 0.016, HR = 0.418) and relapse (P = 0.014, HR = 0.307). We concluded that for AML patients in CR1, CD7 is a negative predictor for allo-transplant outcomes.

Rituximab is used to eliminate B cells as a chimeric monoclonal antibody directed against CD20, a B-cell antigen expressed on B cells. To explore the impact of rituximab administered before transplantation, we implemented a retrospective, monocentric study and utilized real-world data collected at our center between January 2018 and December 2020, and then followed until December 2021. Based on whether a dose of 375mg/m2 rituximab was used at least once within two weeks before transplantation, patients undergoing allo-HSCT were classified into two groups: rituximab (N=176) and non-rituximab (N=344) group. Amongst all the patients, the application of rituximab decreased EBV reactivation (P

Natural killer (NK) cells have been demonstrated as a promising cellular therapy as they exert potent anti-tumor immune responses. However, applications of NK cells to tumor immunotherapy, especially in the treatment of advanced hematopoietic and solid malignancies, are still limited due to the compromised survival and short persistence of the transferred NK cells in vivo. Here, we observed that fucosyltransferase (FUT) 7 and 8 were highly expressed on NK cells, and the expression of CLA was positively correlated with the accumulation of NK cells in clinical B cell lymphoma development. Via enzyme-mediated ex vivo cell-surface fucosylation, the cytolytic effect of NK cells against B cell lymphoma was significantly augmented. Fucosylation also promoted NK cell accumulation in B cell lymphoma-targeted tissues by enhancing their binding to E-selectin. Moreover, fucosylation of NK cells also facilitated stronger T cell anti-tumor immune responses. These findings suggest that ex vivo fucosylation contributes to enhancing the effector functions of NK cells and may serve as a novel strategy for tumor immunotherapy.

BACKGROUND AND OBJECTIVE Nevus of Ota is a benign dermal and mucosal melanocytic nevus that can be cured by Q-switched lasers. However, the incidence rate of post-treatment hyperpigmentation in Asian patients remains high. Low-fluence Q-switched Nd:YAG laser (QSNY) has been proved effective in the early treatment of nevus of Ota. Q-switched alexandrite laser (QSAL) was found to achieve a higher success rate and lower complication rate than QSNY. This study aims to evaluate the efficacy and safety of low-fluence 755 nm QSAL in the treatment of nevus of Ota. MATERIALS AND METHODS A total of 81 patients with nevus of Ota were retrospectively evaluated. Among them, 39 went through the high-fluence QSAL (3 mm spot, 5.0-8.0 J/cm2 ) and 42 were treated by low-fluence QSAL (5 mm spot, 2.2-2.8 J/cm2 ). Treatments were given every 6 months three times. Standard photos of the lesions were taken to evaluate the efficacy. All adverse events were noted. RESULTS The low-fluence QSAL group achieved a significantly higher mean efficacy score than the high-fluence QSAL group after the first treatment (3.62 ± 0.85 vs. 2.9 ± 0.79, P

The lack of representative features between benign nodules, especially level 3 of Thyroid Imaging Reporting and Data System (TI-RADS), and malignant nodules limits diagnostic accuracy, leading to inconsistent interpretation, overdiagnosis, and unnecessary biopsies. We propose a Vision-Transformer-based (ViT) thyroid nodule classification model using contrast learning, called TC-ViT, to improve accuracy of diagnosis and specificity of biopsy recommendations. ViT can explore the global features of thyroid nodules well. Nodule images are used as ROI to enhance the local features of the ViT. Contrast learning can minimize the representation distance between nodules of the same category, enhance the representation consistency of global and local features, and achieve accurate diagnosis of TI-RADS 3 or malignant nodules. The test results achieve an accuracy of 86.9%. The evaluation metrics show that the network outperforms other classical deep learning-based networks in terms of classification performance. TC-ViT can achieve automatic classification of TI-RADS 3 and malignant nodules on ultrasound images. It can also be used as a key step in computer-aided diagnosis for comprehensive analysis and accurate diagnosis. The code will be available at https://github.com/Jiawei217/TC-ViT.

Significance Natural killer (NK) cells belong to a critical innate arm of host immunity against viral infection and malignancies. However, limited expansion and persistence of NK cells in vivo remain major challenges for NK cell-based therapy. Here, we show that platelet-derived growth factor (PDGF)-D−PDGF receptor-beta signaling—a potent stimulator of cell growth and motility—activates NK cells in an autocrine manner and contributes to interleukin-15–mediated NK cell survival but not effector functions, the latter of which were previously shown to depend on the binding of PDGF-D to the NKp44 receptor. Therefore, selectively introducing PDGF signaling into NK cells should benefit NK cell expansion and persistence and/or enhance effector function in NK cell-based immunotherapies., The axis of platelet-derived growth factor (PDGF) and PDGF receptor-beta (PDGFRβ) plays prominent roles in cell growth and motility. In addition, PDGF-D enhances human natural killer (NK) cell effector functions when binding to the NKp44 receptor. Here, we report an additional but previously unknown role of PDGF-D, whereby it mediates interleukin-15 (IL-15)–induced human NK cell survival but not effector functions via its binding to PDGFRβ but independent of its binding to NKp44. Resting NK cells express no PDGFRβ and only a low level of PDGF-D, but both are significantly up-regulated by IL-15, via the nuclear factor κB signaling pathway, to promote cell survival in an autocrine manner. Both ectopic and IL-15–induced expression of PDGFRβ improves NK cell survival in response to treatment with PDGF-D. Our results suggest that the PDGF-D−PDGFRβ signaling pathway is a mechanism by which IL-15 selectively regulates the survival of human NK cells without modulating their effector functions.

Transplantation-associated thrombotic microangiopathy (TA-TMA) is a life-threatening complication for patients undergoing hematopoietic stem cell transplantation (HSCT). N-acetylcysteine (NAC) has recently been considered as a potential treatment for patients with thrombotic thrombocytopenic purpura. To assess the value of NAC for the prevention of TA-TMA, we conducted a prospective study at the First Affiliated Hospital of Soochow University. This open-label, randomized placebo-controlled trial included 160 patients who were scheduled for allogeneic HSCT. Participants were assigned at random 1:1 to either oral NAC (50 mg/kg/day from 9 days before HSCT to 30 days after HSCT) or placebo treatment. The primary outcome was the incidence of TA-TMA. Overall survival (OS) and event-free survival (EFS) were assessed in the NAC and placebo control groups. The incidence of TA-TMA was 9.1% (95% confidence interval [CI], 2% to 16.2%) in the NAC group, compared with 23% (95% CI, 13.2% to 32.8%) in the control group, with a rate ratio of .34 (95% CI, .123 to .911; P = .039). The median time to the onset of TA-TMA was 60 days (interquartile range [IQR], 42 to 129 days) in the NAC group and 36 days (IQR, 30.5 to 51 days) in the control group (P = .063). The 2-year OS rate was 75.4% (95% CI, 28.65% to 73.53%) in the NAC group and 63.0% (95% CI, 50.8% to 73.5%) in the control group, with a hazard ratio (HR) of .622 (95% CI, .334-1.155; P = .132). The EFS rate was 25.8% in the NAC patients and 8.1% in controls (HR, .254; 95% CI, .094 to .692; P = .024). The median time of EFS was 60 days in the NAC group and 38 days in controls. Our findings suggest that NAC may be a potential treatment to reduce the incidence of TA-TMA.

In order to investigate the efficacy of lenalidomide, bortezomib and dexamethasone (VRD) induction chemotherapy regimen combined with tandem autologous stem cell transplantation (ASCT) in treating multi-hit multiple myeloma (MM), we analyzed 252 cases of newly diagnosed MM treated with the bortezomib-containing induction chemotherapy from June 2016 to June 2019. According to the fluorescence in situ hybridization (FISH) results on diagnosis, the patients were divided into multi-hit MM group (47 cases), single-hit MM group (81 cases), and standard-risk group (124 cases). Our analysis showed that R-ISS stageⅢ in transplantation group and R-ISS stageⅢ, multi-hit and VGPR or above was not achieved at the fourth cycle of chemotherapy in non-transplantation group were independent factors for poor prognosis by univariate and multivariate analyses. Moreover, the overall response rate (ORR) of VRD induction chemotherapy group was significantly higher than that of the non-VRD group in the single-hit and multi-hit groups (P = 0.021, P = 0.032); In terms of ASCT, tandem-ASCT can significantly improve the 2-year PFS (77.8 ± 3.9 %) and OS (83.3 ± 5.6 %) of multi-hit MM (P = 0.024, P = 0.037), while single-ASCT only has a limited effect on PFS (61.5 ± 3.0 %) and OS (71.9 ± 4.5 %) (P = 0.115, P = 0.155).

With the goal of improving the population-specific criteria to distinguish KIR genotypes and haplotypes in the region, we examined the KIR gene and haplotype data of Eastern Han based on a large population and analyzed the component genes of centromeric (Cen) and telomeric (Tel) KIR haplotype segments, which may differ in the protection they provide in hematopoietic stem cell transplantation. Samples from 598 families and 2845 unrelated individuals of Eastern Han origin were collected between 2010 and 2017. Genotyping of 17 KIR genes was performed by PCR-SSP and SSO methods. The results showed we obtained the KIR gene distribution of the Eastern Han population. The KIR gene frequencies (GF) in the present study are similar to those observed in other studies on Han but different from other populations. We observed a total of 56 different genotypes, including 1 AA and 55 group B genotypes. The high-frequency KIR genotype profiles found in the present population were consistent with other studies on Han populations but different from those conducted on other populations. In the family panel, a total of 28 KIR haplotypes were identified in the segregation study. The majority of Eastern Han carried group A KIR gene motifs. Comparison of the frequencies of Cen and Tel KIR gene motifs shows that they differ from other populations. The study on the distribution of KIR genes in the population may aid in the development of a complementary population-specific criterion to distinguish between KIR haplotypes and offer a research direction for further gene functional studies.

Blockade of PD-L1 expression on tumor cells via anti–PD-L1 monoclonal antibody (mAb) has shown great promise for successful cancer treatment by overcoming T-cell exhaustion; however, the function of PD-L1 on natural killer (NK) cells and the effects of anti–PD-L1 mAb on PD-L1+ NK cells remain unknown. Moreover, patients with PD-L1− tumors can respond favorably to anti–PD-L1 mAb therapy for unclear reasons. Here, we show that some tumors can induce PD-L1 on NK cells via AKT signaling, resulting in enhanced NK-cell function and preventing cell exhaustion. Anti–PD-L1 mAb directly acts on PD-L1+ NK cells against PD-L1− tumors via a p38 pathway. Combination therapy with anti–PD-L1 mAb and NK cell–activating cytokines significantly improves the therapeutic efficacy of human NK cells against PD-L1− human leukemia when compared with monotherapy. Our discovery of a PD-1–independent mechanism of antitumor efficacy via the activation of PD-L1+ NK cells with anti–PD-L1 mAb offers new insights into NK-cell activation and provides a potential explanation as to why some patients lacking PD-L1 expression on tumor cells still respond to anti–PD-L1 mAb therapy. Significance: Targeting PD-L1 expressed on PD-L1+ tumors with anti–PD-L1 mAb successfully overcomes T-cell exhaustion to control cancer, yet patients with PD-L1− tumors can respond to anti–PD-L1 mAb. Here, we show that anti–PD-L1 mAb activates PD-L1+ NK cells to control growth of PD-L1− tumors in vivo, and does so independent of PD-1. This article is highlighted in the In This Issue feature, p. 1325

Little is known about oropharyngeal colonization microorganisms in patients during allogeneic hematopoietic stem cell transplantation (allo-HSCT), and updated epidemiologic investigations are advisable. This study aimed to characterize oropharyngeal colonization microorganisms in patients during allo-HSCT and confirm whether they were related to clinical outcomes. This retrospective, matched case-control study included 1267 consecutive patients undergoing allo-HSCT between January 2018 and December 2020 at our institution. Patients with oropharyngeal colonization microorganisms were those with a positive throat swab before or on the day of transplantation without the occurrence of any symptoms of infection. Propensity score matching was used. Characteristics of oropharyngeal colonization microorganisms were evaluated among patients in the transplant medicine wards and compared with clinical outcomes within 100 days in positive and negative colonization groups. A total of 127 patients had oropharyngeal colonization microorganisms before or on the day of transplantation. Using propensity score matching, we matched the 127 patients in the positive colonization group with 508 patients in the negative colonization group at a 1:4 ratio (total of 635 cases). None of the differences in clinical traits between the 2 groups remained significant. Among the 127 patients with oropharyngeal colonization microorganisms, 90 patients suffered from the documented infection subsequently, and the others were asymptomatic. A total of 82 single gram-negative bacteria were identified in 127 isolates. There were no differences between the positive and negative colonization groups in the occurrence of oral mucositis, Epstein-Barr virus, or acute graft-versus-host disease and relapse within 100 days. However, the rate of neutrophil or platelet recovery was significantly lower in the positive colonization group compared with the negative colonization group (hazard ratio [HR], .71; 95% confidence interval [CI], .59 to .84; P.001; HR .69; 95% CI, .58 to .83; P = .003; separately). The risk of bloodstream infection was higher in the positive colonization group compared with the negative colonization group (HR, 6.09; 95% CI, 3.16 to 11.75; P.001). The continency rate between the bacteria isolated from the blood samples and oropharyngeal colonization microorganisms among the patients with positive results was 73.3%. Patients in the positive colonization group were more vulnerable to cytomegalovirus infection compared with the negative colonization group (HR, 1.41; 95% CI, 1.00 to 1.99; P = .049). The nonrelapse mortality at day +100 was higher in the positive colonization group (HR, 3.46; 95% CI, 1.69 to 7.08; P.001). The survival probability within 100 days was significantly lower in the positive colonization group (HR, 3.38; 95% CI, 1.78 to 6.41; P.001). Our data show that the presence of oropharyngeal colonization microorganisms is related to clinical outcomes, and that oropharyngeal microorganism monitoring may be useful during allo-HSCT.

Objective To develop high-quality synthetic CT (sCT) generation method from low-dose cone-beam CT (CBCT) images by using attention-guided generative adversarial networks (AGGAN) and apply these images to dose calculations in radiotherapy. Methods The CBCT/planning CT images of 170 patients undergoing thoracic radiotherapy were used for training and testing. The CBCT images were scanned under a fast protocol with 50% less clinical projection frames compared with standard chest M20 protocol. Training with aligned paired images was performed using conditional adversarial networks (so-called pix2pix), and training with unpaired images was carried out with cycle-consistent adversarial networks (cycleGAN) and AGGAN, through which sCT images were generated. The image quality and Hounsfield unit (HU) value of the sCT images generated by the three neural networks were compared. The treatment plan was designed on CT and copied to sCT images to calculated dose distribution. Results The image quality of sCT images by all the three methods are significantly improved compared with original CBCT images. The AGGAN achieves the best image quality in the testing patients with the smallest mean absolute error (MAE, 43.5 ± 6.69), largest structural similarity (SSIM, 93.7 ± 3.88) and peak signal-to-noise ratio (PSNR, 29.5 ± 2.36). The sCT images generated by all the three methods showed superior dose calculation accuracy with higher gamma passing rates compared with original CBCT image. The AGGAN offered the highest gamma passing rates (91.4 ± 3.26) under the strictest criteria of 1 mm/1% compared with other methods. In the phantom study, the sCT images generated by AGGAN demonstrated the best image quality and the highest dose calculation accuracy. Conclusions High-quality sCT images were generated from low-dose thoracic CBCT images by using the proposed AGGAN through unpaired CBCT and CT images. The dose distribution could be calculated accurately based on sCT images in radiotherapy.

With the increasing number of non-matched donor hematopoietic stem cell transplantations (HSCTs) has come increasing evidence regarding factors affecting graft outcomes. One factor affecting graft outcomes currently being evaluated is anti-HLA donor-specific antibodies (DSAs). In this, we analyzed the clinical relevance of anti-HLA DSAs in patients who have undergone HSCT at a population level by conducting a systematic review of existing literature. A comprehensive search was conducted through PubMed, Embase, the Cochrane library, and Web of Science from inception to January 1, 2021. A meta-analysis was performed of the association between anti-HLA DSAs and primary graft failure (PGF) with further subgroup analyses. The search was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. A total of 920 eligible citations were identified, out of which 15 studies were included in the final meta-analyses after application of rigorous selection criteria and independent review. A total of 2436 patients were included in these 15 studies. Patients with anti-HLA DSAs prior to undergoing HSCT had a 7.47-fold increased risk of PGF failure compared with patients without anti-HLA DSAs (odds ratio, 7.47; 95% confidence interval, 4.54 to 12.28, P

Acute graft-versus-host disease (aGVHD) is a major life-threatening complication after allogeneic haematopoietic stem cell transplantation. Interleukin-27 receptor alpha (IL-27Rα) is a co-receptor of IL-27, an inflammatory cytokine that possesses extensive immunological functions. It has been reported that IL-27Rα can exist in its soluble form (sIL-27Rα) in human serum and can function as a natural IL-27 antagonist. In this study, we examined serum sIL-27Rα levels and evaluated their prognostic value in aGVHD. A total of 152 subjects were prospectively recruited and separated into the training group (n = 72) and the validation group (n = 80). Serum sIL-27Rα at neutrophil engraftment was measured by ELISA. In the training set, a cut-off value of sIL-27Rα = 59.40 ng/ml was identified to predict grade II–IV aGVHD (AUC = 0.735, 95% CI 0.618–0.853, P = 0.001). Cumulative incidences of grade II–IV aGVHD (P = 0.004), relapse rate (P = 0.008), and non-relapse mortality (P = 0.008) in patients with low serum sIL-27Rα (≥59.40 ng/ml) were significantly higher than those of patients with high serum sIL-27Rα (P P = 0.029), IL-10 (R = 0.37, P = 0.0015) and HGF (R = 0.27, P = 0.0208), but was negatively correlated with TNFR1 (R = −0.365, P = 0.0022) and ST2 (R = −0.334, P = 0.0041), elafin (R = −0.29, P = 0.0117), and REG3α (R = −0.417, P = 0.0003). More importantly, the threshold value of sIL-27Rα was then validated in an independent cohort of 80 patients (AUC = 0.790, 95% CI 0.688–0.892, P

The aim of this study is to investigate the potential biomarkers associated with chronic myeloid leukemia (CML), reveal the metabolite changes related to the continuous phases of tyrosine kinase inhibitors (TKIs), and find the potential biomarkers associated with treatment effects. Fifty‐two patients with CML and 26 matched healthy people were enrolled as the discovery set. Another 194 randomly selected CML patients treated with TKI were chosen as the external validation set. Plasma samples from the patients and controls were profiled using the gas chromatography‐mass spectrometry‐based metabonomic approach. Multivariate and univariate statistical analyses were combined to select the differential metabolic features. The gas chromatography‐mass spectrometry‐based metabolomics showed a clear clustering and separation of metabolic patterns from healthy controls and pre‐ and post‐TKI treatment CML patients in the discovery set. We identified 9 metabolites that differentiated CML patients from healthy controls, including lactic acid, isoleucine, glycerol, glycine, myristic acid, d‐sorbitol, d‐galactose, d‐glucose, and myo‐inositol. Among the 9 markers, glycerol and myristic acid had the most significant association with TKI treatment effects in both discovery and external validation sets. In the receiver operating characteristic analysis, the combination of glycerol and myristic acid showed a better discrimination performance compared to a single biomarker. The results indicated that metabolic profiling has the potential for diagnosis of CML and the panel of biomarkers including myristic acid and glycerol could be useful in monitoring TKI therapeutic responses.

Background/Aims: Carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), also known as CD66a, is a member of the immunoglobulin (Ig) superfamily that belongs to the carcinoembryonic antigen (CEA) family which plays a dual role in cancer. Previous studies showed high expression of CEACAM1 in multiple myeloma (MM). The aim of this study was to investigate the biological consequences of CEACAM1 overexpression in MM. Methods: pEGFP-N1-CEACAM1 and pcDNA3.1-CEACAM1 expression plasmids were transfected into U-266 and RPMI8266 cell lines . Effect of CEACAM1 overexpression on the proliferation of two cell lines were tested by the CCK8 assay. Cell cycle and Apoptotic changes after CEACAM1 transfection were examined with AnnexinV–FITC/PI by flow cytometry. Hochest staining assay was used to confirm the apoptotic changes. Caspase-3 activity was examined by Western blotting. The cell invasion and migration activity change after CEACAM1 transfection were performed by well chamber assays and a wound healing, respectively. MMP-2 and MMP-9 proteins expression were detected by Western blotting. Flow cytometry immunophenotyping was be evaluated on myeloma cells from bone marrow taken from 50 patients with symptomatic MM newly diagnosed. The correlations between CEACAM1 expression levels and the clinical features across all groups were investigated. Results: CEACAM1 overexpression significantly suppressed MM cell proliferation, induced cell apoptosis, and inhibited cell invasion and migration possibly through activation of caspase-3 and downregulation of MMP-2 and MMP-9. CEACAM1 expression in patients with DS stage I was more frequent (61.5%) than those with DS stage II (21.1%) or III (22.2%). Furthermore, patients with β2-microglobulin levels equal to or less than 3.5 mg/L had higher CEACAM1 expression than those with β2-microglobulin levels greater than 3.5 mg/L. Conclusion: Our findings suggest that CEACAM1 may act as a tumor suppressor in MM.

To investigate the effect of haploidentical allogeneic hematopoietic stem cell transplantation (Haplo-HCT) in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), the outcome of 58 patients with Ph+ ALL who received Haplo-HCT (n=42) or matched unrelated donor transplantation (MUD-HCT) (n=16) during the same period were analyzed retrospectively. All patients received a tyrosine kinase inhibitor (TKI)-based regimen before transplantation, and TKI was resumed primarily after transplantation. At the 3-year follow-up, the overall survival (OS), leukemia-free survival (LFS), the cumulative incidence of relapse (CIR), and non-relapse mortality (NRM) rates in Haplo-HCT group were 69.1, 64.3, 19.0, and 14.3%, respectively, without significant differences from that of MUD-HCT. Haplo-HCT was not related to higher incidences of severe acute graft-versus-host disease (GvHD) (17.6±5.2% vs. 20.0±10.0%, P=0.603) or chronic GvHD (19.5±7.1% vs. 13.3±8.6%, P=0.637) as compared to MUD-HCT. Multivariate analysis showed that chronic GvHD was associated with lower relapse rate in Haplo-HCT group. Haplo-HCT is a promising choice for improving the long-term survival in Ph+ ALL patients.

Stenotrophomonas maltophilia (SM) is an important nosocomial pathogen, particularly in immunocompromised patients due to their adverse antimicrobial susceptibility pattern. The objective of this article was to investigate the clinical impact of SM bacteremia on the 30-day mortality rate and identify the risk factors of the cause of mortality in patients with hematologic disorders. We retrospectively reviewed the clinical data in patients diagnosed with hematological disorders and SM bacteremia over an 8-year period from July 2010 to July 2018 at a 248-bed hematology department. We compared patients’ clinical characteristics and outcomes between the non-survivor and survivor groups. The overall incidence of SM bacteremia was 25.1 per 10,000 admissions. There were 59 patients (median age: 35 years; 57.6% males) included in the study with an overall SM bacteremia-related 30-day mortality of 44.1%. Multi-drug resistance was common. In vitro susceptibility is higher to ceftazidime (72.9%), ciprofloxacin (66.1%) and cefoperazone/sulbactam (59.3%). The risk factors identified in the univariate analysis were catheter re-implantation, accompanying polymicrobial infection, inadequate initial antimicrobial treatment, APACHE II score, temperature > 39 °C, septic shock, respiratory failure, and non-remission post treatment for primary diseases. Multivariate analysis further confirmed that inadequate initial antimicrobial treatment, respiratory failure, and non-remission after treatment for hematological diseases are independent risk factors associated with mortality (P = 0.001, 0.002 and 0.007, respectively). Our study suggests that SM bacteremia is highly associated with increased mortality in patients with hematologic diseases. Early detection, prompt comprehensive management including initiation of combined sensitive antibiotics, respiratory monitoring and support, platelet infusion, and strategies to improve patients’ remission status are recommended to improve the overall survival in patients with SM bacteremia.

Donor killer immunoglobulin-like receptor (KIR) group B profiles (Bx) and homozygous of centromeric motif B (Cen-B/B) are the most preferable KIR gene content motifs for hematopoietic stem cell transplantation (HSCT). The risk of transplant from Bx1 donors and the benefit of the presence of Cen-B (regardless of number) were observed for standard-risk acute myeloid leukemia/myelodysplastic syndrome (AML/MDS) patients in this 4-year retrospective study. A total of 210 Chinese patients who underwent unrelated donor HSCT were investigated. Donor KIR profile Bx was associated with significantly improved overall survival (OS; P = .026) and relapse-free survival (RFS; P = .021) and reduced nonrelapse mortality (NRM; P = .017) in AML/MDS patients. A significantly lower survival rate was observed for transplants from Bx1 donors compared with Bx2, Bx3, and Bx4 donors for patients in first complete remission (n = 82; OS: P = .024; RFS: P = .021). Transplant from donors with Cen-B resulted in improved OS (HR = .256; 95% CI, .084 to .774; P = .016) and RFS (HR = .252; 95% CI, .084 to .758; P = .014) in AML/MDS patients at standard risk. However, this particular effect did not increase with a higher number of Cen-B motifs (cB/B versus cA/B; OS: P = .755; RFS: P = .768). No effect was observed on high-risk AML/MDS, acute lymphoblastic leukemia/non-Hodgkin lymphoma, and chronic myelogenous leukemia patients. Avoiding the selection of HSCT donors of KIR profile Bx1 is strongly advisable for standard-risk AML/MDS patients. The presence of the Cen-B motif rather than its number was more important in donor selection for the Chinese population.

Outcomes for hematopoietic stem cell transplantation (HSCT) in various donor and recipient killer immunoglobulin-like receptor (KIR) genotypes have been studied extensively. The associations between KIR2DS4 and its variant KIR1D with outcomes of HSCT from a sibling-related HLA-matched donor with KIR haplotype A have not been explored, however. To study this, we genotyped donor–recipient pairs and divided 165 recipients of HSCT from a KIR gene haplotype A donor into 3 groups: 2DS4+/2DS4+ (2 intact KIR2DS4 alleles), 2DS4+/1D+ (heterozygous), and 1D+/1D+ (homozygous for the deletion variant KIR1D). No difference in the recovery of neutrophils and platelets among the 3 groups was observed. The cumulative incidence of grade III-IV acute graft-versus-host disease (aGVHD) within day +100 was 28.94% in the 2DS4+/2DS4+ group, 14.11% in the 2DS4+/1D+ group, and 44.44% in the 1D+/1D+ group (P = .0159). Multivariate analysis identified 1D+/1D+ as an independent risk factor for aGVHD (hazard ratio [HR], 4.221; 95% confidence interval [CI], 1.470 to 12.124; P = .007). In contrast, the cumulative incidences of chronic GVHD, 3-year cumulative relapse, and treatment-related mortality did not differ significantly among the 3 groups. The rate of cytomegalovirus (CMV) reactivation was 46.96% in the 2DS4+/2DS4+ group, 20.16% in the 2DS4+/1D+ group, and 53.25% in the 1D+/1D+ group (P = .0017). Multivariate analysis identified 2DS4+/1D+ as an independent protective factor for CMV reactivation (HR, 0.268; 95% CI, 0.125 to 0.574; P = .001). Although overall survival (OS) did not differ among the groups in the first year, the 2DS4+/2DS4+ group had significantly better OS than the other groups after 1 year (P = .0361). In patients with advanced-stage disease, the 3-year probability of disease-free survival was 51.06% in the 2DS4+/2DS4+ group, 34.01% in the 2DS4+/1D+ group, and 0% in the 1D+/1D+ group (P = .0314). Collectively, our data suggest that the KIR 2DS4/1D allelic variance is associated with the outcome of sibling-related HLA-matched HSCT, and that donor subclassification of KIR 2DS4/1D alleles should be considered in this setting.

The National Marrow Donor Program and Center for International Blood and Marrow Transplant Research provided guidelines for the use of anti-HLA antibodies and HLA-DP–mismatched loci in unrelated donor hematopoietic stem cell transplantation (HSCT). However, a deeper understanding of other potentially useful biomarkers for predicting clinical outcomes in HLA-A, -B, -C, -DRB1, -DQB1, and -DQA1 (12/12)–matched unrelated donor HSCT is needed to further improve clinical outcomes. We tested HLA genotyping for 123 pairs of patients and donors. Anti-HLA antibodies using the Luminex method was applied to 123, 117, and 106 serum samples collected before and 1 month and 3 months after transplantation. The presences of anti-HLA antibodies at the 3 time points were 37.4% (46 of 123), 40.2% (47 of 117), and 22.6% (24 of 106). Mismatch of HLA-DPB1 and/or DPA1 allele between patient-donor pairs was 83.6% (92 of 110). Patients with anti-HLA antibodies had delayed platelet recovery. The presence of anti-HLA antibodies and their dynamic changes after transplantation were associated with increased occurrence of grades II to IV acute and chronic graft-versus-host disease (GVHD), higher treatment-related mortality, and reduced overall survival (OS) and disease-free survival, especially in acute myeloid leukemia and myelodysplastic syndrome patients. Multivariate analysis showed that presence of anti-HLA antibodies before transplantation was a risk factor for GVHD and OS. Furthermore, HLA-DP loci–matched subgroup showed a trend towards a lower rate of acute GVHD and a higher OS in the anti-HLA Abs-negative group. Our results suggest that dynamic changes of anti-HLA antibodies independently predict for a negative outcome of HSCT, independent of HLA-DP loci mismatches. Routine monitoring for anti-HLA antibody dynamics should be conducted before and after HSCT.

Accurate regulation of innate immunity is necessary for the host to efficiently respond to invading pathogens and avoid excessive harmful immune pathology. Here we identified OTUD3 as an acetylation-dependent deubiquitinase that restricts innate antiviral immune signaling. OTUD3 deficiency in mice results in enhanced innate immunity, a diminished viral load, and morbidity. OTUD3 directly hydrolyzes lysine 63 (Lys63)-linked polyubiquitination of MAVS and thus shuts off innate antiviral immune response. Notably, the catalytic activity of OTUD3 relies on acetylation of its Lys129 residue. In response to virus infection, the acetylated Lys129 is removed by SIRT1, which promptly inactivates OTUD3 and thus allows timely induction of innate antiviral immunity. Importantly, acetyl-OTUD3 levels are inversely correlated with IFN-β expression in influenza patients. These findings establish OTUD3 as a repressor of MAVS and uncover a previously unknown regulatory mechanism by which the catalytic activity of OTUD3 is tightly controlled to ensure timely activation of antiviral defense.

Type I interferons (IFN-Is) are a family of cytokines that exert direct antiviral effects and regulate innate and adaptive immune responses through direct and indirect mechanisms. It is generally believed that IFN-Is repress tumor development via restricting tumor proliferation and inducing antitumor immune responses. However, recent emerging evidence suggests that IFN-Is play a dual role in antitumor immunity. That is, in the early stage of tumorigenesis, IFN-Is promote the antitumor immune response by enhancing antigen presentation in antigen-presenting cells and activating CD8+ T cells. However, in the late stage of tumor progression, persistent expression of IFN-Is induces the expression of immunosuppressive factors (PD-L1, IDO, and IL-10) on the surface of dendritic cells and other bone marrow cells and inhibits their antitumor immunity. This review outlines these dual functions of IFN-Is in antitumor immunity and elucidates the involved mechanisms, as well as their applications in tumor therapy.

Patients with steroid refractory gastrointestinal (GI) tract graft- vs.-host disease (GvHD) face a poor prognosis and limited therapeutic options. To accurately assess the efficacy and safety of fecal microbiota transplantation (FMT) in treating steroid refractory GI tract GvHD, we conducted a pilot study involving eight patients. Having received FMTs, all patients' clinical symptoms relieved, bacteria enriched, and microbiota composition reconstructed. Compared to those who did not receive FMT, these eight patients achieved a higher progression-free survival. FMT can serve as a therapeutic option for GI tract aGVHD, but its effectiveness and safety need further evaluations. Clinical Trial Registration: NCT03148743.

BACKGROUND There are very few studies investigating metabolic biomarkers to predict acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). Metabolic models can provide a framework for analyzing the information-rich omics data sets in this setting. METHODS Four hundred and fifty-six samples from one hundred and fourteen consecutive patients who underwent HSCT from January 2012 to May 2014 were collected for this study. The changes in serum metabolite levels were investigated using a gas chromatography-mass spectrometry-based metabolomics approach and underwent statistical analysis. RESULTS Significant metabolic changes were observed on day 7. The stearic acid/palmitic acid (SA/PA) ratio was effective in the diagnosis of grade II-IV aGVHD. Multivariate analysis showed that patients with high SA/PA ratios on day 7 after HSCT were less likely to develop II-IV aGVHD than patients with low SA/PA ratios (odds ratio [OR] = 0.06, 95% CI 0.02-0.18, P < 0.001). After the adjustment for clinical characteristics, the SA/PA ratio had no significant effect on overall survival (hazard ratio [HR] = 1.95, 95% CI 0.92-4.14, P = 0.08), and patients in the high SA/PA ratio group were significantly more likely to relapse than those in the low ratio group (HR = 2.26, 95% CI 1.04-4.91, P = 0.04). CONCLUSION Our findings suggest that the SA/PA ratio on day 7 after HSCT is an excellent biomarker to predict both aGVHD and relapse. The serum SA/PA ratio measured on day 7 after transplantation may improve risk stratification for aGVHD and relapse after allogeneic stem cell transplantation. FUNDING National Natural Science Foundation of China (81470346, 81773361), Priority Academic Program Development of Jiangsu Higher Education Institutions, Jiangsu Natural Science Foundation (BK20161204), Innovation Capability Development Project of Jiangsu Province (BM2015004), Jiangsu Medical Junior Talent Person award (QNRC2016707), and NIH (AI129582 and NS106170).

Newly diagnosed acute myeloid leukemia (AML) failed to achieve complete remission after two courses of intensive chemotherapy. This was considered as primary refractory AML (PRR-AML), and still has a dismal prognosis. Allogeneic hematopoietic stem cell transplantation could be the only cure for these patients. However, the role of haploidentical hematopoietic stem cell transplantation (HID-HCT) for PRR-AML is still undetermined. We retrospectively analyzed the outcomes of 45 adult patients with PRR-AML who underwent HID-HCT, and compared it with the result of 53 patients who received HLA-matched related or unrelated donor transplantation (MD-HCT) during the same treatment period. The 3-year overall survival (OS), leukemia-free survival (LFS), cumulative incidence of relapse (CIR), and non-relapse mortality (NRM) rates in the HID-HCT group were 19.0, 16.5, 70.0, and 35.2%, respectively, but showed no significant differences from the results of MD-HCT. Multivariate analysis showed that complex karyotype with del(7) and time > 6 months from diagnosis to transplantation were associated with lower OS and LFS, and chronic GVHD demonstrated better OS and LFS in the entire cohort. Complex karyotype with del(7) was related with higher CIR and chronic GVHD with lower CIR. In conclusion, HID-HCT could be an alternative treatment strategy to improve the long-term survival in PRR-AML adult patients who have no HLA-matched donors.

Drug reaction with eosinophilia and systemic symptoms (DRESS) is characterised by skin rash and multivisceral involvement. The liver is the organ most frequently affected and the degree of liver function impairment often correlates with the mortality rate of DRESS. We aimed to examine the expression of cytotoxic proteins, including soluble Fas ligand (sFasL), TNF-α, granulysin, perforin, and granzyme B in the sera and skin lesions of patients with DRESS and evaluate their clinical significance. Our cohort consisted of 21 patients with DRESS and control groups including 39 patients with Stevens-Johnson syndrome/toxic epidermal necrolysis, 21 patients with maculopapular eruption, and 29 normal controls. Concentrations of cytotoxic proteins in the sera were measured using enzyme-linked immunosorbent assays. Tissue samples were also obtained from typical skin lesions, and immunohistochemical staining was conducted to assess the local expression of cytotoxic proteins. We found that sFasL and granzyme B were significantly overexpressed in the sera of DRESS patients compared to normal controls. Furthermore, the levels of sFasL, perforin, and granzyme B significantly correlated with the serum level of liver enzymes in DRESS patients. Immunohistochemical examination also showed overexpressed cytotoxic proteins in cutaneous DRESS lesions. Cytotoxic proteins may play a vital role in the pathogenesis of DRESS, and serum sFasL, perforin, and granzyme B may also be involved in liver function impairment in DRESS patients.

Lung cancer has very high mortality and glycyrrhizin was found to significantly inhibit the growth of lung cancer cells in vitro and tissues in mice. However, the detailed inhibitory role of glycyrrhizin in the growth of lung cancer is still unclear. In this study, we first found that glycyrrhizin inhibited the growth of lung tumor in PDX mice. And high level of HMGB1 promoted the migration and invasion of lung cancer cells, which was suppressed by glycyrrhizin. Moreover, glycyrrhizin reduced the activity of JAK/STAT signaling pathway, which is the upstream regulator of HMGB1. Therefore, this study revealed a potential mechanism by which glycyrrhizin can inhibit the progression of lung cancer.

DRESS is one of the most severe drug reactions. The aim of this retrospective study was to summarize the clinical presentation, genetic predisposition and prognostic factors of DRESS. A total of 52 patients with DRESS, who were inpatients at a medical referral centre in Shanghai, China, from January 2011 to December 2016, were analysed retrospectively. All the patients had skin eruption, 83% had liver involvement, and ≤10% had other organ involvement. Mean cost of hospitalization was US$5,511±3,050. The 3 most common causative agents were allopurinol (18/52; 35%), salazosulphapyridine (11/52; 21%) and carbamazepine (5/52; 10%). HLA-B*5801 and HLA-B*1302 were associated with allopurinol-induced DRESS. HLA-B*1301 was related to salazosulphapyridine-induced DRESS. The mortality rate was 6% (3/52). Epstein-Barr virus DNA was found in 10 patients (19%) and indicated a poor prognosis. Human herpes virus 6 DNA was detected in 17 patients (33%) and was associated with autoimmune sequelae. Due to its high medical cost and sometimes poor prognosis, prevention of DRESS should be a high priority.

Several studies have reported a significant role of high mobility group box protein 1 (HMGB1) in lung cancer. Nevertheless, there is a lack of knowledge regarding the expression of HMGB1 and its correlation with the clinicopathological features of lung cancer. In addition, the potential molecular mechanisms underlying the role of HMGB1 in lung cancer are still unknown. We therefore investigated the clinicopathological and prognostic significance as well as the potential role of HMGB1 in the development and progression of lung cancer. HMGB1 expression in the tumor tissues of the cohort correlated with clinicopathological features. Moreover, lung cell migration and invasion were significantly increased after treatment with HMGB1. The matrix metalloproteinase-2 (MMP-2) expression and activity were upregulated after treatment with HMGB1, while the upregulated expression of MMP-2 stimulated by HMGB1 in lung cancer cells was significantly reduced with the blockage of si-p65. These results indicated that HMGB1 expression was significantly associated with lung cancer progression. We also showed that HMGB1 promoted lung cancer invasion and metastasis by upregulating the expression and activity of MMP-2 in an NF-κB-dependent manner. Taken together, these data suggested that HMGB1 may be a potential prognosis and therapeutic marker for lung cancer.

Natural killer (NK) cells are one group of innate lymphocytes that are important for host defense against malignancy and viruses. MicroRNAs (miRNAs) play a critical role in regulating responses of immune cells including NK cells. Accumulating evidence suggests that miR-146a is involved in the regulation of immune responses. However, the mechanism by which miR-146a regulates NK cell function is largely unknown. In the current study, we found that miR-146a intrinsically regulated NK cell function. Forced overexpression of miR-146a decreased IFN-γ production, whereas downregulation of miR-146a by anti-miR-146a significantly enhanced IFN-γ production in the human NK-92 cell line and primary human NK cells upon stimulation with IL-12 or co-stimulation with IL-12 and IL-18. Mechanistically, miR-146a regulated IFN-γ production via NF-κB, as evidenced in NK-92 cells, by downregulation of NF-κB p65 phosphorylation when miR-146a was overexpressed but upregulation of NF-κB p65 phosphorylation when anti-miR-146a was overexpressed. miR-146a directly targeted IRAK1 and TRAF6, the upstream signaling components of the NF-κB signaling pathway. This direct targeting mechanism confirmed the above gain- and loss-of-function approaches. However, the potent IFN-γ-producing subset, CD56bright NK cells, expressed higher levels of miR-146a than the lesser IFN-γ-producing subset, CD56dim NK cells. We also observed that co-stimulation of IL-12 and IL-18 significantly increased miR-146a expression in bulk NK cells and in the CD56bright subset in a time-dependent manner, correlating with augmented IFN-γ production. These data suggest that miR-146a plays a negative role in IFN-γ production by human NK cells and this miRNA may be critical in preventing NK cells from being super activated and overproducing IFN-γ.

After hematopoietic stem cell transplantation (HSCT), natural killer (NK) cell alloreactivity in HLA cells of recipients is regulated by killer immunoglobulin-like receptors (KIRs) on donor NK cells. The effect of KIRs on HSCT outcomes is controversial, particularly in those undergoing HLA-identical sibling HSCT. In this study, effects of KIR and HLA genotypes on the HSCT outcome were investigated in a 5-year retrospective study comprising 219 patient-donor pairs undergoing HLA-identical sibling HSCT for myeloid and lymphoid malignancies. We found that 39.7% (87 of 219) of these pairs, which were KIR mismatched, had better overall survival (OS) and reduced grade III to IV acute graft-versus-host disease (aGVHD), especially in acute myeloid leukemia (AML) patients. Bx1 donor KIR genotype with haplotype B on a telomeric region was a risk factor for the OS and relapse-free survival (RFS). Donor centromeric (c) and telomeric (t) KIR haplotype analysis showed that donor KIR cB-tA/tB was associated with improved OS and RFS compared with cA-tA or cA-tB. Furthermore, donor KIR B haplotype of the centromeric motifs (Cen-B) was an independent beneficial factor in improving OS and RFS and in protecting from relapse after HSCT. In AML patients, the occurrence of aGVHD was significantly lower in HLA-C1 group compared with that in HLA-C2 group, although such effect was not observed in patients with acute lymphoblastic leukemia or chronic myelogenous leukemia. Our results suggest that KIR could impact outcome and donor KIR haplotype with Cen-B confer significant survival benefits to HLA-identical sibling HSCT.

The role of Th17 cells and Th17-associated cytokines in the development of acute graft-versus-host disease (aGVHD) in clinical allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients is not well established. In the current study, a cohort of 69 allo-HSCT patients was examined for the percentages of Th17 and FoxP3+ Treg cells and the expressions of RORγt and FoxP3 in peripheral blood mononuclear cells (PBMCs). The Th17 percentage and RORγt expression were significantly higher, whereas Treg percentage and FoxP3 expression were significantly lower in severe aGVHD (grade 3 to 4) and mild aGVHD (grade 1 to 2) patients than in patients without aGVHD (grade 0) and healthy donors. We then investigated the expressions of Th17-associated cytokines, including TGF-β, IL-6, IL-1β, IL-17, IL-21, IL-22, IL-23, as well as IL-23R in the PBMCs of patients after allo-HSCT. The expressions of IL-17 and IL-22 in CD4+ T cells were also examined. The results showed that the expressions of IL-6, IL-1β, IL-17, IL-21, IL-23, and IL-23R were all increased, whereas IL-22 expression was decreased in aGVHD patients. The changes were also correlated with the severity of aGVHD. We also investigated the dynamic changes of Th17/Treg cells and Th17-associated cytokines in patients during the onset and resolution of aGVHD. The results demonstrated a reciprocal relationship between Treg and Th17 cells. Th17-associated cytokine expressions, namely IL-17 and IL-23, were closely related to the occurrence and resolution of aGVHD. We conclude that the dynamic balance between the Th17 and FoxP3+ Treg cells and the changes of Th17-associated cytokines could be the indicators of the disease progression and promising candidates of prognostic biomarkers of aGVHD.

Background aims Cord blood (CB) hematopoietic stem cell transplantation has often been limited by the scarcity of stem cells. Therefore, the number of CB hematopoietic stem/progenitor cells (HSPCs) should be increased while maintaining the stem cell characteristics. Methods We designed an ex vivo culture system using endothelial progenitor cells (EPCs) as stroma to determine the capacity of expanding CB-HSPCs in a defined medium, the effect on engraftment of the expanded cells in a mouse model and the underlying mechanism. Results After 7 days of culture, compared with those cultured with cytokines alone (3.25 ± 0.59), CD34+ cells under contact and non-contact co-culture with EPCs were expanded by 5.38 ± 0.61 ( P = 0.003) and 4.06 ± 0.43 ( P = 0.025)–fold, respectively. Direct cell-to-cell contact co-culture with EPCs resulted in more primitive CD34+ CD38− cells than stroma-free culture (156.17 ± 21.32 versus 79.12 ± 19.77–fold; P = 0.010). Comparable engraftment of day 7 co-cultured HSPCs with respect to HSPCs at day 0 in nonobese diabetic-severe combined immunodeficiency disease (NOD/SCID) mice was measured as a percentage of chimerism (13.3% ± 11.0% versus 16.0% ± 14.3%; P = 0.750). EPCs highly expressed interleukin 6 ( IL6 ) and angiopoietin 1 ( ANGPT1 ), the hematopoietic- related cytokines. A higher transcriptional level of WNT5A genes in EPCs and co-cultured HSPCs suggests that the activation of Wnt signaling pathway may play a role in HSPCs' expansion ex vivo . Discussion These data demonstrated that EPCs improve the CD34+ population but do not compromise the repopulating efficacy of the amplified HSPCs, possibly via cytokine secretion and Wnt signaling pathway activation.

Gossypol, a male contraceptive drug, has been demonstrated to have antiproliferative and antimetastatic effects on many kinds of cancer cells in vitro. HT-29 human carcinoma cell line is one of the most susceptible cell lines to gossypol-induced cell death. Here, it is shown that treatment of HT-29 cells with gossypol not only induces cell cycle arrest on the G0/G1 phase, but also induces apoptosis. With a serial of Western blot analysis, it is revealed that gossypol-induced cell cycle arrest is involved in P21 up-regulation and cyclin D1 down-regulation; gossypol-induced apoptosis triggers down-regulation of anti-apoptosis Bcl-2 members: Bcl-X(L), Bag-1 and Mcl-1, up-regulation of pro-apoptosis Bcl-2 member Bak, activation of caspase-3, -6, -7, -8, and -9, up-regulation of Apaf-1, release of cytochrome c (cyto-c) from mitochondria, and activation of both DFF45 and PARP. Taken together, gossypol-induced cell death initiates extensive alterations of cell cycle and apoptosis proteins. Gossypol-induced apoptosis of HT-29 cells is through first the mitochondrial pathway, then the death receptor pathway, and the mitochondria pathway is, at least in part, involved in cyto-c release.

To investigate the efficacy and safety of second-generation tyrosine kinase inhibitors (TK-II) combined with allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the treatment of high-risk Philadelphia chromosome positive (Ph⁺) leukemia.The clinical data of 17 cases of high-risk Ph⁺ leukemia patients underwent allo-HSCT were retrospectively analyzed, including 1 case in accelerated phase and 7 cases in blast crises of chronic myeloid leukemia, and 9 cases of Ph⁺ acute lymphoblastic leukemia. Nilotinib or Dasatinib were administered before and (or) after allo-HSCT in all patients.All patients successfully engrafted. Median times to neutrophil and platelet recovery were 12 days (range 10-14) and 15 days (range 11- 23), respectively. Acute GVHD developed in 7 patients: 6 patients had grade 1 to 2 and 1 patient grade 3. Chronic GVHD developed in 6 patients, all were limited and no lethal GVHD occurred. At a median follow-up of 17(range 3-60) months, 11(64.7%) patients survived disease free, 6 patients relapsed and 5 died.TK-II combined with allo-HSCT effectively improved the remission rate of high-risk Ph⁺ leukemia and reduced recurrence after allo-HSCT, which represented an important improvement in the treatment of patients with high-risk Ph+ leukemia.

A total of 123 consecutive patients with advanced-stage, acute leukemia undergoing HSCT from HLA-identical sibling donors were analyzed. A G-CSF-primed DLI was planned within day 60 post-transplantation before hematologic relapse was diagnosed. Fifty of the 123 individuals received prophylactic DLI, and 73 individuals received no prophylactic treatment. The incidence of grades II-IV acute graft-versus-host disease (GVHD) was 17% for patients receiving DLI and 23% for patients not receiving DLI (p = 0.35). The incidence of chronic GVHD was 38% for patients receiving DLI and 17% for patients not receiving DLI (p = 0.021). The two-yr cumulative incidence of relapse was significantly lower in patients who received prophylactic DLI (46%) compared with patients who did not receive prophylactic DLI (66%) (p = 0.02). The three-yr probability of overall survival was higher in patients who received prophylactic DLI (36%) than in patients who did not receive prophylactic DLI (11%) (p = 0.001). The leukemia-free survival was also higher in patients who received prophylactic DLI (29%) than in patients who did not receive prophylactic DLI (9%) (p = 0.001). Our comparisons suggest that the prophylactic use of DLI can significantly increase survival of patients with advanced-stage, acute leukemia who receive HLA-identical sibling HSCT.

Toll like receptors (TLRs) are the major agents for innate immunity that recognize invading microbial products and regulate the growth of normal and malignant human B lymphocytes. Multiple myeloma (MM) is a clonal plasma cell malignancy, though the regulatory role of TLRs in MM plasma cells has been reported, the molecular mechanism remains unclear. We first compared the transcripts of TLR1 to TLR10 in MM patients and healthy donors and found that TLR2, -4 and -9 transcripts were higher in bone marrow mononuclear cells (BMMCs) from patients than those from donors; in addition the expression of TLR4 and TLR9 were higher in MM cells than normal cells as demonstrated by flow cytometric analyses. The ligands of these two TLRs were capable to promote the growth of MM cells and protect them from serum-deprivation-induced apoptosis but not normal plasma cells, which could be attenuated with anti-IL6 neutralizing antibodies or blockage of NF-kappaB activities. Further investigation demonstrated that these TLR ligands could trigger the nuclear translocation of NF-kappaB p65 and the activated NF-kappaB was sufficient to increase the expression of IL6 transcript in MM cells. These data suggested that activated NF-kappaB signalling probably plays a crucial role for the ligands of TLR4 and TLR9 to promote the growth and survival of MM cells partially through IL6 autocrine.

Cytomegalovirus (CMV) can be classified into 4 subgroups based on genotype variation of the glycoprotein B (gB) encoded by UL55 gene. Little is known about the CMV gB genotype distribution and its clinical implication in patients who receive hematopoietic stem cell transplant (HSCT) in China. In this study, which comprises 101 HSCT patients with CMV infection, we have found that 36 patients (35.64%) were infected with CMV genotype gB1, 3 patients (2.97%) with gB2, 39 patients (38.61%) with gB3, 1 patient (0.99%) with gB4, and 17 patients (16.83%) were infected with mixed CMV genotypes. We also found that CMV gB3 was associated with a high risk of CMV pneumonitis; nevertheless, there were no significant differences among patients with gB genotypes with respect to the other CMV diseases; no significant differences between patients with gB genotypes with respect to type II-IV acute graft-verses-host disease (aGVHD) and chronic GVHD (cGVHD) was found either. Interestingly, 5 patients (4.95%) were infected with a CMV variant that lacked a signature RsaI digestion site determined by Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), subsequent cloning and sequencing identified this CMV RsaI minus variant to be novel, herein designated as gB5. Overall, these findings suggest that CMV gB1 and gB3 are prevalent among HSCT recipients with CMV infections, and gB3 CMV infection is a risky indicator for CMV pneumonitis; furthermore, a novel CMV variant in a subset of Chinese HSCT recipients is identified and designated as gB5.

Treatment of acute lymphoblastic leukemia (ALL) has achieved significant progress, however the long-term disease free survival (DFS) of adult ALL patients still does not exceed 20%38% [1-3]. Allogeneic HSCT (allo-HSCT) has been proved to be the most effective treatment for a variety of hematologic malignancies, but the benefits were limited [4]. Although donor lymphocyte infusion (DLI) could restore complete remission (CR) in many patients after transplantation, patients received prophylactic DLI with the risk of fatal graft versus host disease (GVHD). Monitoring minimal residual disease (MRD) allowed for the early detection of trance amount of tumor cells in ALL patients[56]. Whereas, the value of monitoring MRD in relapsed/refractory ALL patients with DLI as intervention after allo-HSCT remains to be evaluated. In this investigation, we reported monitoring MRD in 47 cases of relapsed/refractory ALL after allo-HSCT for 43 months in median and observed that among them 19 patients with a high risk for disease relapse after allo-HSCT were treated with DLI under the guidance of monitoring MRD. Notably, 6 among the 19 cases had no leukemic progression after DLI, suggesting that MRD monitoring has a value in the treatment of relapsed/refractory ALL patients using DLI as intervention after allo-HSCT.

AKT is a promising target for anticancer drug development. In this work, a bioinformatics approach was applied to search for AKT inhibitors based on the correlation analysis between phospho-Ser473 AKT expression level and the antiproliferative data of NCI small molecule compounds against NCI 60 cancer cell lines, the candidate compounds were then subject to AKT kinase assay. The possible effects of potent compound on PI3K/AKT, PDK1, and MAPK, its antiproliferative and apoptosis-inducing effects on breast cancer cells which have high-levels of AKT activation were assessed by Western blot analysis, cell viability assay, and apoptosis assay. One compound, CMEP (NSC632855, 9-chloro-2-methylellipticinium acetate) was identified with all three correlation algorithm, Pearson's, Sperman's, and Kendall's, showing a high-ranked correlation coefficient. CMEP inhibits only AKT, but does not inhibit PI3K, PDK1, or MAPK. CMEP also inhibits heregulin-induced AKT activation, does not inhibit heregulin-induced MAPK activation in MCF-7 breast cancer cells. Increased concentrations of ATP reverse the AKT inhibitory effect of CMEP. CMEP inhibits growth and induces apoptosis in breast cancer cells which have high-levels of AKT activation and lack functional PTEN; however, CMEP only shows a minimal activity in NIH3T3 cells which do not have AKT activation. In conclusion, a lead compound CMEP, as an AKT selective inhibitor has been identified started with a bioinformatics-based approach. CMEP inhibits growth and induces apoptosis in cancer cells which have high-levels of AKT activation and lack PTEN or harbor PTEN mutation.

Thrombotic events are common and potentially fatal complications in patients receiving hematopoietic stem cell transplantation (HSCT). Early diagnosis is crucial but remains controversial. In this study, we investigated the early alterations of hemostatic parameters in allogeneic HSCT recipients and determined their potential diagnostic values in transplantation-related thrombotic complications and other post-HSCT events. Results from 107 patients with allogeneic HSCT showed higher levels of plasma plasminogen activator inhibitor-1 (PAI-1), fibrinogen, and tissue-plasminogen activator (t-PA) and a lower level of plasma protein C after transplantation. No change was found for prothrombin time, antithrombin III, d-dimer, and activated partial thromboplastin time following HSCT. Transplantation-related complications (TRCs) in HSCT patients were defined as thrombotic (n = 8), acute graft-versus-host disease (aGVHD, n = 45), and infectious (n = 38). All patients with TRCs, especially the patients with thrombotic complications, presented significant increases in the mean and maximum levels of PAI-1 during the observation period. Similarly, a high maximum t-PA level was found in the thrombotic group. In contrast, apparent lower levels of mean and minimum protein C were observed in the TRC patients, especially in the aGVHD group. Therefore, the hemostatic imbalance in the early phase of HSCT, reflecting prothrombotic state and endothelial injury due to the conditioning therapy or TRCs, might be useful in the differential diagnosis of the thrombotic complication from other TRCs.