Comparison of four pre-oxidants coupled powdered activated carbon adsorption for odor compounds and algae removal: Kinetics, process optimization, and formation of disinfection byproducts.

Pre-oxidation and powdered activate carbon (PAC) are usually used to remove algae and odorants in drinking waterworks. However, the influence of interaction between oxidants and PAC on the treatment performance are scarcely known. This study systematically investigated the combination schemes of four oxidants (KMnO4, NaClO, ClO2, and O3) and PAC on the inactivation of Microcystis aeruginosa cells and removal of four frequently detected odorants in raw water (diethyl disulfide (DEDS), 2,2'-oxybis(1chloropropane) (DCIP), 2-methylisoborneol (2-MIB) and geosmin (GSM)). O3 showed highest pseudo-first-order removal rate for all four compounds and NaClO exhibited highest inactivation rates for the cell viability and Chlorophyll a (Chl-a). The Freundlich model fitted well for the adsorption of DEDS and DCIP by PAC. When treated by combined oxidation/PAC, the removal ratio of algae cells and odorants were lower (at least 1.6 times) than the sum of removal ratios obtained in oxidation or PAC adsorption alone. Among these four oxidants, the highest synchronous control efficiency of odorants (52 %) and algae (66 %) was achieved by NaClO/PAC. Prolonging the dosage time interval promoted the removal rates. The pre-PAC/post-oxidation processes possessed comparable efficiency for the removal of odorants and algae cells comparing with pre-oxidation/post-PAC process, but significantly inhibited formation of disinfection byproducts (DBPs), especially for the formation of C-DBPs (for NaClO and ClO2), bromate (for O3) and chlorate/chlorite (for ClO2). This study could provide a better understanding of improving in-situ operation of the combined pre-treatments of oxidation and PAC for source water.

Effects of human umbilical cord blood mononuclear cells on ovalbumin-induced asthma in mice.

Background: Umbilical cord blood mononuclear cells (UCMNCs) show broad immune-modulation effects, which may be helpful for treating asthma. Effects of UCMNCs on asthma were investigated with mouse model in present study. Methods: Asthma was induced in BALB/c mice by ovalbumin (OVA) immunization and challenge. Asthmatic mice were then treated on days 7 and 20 with intravenous injections of UCMNCs in doses of 4×105, 2×106, and 107 cells per mouse for the low-dose UCMNC (UCMNCL), medium-dose UCMNC (UCMNCM), and high-dose UCMNC (UCMNCH) groups, respectively. Fetal mouse blood mononuclear cells (FMMNCs) were administered to FMMNC group at a dose of 2×106 cells per mouse as approximate allograft control. Airway hyperresponsiveness (AHR), airway inflammation indexes, and CD4/CD8 T cell subsets were measured at day 25. Results: Compared with the model group, AHR in the UCMNCL group, inflammation score of lung tissue in the UCMNCM group, interleukin (IL)-5 in bronchoalveolar lavage fluid (BALF) in UCMNCL group, IL-5 and IL-13 in BALF in UCMNCM group, and IL-17 in serum in UCMNCH group were significantly inhibited. Compared with the model group, CD4+CD8+ T cells were reduced in the UCMNCL group, while decrease of CD4-CD8- T cells and increase of CD4+CD8- T cells were further strengthened in UCMNCM group. FMMNC treatment significantly reduced the IL-13 and IL-17 in serum, decreased CD4-CD8- and CD4+CD8- T cells, and increased the CD4+CD8+ and CD4-CD8+ T cells in BALF. Conclusions: UCMNCs can modulate AHR, T-helper (Th)2 inflammation, and airway injury in experimental asthma at appropriate dose.

Autologous Airway Basal Cell Transplantation Alleviates Airway Epithelium Defect in Recurrent Benign Tracheal Stenosis.

BACKGROUND: Airway epithelium defects are a hallmark of recurrent benign tracheal stenosis (RBTS). Reconstructing an intact airway epithelium is of great importance in airway homeostasis and epithelial wound healing and has great potential for treating tracheal stenosis. METHODS: An experimental study was conducted in canines to explore the therapeutic effect of autologous basal cell transplantation in restoring airway homeostasis. First, airway mucosae from human patients with recurrent tracheal stenosis were analyzed by single-cell RNA sequencing. Canines were then randomly divided into tracheal stenosis, Stent, Stent + Cells, and Stent + Cells + Biogel groups. Autologous airway basal cells of canines in the Stent + Cells and Stent + Cells + Biogel groups were transplanted onto the stenotic airway after modeling. A biogel was coated on the airway prior to basal cell transplantation in the Stent + Cells + Biogel group. After bronchoscopic treatments, canines were followed up for 16 weeks. RESULTS: Single-cell RNA sequencing demonstrated packed airway basal cells and an absence of normal airway epithelial cells in patients with RBTS. Autologous airway basal cell transplantation, together with biogel coating, was successfully performed in the canine model. Follow-up observation indicated that survival time in the Stent + Cells + Biogel group was significantly prolonged, with a higher (100%) survival rate compared with the other groups. In terms of pathological and bronchoscopic findings, canines that received autologous basal cell transplantation showed a reduction in granulation hyperplasia as well as airway re-epithelialization with functionally mature epithelial cells. CONCLUSIONS: Autologous airway basal cell transplantation might serve as a novel regenerative therapy for airway re-epithelialization and inhibit recurrent granulation hyperplasia in benign tracheal stenosis.

Outcomes after HSCT for mucolipidosis II (I-cell disease) caused by novel compound heterozygous GNPTAB mutations.

Background: Mucolipidosis type II (MLII), or I-cell disease, is a rare lysosomal storage disease (LSD) caused by variants in the GNPTAB gene. MLII patients exhibit clinical phenotypes in the prenatal or neonatal stage, such as marked dysmorphic features, cardiac involvement, respiratory symptoms, dysostosis multiplex, severe growth abnormalities, and mental and motor developmental abnormalities. The median age at diagnosis for MLII is 0.7 years, the median survival is 5.0 years, and the median age at death is 1.8 years. No cure for MLII exists. Methods: Sanger sequencing of the GNPTAB gene identified the compound heterozygous mutations c.673C > T in exon 7 and c.1090C > T in exon 9, which were novel double heterozygous mutations first reported in China. For the first time, we describe our experience in the use of HSCT for MLII. Our patient underwent HSCT with cells from a 9/10 human leukocyte antigen (HLA)-matched unrelated donor at 12 months of age. Myeloid neutrophil and platelet engraftment occurred on Days 10 and 11, respectively. Results: The patient's limb muscle tension was significantly reduced, and his gross and fine motor skills were improved four months after transplantation. DST(Developmental Screen Test) results showed that the patient's fine motor skills and mental development were improved compared with before HSCT. Conclusion: MLII is a very severe lysosomal storage disease, to date, only 3 cases have been reported on the use of HSCT to treat MLII. Our data show that HSCT is a potential way to prolong the life of patients and improve their quality of life. Due to the lack of comparable data and time, the exact benefit remains unclear in MLII patients. Longer-term follow-up and in-depth prospective studies are indispensable.

"Sandwich" protocol based on modified SMILE regimen for children with newly extranodal NK/T cell lymphoma, nasal type: a single-arm, single-center clinical study.

Extranodal NK/T-cell lymphoma, nasal type (ENKTL), which is a rare form of mature T/NK cell lymphoma in children, currently lacks a standardized first-line treatment approach. However, a treatment protocol known as the "sandwich" regimen has been used in children newly diagnosed with ENKTL. This protocol combines the administration of methotrexate, ifosfamide, etoposide, pegaspargase, and dexamethasone (referred to as SMILE) with the addition of radiotherapy (RT). From September 2017 to December 2020, a total of five patients were included in the study, consisting of three males and two females. The median age of onset was 10.6 years (range, 9.8 to 14.0 years). Among the patients, four had nasal/nasopharyngeal disease at stage II, while one patient had extra nasal disease involving the skin at stage IV. The median EBV-DNA level in plasma was 1.68 × 103 copies/ml (range, 0.44 to 21.1 × 103copies/ml). All the patients had good overall response after 2 cycles of chemotherapy and radiotherapy, including 4 of the patients who had a complete response and 1 of the patients with partial remission. The patient with stage IV received allogeneic hematopoietic stem cell transplantation after the EBV-DNA level was elevated again during treatment. One patient in the low-risk group experienced grade 4 oral mucositis, while no other severe complications or treatment-related deaths were observed. The median follow-up period was 22 months (range, 5 to 57 months). All five patients successfully completed their treatment, with four patients achieving event-free survival, and one patient was lost to follow-up. The median OS time and EFS time was 33 months (range: 18-57 months) and 20 months (range: 5-47 months), respectively. The sandwich protocol has demonstrated a high response rate, good tolerance to chemotherapy, and no treatment-related fatalities. However, further confirmation is necessary through additional clinical studies involving larger sample sizes. Clinical trial registration number: Due to modified SMILE regimens with sandwiched radiotherapy yielded promising outcomes in children ENKTL, we have carried out a phase II multicenter clinical trial (ChiCTR220005954) for children ENKTL in China to further verify the efficacy and safety.

Upregulation of FGF7 Induced Intravesical Prostatic Protrusion of Benign Prostatic Hyperplasia via the ERK1/2 Signaling Pathway.

INTRODUCTION: Intravesical prostatic protrusion (IPP) has been reported to be associated with bladder outlet obstruction and is the main cause of lower urinary tract symptoms (LUTS) during the development of benign prostatic hyperplasia (BPH). However, the molecular mechanism of IPP remains unclear. METHODS: Clinical data analysis was performed to analyze the association between IPP and long-term complications in patients with BPH. RNA sequencing was performed on prostate tissues (IPP or not). Stromal cells were obtained from IPP-derived primary cultures to explore the molecular mechanism of IPP formation. Cell proliferation was evaluated by a CCK-8 assay. Multiple proteins in the signaling pathway were assessed using Western blot. RESULTS: First, we confirmed that IPP is a prognostic factor for long-term complications in patients with BPH. Then, we observed that FGF7 was upregulated in both IPP tissues and IPP primary stromal cells through immunohistochemistry, Western blot, and quantitative real-time PCR. Furthermore, FGF7 was significantly upregulated in high IPP-grade prostate tissues. The coculture experiments showed that the downregulation of FGF7 in IPP-derived stromal cells inhibited the proliferation and migration of the prostate epithelial cells. Additionally, FGF7 was bound to FGFR2 to induce the epithelial-mesenchymal transition process through binding to FGFR2. RNA sequencing analysis also revealed the activation of the MAPK/ERK1/2 signaling pathway. The MAPK/ERK1/2 was downregulated by a specific inhibitor affecting the FGF7 stimulation in vitro. CONCLUSIONS: Our data reveal a novel amplification effect, i.e., stromal cell-derived FGF7 promotes epithelial cell proliferation and stromal cell phenotype, ultimately inducing IPP formation. Targeting FGF7 can significantly reduce epithelial to stromal transition and provide a potential therapeutic target for BPH progression.

miR-495-3p depresses cell proliferation and migration by downregulating HMGB1 in colorectal cancer.

BACKGROUND: MicroRNAs play an important role in the genesis and progression of tumours, including colorectal cancer (CRC), which has a high morbidity and mortality rate. In this research, the role of miR-495-3p and HMGB1 in CRC was investigated. METHODS: We performed qRT-PCR to detect the expression of miR-495-3p in colorectal cancer tissues and cell lines. Functional experiments, such as CCK-8, EdU, Transwell and apoptosis assays, were conducted to explore the effects of miR-495-3p on the proliferation, migration and apoptosis of CRC cells in vitro. Then, database prediction, dual-luciferase reporter gene assays and functional experiments verified the role of the miR-495-3p target gene HMGB1 in CRC. Finally, rescue experiments were performed to investigate whether overexpression of HMGB1 could reverse the inhibitory effect of miR-495-3p on CRC cell proliferation in vivo and in vitro. RESULTS: miR-495-3p was downregulated in colorectal cancer tissues and cell lines, inhibited the proliferation and migration of colorectal cancer cells and promoted cell apoptosis. Database prediction and dual-luciferase reporter gene assays showed that HMGB1 was the downstream target gene of miR-495-3p. We finally demonstrated that miR-495-3p inhibited CRC cell proliferation by targeting HMGB1 in vitro and in vivo. CONCLUSION: Our research shows that miR-495-3p inhibits the progression of colorectal cancer by downregulating the expression of HMGB1, which indicates that miR-495-3p may become a potential therapeutic target for colorectal cancer.

Identification of prognostic biomarkers in papillary renal cell carcinoma and PTTG1 may serve as a biomarker for predicting immunotherapy response.

OBJECTIVE: This study aims to identify potential prognostic and therapeutic biomarkers in papillary renal cell carcinoma (pRCC). METHODS: Two microarray datasets were downloaded from the Gene Expression Omnibus (GEO) database and differentially expressed genes (DEGs) were identified. The protein-protein interaction (PPI) networks and functional annotations of DEGs were established. Survival analysis was utilized to evaluate the prognostic significance of the DEGs and the association between the expression level of candidate biomarkers and various tumour-infiltrating immune cells was explored. The role of PTTG1 in tumour microenvironments (TME) was further explored using Single-cell RNA-seq and its prognostic and therapeutic significance was validated in Fudan University Shanghai Cancer Centre (FUSCC) cohort. RESULTS: Eight genes, including BUB1B, CCNB1, CCNB2, MAD2L1, TTK, CDC20, PTTG1, and MCM were found to be negatively associated with patients' prognosis. The expression level of PTTG1 was found to be significantly associated with lymphocytes, immunomodulators, and chemokine in the TCGA cohort. Single-cell RNA-seq information indicated that PTTG1 was strongly associated with the proliferation of T cells. In the FUSCC cohort, the expression level of PTTG1 was also statistically significant for both progression-free survival (PFS) and overall survival (OS) prediction (HR = 2.683, p < .001; HR = 2.673, p = .001). And higher expression level of PTTG1 was significantly associated with immune checkpoint blockade (ICB) response in the FUSCC cohort (χ2=3.99, p < .05). CONCLUSIONS: Eight genes were identified as a prognostic biomarker and the expression level of PTTG1 was also found to serve as a potential predictor for ICB response in pRCC patients.Key messages:Eight genes, including BUB1B, CCNB1, CCNB2, MAD2L1, TTK, CDC20, PTTG1, and MCM were found to be negatively associated with pRCC patients' prognosis.Expression level of PTTG1 was significantly associated with tumour microenvironment including lymphocytes, immunomodulators, and chemokines.Higher expression level of PTTG1 was significantly associated with immune checkpoint blockade (ICB) response in FUSCC cohort.

Nano-Silver Medical Antibacterial Dressing Combined with High-Flow Oxygen Therapy Facilitates Ulcer Wound Healing of Superficial Malignant Tumors.

BACKGROUND: Due to the poor healing of superficial malignant tumor ulcer wounds, patients suffer great pain and significantly reduced quality of life. Related research shows that oxygen therapy can reduce wound bleeding and promote wound healing. OBJECTIVE: This study aims to explore the therapeutic effect of nano-silver antibacterial dressing combined with high-flow oxygen therapy on surface malignant tumor ulcers. METHODS: In this retrospective analysis, 64 patients with superficial malignant tumors and ulcer infection were included and divided into the research group and the control group, with 32 cases in each group. After conventional debridement, the control group was treated with vaseline dressing, while the research group was treated with nano-silver medical antibacterial dressing combined with high-flow oxygen therapy. Both groups were treated for 7 days. The frequency of dressing change and the number of times of blood oozing between the two groups after treatment were recorded. The pain, clinical efficacy, and levels of procalcitonin (PCT) and C-reactive protein (CRP) were compared between the two groups before and after treatment. RESULTS: The dressing changes and blood oozing were less frequent in the research group compared with the control group. The pain score and the levels of PCT and CRP in the research group were lower than those in the control group. The overall response rate was significantly higher in the research group as compared to the control group. All the above differences were statistically significant (P<0.05). CONCLUSION: Nano-silver medical antibacterial dressing combined with high-flow oxygen therapy can reduce the frequency of dressing changes in patients, relieve pain, reduce inflammation, and accelerate the healing of superficial malignant tumor ulcer wounds.

Primary tumor surgery improves survival in non-metastatic primary urethral carcinoma patients: a large population-based investigation.

BACKGROUND: Primary urethral carcinoma (PUC) is a rare genitourinary malignancy with a relatively poor prognosis. The aim of this study was to examine the impact of surgery on survival of patients diagnosed with PUC. METHODS: A total of 1544 PUC patients diagnosed between 2004 and 2016 were identified based on the SEER database. The Kaplan-Meier estimate and the Fine and Gray competing risks analysis were performed to assess overall survival (OS) and cancer-specific mortality (CSM). The multivariate Cox regression model and competing risks regression model were used to identify independent risk factors of OS and cancer-specific survival (CSS). RESULTS: The 5-yr OS was significantly better in patients who received either local therapy (39.8%) or radical surgery (44.7%) compared to patients receiving no surgery of the primary site (21.5%) (p < 0.001). Both local therapy and radical surgery were each independently associated with decreased CSM, with predicted 5-yr cumulative incidence of 45.4 and 43.3%, respectively, compared to 64.7% for patients receiving no surgery of the primary site (p < 0.001). Multivariate analyses demonstrated that primary site surgery was independently associated with better OS (local therapy, p = 0.037; radical surgery, p < 0.001) and decreased CSM (p = 0.003). Similar results were noted regardless of age, sex, T stage, N stage, and AJCC prognostic groups based on subgroup analysis. However, patients with M1 disease who underwent primary site surgery did not exhibit any survival benefit. CONCLUSION: Surgery for the primary tumor conferred a survival advantage in non-metastatic PUC patients.

Optimizing conditioning regimen with low-dose irradiation or busulfan enables the outcome of transplantation from a 6-7/8 HLA-matched donor comparable to that from an 8/8 HLA-matched unrelated donor in severe aplastic anemia patients under 40 years.

With the dramatic improvements in outcomes following alternative donor hematopoietic stem cell transplantation (HSCT), interest in the use of alternative donors in severe aplastic anemia (SAA) is increasing. We conducted a multicenter prospective study to explore the efficiency and safety of upfront HSCT from a 6-8/8 HLA-matched unrelated donor (MUD) or 6-7/8 HLA-matched related donor (MRD) in acquired SAA patients under 40 years. Between August 2014 and July 2017, 115 patients were enrolled, including 48 (41.7%) patients receiving grafts from an 8/8 MUD, 25 (21.7%) from a 6-7/8 MRD, and 42 (36.5%) from a 6-7/8 MUD. The incidence of grade II-IV acute graft-versus-host disease (GVHD) was higher in the 6-7/8 MUD group than in the 8/8 MUD group (42.9% vs. 12.8%, P=0.001). The corresponding incidence in the 6-7/8 MRD group was comparable to that in the 8/8 MUD group (21.7% vs. 12.8%, P=0.332). There was no significant difference in the incidence of chronic GVHD (24.3%, 13.6%, and 17.9%, P=0.676), graft failure (2.4%, 8.0%, and 6.3%, P=0.551), overall survival (85.7%, 96.0%, and 87.5%, P=0.424), and failure-free survival (83.3%, 88.0%, and 83.3%, P=0.885) among the three groups (6-7/8 MUD, 6-7/8 MRD, and 8/8 MUD). In multivariate analysis, conditioning regimen without low-dose irradiation or busulfan was associated with an inferior failure-free survival (HR=2.973, P=0.042). In conclusion, after an intensified conditioning regimen with additional low-dose irradiation or busulfan, the outcome of HSCT from a 6-7/8 MRD or 6-7/8 MUD is comparable to that from an 8/8 MUD.

Prognostic Value of an Immunohistochemical Signature in Patients With Bladder Cancer Undergoing Radical Cystectomy.

BACKGROUND: This study aimed to assess the prognostic value of various diagnostic immunohistochemical (IHC) markers and develop an IHC-based classifier to predict the disease-free survival (DFS) of patients with bladder cancer undergoing radical cystectomy. METHODS: IHC was performed on tumor specimens from 366 patients with transitional cell bladder cancer. The least absolute shrinkage and selection operator (LASSO) Cox regression model was used to develop a multi-marker classifier for predicting DFS of patients with bladder cancer. The Kaplan-Meier estimate was performed to assess DFS, and unadjusted and adjusted Cox regression models were used to identify independent risk factors to predict DFS of patients with bladder cancer. RESULTS: Based on the LASSO Cox regression model, nine prognostic markers were identified in the training cohort. Patients were stratified into low- and high-risk groups using the IHC-based classifier. In the training cohort, the 10-year DFS was significantly better in low-risk patients (71%) compared with high-risk patients (18%) (p < 0.001); in the validation cohort, the 10-year DFS was 86% for the low-risk group and 20% for the high-risk group (p < 0.001). Multivariable Cox regression analyses showed that the high-risk group based on the classifier was associated with poorer DFS adjusted by clinicopathological characteristics. Finally, a nomogram comprising the classifier and clinicopathological factors was developed for clinical application. CONCLUSION: The nine-IHC-based classifier is a reliable prognostic tool, which can eventually guide clinical decision making regarding treatment strategy and follow-up scheduling of bladder cancer.

Construction of an immune-related LncRNA signature with prognostic significance for bladder cancer.

Bladder cancer (BLCA) is one of the most common urological cancer with increasing cases and deaths every year. In the present study, we aim to construct an immune-related prognostic lncRNA signature (IRPLS) in bladder cancer (BLCA) patients and explore its immunogenomic implications in pan-cancers. First, the immune-related differentially expressed lncRNAs (IRDELs) were identified by 'limma' R package and the score of IRPLS in every patient were evaluated by Cox regression. The dysregulation of IRDELs expression between cancer and para-cancer normal tissues was validated through RT-qPCR. Then, we further explore the biological functions of a novel lncRNA from IRPLS, RP11-89 in BLCA using CCK8 assay, Transwell assay and Apoptosis analysis, which indicated that RP11-89 was able to promote cell proliferation and invasive capacity while inhibits cell apoptosis in BLCA. In addition, we performed bioinformatic methods and RIP to investigate and validate the RP11-89/miR-27a-3p/PPARγ pathway in order to explore the mechanism. Next, CIBERSORT and ESTIMATE algorithm were used to evaluate abundance of tumour-infiltrating immune cells and scores of tumour environment elements in BLCA with different level of IRPLS risk scores. Finally, multiple bioinformatic methods were performed to show us the immune landscape of these four lncRNAs for pan-cancers. In conclusion, this study first constructed an immune-related prognostic lncRNA signature, which consists of RP11-89, PSORS1C3, LINC02672 and MIR100HG and might shed lights on novel targets for individualized immunotherapy for BLCA patients.

Intravesical Recurrence After Radical Nephroureterectomy of Upper Urinary Tract Urothelial Carcinoma: A Large Population-Based Investigation of Clinicopathologic Characteristics and Survival Outcomes.

Background: Of patients with upper urinary tract urothelial carcinoma (UTUC), 22-47% developed bladder recurrence after radical nephroureterectomy. Furthermore, the effect of surgery for UTUC-bladder cancer (BC) has not been well validated. The aim of this study was to assess the impact of standard primary BC surgical strategy on survival of patients diagnosed with UTUC-BC. Patients and Methods: A total of 676 UTUC-BC patients and 197,753 primary BC patients diagnosed from 2004 to 2016, were identified based on the SEER database. The Kaplan-Meier method and the Fine and Gray competing risks analysis were performed to assess overall survival (OS) and cancer-specific mortality (CSM). Multivariate Cox regression model and competing risks regression model were used to identify independent risk factors. Propensity score matching (PSM) was also performed to adjust potential confounding factors. Results: The baseline characteristics and survival outcomes of the two BC patient cohorts are quite different. For UTUC-BC patients, no significant difference in OS (NMIBC: p = 0.88; MIBC: p = 0.98) or cumulative incidence of CSM (NMIBC: p = 0.12; MIBC: p = 0.96) were noted for various surgical procedures. Local tumor treatment and partial cystectomy for UTUC-NMIBC patients produced lower 1-year (6.1%) and 3-year CSM (16.2%). Radical cystectomy for UTUC-MIBC patients produced lower 1-year (11.8%) but higher 3-year CSM (62.7%). After PSM for covariates, UTUC-BC patients still had a worse prognosis after surgery compared with primary BC patients. Based on regression models, older age, advanced T stage, N positive disease, M positive disease, and shorter interval between UTUC and BC were identified as independent risk factors for UTUC-BC patients. Conclusion: Standard primary BC surgical strategy did not provide significant survival benefit for UTUC-BC patients. Compared with primary BC patients, UTUC-BC patients had a worse prognosis after surgery, suggesting that current primary BC surgical guidelines are not entirely appropriate for UTUC-BC patients. Our findings underscore the continued importance and need for better prognosis and improved guidelines for management of UTUC-BC patients.

Excellent Outcome Following Sibling Peripheral Blood Hematopoietic Stem Cell Transplantation for Glanzmann Thrombasthenia: A Case Report.

Glanzmann thrombasthenia (GT) is a rare autosomal recessive platelet disorder due to a qualitative or quantitative anomaly of the platelet membrane glycoprotein GPIIb/IIIa. Its clinical manifestations include mild to severe bleeding. GT diagnosis mainly depends on platelet function analysis, flow cytometry, and gene detection. Treatment methods include conservative symptomatic treatment and allogeneic hematopoietic stem cell transplantation (allo-HSCT). Allo-HSCT is the only clinical radical method for GT. Herein, we report a 2-year-old boy with GT successfully cured by related identical peripheral blood stem cell transplantation (PBSCT). The platelet disorder was corrected to a normal level after PBSCT, with no significant complication related to the transplantation. Hematopoietic stem cell transplantation with full-matched donor in early stage could be a treatment option for GT.

High Expression of CD39 is Associated with Poor Prognosis and Immune Infiltrates in Clear Cell Renal Cell Carcinoma.

INTRODUCTION: The cell-surface ectonucleotidase CD39 is a key molecule of the immunosuppressive adenosine pathway within the tumor microenvironment. However, the relationship between CD39 and clear cell renal cell carcinoma (ccRCC) is rarely reported and still remains unclear. METHODS: CD39 expression was first analyzed using the Oncomine and the Tumor IMmune Estimation Resource (TIMER) databases, and then examined in ccRCC patients (n=367) who had undergone radical nephrectomy using immunohistochemistry (IHC) and real-time quantitative PCR analysis (qPCR). The prognosis value of CD39 in ccRCC was evaluated by Cox proportional hazards analysis. Functional and gene set enrichment analysis (GSEA) was performed using transcriptomic data of ccRCC from TCGA. Correlation analysis between CD39 and tumor-infiltrating lymphocytes (TILs) was performed using the TISIDB database. The impact of CD39 on immune checkpoint therapy (ICT) was evaluated by two public cohorts. RESULTS: CD39 mRNA and protein expression was upregulated in tumor tissues from ccRCC patients and aberrant expression of CD39 was associated with advanced tumor stage and poor prognosis in ccRCC patients. EMT, IL-2/STAT5, inflammatory response, interferon gamma and KRAS hallmark gene sets were identified as CD39-related signaling pathway. The expression level of CD39 was significantly and positively correlated with high abundance of the regulatory TILs including NK cells, macrophages, Th cells and Treg cells. CD39 was correlated with expression of several immune checkpoints and higher CD39 expression was associated with better OS of ccRCC patients who received ICT. CONCLUSION: CD39 is a powerful prognostic marker of ccRCC patients. Increased tumor expression of CD39 mRNA is significantly correlated with infiltrating levels of TILs, and better efficacy of ICT to ccRCC. CD39 could be a novel therapeutic target for ccRCC.

Identification and validation of novel metastasis-related signatures of clear cell renal cell carcinoma using gene expression databases.

Patients with clear cell renal cell carcinoma (ccRCC) typically face aggressive disease progression when metastasis occurs. Here, we screened and identified differentially expressed genes in three microarray datasets from the Gene Expression Omnibus database. We identified 112 differentially expressed genes with functional enrichment as candidate prognostic biomarkers. Lasso Cox regression suggested 10 significant oncogenic hub genes involved in earlier recurrence and poor prognosis of ccRCC. Receiver operating characteristic curves validated the specificity and sensitivity of the Cox regression penalty used to predict prognosis. The area under the curve indexes of the integrated genes scores were 0.758 and 0.772 for overall and disease-free survival, respectively. The prognostic values of ADAMTS9, C1S, DPYSL3, H2AFX, MINA, PLOD2, RUNX1, SLC19A1, TPX2, and TRIB3 were validated through an analysis of 10 hub genes in 380 patients with ccRCC from a real-world cohort. The expression levels of were of high prognostic value for predicting metastatic potential. These findings will likely significantly contribute to our understanding of the underlying mechanisms of ccRCC, which will enhance efforts to optimize therapy.

Maternal exposure to Di-n-butyl phthalate (DBP) aggravate gestational diabetes mellitus via FoxM1 suppression by pSTAT1 signalling.

The study focused on the toxicological effect of Di-n-butyl phthalate (DBP) on the expression of Phosphorylated signal transducer and activator of transcription 1 (pSTAT1) -regulated Forkhead box protein M1 (FoxM1), which might provide a new understanding of gestational diabetes mellitus (GDM) development and a potential target for treatment. Streptozotocin (STZ) (40 mg/kg) was introduced in maternal rats by intraperitoneal injection on gestation day 0 (GD 0) in the STZ and STZ + DBP groups. DBP was introduced in maternal rats by oral feeding in the STZ + DBP group over the following 3 days (750 mg/kg/day). The changes in fasting blood glucose level in rats were detected on GD 1 and GD 5. The insulin levels in maternal rats and PIBCs were measured on GD 18. The Oral Glucose Tolerance Test (OGTT) test was performed on GD 18 to check the stability of the GDM model. The primary islet ß cells (PIBCs) were established for in vitro experiments. We examined the FoxM1 and pSTAT1 expression in pancreas by immunohistochemistry. Real-time PCR and Western blot were used to detect the pSTAR1 and FoxM1 protein and mRNA gene expression levels in PIBCs. Cell Counting Kit-8 (CCK-8) and flow cytometric analysis was used to test the viability and apoptosis of cells. The results showed that the STZ + DBP group had higher glucose and lower insulin secretion levels than the other groups by both fasting test and OGTT. FoxM1 was significantly suppressed while pSTAT1 was highly expressed after DBP exposure. FoxM1 could be regulated by pSTAT1. DBP can influence the progression of GDM through its toxicological effect, which significantly increases the expression of pSTAT1 and suppresses FoxM1, causing a decline in ß cell viability.

In utero di-n-butyl phthalate exposure induced abnormal autophagy in renal tubular cells via hedgehog signaling in newborn rats.

Di-n-butyl phthalate (DBP) is a pollutant that is widely present in the environment. We have previously demonstrated that maternal exposure to DBP resulted in renal fibrosis in offspring, but the underlying mechanism was not well elucidated. Therefore, the current study aims to understand the underlying molecular mechanisms in these sex-specific developmental alterations. Here, we used RNA-seq analysis to explore the underlying molecular mechanisms of DBP-associated renal fibrosis. Pregnant rats received DBP orally at a dose of 850 mg/kg BW/day during gestational days 14-18. Upregulated autophagy in renal tubules in offspring was confirmed in the DBP-treated group via accessing LC3Ⅱ/Ⅰ protein expression. Increased expression of the HhIP gene was found in the DBP-treated group via RNA-seq analysis. Immunohistochemistry (IHC) staining and Western blot analysis confirmed increased expression of HhIP protein and inhibited hedgehog signaling. Increased HhIP expression further leaded to impaired activation of hedgehog signaling, which is critical for normal embryonic development. Additional in vitro experiments on renal tubular cells suggest that inactivation of hedgehog signaling induced autophagy in renal tubular cells. Taken together, our findings show that maternal exposure to DBP induced autophagy through regulation of hedgehog signaling via overexpression of HhIP in foetal renal tubular cells, which may be essential for renal fibrosis development.