Glioblastoma(GBM)is a lethal cancer with limited therapeutic options.Dendritic cell(DC)-based cancer vaccines provide a promising approach for GBM treatment.Clinical studies suggest that other immu-notherapeutic agents may be combined with DC vaccines to further enhance antitumor activity.Here,we report a GBM case with combination immunotherapy consisting of DC vaccines,anti-programmed death-1(anti-PD-1)and poly I:C as well as the chemotherapeutic agent cyclophosphamide that was integrated with standard chemoradiation therapy,and the patient remained disease-free for 69 months.The patient received DC vaccines loaded with multiple forms of tumor antigens,including mRNA-tumor associated antigens(TAA),mRNA-neoantigens,and hypochlorous acid(HOCl)-oxidized tumor lysates.Furthermore,mRNA-TAAAs were modified with a novel TriVac technology that fuses TAAs with a destabilization domain and inserts TAAs into full-length lysosomal associated membrane protein-1 to enhance major histo-compatibility complex(MHC)class Ⅰ and Ⅱ antigen presentation.The treatment consisted of 42 DC cancer vaccine infusions,26 anti-PD-1 antibody nivolumab administrations and 126 poly I:C injections for DC infusions.The patient also received 28 doses of cyclophosphamide for depletion of regulatory T cells.No immunotherapy-related adverse events were observed during the treatment.Robust antitumor CD4+and CD8+T-cell responses were detected.The patient remains free of disease progression.This is the first case report on the combination of the above three agents to treat glioblastoma patients.Our results suggest that integrated combination immunotherapy is safe and feasible for long-term treatment in this patient.A large-scale trial to validate these findings is warranted.

OBJECTIVE: To evaluate the efficacy and safety of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with decitabine (Dec)-conditioning regimen in the treatment of myelodysplastic syndrome (MDS) and MDS transformed acute myeloid leukemia (MDS-AML). METHODS: The characteristics and efficacy data of 93 patients with MDS and MDS-AML who received allo-HSCT in our center from April 2013 to November 2021 were retrospectively analyzed. All patients were administered by myeloablative conditioning regimen containing Dec (25 mg/m² /d×3 d). RESULTS: Among the 93 patients, 63 males and 30 females, were diagnosed as MDS（n ＝77）, MDS-AML（n ＝16）. The incidence of I/II grade regimen-related toxicity (RRT) was 39.8%, and III grade RRT was only found in 1 patient (1%). Neutrophil engraftment was successful in 91 (97.8%) patients after a median neutrophil engraftment time of 14 (9-27) days; Successful platelet engraftment was achieved in 87 (93.5%) patients, with a median engraftment time of 18 (9-290) days. The incidence of acute graft versus host disease（aGVHD） and grade III-IV aGVHD was 44.2% and 16.2%, respectively. The incidence of chronic graft versus host disease（cGVHD） and moderate-to-severe cGVHD was 59.5% and 37.1%, respectively. Of the 93 patients, 54 (58%) developed posttransplant infections, among which lung infection (32.3%) and bloodstream infection (12.9%) were the most common. The median follow-up after transplantation was 45 (0.1-108) months. The 5-year overall survival (OS) rate, disease-free survival (DFS) rate, treatment-related mortality, and cumulative incidence of relapse were 72.7%, 68.4%, 25.1%, and 6.5%, respectively. And the 1-year graft-versus-host disease/relapse-free survival rate was 49.3%. The patients in different group of relative high-risk prognostic scoring or low-risk prognostic scoring, with or without poor-risk mutation(s), with mutations number ≥3 or <3 had similar 5-year OS rate (more than 70%). Multivariate analysis showed that the incidence of grade III-IV aGVHD was the independent risk factor affecting OS（P =0.008）and DFS (P =0.019). CONCLUSION Allo-HSCT with Dec-conditioning regimen is feasible and effective in the treatment of patients with MDS and MDS-AML, especially those in high prognostic risk and with poor-risk mutations.
Male ; Female ; Humans ; Decitabine ; Retrospective Studies ; Transplantation, Homologous/adverse effects* ; Transplantation Conditioning/adverse effects* ; Myelodysplastic Syndromes/complications* ; Leukemia, Myeloid, Acute/therapy* ; Hematopoietic Stem Cell Transplantation/adverse effects* ; Chronic Disease ; Graft vs Host Disease/therapy* ; Recurrence

Objective: To explore the role and significance of pyroptosis in gas explosion-induced acute lung injury (ALI) in rats. Methods: In February 2018, 126 SPF male SD rats were selected and randomly divided into blank control group (18 rats) and experimental group (40 m, 80 m, 120 m, 160 m, 200 m and 240 m, 18 per group) . The experimental group carried out gas explosion in the roadway to build the ALI model, the control group did not carry out gas explosion, and other conditions were consistent with the experimental group. Respiratory function indexes such as respiratory frequency (f) , tidal volume (TV) , minute ventilation (MV) and airway stenosis index (Penh) were measured 24 hours after the explosion. 5 rats in each group were sacrificed after anesthesia, Hematoxylin-Eosin (HE) staining was used to observe the pathological morphology of lung tissue. Immunohistochemistry was used to detect the content of Caspase-1. Western blotting was used to detect the content of cell pyroptosis including nucleotide-binding oligomerization domain-like receptor protein 3 (NLRP3) , Caspase-1, interleukin-1β (IL-1β) and interleukin-18 (IL-18) in lung tissue related protein expression. Results: The f and MV of rats in the experimental group were higher than those in the control group (P<0.05) . Except for the 40 m and 80 m groups, the TV of rats in the other experimental groups were higher than those in the control group (P<0.05) . Except for the 40 m group, the Penh of rats in the experimental groups were lower than those in the control group (P<0.05) . HE staining showed that the lung tissue of the experimental groups at different distance points showed obvious edema of the pulmonary interstitium and alveoli, a large number of red blood cells and inflammatory cells exuded in the alveolar space, thickening of the pulmonary interstitium, and increased lung injury score (P<0.05) . The results of immunohistochemistry showed that the positive expression of Caspase-1 in each experimental group was higher than that in the control group (P<0.05) . Western blotting results showed that the expression of pyroptosis-related proteins in each experimental group was higher than that in the control group (P<0.05) . Conclusion: Pyroptosis is involved in the pathophysiological process of gas explosion-induced ALI in rats.
Acute Lung Injury/pathology* ; Animals ; Explosions ; Lung/pathology* ; Male ; Pyroptosis ; Rats ; Rats, Sprague-Dawley

The transition from spermatogonia to spermatocytes and the initiation of meiosis are key steps in spermatogenesis and are precisely regulated by a plethora of proteins. However, the underlying molecular mechanism remains largely unknown. Here, we report that Src homology domain tyrosine phosphatase 2 (Shp2; encoded by the protein tyrosine phosphatase, nonreceptor type 11 [Ptpn11] gene) is abundant in spermatogonia but markedly decreases in meiotic spermatocytes. Conditional knockout of Shp2 in spermatogonia in mice using stimulated by retinoic acid gene 8 (Stra8)-cre enhanced spermatogonial differentiation and disturbed the meiotic process. Depletion of Shp2 in spermatogonia caused many meiotic spermatocytes to die; moreover, the surviving spermatocytes reached the leptotene stage early at postnatal day 9 (PN9) and the pachytene stage at PN11-13. In preleptotene spermatocytes, Shp2 deletion disrupted the expression of meiotic genes, such as disrupted meiotic cDNA 1 (Dmc1), DNA repair recombinase rad51 (Rad51), and structural maintenance of chromosome 3 (Smc3), and these deficiencies interrupted spermatocyte meiosis. In GC-1 cells cultured in vitro, Shp2 knockdown suppressed the retinoic acid (RA)-induced phosphorylation of extracellular-regulated protein kinase (Erk) and protein kinase B (Akt/PKB) and the expression of target genes such as synaptonemal complex protein 3 (Sycp3) and Dmc1. Together, these data suggest that Shp2 plays a crucial role in spermatogenesis by governing the transition from spermatogonia to spermatocytes and by mediating meiotic progression through regulating gene transcription, thus providing a potential treatment target for male infertility.
Animals ; Cell Cycle Proteins/genetics* ; Cell Line ; Cell Survival ; Chondroitin Sulfate Proteoglycans/genetics* ; Chromosomal Proteins, Non-Histone/genetics* ; Gene Expression Regulation ; Gene Knockdown Techniques ; Infertility, Male ; Male ; Meiosis/genetics* ; Mice ; Mice, Knockout ; Mice, Transgenic ; Phosphate-Binding Proteins/genetics* ; Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics* ; Rad51 Recombinase/genetics* ; Real-Time Polymerase Chain Reaction ; Spermatocytes/metabolism* ; Spermatogenesis/genetics* ; Spermatogonia/metabolism*

OBJECTIVETo investigate the effects and mechanisms of diethylhexylphthalate (DEHP) on morphology and function of progenitor Leydig cells (PLC) in rats.

METHODSTwenty pregnant SD rats were randomly divided into 4 groups ( n = 5): normal control group, DEHP low dose group , middle dose group, and high dose group, which were treated from postnatal day (PND) 1 to PND 21 of the pubs with DEHP at the doses of 0, 10, 100, 750 mg/(kg · d) in 0.5 ml of corn oil by gavage respectively. At the end of the treatment, the male pups were killed and blood samples were collected for determination of serum testosterone concentration by chemiluminescence method. The body weight, testis weight and anogenital distance (AGD) were measured. The morphology of PLC was observed by light and transmission electron microscopy. The protein expression of steroidogenic acute regulatory protein(StAR) in PLC was determined by immunohistochemistry. The mRNA expression of insulin-like growth factor-I (IGF-I) in the testis was assayed by real-time PCR.

RESULTSCompared with normal control group, the serum testosterone and AGD of male pubs from the middle and high dose groups were declined significantly (P < 0.01), the testis weight and body weight from high dose group were decreased significantly (P < 0.01), while the testis weight increased in the low dose group (P < 0.05). Under light microscope, PLC showed hyperplasia and cluster aggregation in the low dose group and focal hyperplasia in the middle and high dose group. The spermatogenic cells in seminiferous tubules showed decrease, apoptosis and unfix in the high dose group. Under transmission electron microscope, the PLC showed decreased lipid droplets, smooth endoplasmic reticulum and mitochondriae in the treated group. The mRNA expression of IGF-I increased in the low dose group, and the protein expression of StAR decreased in the middle and high dose group.

CONCLUSIONLactating exposure to DEHP may interfere with the synthesis of testosterone of PLC in male pubs, the decrease of StAR and the damage of PLC may be involved in it.

Animals ; Body Weight ; Diethylhexyl Phthalate ; adverse effects ; Female ; Germ Cells ; drug effects ; Insulin-Like Growth Factor I ; metabolism ; Lactation ; Leydig Cells ; cytology ; drug effects ; Male ; Organ Size ; Phosphoproteins ; metabolism ; Pregnancy ; Rats ; Rats, Sprague-Dawley ; Stem Cells ; cytology ; drug effects ; Testis ; Testosterone ; blood

OBJECTIVESTo compare the sensitivity of mammogram and breast dedicated MRI in detecting ductal carcinoma in situ with microinvaion (DCIS-MI) and ductal carcinoma in situ (DCIS) lesions, and to further investigate the independent predictive factors of mammogram and MRI sensitivity.

METHODSFrom August 2009 to November 2011, 122 consecutive confirmed breast cancer patients who had received operations were recruited for this clinical research. These patients were divided into two groups including DCIS (72 cases) and DCIS-MI (50 cases) based on pathologic reports. All the patients were female, with mean ages of 52.6 years and 54.4 years. Preoperative bilateral breast mammogram, breast dedicated MRI depictions and reports as well as histopathological reports were collected.

RESULTSSensitivity of MRI outstood mammogram in each subgroups: 84.7% vs. 42.4% in DCIS (χ(2) = 27.028, P = 0.000), 94.0% vs. 80.0% in DCIS-MI group (χ(2) = 4.540, P = 0.040). And further analysis showed that MRI was more sensitive to high nuclear grade DCIS and DCIS-MI lesions than low nuclear grade ones (OR = 3.471, P = 0.031).

RESULTSof logistic regression analysis proved microcalcification was an independent predictive factor of mammogram sensitivity (OR = 11.287, P = 0.001).

CONCLUSIONSSensitivity of breast dedicated MRI is superior to mammogram in detecting DCIS and DCIS-MI groups. Lesions with microcalcifiation is an independent predictive marker which meant that mammogram would achieve high detection rate in cancers presented calcification on mammogram image when compared with non-calcification. Diagnostic performance of breast MRI is less affected by clinical and pathological characteristics of the early stage breast cancer patients but further increased detection rate is observed in DCIS and DCIS-MI with high nuclear grade lesions which indicated that MRI could detect more early stage cancers with relative more aggression biological behaviour and provide these patients with early surgical interventions before possible progression to invasive breast cancers.

Breast Neoplasms ; diagnosis ; Calcinosis ; diagnosis ; Carcinoma, Ductal, Breast ; diagnosis ; Carcinoma, Intraductal, Noninfiltrating ; diagnosis ; Female ; Humans ; Magnetic Resonance Imaging ; Mammography ; Middle Aged ; Sensitivity and Specificity

Objective To study the COLIXA3 gene polymorphism of patients with fluorosis and to explore the pathogenesis of COLIXA3 gene in endemic fluorosis.Methods Fifty one cases of patients with drinking-water borne fluorosis were selected as the case group in Xinzhou city,Shanxi province and 28 cases of healthy people were as the control group.Dental fluorosis was detected by Dean method and skeletal fluorosis was examined by X-ray.COLIXA3 of exon 5 gene product of 103 points was amplified by PCR and the gene locus genotype was sequenced.Results Ten cases of mild dental fluorosis,14 cases of moderate dental fluorosis,15 cases of severe dental fluorosis were detected among the 51 patients.The control group was free of dental fluorosis.All the 51 cases of patients with fluorosis had varying degrees of skeletal fluorosis,mainly osteosclerosis lesions,accounting for 86.27％(44/51 ),and mild skeletal fluorosis patients were all osteosclerosis lesions,and osteosclerosis lesions and multiple skeletal lesions were found among moderate and severe skeletal fluorosis patients in the case group,while control group had no skeletal fluorosis.The differences between genotypes of frequency distribution of AA,Aa,aa of COLIXA3 of case and control groups were not statistically significant [96.08％(49/51 ),3.92％(2/51 ),0.00％(0/51) and 96.43％(27/28),3.57％(1/28),0.00％(0/28),x2 =0.94,P ＞ 0.05].ConclusionsCOLIXA3 gene polymorphism is not significantly correlated to fluorosis.

OBJECTIVETo evaluate the feasibility of HLA haploidentical peripheral blood hematopoietic stem cell transplantation (PBSCT) for patients with β thalassemia major.

METHODSSixteen patients with β thalassemia major received HLA haploidentical PBSCT from parents. Two conditioning regimens were used. Regimen A was adopted before December 2007, which consisted of fludarabine (total 150 mg/m²), busulfex (total 520 mg/m²), cyclophosphamide (CTX, total 100 mg/kg), antithymocyte globulin (ATG, total 10 mg/kg) and total body irradiation of 3 Gy. Regimen B was adopted after December 2007, which consisted of fludarabine (total 240 mg/m²), busulfex (total 520 mg/m²), CTX (total 100 mg/kg), and ATG (total 10 mg/kg). Combination of cyclosporin (CsA), methotrexate (MTX) and mycophenolate mofetil (MMF) were used for prophylaxis of graft-versus-host disease (GVHD).

RESULTSOf 16 patients, 14 (87.5%) had sustained engraftment. The median days of neutrophil exceeding 0.5 × 10⁹/L and platelet exceeding 20 × 10⁹/L were 13 days (range 10 - 17 days) and 15 days (range 14 - 20 days) after PBSCT, respectively. Complete chimerism was achieved in all the 14 patients at one month after PBSCT. One patient lost his graft with autologous reconstitution 52 days after transplantation. Four patients had grade II-IV acute GVHD and one patient had chronic extensive GVHD. In the 49-month median follow-up duration, 13 of 16 patients were alive in disease-free situation.

CONCLUSIONHLA haploidentical PBSCT, which could provide stable and sustained engraftment for thalassemia major patients with no HLA identical donor, is a promising treatment strategy.

Child ; Child, Preschool ; Female ; HLA Antigens ; genetics ; Haploidy ; Humans ; Male ; Peripheral Blood Stem Cell Transplantation ; Tissue Donors ; beta-Thalassemia ; therapy

OBJECTIVETo compare the efficacy of nasal synchronized intermittent mandatory ventilation (nSIMV) and nasal continuous positive airway pressure (nCPAP) in preterm infants with respiratory distress syndrome (RDS).

METHODSFifty preterm infants with RDS who received pulmonary surfactant were randomized to nSIMV and nCPAP groups after extubation. Clinical signs, symptoms and blood gas results following nSIMV or nCPAP were compared in the two groups.

RESULTSCompared with the nCPAP group, the nSIMV group had a lower incidence of failure respiratory support (24% vs 60%; P<0.05), a lower incidence of hypercarbonia (12% vs 40%; P<0.05) and a lower incidence of hypoxia (24% vs 36%; P<0.05).

CONCLUSIONSnSIMV is more effective in respiratory support in preterm infants with RDS.

Continuous Positive Airway Pressure ; methods ; Humans ; Infant, Newborn ; Infant, Premature ; Intermittent Positive-Pressure Ventilation ; methods ; Respiratory Distress Syndrome, Newborn ; therapy

OBJECTIVETo explore the role of paternal veto cells in preventing graft-versus-host disease (GVHD) after related HLA- haploidentical stem cell transplantation in mice.

METHODSMHC-haploidentical recipient B6CF1(H-2 b/d) mice pretreated with total body irradiation at 9.0 Gy for 4 h before transplantation. The recipient mice were divided into 4 groups, and in the irradiation group, only injection of 0.3 ml D-Hank's liquid was given through the tail vein; in the control group, the mice received injection through the tail vein of 4.5x10(6) bone marrow cells mixed with 3.0x10(7) spleen cells from C57BL/6 mice without the preventive measures of GVHD; the mice in the two experiment groups received cell transplantation in the same manner, and on day 4 after transplantation, 5.0x10(6) and 1.0x10(7)spleen cells from BALB/c mice were injected through tail vein, respectively. The hematopoietic recovery, engraftment and GVHD of the recipient mice were observed.

RESULTSWithout any treatment, all mice in the control group developed GVHD and died after transplantation. In the 10 mice with injection of 5.0x10(6) spleen cells, GVHD occurred in 5 mice with a 30-day survival rate of 50%; the median survival time of the mice with GVHD was 20 days, significantly longer than that of the control mice (14 days, P<0.05). In the 10 mice injected with 1.0x10(7) spleen cells, 2 developed GVHD and the 30-day survival rate was 80% (8/10) with a median survival time of 30 days, significantly longer than that of mice with injection of 5.0x10(6) spleen cells and the control mice (P<0.05).

CONCLUSIONPaternal veto cell transplantation can decrease the occurrence of GVHD after related HLA haploidentical stem cell transplantation in mice.

Animals ; Cell Transplantation ; methods ; Female ; Graft vs Host Disease ; etiology ; prevention & control ; HLA Antigens ; immunology ; Hematopoietic Stem Cell Transplantation ; adverse effects ; methods ; Male ; Mice ; Mice, Inbred BALB C ; Mice, Inbred C57BL ; Spleen ; cytology ; immunology ; T-Lymphocytes ; cytology ; drug effects ; Transplantation, Homologous