Frontostriatal circuit dysfunction leads to cognitive inflexibility in neuroligin-3 R451C knockin mice.

Cognitive and behavioral rigidity are observed in various psychiatric diseases, including in autism spectrum disorder (ASD). However, the underlying mechanism remains to be elucidated. In this study, we found that neuroligin-3 (NL3) R451C knockin mouse model of autism (KI mice) exhibited deficits in behavioral flexibility in choice selection tasks. Single-unit recording of medium spiny neuron (MSN) activity in the nucleus accumbens (NAc) revealed altered encoding of decision-related cue and impaired updating of choice anticipation in KI mice. Additionally, fiber photometry demonstrated significant disruption in dynamic mesolimbic dopamine (DA) signaling for reward prediction errors (RPEs), along with reduced activity in medial prefrontal cortex (mPFC) neurons projecting to the NAc in KI mice. Interestingly, NL3 re-expression in the mPFC, but not in the NAc, rescued the deficit of flexible behaviors and simultaneously restored NAc-MSN encoding, DA dynamics, and mPFC-NAc output in KI mice. Taken together, this study reveals the frontostriatal circuit dysfunction underlying cognitive inflexibility and establishes a critical role of the mPFC NL3 deficiency in this deficit in KI mice. Therefore, these findings provide new insights into the mechanisms of cognitive and behavioral inflexibility and potential intervention strategies.

[Source Analysis and Health Risk Assessment of PAHs in PM2.5, Lüliang City].

To investigate the seasonal variation, health risks, and potential sources of polycyclic aromatic hydrocarbons(PAHs) in PM2.5 in the Lüliang area, PM2.5 samples were collected in Lishi District(downtown area) and Xiaoyi City(suburban area) from October 23, 2018 to July 1, 2019, and the concentrations of 14 PAHs were determined using gas chromatography-mass spectrometry(GC-MS). The annual average concentration of PAHs was 95.50 ng·m-3, and the concentration of 5-6 ring PAHs was mainly(49.7%), with 3 ring PAHs accounting for a relatively low proportion(8.3%).The concentration of PAHs in Lüliang City showed a seasonal pattern of winter>autumn>spring>summer. The results of the ILCRs model and Monte Carlo simulation showed that the toxicity of PAHs in Lüliang City followed the rule of adults>youth>children. Except in summer, the ILCRs values in the Lishi area were between 10-6 and 10-4, much higher than those in Xiaoyi City, indicating that there was a high potential risk of polycyclic aromatic hydrocarbons in the urban area. Through the characteristic ratio method and positive matrix factorization(PMF), it was shown that the PAHs in Lüliang City were mainly from the combustion of coal and biomass(61.9%) and vehicle exhaust emissions(38.1%). Based on the backward trajectory and potential source factor contribution analysis model, it was determined that the potential sources of PAHs in Lüliang City were mainly distributed in southern Shanxi, northern Shaanxi, and western Inner Mongolia.

Targeted VEGFA therapy in regulating early acute kidney injury and late fibrosis.

Damage to peritubular capillaries is a key process that contributes to acute kidney injury (AKI) progression. Vascular endothelial growth factor A (VEGFA) plays a critical role in maintaining the renal microvasculature. However, the physiological role of VEGFA in various AKI durations remains unclear. A severe unilateral ischemia‒reperfusion injury model was established to provide an overview of VEGFA expression and the peritubular microvascular density from acute to chronic injury in mouse kidneys. Therapeutic strategies involving early VEGFA supplementation protecting against acute injury and late anti-VEGFA treatment for fibrosis alleviation were analyzed. A proteomic analysis was conducted to determine the potential mechanism of renal fibrosis alleviation by anti-VEGFA. The results showed that two peaks of extraglomerular VEGFA expression were observed during AKI progression: one occurred at the early phase of AKI, and the other occurred during the transition to chronic kidney disease (CKD). Capillary rarefaction progressed despite the high expression of VEGFA at the CKD stage, and VEGFA was associated with interstitial fibrosis. Early VEGFA supplementation protected against renal injury by preserving microvessel structures and counteracting secondary tubular hypoxic insults, whereas late anti-VEGFA treatment attenuated renal fibrosis progression. The proteomic analysis highlighted an array of biological processes related to fibrosis alleviation by anti-VEGFA, which included regulation of supramolecular fiber organization, cell-matrix adhesion, fibroblast migration, and vasculogenesis. These findings establish the landscape of VEGFA expression and its dual roles during AKI progression, which provides the possibility for the orderly regulation of VEGFA to alleviate early acute injury and late fibrosis.

[Effect of Body Mass Index on the Prognosis of Mantle Cell Lymphoma].

OBJECTIVE: To explore the correlation between different body mass index (BMI) and prognosis of mantle cell lymphoma (MCL). METHODS: The clinical characteristics and biological indices of 108 patients with MCL treated in Fujian Medical University Union Hospital were retrospectively analyzed, and the effects of different BMI on overall survival (OS) and progression-free survival (PFS) were analyzed. The correlation between BMI and B symptoms, LDH and Ki-67 was further observed. Furthermore，the differences of BMI between Autologous peripheral blood stem cell transplantation(Auto-PBSCT) and conventional chemotherapy groups were explored. RESULTS: Among 108 patients, the median age at diagnosis was 59（25-79） years old, and the male to female ratio was 4.4∶1. 88.89% of patients with Ann Arbor staging III-IV, 63.89% with bone marrow involvement, and 49.07% with splenic infiltration. Patients with BMI ≥ 24 kg/m2 were divided into two groups: the high BMI group and the low BMI group. The 5-year PFS and OS of patients in the low BMI group were 31.9% and 47.0%, respectively, while those in the high BMI group were 64.6% and 68.7%, respectively. The incidence of death in the high BMI group was lower than that of the low BMI group (P＜0.01). In multivariate analysis, BMI was an independent predictor of PFS (HR=0.282; 95% CI: 0.122-0.651; P=0.003) and an independent predictor of OS (HR=0.299; 95% CI: 0.129-0.693; P=0.005). Also, patients with B symptoms had a lower BMI than those without B symptoms (P=0.01), but BMI had no effect on patients' LDH and Ki-67. The prognosis of 16 patients treated with Auto-PBSCT was significantly better than that of the conventional chemotherapy group. There was no significant difference in BMI between Auto-PBSCT group and conventional chemotherapy group. CONCLUSION: BMI is an independent prognostic factor for PFS and OS in MCL, and may be influenced by the effect of B symptoms on BMI.

A multicenter retrospective study on the real-world outcomes of autologous vs. allogeneic hematopoietic stem cell transplantation for peripheral T-cell lymphoma in China.

BACKGROUND: There were few studies on real-world data about autologous hematopoietic stem cell transplantation (auto-HSCT) or allogeneic HSCT (allo-HSCT) in peripheral T-cell lymphoma (PTCL). This study aimed to investigate the clinical outcomes of patients who received auto-HSCT or allo-HSCT in China. METHODS: From July 2007 to June 2017, a total of 128 patients who received auto-HSCT (n  = 72) or allo-HSCT (n  = 56) at eight medical centers across China were included in this study. We retrospectively collected their demographic and clinical data and compared the clinical outcomes between groups. RESULTS: Patients receiving allo-HSCT were more likely to be diagnosed with stage III or IV disease (95% vs. 82%, P = 0.027), bone marrow involvement (42% vs. 15%, P = 0.001), chemotherapy-resistant disease (41% vs. 8%, P = 0.001), and progression disease (32% vs. 4%, P < 0.001) at transplantation than those receiving auto-HSCT. With a median follow-up of 30 (2-143) months, 3-year overall survival (OS) and progression-free survival (PFS) in the auto-HSCT group were 70%(48/63) and 59%(42/63), respectively. Three-year OS and PFS for allo-HSCT recipients were 46%(27/54) and 44%(29/54), respectively. There was no difference in relapse rate (34%[17/63] in auto-HSCT vs. 29%[15/54] in allo-HSCT, P = 0.840). Three-year non-relapse mortality rate in auto-HSCT recipients was 6%(4/63) compared with 27%(14/54) for allo-HSCT recipients (P = 0.004). Subanalyses showed that patients with lower prognostic index scores for PTCL (PIT) who received auto-HSCT in an upfront setting had a better outcome than patients with higher PIT scores (3-year OS: 85% vs. 40%, P = 0.003). Patients with complete remission (CR) undergoing auto-HSCT had better survival (3-year OS: 88% vs. 48% in allo-HSCT, P = 0.008). For patients beyond CR, the outcome of patients who received allo-HSCT was similar to that in the atuo-HSCT group (3-year OS: 51% vs. 46%, P = 0.300). CONCLUSIONS: Our study provided real-world data about auto-HSCT and allo-HSCT in China. Auto-HSCT seemed to be associated with better survival for patients in good condition (lower PIT score and/or better disease control). For patients possessing unfavorable characteristics, the survival of patients receiving allo-HSCT group was similar to that in the auto-HSCT group.

Removable retropubic uterine compression suture for controlling postpartum hemorrhage.

OBJECTIVE: To minimize the adverse events of uterine compression suture in controlling postpartum hemorrhage (PPH) and to search for a prophylactic approach to potential PPH. METHODS: A retrospective analysis was performed in 39 women with removable retropubic uterine compression suture (RRUCS) to stop PPH due to uterine atony during cesarean section (CS). The procedure was to suspend and compress the uterus to the retropubic abdominal wall using an absorbable suture. RESULTS: The technique was sufficient to stanch bleeding immediately in 36 patients (92.31%, 36/39). No morbidity or abnormalities occurred in women who underwent RRUCS. Subsequent pregnancies occurred in 10 cases, but the others lacked the desire for future pregnancy. CONCLUSION: RRUCS is a simple, safe, and effective technique in controlling atonic PPH; it is also used as a prophylactic application in patients with potential PPH after CS.

Efficient, green, and rapid strategy for separating actinomycin D and X2 using supercritical fluid chromatography.

Actinomycin D has long been used as a first-line antitumor drug in clinical practice. Actinomycin X2, a new drug lead, is often isolated along with actinomycin D. The minor differences between the two actinomycin analogs pose a daunting challenge in separation. In this study, supercritical fluid chromatography (SFC) was successfully utilized for the purification of actinomycin X2 and actinomycin D from a marine derived Streptomyces sp. DQS-5. After one-step SFC purification, the purities of these two compounds were determined to be 97.3 % and 97.8 %, respectively. This method provides a green alternative for the separation of these pharmacologically important actinomycin antibiotics. This study also demonstrated the development of a simple and rapid method for the separation of natural products based on SFC.

Macrophage regulation of graft-vs-host disease.

Hematopoietic stem cell transplantation has become a curative choice of many hematopoietic malignancy, but graft-vs-host disease (GVHD) has limited the survival quality and overall survival of hematopoietic stem cell transplantation. Understanding of the immune cells' reaction in pathophysiology of GVHD has improved, but a review on the role of macrophages in GVHD is still absent. Studies have observed that macrophage infiltration is associated with GVHD occurrence and development. In this review, we summarize and analyze the role of macrophages in GVHD based on pathophysiology of acute and chronic GVHD, focusing on the macrophage recruitment and infiltration, macrophage polarization, macrophage secretion, and especially interaction of macrophages with other immune cells. We could conclude that macrophage recruitment and infiltration contribute to both acute and chronic GVHD. Based on distinguishing pathology of acute and chronic GVHD, macrophages tend to show a higher M1/M2 ratio in acute GVHD and a lower M1/M2 ratio in chronic GVHD. However, the influence of dominant cytokines in GVHD is controversial and inconsistent with macrophage polarization. In addition, interaction of macrophages with alloreactive T cells plays an important role in acute GVHD. Meanwhile, the interaction among macrophages, B cells, fibroblasts, and CD4+ T cells participates in chronic GVHD development.

Ring compression suture for controlling post-partum hemorrhage during cesarean section.

AIM: To avoid complications associated with uterine compression sutures, we devised a ring compression suture (RCS). METHODS: The RCS was performed on 12 patients with post-partum hemorrhage (PPH) during cesarean section. The suture was inserted 0.5 cm below the attachment point of the uterosacral ligament into the uterine cavity and pushed downward through the cervical canal into the vagina. The other end of the stitch was threaded through the lower abdominal wall, from the inside of the abdomen cavity to the outside of the abdominal wall, emerging at the external surface of the lower abdomen 2 cm lateral to the ventral median line and 1 cm above the symphysis pubis. Then, the two ends of the suture (the end in the vagina had been pulled out in advance) were tied tightly on the pudendum. The same stitch was repeated on the contralateral side. After 48 h postoperatively, the suture was removed through the vagina under sterilization. RESULTS: All 12 women with PPH who underwent RCS achieved hemostasis, and complications related to RCS were not seen. Two of them had successful pregnancies postoperatively. The remaining women had no desire for a further pregnancy. CONCLUSION: The procedure can be used as an alternative to peripartum hysterectomy and also as a prophylactic application in PPH.

ETS1 and SP1 drive DHX15 expression in acute lymphoblastic leukaemia.

DHX15 plays a role in leukaemogenesis and leukaemia relapse. However, the mechanism underlying the transcriptional regulation of DHX15 in ALL has not been elucidated. Our present study aimed to explore the functional promoter region of DHX15 and to investigate the transcription factors controlling the transcription of this gene. A luciferase assay performed with several truncated constructs identified a 501-bp region as the core promoter region of DHX15. Site-directed mutagenesis, electrophoretic mobility shift and chromatin immunoprecipitation assays showed that ETS1 and SP1 occupied the DHX15 promoter. Furthermore, knockdown of ETS1 and SP1 resulted in suppression of DHX15, whereas the overexpression of these genes led to up-regulation of DHX15. Interestingly, in samples obtained from patients with ALL at diagnosis, both ETS1 and SP1 correlated positively with DHX15 expression. Additionally, differences in methylation of the DHX15 core promoter region were not observed between the patients and controls. In conclusion, we identified the core promoter region of DHX15 and demonstrated that ETS1 and SP1 regulated DHX15 expression in ALL.

Recombinant Adenovirus-p53 Gene Therapy for Advanced Unresectable Soft-Tissue Sarcomas.

Patients with unresectable advanced soft-tissue sarcomas (STS) receiving radiotherapy or/and chemotherapy still have a poor prognosis. This study aimed to evaluate retrospectively the efficacy and safety of recombinant adenovirus-p53 (rAd-p53) gene therapy combined with radiotherapy and hyperthermia for advanced STS. A total of 71 patients with advanced unresectable STS treated at the authors' center from April 2007 to November 2014 were included. Of these 71 patients, 36 cases received rAd-p53 therapy combined with radiotherapy and hyperthermia (p53 group), while 35 cases received radiotherapy and hyperthermia alone (control group). Short-term therapeutic efficacies, long-term survival outcomes, and adverse events were evaluated and compared between groups. Compared to the control group, the p53 group had a significantly higher disease control rate (83.33% vs. 54.29%; p = 0.008) and a lower progressive disease rate (16.67% vs. 45.71%; p = 0.018). In addition, rAd-p53 treatment significantly improved the progression-free survival and overall survival of STS patients. Cox regression indicated that rAd-p53 treatment significantly reduced the risks for disease progression or death event for STS patients. Furthermore, there was no significant difference in all adverse events, except for transient fever, which occurred in 89% of patients with rAd-p53 therapy. rAd-p53 combined with radiotherapy and hyperthermia can effectively improve the therapeutic efficacy and survival outcomes in patients with advanced unresectable STS, providing a new therapeutic strategy.

Two-week Course of Preoperative Radiotherapy for Locally Advanced Rectal Adenocarcinoma: 8 Years' Experience in a Single Institute.

OBJECTIVES: To evaluate local control and survival in locally advanced rectal adenocarcinoma patients who underwent a preoperative 2-week course of radiotherapy (RT) and to identify prognostic factors influencing the survival rate. METHODS: We analyzed 377 consecutively treated patients with locally advanced (T3/T4 or node positive) rectal adenocarcinoma. All patients underwent a preoperative 2-week course of RT (30 Gy in 10 fractions) followed by curative surgery. Regression model was used to examine prognostic factors for the disease-free survival (DFS) and overall survival (OS) rates. The Statistical Analysis System software package, version 9.3, was used for analysis. RESULTS: The median follow-up for all living patients was 63.8 months (range, 5.1 to 131.7). The 5-year DFS and OS rates were 64.5% (95% CI, 59.0-69.4) and 75.6% (95% CI, 70.5-80.0), respectively. The 5-year cumulative incidences of local recurrence and distant metastases were 5.4% (95% CI, 2.9-7.9) and 29.0% (95% CI, 23.9-30.1), respectively. The pathologic complete response rate was achieved in 17 patients (4.5%). The Multivariate Cox Regression model showed that factors affecting DFS were the surgical technique, pre-RT pathologic grade, ypT, ypN, and comorbidity; and factors improving OS were low anterior resection, low pre-RT grade, low ypT, and low ypN. CONCLUSIONS: Patients treated with preoperative RT with 30 Gy in 10 fractions had similar local control, 5-year DFS and OS to reported long course RT regimen. The surgical technique, pre-RT pathologic grade, ypT, and ypN seemed to affect the OS. Further study on combining a 2-week course of preoperative RT with concurrent chemotherapy would be warranted.

Effect and Safety of Recombinant Adenovirus-p53 Transfer Combined with Radiotherapy on Long-Term Survival of Locally Advanced Cervical Cancer.

Detection of exogenous p53 gene and target gene expression in cervical cancer cell lines SiHa and C33A infected by recombinant adenovirus-p53 (rAd-p53) in vitro. The rAd-p53 infection evidently increased the expression of exogenous p53 gene, p21 gene, and Bax gene. The radiosensitization rates of rAd-p53 were 1.19 in SiHa and 1.18 in C33A in vitro. To evaluate the effect and safety of rAd-p53 transfer combined with radiotherapy (RT) in patients with cervical cancer, rAd-p53 transfer combined with radiotherapy (group PRT) in 69 patients with cervical cancer was compared with a control group treated with radiotherapy alone (group RT) in 35 patients with cervical cancer. Patients were intratumorally injected with rAd-p53 (1 × 1012 virus particles) once a week for 6 weeks. Concurrent pelvic RT plus brachytherapy to take point A to 76.0 Gray units (Gy) (range 75-80 Gy). The 5-year overall survival rate of the PRT group was 17.5% higher than that of the RT group (HR = 0.551, 95% CI 0.278-1.095, p = 0.084). The 5-year progress-free survival rate of the PRT group was 17.1% higher than that of the RT group (HR = 0.485, 95% CI 0.234-1.006, p = 0.047). rAd-p53 administration did not increase the adverse events caused by radiotherapy, except for transient fever after rAd-p53 administration. rAd-p53 was safe and biologically active in improving radiotherapeutic survival rates in patients with cervical cancer.

[Screening and Enzyme Production Characteristics of Thermophilic Cellulase-producing Strains].

A total of 6 thermophilic cellulase-producing strainswere isolated from organic garden waste mixed chicken composting at thermophilic period. These isolates were identified as Streptomyces thermoviolaceus, S. thermodiastaticus, S. thermocarboxydus, S. albidoflavus, S. thermovulgaris and Brevibacillus borstelensis through 16S rRNA gene sequence alignment and phylogenetic tree analysis. The cellulose-degrading microbial community has been investigated in few researches so far both at home and abroad. In this study, the mixed strains M-1 was made up of the 6 cellulose-decomposing microorganisms. The CMCase activity of the mixed strains M- 1 was stronger than any of the 6 single strains. Production of CMCase from mixed strains M-1 was studied by optimizing different physico-chemical parameters. The Maximum CMCase production (135.9 U · mL⁻¹) of strains M-1 was achieved at 45 °C in a liquid medium (pH 4) inoculated with 1% (volume fraction), containing a mixture of wheat bran and starch, corn flour and KNO3. After optimization of separation conditions, CMCase production capacity was improved by 1.8 times.