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.

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.

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.

Intensity-modulated radiation therapy for pelvic oligo-recurrence from rectal cancer: long-term results from a single institution.

BACKGROUND: Pelvic oligo-recurrence is common in rectal cancer patients, and some could not achieve radical resection. OBJECTIVE: The study was to analyze long-term outcomes and prognostic factors associated with survival in patients treated with intensity-modulated radiation therapy (IMRT). METHODS: Study participants were identified from rectal patients with pelvic oligo-recurrence without distant metastases, who were not suitable for surgery (n=135). Patients were recommended to receive concurrent chemotherapy in the course of IMRT (median dose 64.5 Gy, range: 45-70 Gy). Additionally, 24.4% (33/135) of patients received radical surgery after preoperative radiotherapy. Median time to pelvic failure was 25.4 months (range: 1-144 months). With a median follow-up period of 45.5 months (range: 3-104 months), 5-year overall survival (OS) and disease-free survival (DFS) were 55.6% and 45.5%, respectively. RESULTS: In univariate survival analysis, OS stratified by subsites indicated that 5-year OS for anastomotic recurrence (80.5%) was better than for anterior recurrence (57.7%) and other pelvic oligo-recurrences (44.5%) (P=0.005). Five-year DFS in the three groups was 60.3%, 49% and 36.6%, respectively (P=0.037). In multivariate survival analysis, pelvic oligo-recurrence and symptomatic recurrence patterns were independently associated with OS in recurrent rectal cancer after pelvic radiotherapy (RT). CONCLUSIONS: These results indicate that RT for rectal cancer patients with pelvic oligo-recurrence had favorable prognosis, especially for patients with anastomotic recurrence.

[Expression of Hydrodynamic Injection-mediated PD-L1 in Myeloablative Conditioning Mouse Model].

OBJECTIVE: To establish the mouse model for the expression of PD-L1 by hydrodynamic injection and to study the effects of myeloablative conditioning on hydrodynamic injection-mediated PD-L1 expression. METHODS: Plasmid amplification, hydrodynamic injection, collagenase perfusion, real time PCR, ELISA and flow cytometry were applied to test the expression and function of PD-L1. Also, animal models were set up to test the effects of chemical or radiactive myeloablative conditioning on hydrodynamic injection-mediated PD-L1 expression. RESULTS: The expression of PD-L1 mRNA and protein could be detected as early as 8 h after hyrodynamic injection and reached peak expression by 24 h, and returned to baseline level by 7 d after injection. Serum PD-L1 level reached to 100 µg/ml as early as 24 h after injection and plateaued at 7 d after injection. Serum PD-L1 persisted for 3 weeks and declined to baseline after 1 month of hydrodynamic injection. The PD-L1 function induced by hydrodynamic injection was consistent with literature reports. At each time point, the PD-L1 expression was not different significantly between the myeloablative conditioning group and control group; the mice transfected with PD-L1 showed a higher survival rate than that in control group. CONCLUSION: Myeloablative conditioning does not affect hydrodynamic injection-mediated PD-L1 expression, indicating that the PD-L1 can be used in HSCT mouse model.

Reflexed Compression Suture for the Management of Atonic Postpartum Hemorrhage with an Abnormally Adherent Placenta.

BACKGROUND/AIMS: Postpartum hemorrhage (PPH) is a life-threatening condition with a worldwide occurrence. The purpose of this study is to evaluate the efficacy and safety of a reflexed compression suture in controlling severe atonic PPH with placenta accreta. METHODS: Eleven women with severe PPH due to uterine inertia or placenta accreta were administered the reflexed compression suture. The procedure was to reflex the fundus onto the anterior wall of the uterus for compressing hemostasis and to form a 'belt-like' binding suture to reinforce the effectiveness of pressing the myometrium. RESULTS: Ten of the 11 women (90.9%) were successfully treated with the suture, and the uterus was preserved. None of these patients developed complications related to this method. Only in 1 patient with placenta increta could the bleeding not be stanched, and a peripartum hysterectomy was performed. Two women had pregnancies after the suture. CONCLUSION: The reflexed compression suture is a simple, swift, safe and effective technique of controlling uterine atonic bleeding, particularly in patients with an abnormally adherent placenta. The advantage of not having to conduct a hysterotomy also lies in reducing the duration of anesthesia and blood loss.

Generation of insulin-producing cells from C3H10T1/2 mesenchymal progenitor cells.

Mesenchymal stem cells (MSCs) have been reported to be an attractive source for the generation of transplantable surrogate ß cells. A murine embryonic mesenchymal progenitor cell line C3H10T1/2 has been recognized as a model for MSCs, because of its multi-lineage differentiation potential. The purpose of this study was to explore whether C3H/10T1/2 cells have the potential to differentiate into insulin-producing cells (IPCs). Here, we investigated and compared the in vitro differentiation of rat MSCs and C3H10T1/2 cells into IPCs. After the cells underwent IPC differentiation, the expression of differentiation markers were detected by immunocytochemistry, reverse transcription-polymerase chain reaction (RT-PCR), quantitative real-time RT-PCR (qRT-PCR) and Western blotting. The insulin secretion was evaluated by enzyme-linked immunosorbent assay (ELISA). Furthermore, these differentiated cells were transplanted into streptozotocin-induced diabetic mice and their biological functions were tested in vivo. This study reports a 2-stage method to generate IPCs from C3H10T1/2 cells. Under specific induction conditions for 7-8 days, C3H10T1/2 cells formed three-dimensional spheroid bodies (SBs) and secreted insulin, while generation of IPCs derived from rat MSCs required a long time (more than 2 weeks). Furthermore, these IPCs derived from C3H10T1/2 cells were injected into diabetic mice and improves basal glucose, body weight and exhibited normal glucose tolerance test. The present study provided a simple and faithful in vitro model for further investigating the mechanism underlying IPC differentiation of MSCs and cell replacement therapy for diabetes.

[Clinical observation of accelerated partial-breast intensity-modulated radiotherapy in patients with early-stage breast cancer after breast-conserving surgery].

OBJECTIVE: To explore the clinical feasibility of accelerated partial breast irradiation (APBI) by intensity-modulated radiotherapy (IMRT). METHODS: Twenty-six patients with T1N0M0 breast cancer were enrolled into a prospective accelerated partial-breast IMRT protocol between January 2008 and January 2010. Inverse planning of IMRT was employed at a prescribed dose of 34 Gy/10 f/5 d. Acute radiation skin responses and clinical effects were observed. RESULTS: All of them completed radiation. During the radiation, Grade 1 of acute radiation skin reaction (mild hyperpigmentation) was seen in 8 patients and there was not > grade 2 of skin reaction. At Month 1 post-radiation, Grade 1 of acute radiation skin reaction (mild hyperpigmentation) was seen in all patients and there was not > grade 2 of skin reaction. At Month 3 post-radiation, all instances of acute radiation skin reactions recovered. The median follow-up period was 51 months (range: 35 - 59). The follow-up period of 23 patients were over 3 years. No local recurrences developed. The 3-year disease-free survival was 100%. Cosmesis was good or excellent in all cases at Year 2. CONCLUSION: External beam-partial breast irradiation delivered by IMRT is feasible for selected Chinese early-stage breast cancer patients after breast-conserving surgery. The cosmetic effect, local control rate and long-term survival rate are satisfactory. And acute radiation toxicity is quite low.

[Comparison of two different chemotherapy regimens for concurrent chemoradiotherapy in stage Ib2 to IVa squamous cell carcinoma of the uterine cervix].

OBJECTIVE: To compare the clinical efficacy and safety of two chemotherapy regimens for concurrent chemoradiotherapy in patients with stage Ib2 to IVa squamous cell carcinoma of the uterine cervix. METHODS: Between November 2007 and November 2011, 146 patients with stage Ib2 to IVa squamous cell carcinoma of the uterine cervix who received concurrent chemoradiotherapy in Peking University Cancer Hospital were analyzed. All cases were divided into two groups according to the different chemotherapy regimens during radiation therapy, the group receiving radiotherapy concomitant with weekly cisplatin or nedaplatin alone (platinum alone group, n = 59), the group receiving radiotherapy concomitant with cisplatin plus fluorouracil or nedaplatin plus tegafur every 3 weeks (combined group, n = 87). There were no statistical difference in the clinical and pathological characteristics between the two groups. RESULTS: Patients were evaluated by pelvic examination and pelvic MRI after chemoradiotherapy for 3 months according to WHO criteria. The response rate were respectively 97% (57/59) and 93% (81/87) in platinum alone group and combined group, in which there was no significant difference (P = 0.249). The five-year overall survival and the five-year progression-free survival of platinum alone group and combined group were respectively 61.2% versus 69.5% (P > 0.05) and 43.3% versus 24.4% (P > 0.05). There were also no statistically significant differences between platinum alone group and combined group in the five-year local recurrence rate and five-year distant metastasis (11.8% versus 9.8%, 29.4% versus 38.7%; all P > 0.05). Acute gastrointestinal toxicities (nausea and vomiting) in combined group were exactly higher than that in the other group [78% (68/87) versus 51% (30/59), P < 0.01]. Moreover, anaemia was slightly more common in combined group [53% (46/87) versus 25% (15/59), P = 0.019]. However, the occurrence rate of the acute or late proctitis and cystitis did not reveal difference between two groups (P > 0.05). CONCLUSIONS: Both concurrent chemoradiotherapy regimens had similar efficacy on cervical cancer patients with stage Ib2 to IVa. But the toxicity was lower in patients with weekly platinum than those with platinum-based combined regimens during radiation therapy.