Mechanisms and protective measures for radiation-induced brachial plexus nerve injury.

Radiation therapy is a common treatment modality for patients with malignant tumors of the head and neck, chest and axilla. However, radiotherapy inevitably causes damage to normal tissues at the irradiated site, among which damage to the brachial plexus nerve(BP) is a serious adverse effect in patients receiving radiation therapy in the scapular or axillary regions, with clinical manifestations including abnormal sensation, neuropathic pain, and dyskinesia, etc. These adverse effects seriously reduce the living quality of patients and pose obstacles to their prognosis. Therefore, it is important to elucidate the mechanism of radiation induced brachial plexus injury (RIBP) which remains unclear. Current studies have shown that the pathways of radiation-induced BP injury can be divided into two categories: direct injury and indirect injury, and the indirect injury is closely related to the inflammatory response, microvascular damage, cytokine production and other factors causing radiation-induced fibrosis. In this review, we summarize the underlying mechanisms of RIBP occurrence and possible effective methods to prevent and treat RIBP.

Quality assurance in a phase III, multicenter, randomized trial of POstmastectomy radioThErapy in Node posiTive breast cancer with or without Internal mAmmary nodaL irradiation (POTENTIAL): a planning benchmark case.

PURPOSE: To report the planning benchmark case results of the POTENTIAL trial-a multicenter, randomized, phase 3 trial-to evaluate the value of internal mammary nodal (IMN) irradiation for patients with high-risk breast cancer. METHODS: All participating institutions were provided the outlines of one benchmark case, and they generated radiation therapy plans per protocol. The plans were evaluated by a quality assurance team, after which the institutions resubmitted their revised plans. The information on beams arrangement, skin flash, inhomogeneity corrections, and protocol compliance was assessed in the first and final submission. RESULTS: The plans from 26 institutions were analyzed. Some major deviations were found in the first submission. The protocol compliance rates of dose coverage for the planning target volume of chest wall, supraclavicular fossa plus axilla, and IMN region (PTVim) were all significantly improved in the final submission, which were 96.2% vs. 69.2%, 100% vs. 76.9%, and 88.4% vs. 53.8%, respectively. For OARs, the compliance rates of heart Dmean, left anterior descending coronary artery V40Gy, ipsilateral lung V5Gy, and stomach V5Gy were significantly improved. In the first and final submission, the mean values of PTVim V100% were 79.9% vs. 92.7%; the mean values of heart Dmean were 11.5 Gy vs. 9.7 Gy for hypofractionated radiation therapy and 11.5 Gy vs. 11.0 Gy for conventional fractionated radiation therapy, respectively. CONCLUSION: The major deviations were corrected and protocol compliance was significantly improved after revision, which highlighted the importance of planning benchmark case to guarantee the planning quality for multicenter trials.

Dose-Volume Predictors for Radiation Esophagitis in Patients With Breast Cancer Undergoing Hypofractionated Regional Nodal Radiation Therapy.

PURPOSE: Our objective was to assess the incidence and dose-volume predictors of radiation esophagitis (RE) in patients with breast cancer undergoing hypofractionated regional nodal irradiation. METHODS AND MATERIALS: Eligible patients who received intensity modulated radiation therapy (RT) at the chest wall, the supraclavicular/infraclavicular fossa, level II axilla, and/or the internal mammary chain after mastectomy were included. The prescribed dose was 43.5 Gy in 15 fractions. RE was evaluated weekly during RT and at 1 and 2 weeks, followed by 3 and 6 months after RT, and was graded according to National Cancer Institute Common Toxicity Criteria for Adverse Events, version 3.0. The esophagus was contoured from the lower border level of the cricoid cartilage to the lower margin of the aortic arch. Esophageal total volume, mean dose, maximum dose, and the relative volumes (RV) and absolute volumes (AV) receiving at least 5 to 45 Gy by 5-Gy increments (RV5-RV45 and AV5-AV45) were evaluated. Univariable and multivariable logistic regression analyses were performed to determine risk factors for RE, and receiver operating characteristic curves were obtained to identify the thresholds of esophageal dosimetric parameters. RESULTS: In total, 298 patients were included between May 8, 2020, and January 5, 2022 (minimum post-RT follow-up: 6 months). Grade 2 and 3 RE incidence was 40.9% (122/298) and 0.3% (1/298), respectively. No grade 4 or 5 RE was observed. Esophageal RV20-RV40 and AV35-AV40 were significantly associated with the risk of grade ≥2 RE after adjusting for tumor laterality and internal mammary nodal irradiation. RV25 and AV35 were optimum dose-volume predictors for grade ≥2 RE at thresholds 20% for RV25 (35.9% vs 60.9%; P = .04) and 0.27 mL for AV35 (31.0% vs 54.6%; P = .04). CONCLUSIONS: RE is common in patients with breast cancer undergoing hypofractionated regional nodal irradiation. Maintaining the upper esophageal V25 at <20% and V35 at <0.27 mL may decrease the risk of RE.

[Expression of TCF3 in Burkitt's Lymphoma and Its Proliferative Effect and Prognostic Significance].

OBJECTIVE: To observe the mutation and expression of TCF3 gene in Burkitt's lymphoma (BL), and explore its effect on the proliferation of BL cells and clinical efficacy and prognosis. METHODS: The mutation and expression of TCF3 in tumor tissues from BL patients were observed by the second-generation sequencing and real-time quantitative PCR. The proliferation and apoptosis of lymphoma cells after TCF3 knocked down were observed by siRNA interference technique and CCK-8 method. Survival analysis was used to observe the relationship between TCF3 mutation and the treatment efficacy and prognosis of BL patients. RESULTS: There were high frequency mutation rate (mutation rate was 23.7%) and high expression of TCF3 in BL patients. After TCF3 knocked down, cell proliferation was inhibited and apoptosis was promoted. In TCF3-siRNA group and control group, the cell proliferation rate at 48 h was (50.2±5.9)% and (96.6±11.4)%, and apoptosis rate was 30.1% and 1.5%, respectively, which showed significantly different between the two groups (P<0.001, P=0.005). The complete remission rate of patients with TCF3 mutation was low. The complete remission rate of mutant group and wild-type group was 44.4% and 82.8%, respectively (P=0.023). The 2-year progression-free survival rate and overall survival rate of the patients with TCF3 mutation was 55.6% and 61.0%, respectively, which was lower than 83.2% and 85.2% of the patients without mutation, but the differences were not statistically significant. CONCLUSION: There are mutation and abnormal expression of TCF3 in patients with BL. Patients with TCF3 mutations have low remission rate and poor prognosis.

Variability of Target Volumes and Organs at Risk Delineation in Breast Cancer Radiation Therapy: Quality Assurance Results of the Pretrial Benchmark Case for the POTENTIAL Trial.

PURPOSE: To estimate the variations in clinical target volumes (CTVs) and organs at risk delineation within the quality assurance (QA) program of the POTENTIAL trial, which is a multicenter, randomized phase 3 trial evaluating postmastectomy radiation therapy (RT), with or without internal mammary nodal irradiation, for patients with high-risk breast cancer. METHODS AND MATERIALS: The simulating computed tomography scan data set of a benchmark case was sent to the participating centers, and the delineation of CTVs and organs at risk was required to be completed by the investigators following protocol guidelines. All submitted contours were reviewed and compared with the reference contours created by the QA team, using quantitative geometric analysis regarding volume and the Jaccard Index (JCI), Dice similarity coefficient, Geographic Miss Index, Discordance Index, and mean distance to agreement. In addition to the whole-volume analysis of all structures, the combination contour of the supraclavicular fossa and level III and II axilla (CTVsc + axIII + axII) was further analyzed on a slice-by-slice basis. RESULTS: The contours from 26 centers were reviewed and variations were observed between submission and reference. The variations of the CTV of the chest wall, contralateral breast, and heart were small, for which the mean JCI values were 0.62, 0.68, and 0.87, respectively. However, the mean JCI values of the CTV of the internal mammary nodal region, ipsilateral brachial plexus, left anterior descending coronary artery, and right coronary artery were 0.38, 0.21, 0.29, and 0.18, respectively, suggesting marked variations. In addition, marked under- and overoutlining variations were identified on 4 slices of CTVsc + axIII + axII on slice-by-slice analysis. CONCLUSIONS: There were residual contouring variations despite a detailed protocol being provided, confirming the importance of pretrial QA in RT and highlighting the need for education and consideration of a real-time central review of the target delineation before the trial participants begin RT.

Reduced serum miR-202 may promote the progression of Alzheimer's disease patients via targeting amyloid precursor protein.

The current study investigated whether the expression of miR-202 was abnormal in the serum of patients with Alzheimer's disease (AD) and evaluated the potential clinical significance, thereby shedding light on the diagnosis of AD. Here, our data showed that the level of miR-202 decreased significantly in the serum of AD patients (n = 121) compared with that of healthy controls (n = 86). Further analysis showed that the level of serum miR-202 was gradually decreased in the mild AD group (n = 31), moderate AD group (n = 52) and severe AD group (n = 38) compared with the healthy control group. Receiver operating characteristic (ROC) curve analysis demonstrated that serum miR-202 could differentiate AD patients from healthy controls, with an AUC of 0.892. Spearman correlation analysis showed that serum miR-202 was positively correlated with the Mini-Mental State Examination (MMSE). Based on TargetScan, a conserved binding site was identified in the 3'UTR of amyloid precursor protein (APP). The dual luciferase assay showed that miR-202 suppressed the relative luciferase activity of pmirGLO-APP-3'UTR. Western blot assays indicated that overexpression of miR-202 suppressed the expression of APP, while the expression of APP was enhanced after inhibition of miR-202 in PC12 cells, indicating that APP was a possible target gene of miR-202. Moreover, the cell apoptosis induced by transfection of miR-202 inhibitor was abolished by silencing APP. In summary, we showed novel data that downregulation of serum miR-202 may be used as a potential biomarker for AD and may promote the development of AD by targeting APP.

Metastatic thymic-enteric adenocarcinoma responding to chemoradiation plus anti-angiogenic therapy: A case report.

BACKGROUND: Thymic-enteric adenocarcinoma with positive expression of CDX2 and CK20 is rare in adults, with only 16 reported cases. However, standard treatment options for this type of thymic adenocarcinoma has not yet been established. Therefore, we report a case of stage IV thymic-enteric adenocarcinoma treated with radiotherapy, chemotherapy, and anti-angiogenesis therapy. CASE SUMMARY: We report a case of thymic-enteric adenocarcinoma occurring in a 44-year-old woman. The tumor was considered unresectable owing to its invasiveness. The patient was treated with six cycles of oxaliplatin (130 mg/m2, day 1) and capecitabine (1000 mg/m2 BID, days 1-14). During the first three cycles of chemotherapy, concurrent radiotherapy (60 Gy/30 fractions) and anti-angiogenic therapy using apatinib were recommended. The primary tumor achieved partial remission based on the Response Evaluation Criteria in Solid Tumors. During follow-up, there was no evidence of disease relapse, except a high serum CA19-9 level. The patient is alive and regularly followed. Based on the previous literature and the present case, we believe that early diagnosis of thymic-enteric adenocarcinoma is important. CONCLUSION: XELOX (capecitabine plus oxaliplatin) combined with radiotherapy is an optional therapy for inoperable thymic-enteric adenocarcinoma.

CircKDM4C upregulates P53 by sponging hsa-let-7b-5p to induce ferroptosis in acute myeloid leukemia.

To investigate the role of circKDM4C in acute myeloid leukemia (AML), the expression of circKDM4C, hsa-let-7b-5p, and P53 was measured by qRT-RCR. AML cell lines(K-562 and HL-60) were transfected correspondingly and investigated for cell proliferation, migration, and invasion abilities by CCK-8, colony formation, transwell, and wound healing assays, respectively. The levels of P53, ACSL4, PTGS2, GPX4, and FTH1 in the K-562, and HL-60 cells were measured by western blotting. Also, circKDM4C mediated regulation of ferroptosis was studied. The Phen Green SK probe and confocal laser scanning microscope were used to assess the cellular iron levels. The reactive oxygen species levels were analyzed by fluorescence-activated cell sorting using the C11-BODIPY probe. Bioinformatics analysis predicted the putative binding sites among circKDM4C, hsa-let-7b-5p, and P53. These were verified using the dual-luciferase reporter assay, RNA pull-down, and RNA immunoprecipitation assays. Finally, in vitro findings were also verified in vivo using the nude mice. CircKDM4C was significantly down-regulated in AML patients. The overexpression of circKDM4C in AML cell lines inhibited the cell proliferation, migration, invasion, and promoted ferroptosis. We found that circKDM4C acts as a sponge of hsa-let-7b-5p and thereby regulates p53 which is a target gene of hsa-let-7b-5p. Also, the expression of circKDM4C and hsa-let-7b-5p are negatively correlated, while circKDM4C and p53 are positively correlated to AML patients. Moreover, we found that circKDM4C induces ferroptosis by sponging hsa-let-7b-5p which upregulates the expression of P53. This work emphasizes the role of circKDM4C in AML patients, which could be explored for the therapeutic role.

CEOP/IVE/GDP alternating regimen compared with CEOP as the first-line therapy for newly diagnosed patients with peripheral T cell lymphoma: results from a phase 2, multicenter, randomized, controlled clinical trial.

BACKGROUND: Cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP)/CHOP-like chemotherapy is widely used in peripheral T cell lymphoma (PTCL). Here we conducted a phase 2, multicenter, randomized, controlled trial, comparing the efficacy and safety of CEOP/IVE/GDP alternating regimen with CEOP in newly diagnosed PTCL. METHODS: PTCL patients, except for anaplastic large cell lymphoma-anaplastic lymphoma kinase positive, were 1:1 randomly assigned to receive CEOP/IVE/GDP (CEOP, cyclophosphamide 750 mg/m2, epirubicin 70 mg/m2, vincristine 1.4 mg/m2 [maximum 2 mg] on day 1, and prednisone 60 mg/m2 [maximum 100 mg] on days 1-5 every 21 days, at the first and fourth cycle; IVE, ifosfamide 2000 mg/m2 on days 1-3, epirubicin 70 mg/m2 on day 1, and etoposide 100 mg/m2 on days 1-3 every 21 days, at the second and fifth cycle; and GDP, gemcitabine 1000 mg/m2 on days 1 and 8, cisplatin 25 mg/m2 on days 1-3, and dexamethasone 40 mg on days 1-4 every 21 days, at the third and sixth cycle) and CEOP (every 21 days for 6 cycles). Analysis of efficacy and safety was of the intent-to-treatment population. The primary endpoint was a complete response rate at the end of treatment. Meanwhile, whole exome sequencing and targeted sequencing were performed in 62 patients with available tumor samples to explore prognostic biomarkers in this cohort as an exploratory post hoc analysis. RESULTS: Among 106 patients, 53 each were enrolled to CEOP/IVE/GDP and CEOP. With 51 evaluable patients each in two groups, a complete response rate of the CEOP/IVE/GDP group was similar to that of the CEOP group (37.3% vs. 31.4%, p = 0.532). There was no difference in median progression-free survival (PFS; 15.4 months vs. 9.2 months, p = 0.122) or overall survival (OS; 24.3 months vs. 21.9 months, p = 0.178). Grade 3-4 hematological and non-hematological adverse events were comparable. Histone modification genes were most frequently mutated (25/62, 40.3%), namely KMT2D, KMT2A, SETD2, EP300, and CREBBP. Multivariate analysis indicated that CREBBP and IDH2 mutations were independent factors predicting poor PFS and OS (all p < 0.001), while KMT2D predicting poor PFS (p = 0.002). CONCLUSIONS: CEOP/IVE/GDP alternating regimen showed no remission or survival advantage to standard chemotherapy. Future clinical trials should aim to develop alternative regimen targeting disease biology as demonstrated by recurrent mutations in epigenetic factors. TRIAL REGISTRATION: The study was registered on ClinicalTrial.gov (NCT02533700) on August 27, 2015.

Gut commensal bacteria, Paneth cells and their relations to radiation enteropathy.

In steady state, the intestinal epithelium forms an important part of the gut barrier to defend against luminal bacterial attack. However, the intestinal epithelium is compromised by ionizing irradiation due to its inherent self-renewing capacity. In this process, small intestinal bacterial overgrowth is a critical event that reciprocally alters the immune milieu. In other words, intestinal bacterial dysbiosis induces inflammation in response to intestinal injuries, thus influencing the repair process of irradiated lesions. In fact, it is accepted that commensal bacteria can generally enhance the host radiation sensitivity. To address the determination of radiation sensitivity, we hypothesize that Paneth cells press a critical "button" because these cells are central to intestinal health and disease by using their peptides, which are responsible for controlling stem cell development in the small intestine and luminal bacterial diversity. Herein, the most important question is whether Paneth cells alter their secretion profiles in the situation of ionizing irradiation. On this basis, the tolerance of Paneth cells to ionizing radiation and related mechanisms by which radiation affects Paneth cell survival and death will be discussed in this review. We hope that the relevant results will be helpful in developing new approaches against radiation enteropathy.

Postnatal germ cell development in cryptorchid boys.

Cryptorchidism is associated with infertility in adulthood. Early orchiopexy is suggested to reduce the risk. Information is lacking on the potential link between infant germ cell maturation and the risk of future infertility. The objective of the study was to evaluate age-related germ cell development in cryptorchidism. Immunostaining for markers of germ cell development (octamer-binding transcription factor 3/4 [OCT3/4], placental alkaline phosphatase [PLAP], KIT proto-oncogene [C-KIT], podoplanin [D2-40], Lin-28 homolog A [LIN28], and G antigen 7 [GAGE-7]) was performed in testicular biopsies from 40 cryptorchid boys aged 4-35 months. Germ cell numbers and distributions were evaluated in cross sections of seminiferous tubules, with and without immunostaining. OCT3/4, D2-40, and LIN28 were generally expressed in the early stages of germ cell development, as shown by positive expression in germ cells in the central region of seminiferous tubules. In contrast, PLAP and GAGE-7 were expressed in both central and peripheral parts of the tubules in the early stages of development and expressed mainly in a peripheral position with advancing age. Germ cell maturation was delayed in this study population as compared with that observed in our previous study on germ cell markers in a healthy population. The number of GAGE-7-positive germ cells per tubular cross section obtained by immunostaining was significantly higher than that obtained by standard hematoxylin and eosin staining. Double immunostaining revealed heterogeneity in germ cell development in cryptorchid testes. These results shed light on the pathophysiology of germ cell development in boys with cryptorchidism.

Local analgesic effect of a bioadhesive barrier-forming oral liquid in cancer patients with oral mucositis caused by chemotherapy and/or radiotherapy: a randomized multicenter, single-use, positive-controlled, open-label study.

OBJECTIVE: CAM2028 (Episil®; Camurus AB, Lund, Sweden) is a liquid for use in the oral cavity to treat various pains associated with mouth injuries. Upon contact with the swollen oral mucosa, the oral liquid forms a thin protective film that acts as a mechanical barrier to relieve pain. This study was the first in China to evaluate the local analgesic effect of oral liquid in cancer patients who developed oral mucositis following chemotherapy and/or radiotherapy. METHODS: A total of 60 patients were randomized in a 1:1 ratio to the CAM2028 group (the pump device was firmly pressed three times and the fluid was distributed to the painful area of the oral cavity) or KS (a mucoadhesive oral wound rinse, Kangsu™; Luye Pharmaceutical Co. Ltd, Nanjing, China) group (5 mL of the oral rinse was poured into and kept in the oral cavity for at least 1 minute). The primary endpoint was the area under the oral mucosal pain score-time curve (AUC) within 6 hours of treatment in the trial and control groups. Medical device adverse events were assessed according to the National Cancer Institute's Common Terminology Criteria for Adverse Events, version 4.0. Statistical analyses were performed using the chi-squared test (Fisher's exact test), independent-samples t-test, and analysis of covariance. RESULTS: Sixty patients were included in the per-protocol set population analysis. The average (mean ± SD) 6-hour AUC of the CAM2028 group and the KS group was 14.20±10.29 and 24.46±14.15, respectively. The difference between the groups was statistically significant (P=0.0022). The incidence of adverse events in the trial group and the control group was 16.67% and 30.0%, respectively, and there was no statistical difference. CONCLUSIONS: CAM2028 displayed an efficacious local analgesic effect in cancer patients who developed oral mucositis following chemotherapy and/or radiotherapy. The results demonstrated its potential value in clinical applications.

Berberine promotes nerve regeneration through IGFR­mediated JNK­AKT signal pathway.

Berberine presents therapeutic ability for various central nervous system disorders, including Alzheimer's disease and cerebral ischemia. The present study investigated the role of berberine in nerve regeneration and analyzed the potential mechanism mediated by berberine in hippocampal pyramidal neurons. Reverse transcription­quantitative poylmerase chain reaction, western blot, TUNEL assay and immunofluorescence were used to analyze the therapeutic effects of berberine on nerve regeneration. Berberine treatment increased growth and viability of hippocampal pyramidal neurons. Berberine treatment inhibited apoptosis of hippocampal pyramidal neurons and increased apoptosis regulator Bcl­2 and Bcl­w expression. Neuroinflammation of tumor necrosis factor α, interleukin (IL)1ß, IL6 levels and autophagy­related proteins microtubule­associated proteins 1A/1B light chain 3B, autophagy related 16 like 1 and autophagy related 7 were downregulated by berberine treatment in hippocampal pyramidal neurons. Notably, study has found that berberine increased insulin-like growth factor receptor (IGFR) and decreased c­Jun N­terminal kinase (JNK) and protein kinase B (AKT) expression in hippocampal pyramidal neurons. IGFR antagonist abolished berberine­increased growth of hippocampal pyramidal neurons. In conclusion, these results indicate that berberine can promote nerve regeneration through IGFR­mediated JNK­AKT signal pathway.

Betulin inhibits lipopolysaccharide/D-galactosamine-induced acute liver injury in mice through activating PPAR-γ.

Betulin is a phenolic flavonoid which has been reported to possess a mass of pharmacological properties, especially anti-inflammatory activity. The purpose of this study was to explore the protective effects and possible mechanism of betulin against lipopolysaccharide/D-galactosamine (LPS/D-Gal)-induced acute liver injury. D-Gal and LPS were intraperitoneally injected to develop acute liver injury animal model. Betulin (2, 4 or 8 mg/kg) were given 1 h before LPS/D-Gal instillation. Liver tissues and plasma samples were collected 9 h after LPS/D-Gal were given. The results indicated that betulin dramatically decreased liver pathologic changes, myeloperoxidase (MPO) activity, serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Simultaneously, the levels of interleukin (IL-1ß) and tumor necrosis factor (TNF-α) in serum and liver tissues were both attenuated by betulin. Besides, betulin suppressed NF-κB pathway activation in a dose-dependently manner. Betulin increased the expression of PPAR-γ in a dose-dependent manner. In conclusion, all these results revealed that betulin could possess potential therapeutic effect for LPS/D-Gal-induced acute liver injury.

[Enzymatic characteristics of peroxidase from Chrysanthemum morifolium cv. Bo-ju].

The enzymatic browning is one of the main reasons for affecting the quality of medicinal flowers. In the process of chrysanthemum harvesting and processing, improper treatment will lead to the browning and severely impact the appearance and quality of chrysanthemum. Peroxidase enzyme is one of the oxidoreductases that cause enzymatic browning of fresh chrysanthemum. The enzymatic characteristics of peroxidase (POD) in chrysanthemum were studied in this paper. In this experiment, the effects of different reaction substrates and their concentrations, PH value of buffer and reaction temperatures on the activity of POD enzyme were investigated. The results showed that the optimal substrate of POD was guaiacol, and the optimal concentration of POD was 50 mmol·L⁻¹. The optimal pH value and reaction temperature were 4.4 and 30-35 °C, respectively. Michaelis-Menten equation was obtained to express the kinetics of enzyme-catalyzed reaction of POD, Km=0.193 mol·L⁻¹, Vmax=0.329 D·min⁻¹. In addition, the results of POD enzyme thermal stability test showed that the POD enzyme activity was inhibited when being treated at 80 °C for 4 min or at 100 °C for 2 min. The above results were of practical significance to reveal the enzymatic browning mechanism, control the enzymatic browning and improve the quality of chrysanthemum, and can also provide the basis for the harvesting and processing of medicinal materials containing polyphenols.

A comparison between oral chemotherapy combined with radiotherapy and radiotherapy for newly diagnosed glioblastoma: A systematic review and meta-analysis.

The prognosis of glioblastoma (GBM), a major subtype of grade IV glioma, is rather poor nowadays. The efficiency of chemotherapy serving as the adjunct to radiotherapy (RT) for treating GBM is still controversial. In this study, we aim to investigate the overall survival (OS) and progression-free survival (PFS) in patients with newly diagnosed GBM received RT plus chemotherapy or with RT alone.Literatures were searched from the PubMed, Embase, and Cochrane Library between January 2001 and June 2015. Study selection was conducted based on the following criteria: randomized clinical trial (RCT) of adjuvant RT plus chemotherapy versus RT alone; studies comparing OS and/or PFS; and studies including cases medically confirmed of newly diagnosed GBM.Five RCTs (1655 patients) were eligible in this study. The meta-analysis showed a significant improvement in OS of patients treated with RT plus oral chemotherapy compared with that of RT alone (hazard ratio 0.70; 95% confidence interval, 0.56-0.88, P = .002).Adjuvant chemotherapy confers a survival benefit in patients newly diagnosed with GBM.

MSC-derived cytokines repair radiation-induced intra-villi microvascular injury.

Microvascular injury initiates the pathogenesis of radiation enteropathy. As previously demonstrated, the secretome from mesenchymal stem cells contains various angiogenic cytokines that exhibited therapeutic potential for ischemic lesions. As such, the present study aimed to investigate whether cytokines derived from mesenchymal stem cells can repair endothelial injuries from irradiated intestine. Here, serum-free medium was conditioned by human adipose-derived mesenchymal stem cells, and we found that there were several angiogenic cytokines in the medium, including IL-8, angiogenin, HGF and VEGF. This medium promoted the formation of tubules between human umbilical cord vein endothelial cells and protected these cells against radiation-induced apoptosis in vitro. Likewise, our in vivo results revealed that repeated injections of mesenchymal stem cell-conditioned medium could accelerate the recovery of irradiated mice by reducing the serum levels of pro-inflammatory cytokines, including IL-1α, IL-6 and TNF-α, and promoting intra-villi angiogenesis. Herein, intervention by conditioned medium could increase the number of circulating endothelial progenitors, whereas neutralizing SDF-1α and/or inhibiting PI3K would hamper the recruitment of endothelial progenitors to the injured sites. Such results suggested that SDF-1α and PI3K-mediated phosphorylation were required for intra-villi angiogenesis. To illustrate this, we found that conditioned medium enabled endothelial cells to increase intracellular levels of phosphorylated Akt Ser473, both under irradiated and steady state conditions, and to up-regulate the expression of the CXCR4 and CXCR7 genes. Collectively, the present results revealed the therapeutic effects of mesenchymal stem cell-derived cytokines on microvascular injury of irradiated intestine.

Accumulation of Smooth Muscle 22α Protein Accelerates Senescence of Vascular Smooth Muscle Cells via Stabilization of p53 In Vitro and In Vivo.

OBJECTIVE: Smooth muscle (SM) 22α, an actin-binding protein, displays an upregulated expression as a marker during cellular senescence. However, the causal relationship between SM22α and senescence is poorly understood. This study aimed to investigate the role of SM22α in angiotensin II (Ang II)-induced senescence of vascular smooth muscle cells (VSMCs). APPROACH AND RESULTS: We prepared a model of VSMC senescence induced by Ang II and found that the expression of SM22α in VSMCs was increased in response to chronic Ang II treatment. Overexpression of SM22α promoted Ang II-induced VSMC senescence, whereas knockdown of SM22α suppressed this process. Moreover, this effect of SM22α was p53 dependent. Increased SM22α protein obstructed ubiquitination and degradation of p53 and subsequently improved its stability. Furthermore, SM22α inhibited phosphorylation of Mdm2 (mouse double minute 2 homolog), an E3 ubiquitin-protein ligase, accompanied by a decreased interaction between Mdm2 and p53. Using LY294002, a PI3K/Akt inhibitor, we found that PI3K/Akt-mediated Mdm2 phosphorylation and activation was inhibited in senescent or SM22α-overexpressed VSMCs, in parallel with decreased p53 ubiquitination. We further found that SM22α inhibited activation of PI3K/Akt/Mdm2 pathway via strengthening actin cytoskeleton. In the in vivo study, we showed that the disruption of SM22α reduced the increase of blood pressure induced by Ang II, associated with decreased VSMC senescence through a mechanism similar to that in VSMCs in vitro. CONCLUSIONS: In conclusion, these findings suggest that the accumulation of SM22α promotes Ang II-induced senescence via the suppression of Mdm2-mediated ubiquitination and degradation of p53 in VSMCs in vitro and in vivo.

[Clinical Efficacy of EPOCH±R Followed by DICE±R Regimen for Primary Breast Diffuse Large B-Cell Lymphoma].

OBJECTIVE: To explore the clinical efficacy and safety of EPOCH±R followed by DICE±R regimen for primary breast diffuse large B-cell lymphoma. METHODS: Forty-three patients with primary breast diffuse large B-cell lymphoma were admitted in our hosptial from January 2000 to April 2016. Among them 24 patients were treated with CHOP±R regimen, 19 patients were treated with EPOCH±R followed by DICE±R regimen. The clinical efficacy, survival rate and adverse effects were observed and compared between them. RESULTS: The complete rate in EPOCH±R followed by DICE±R regimen group was higher than that in the CHOP±R group (84.2% vs 70.8%), and the relapsed rate was lower in EPOCH±R followed by DICE±R regimen group than that in the CHOP±R group (6.25% vs 35.3%). Progression-free survival (PFS) and overall survival (OS) rates of 5 years after diagnosis in the EPOCH±R followed by DICE±R group were significantly higher as compared with that in CHOP±R group (PFS, 75% vs 47.4%, P=0.035; OS, 73.3% vs 45.2%, P= 0.043). Treatment-related hematologic adverse events were more serious in the EPOCH±R followed by DICE±R group(63.2% vs 25%). However, these adverse events were controlled and no treatment-related deaths were observed. Multivariate analysis showed that age (P=0.008; 95% CI, 0.026 to 0.579), radiotherapy (P=0.045; 95% CI, 1.028 to 14.719) and LDH level (P=0.007; 95% CI, 0.017 to 0.531) were independent prognostic factors for 5 year overall survival. CONCLUSION: EPOCH±R followed by DICE±R regimen is an effective and safe treatment regimen for PB-DLBCL. Prognostic factors for survival are age, LDH level and radiotherapy.

CKII-SIRT1-SM22α loop evokes a self-limited inflammatory response in vascular smooth muscle cells.

AIMS: Sirtuin 1 (SIRT1) inhibits nuclear factor kappa B (NF-κB) activity in response to the inflammatory cytokine tumour necrosis factor alpha (TNF-α). Smooth muscle (SM) 22α is a phosphorylation-regulated suppressor of IKK-IκBα-NF-κB signalling cascades in vascular smooth muscle cells (VSMCs). Sm22α knockout results in increased expression of pro-inflammatory genes in the aortas which are controlled by NF-κB. This study aimed to investigate the relationship between SM22α and SIRT1 in the control of vascular inflammation. METHODS AND RESULTS: The ligation injury model of Sirt1-Tg/Sm22α-/- mice displayed an increased level of the inflammatory molecules in the carotid arteries compared with Sirt1-Tg mice, accompanied with aggravating neointimal hyperplasia. In the in vitro study, on the one hand, we showed that TNF-α induced the epigenetic silencing of SM22α transcription via EZH2-mediated H3K27 methylation in the SM22α promoter region, contributing to inflammatory response. On the other hand, TNF-α simultaneously induced SIRT1 phosphorylation via CKII and thereby protected against inflammation. Phosphorylated SIRT1 interacted with and deacetylated EZH2 and, subsequently, promoted SM22α transcription by inhibiting EZH2 activity. Increased SM22α in turn facilitated the phosphorylation and activation of SIRT1 via recruitment of CKII to SIRT1, which amplified the anti-inflammatory effect of SIRT1. CONCLUSION: Our findings demonstrate that, in response to TNF-α stimulation, CKII-SIRT1-SM22α acts in a loop to reinforce the expression of SM22α, which limits the inflammatory response in VSMCs in vivo and in vitro. The anti-inflammatory effect of SIRT1 may be dependent on SM22α to some extent. Our data point to targeted activation of SIRT1 in VSMCs as a promising therapeutic avenue in preventing cardiovascular diseases.