Automatic dose prediction using deep learning and plan optimization with finite-element control for intensity modulated radiation therapy.

BACKGROUND: Automatic solutions for generating radiotherapy treatment plans using deep learning (DL) have been investigated by mimicking the voxel's dose. However, plan optimization using voxel-dose features has not been extensively studied. PURPOSE: This study aims to investigate the efficiency of a direct optimization strategy with finite elements (FEs) after DL dose prediction for automatic intensity-modulated radiation therapy (IMRT) treatment planning. METHODS: A double-UNet DL model was adapted for 220 cervical cancer patients (200 for training and 20 for testing), who underwent IMRT between 2016 and 2020 at our clinic. The model inputs were computed tomography (CT) slices, organs at risk (OARs), and planning target volumes (PTVs), and the outputs were dose distributions of uniformly generated high-dose region-controlled plans. The FEs were discretized into equal intervals of the dose prediction value within the [OARs avoid PTV(O-P)] and [body avoids OARs & PTV(B-OP)] regions in the test cohort and used to define the objectives for IMRT plan optimization. The plans were optimized using a two-step process. In the beginning, the plans of two extra cases with and without low-dose region control were compared to pursue robust and optimal dose adjustment degree pattern of FEs. In the first step, the mean dose of O-P FEs were constrained to differing degrees according to the pattern. The further the FEs from the PTV, the tighter the constraints. In the second step, the mean dose of O-P FEs from first step were constrained again but weakly and the dose of the B-OP FEs from dose prediction and PTV were tightly regulated. The dosimetric parameters of the OARs and PTV were evaluated and compared using an interstep approach. In another 10 cases, the plans optimized via the aforementioned steps (method 1) were compared with those directly generated by the double-UNet dose prediction model trained by low and high region-controlled plans (method 2). RESULTS: The mean differences in dose metrics between the UNet-predicted dose and the clinical plans were: 0.47 Gy for bladder D50% ; 0.62 Gy for rectum D50% ; 0% for small intestine V30Gy ; 1% for small intestine V40Gy ; 4% for left femoral head V30Gy ; and 6% for right femoral head V30Gy . The reductions in mean dose (p < 0.001) after FE-based optimization were: 4.0, 1.9, 2.8, 5.9, and 5.7 Gy for the bladder, rectum, small intestine, left femoral head, and right femoral head, respectively, with flat PTV homogeneity and conformity. Method 1 plans produced lower mean doses than those of method 2 for the bladder (0.7 Gy), rectum (1.0 Gy), and small intestine (0.6 Gy), while maintaining  PTV homogeneity and conformity. CONCLUSION: FE-based direct optimization produced lower OAR doses and adequate PTV doses after DL prediction. This solution offers rapid and automatic plan optimization without manual adjustment, particularly in low-dose regions.

Yue-bi-tang attenuates adriamycin-induced nephropathy edema through decreasing renal microvascular permeability via inhibition of the Cav-1/ eNOS pathway.

Edema is one of the most typical symptoms of nephrotic syndrome. Increased vascular permeability makes a significant contribution to the progression of edema. Yue-bi-tang (YBT) is a traditional formula with excellent clinical efficacy in the treatment of edema. This study investigated the effect of YBT on renal microvascular hyperpermeability-induced edema in nephrotic syndrome and its mechanism. In our study, the content of target chemical components of YBT was identified using UHPLC-Q-Orbitrap HRMS analysis. A nephrotic syndrome model was replicated based on male Sprague-Dawley rats with Adriamycin (6.5 mg/kg) by tail vein injection. The rats were randomly divided into control, model, prednisone, and YBT (22.2 g/kg, 11.1 g/kg, and 6.6 g/kg) groups. After 14 d of treatment, the severity of renal microvascular permeability, edema, the degree of renal injury, and changes in the Cav-1/eNOS pathway were assessed. We found that YBT could regulate renal microvascular permeability, alleviate edema, and reduce renal function impairment. In the model group, the protein expression of Cav-1 was upregulated, whereas VE-cadherin was downregulated, accompanied by the suppression of p-eNOS expression and activation of the PI3K pathway. Meanwhile, an increased NO level in both serum and kidney tissues was observed, and the above situations were improved with YBT intervention. It thus indicates YBT exerts therapeutic effects on the edema of nephrotic syndrome, as it improves the hyperpermeability of renal microvasculature, and that YBT is engaged in the regulation of Cav-1/eNOS pathway-mediated endothelial function.

Benefits of combination therapy with immune checkpoint inhibitors and predictive role of tumour mutation burden in hepatocellular carcinoma: A systematic review and meta-analysis.

OBJECTIVES: To investigate the clinical benefits of combination therapy with immune checkpoint inhibitors (ICIs) and best combination regimen for people with advanced hepatocellular carcinoma (HCC) and to explore the predictive performance of tumour mutation burden (TMB). METHODS: We conducted a systematic literature search to identify clinical trials. Meta-analysis and subgroup analyses were performed to estimate the benefits of combination regimens with PD-1/PD-L1 inhibitors for patients with advanced HCC and compare the effectiveness of PD-1/PD-L1 inhibitors and sorafenib as first-line therapy. Individualized analysis and Kaplan-Meier were used to assess the prognostic value of TMB. RESULTS: A total of 29 studies with 5396 patients were included. ICIs' combination therapy had higher ORR (26 % vs 15 %) and DCR (73 % vs 55 %), longer PFS (5.5 vs 3.1 months) and OS (15.9 vs 12.6 months) compared to monotherapy. Anti-PD-1/PD-L1 agents provided improved ORR, DCR, PFS and OS compared to sorafenib. The overall ORs of ORR and DCR in subgroup analysis were 3.49 (95 % CI 2.36-5.17, p < 0.01) and 1.60 (95 % CI 1.15-2.21, p < 0.01). The overall HRs of PFS and OS were 0.68 (95 % CI 0.48-0.96, p = 0.03) and 0.73 (95 % CI 0.62-0.85, p < 0.01). PD-1/PD-L1 inhibitors plus anti-VEGF agents had an advantage in DCR (0.80 vs 0.48, meta-regression =  - 0.32, P < 0.001), but an equal ORR (0.29 vs 0.26) compared to dual immune checkpoint inhibitors. The total OS in Dua-ICIs were 16.5 months (95 % CI 14.2-18.7), yet not reached in the major studies of ICI plus anti-VEGF regimen. In individualized analysis, the 1-year OS was superior for patients who had high-TMB (>10, mutations/Mb) than moderate-TMB (1-10, mutations/Mb; 28 % vs 15 %, P = 0.025). CONCLUSION: Immune checkpoint inhibitors' combination therapy improved clinical outcomes in the management of advanced hepatocellular carcinoma. However, the overall objective response rate still did not exceed 30%. PD-1/PD-L1 inhibitors plus anti-angiogenic agents and dual immunotherapy provided significantly increased survival over sorafenib, which also pose new challenges for future research, and more appropriate and guided control regimens are required. Also, TMB may be a promising prognostic biomarker for immunotherapy in HCC. However, the validation of prospective and large sample studies is needed.

Capecitabine inhibits epithelial-to-mesenchymal transition and proliferation of colorectal cancer cells by mediating the RANK/RANKL pathway.

Colorectal cancer (CRC) is the third most prevalent malignancy globally. Capecitabine is an important form of chemotherapy for colorectal cancer. The present study aims to investigate the underlying mechanism of action of the drug in CRC cells. In the present study, 50 pairs of CRC and adjacent normal tissues were collected, and CRC cell lines (SW480, SW620, HT29, LOVO and HCT116) and NCM460 colonic epithelial cells were also purchased and used. Western blotting was used to measure the expression levels of proteins involved in the receptor activator of nuclear factor-κB (RANK)/receptor activator of nuclear factor-κB ligand (RANKL) pathway and epithelial-to-mesenchymal transition (EMT), including RANK, RANKL, osteoprotegerin (OPG), E-cadherin, vimentin and N-cadherin. Proliferation and migration were measured using MTT, Cell Counting Kit-8, EdU, Transwell and wound healing assays, respectively. In the present study, it was found that the RANK/RANKL pathway was activated in cancer tissues and cells. Additionally, it was observed that capecitabine treatment reduced the protein expression of RANK, RANKL and OPG in HT29 cells, suggesting that capecitabine has a repressive effect on the RANK/RANKL pathway. Furthermore, functional experiments revealed that the proliferative ability and the EMT process observed in HT29 cells were inhibited after they were treated with capecitabine or transfected with si-RANK. Rescue assays were then performed, which revealed that the promotion of RANK via transfection of cells with 50 nM pcDNA3.1-RANK reversed the inhibitory effects of capecitabine on HT29 cell proliferation and EMT. These findings suggest that the regulatory role of capecitabine is at least partially mediated through the RANK/RANKL pathway in colorectal cancer. The present study demonstrated that capecitabine-induced repression of CRC is exerted by inhibiting the RANK/RANKL pathway, where this new mechanism potentially provides a novel therapeutic target.

Gastrodin inhibits high glucose-induced inflammation, oxidative stress and apoptosis in podocytes by activating the AMPK/Nrf2 signaling pathway.

Diabetic nephropathy (DN) is a serious and common complication of type 1 and 2 diabetes. Gastrodin has been reported to suppress high glucose (HG)-induced inflammation and oxidative stress in vivo and in vitro. However, the effect of gastrodin on DN has not been fully elucidated. The present study aimed to investigate the underlying mechanism involved in the effect of gastrodin on podocyte injury caused by DN. Cell viability was evaluated using Cell Counting Kit-8 assay and secretion levels of TNF-α, IL-1ß and IL-6 were measured using ELISA. The levels of malondialdehyde, activities of lactate dehydrogenase and superoxide dismutase were quantified using corresponding assay kits. Additionally, cell apoptosis was analyzed by TUNEL assay, whilst protein expressions related to inflammation, apoptosis and the 5'-AMP-activated protein kinase (AMPK)/nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway were measured by western blot analysis. The results showed that gastrodin increased the viability of MPC5 cells following HG stimulation. Gastrodin also alleviated HG-induced inflammation, oxidative stress and apoptosis in MPC5 cells. Furthermore, gastrodin promoted activation of the AMPK/Nrf2 pathway in MPC5 cells. Treatment with the AMPK inhibitor, compound C, reversed the inhibitory effects of gastrodin on inflammation, oxidative stress and cell apoptosis. To conclude, treatment of MPC5 cells with gastrodin can attenuate HG-induced inflammation, oxidative stress and cell apoptosis by activating the AMPK/Nrf2 signaling pathway. Results from the current study suggest that gastrodin can be used as an effective therapeutic agent against HG-induced podocyte injury in DN.

Effects of resveratrol on renal ischemia-reperfusion injury: A systematic review and meta-analysis.

Renal ischemia-reperfusion (I/R) injury may lead to acute kidney injury, which is characterized by high morbidity and mortality rates. Resveratrol (RSV) can be extracted from Chinese herbs, and multiple animal experiments have demonstrated its potential for renal protection. This systematic review evaluates the protective effect of RSV against renal I/R injury in animal models. The PubMed, Embase, Web of Science, and Science Direct databases were searched for animal experiments related to RSV in renal I/R injury from their establishment to June 2022. In total, 19 studies were included with 249 animals (129 treated with RSV and 120 as controls). The pooled analysis revealed that RSV administration significantly decreased serum creatinine (SCr) levels (16 studies, n = 243, WMD = -58.13, 95% CI = -79.26 to -37.00, p < 0.00001) and blood urea nitrogen (BUN) levels (12 studies, n = 163, WMD = -34.37, 95% CI = -46.70 to -22.03, p < 0.00001) in the renal I/R injury model. The level of malondialdehyde (MDA), an oxidative stress index, was alleviated [7 studies, n = 106, standardized mean difference (SMD) = -6.05, 95% CI = -8.90 to -3.21, p < 0.0001] and antioxidant enzymes such as glutathione (GSH) (7 studies, n = 115, SMD = 9.25, 95% CI = 5.51-13.00, p < 0.00001) and catalase (CAT) (4 studies, n = 59, SMD = 8.69, 95% CI = 4.35-13.03, p < 0.0001) were increased after treatment of RSV. The subgroup analysis suggested that 5-10 mg/kg of RSV optimally protects against renal I/R injury as both the BUN and SCr levels were significantly decreased at this dosage. The protective effects of RSV against renal I/R injury might be attributed to multiple mechanisms, such as inhibiting oxidative stress, apoptosis, inflammation, fibrillation, and promoting autophagy. For a deeper understanding of the protective effects of RSV, experimental studies on animal models and large randomized controlled trials in humans are needed.

New Insights Into the Effects of Individual Chinese Herbal Medicines on Chronic Kidney Disease.

The clinical and experimental study into the effects of Chinese herbal medicines on chronic kidney disease has evolved over the past 40 years with new insight into their mechanism and evidence of their clinical effects. Among the many traditional Chinese herbs examined in chronic renal disease, five were found to have evidence of sufficient clinical efficacy, high frequency of use, and well-studied mechanism. They are: Abelmoschus manihot and Huangkui capsule, Salvia miltiorrhiza and its components (tanshinone II A, salvianolic acid A and B); Rhizoma coptidis and its monomer berberine; Tripterygium wilfordii and its components (triptolide, tripterygium glycosides); Kudzu root Pueraria and its monomer Puerarin. These Chinese herbal medications have pharmaceutical effects against fibrosis, inflammation and oxidative stress and also promote renal repair and regeneration. This article reviews their clinical efficacy, anti-fibrotic effects in animal models, and molecular mechanism of action.

[Myricetin reduces the reproductive toxicity of cyclophosphamide in male mice].

OBJECTIVE: To explore the effect of myrica flavone on male reproductive toxicity induced by cyclophosphamide and its mechanism. METHODS: Thirty 6-week-old male ICR mice were randomly divided into 5 groups: blank control group, cyclophosphamide reproductive injury model group, myricetin low-medium high-dose intervention group. Except the blank control group, the other groups were intraperitoneally injected with cyclophosphamide 50 mg/kg daily for 7 consecutive days. The myricetin group received intragastric administration of 100, 200, and 400 mg/kg myricetin daily for 30 consecutive days since the second day of modeling. The blank control group and the model control group were given an equal volume of a 0. 25% sodium carboxymethyl cellulose solution. The body weight was measured every 3 days, and the day after the last administration, the mice were sacrificed by cervical dislocation, and the epididymis and testes were quickly taken. Testicular weighing, testicular index calculation, epididymis to obtain sperm, sperm analyzer to analyze sperm density and vitality. The expression of Bax and Bcl-2 in testicular tissues was detected by immunoblotting, and the mitochondrial membrane potential of sperm was detected by flow cytometry. RESULTS: After 9 days of modeling, the weight of mice in the model group was lower than that of the blank control group, which was statistically different(P<0. 05). There was no difference between the myricetin treatment group and the model group. The testis index of the model group was(3. 93±0. 91)mg/g, which was significantly lower than that of the blank control group(6. 93±0. 98)mg/g, and the difference was statistically significant(P<0. 05). After treatment with bayberry flavonoids, the testis index increased, in the 100 and 200 groups and 400 mg/kg testis index were(3. 94±1. 21) mg/g, (4. 33±0. 88) mg/g, and(4. 80±0. 43) mg/g, respectively. Compared with model control group, The difference was statistically significant(P<0. 05 and P<0. 01). Compared with the control group, the sperm density, sperm rate of forward movement, sperm rate of non-forward movement, and decreased sperm rate of non-moving sperm increased in the model group. After treatment with bayberry flavonoids, compared with the model group, the sperm density, sperm rate of forward motion, and sperm rate of non-forward motion increased, and the immobility sperm rate decreased. The 200 and 400 mg/kg groups had statistical significance(P<0. 05 or P<0. 01); the normal rate of sperm mitochondrial membrane potential in the model group was(54. 70±5. 45)%, and the normal mitochondrial membrane potential rate after treatment with myricetin of 100, 200 and 400 mg/kg(59. 10±9. 97)%, (62. 10±6. 07)% and(77. 10±8. 87)%, of which the 400 mg/kg group was statistically significant(P<0. 05); the ratio of Bax/Bcl-2 in the model group was 5. 92±1. 45, and the ratio of Bax/Bcl-2 decreased after treatment with myricetin of 100, 200 and 400 mg/kg, which were 2. 52±0. 51, 1. 71±0. 52 and 1. 07±0. 29. There were statistical differences(P<0. 05 or P<0. 01). CONCLUSION: Myrica flavone can protect sperm mitochondrial membrane potential, inhibit testicular cell apoptosis, and protect the male mice from reproductive toxicity induced by cyclophosphamide.

Investigation of Potential Mechanisms Associated with Non-small Cell Lung Cancer.

This study aimed at investigating the crucial mechanisms underlying non-small cell lung cancer (NSCLC). NSCLC-related microarray data GSE27262 were downloaded from Gene Expression Omnibus, including 7 NSCLC 1a samples, 18 NSCLC 1b samples, and their matched normal samples. The common differentially expressed genes (DEGs) between NSCLC 1a and NSCLC 1b samples were identified, followed by protein-protein interaction (PPI) network construction, functional enrichment analysis, and weighted gene co-expression network analysis (WGCNA). Further, the key DEGs were confirmed based on the lung adenocarcinoma (LUAD) data from the Cancer Genome Atlas (TCGA) database, followed by clinical prognostic analysis. There were 802 (NSCLC 1a) and 734 (NSCLC 1b) DEGs identified. By intersection analysis, we obtained 255 upregulated and 97 downregulated common DEGs. Upregulated DEGs were significantly enriched in the plasma membrane and extracellular region, whereas the downregulated DEGs were significantly enriched in the cytoskeleton and cell cycle process. Topoisomerase (DNA) II alpha (TOP2A) and cyclin B1 (CCNB1) were hub nodes in the PPI network. Based on WGCNA, 5 modules were obtained. In the module MEgreen, DEGs were significantly enriched in cytokine-cytokine receptor interaction and focal adhesion. Notably, 1797 DEGs were identified based on the LUAD data from the TCGA database; among them, 285 DEGs were common DEGs identified from GSE27262 data. Upregulation of TOP2A and CCNB1 was correlated with poor survival of patients. The hub genes and key pathways identified in this study are helpful for a comprehensive knowledge of the molecular mechanisms of NSCLC.

MicroRNA 362-3p Reduces hERG-related Current and Inhibits Breast Cancer Cells Proliferation.

BACKGROUND/AIM: hERG potassium channels enhance tumor invasiveness and breast cancer proliferation. MicroRNA (miRNA) dysregulation during cancer controls gene regulation. The objective of this study was to identify miRNAs that regulate hERG expression in breast cancer. MATERIALS AND METHODS: Putative miRNAs targeting hERG were identified by bioinformatic approaches and screened using a 3'UTR luciferase assay. Functional assessments of endogenous hERG regulation were made using whole-cell electrophysiology, proliferation assays, and cell-cycle analyses following miRNA, hERG siRNA, or control transfection. RESULTS: miR-362-3p targeted hERG 3'UTR and was associated with higher survival rates in patients with breast cancer (HR=0.39, 95%CI=0.18-0.82). Enhanced miR-362-3p expression reduced hERG expression, peak current, and cell proliferation in cultured breast cancer cells (p<0.05). CONCLUSION: miR-362-3p mediates the transcriptional regulation of hERG and is associated with survival in breast cancer. The potential for miR-362-3p to serve as a biomarker and inform therapeutic strategies warrants further investigation.

Factors Affecting the Survival of Patients with Oligometastatic Non-Small-Cell Lung Cancer: A Meta-Analysis.

Background: The aim was to investigate the potential factors related with overall survival of oligometastatic non-small-cell lung cancer (NSCLC) patients. Methods: A literature search was conducted in databases including PubMed, Embase, and Cochrane library up to March 2017. The hazard radio (HR) as well as the corresponding 95% confidence interval (CI) were calculated, and all the statistics analysis was performed by the R 3.12. Heterogeneity was analyzed using I-squared and Cochran Q tests. Furthermore, sensitivity analysis was performed to evaluate the stability of results. Results: In total, 6 articles were included in the meta-analysis. Nodal status was significantly correlated with the overall survival rate of NSCLC oligometastatic patients (HR: 1.69, 95% CI: 1.23-2.32, Z=3.20, P=0.001). No significant relationship was found between overall survival rate of NSCLC oligometastatic patients and the indicators including sex, stage, smoker, age, and histology. Notably, sensitivity analysis on data evaluating relationship between patients survival and the stage and histology showed that results were reversed after removing one of the studies. Conclusions: Nodal status might be associated with the overall survival of oligometastatic NSCLC patients.

Increased expression of O-GlcNAc transferase (OGT) is a biomarker for poor prognosis and allows tumorigenesis and invasion in colon cancer.

Recent studies suggest that Elevated O-GlcNAcylation by increased O-GlcNAc transferase (OGT) and/or decreasing O-GlcNAcase (OGA) levels is associated with cancer initiation, progression, invasion, and metastasis. However, the function of OGT in colon cancer tumorigeneses remains unclear. Here, we showed OGT expression is elevated in human colon cancer tissue compared with adjacent normal tissue, and cases with higher OGT expression had shorter survival time. Additionally, OGT mRNA expression was positively correlated with pathologic TNM stage from TCGA public database. Finally, we found knock-down of OGT expression by RNA interference inhibits cell proliferation, migration and invasion in colon cancer cell lines. Taken together, this study imply that elevated OGT expression had an important function in colon cancer formation and progression, and OGT may be a valuable prognostic factor and therapeutic target.

OCT4 Potentiates Radio-Resistance and Migration Activity of Rectal Cancer Cells by Improving Epithelial-Mesenchymal Transition in a ZEB1 Dependent Manner.

Radiotherapy is an important strategy for rectal cancer patient treatment. However, the efficiency of radiation is usually poor, especially in patients with advanced stage rectal cancer due to the radio-resistance developed. At the present study, OCT4 was found to play a critical role in radio-resistance development in human rectal cancer cells by improving the epithelial-mesenchymal transition process (EMT). Endogenous OCT4 expression could confer resistant phonotype on human rectal cancer cells, which was supported by the data from clonogenic forming assay and cell cycle arrest recovering experiment. EMT related transcription factor ZEB1 might take part in the radio-resistance induced by OCT4, as its expression could be upregulated by OCT4 and its silence could reverse the OCT4 induced resistance to radiation in SW480 cells. More interestingly, CHK1 was also upregulated in OCT4/ZEB1 dependent manner conferring stronger DNA damage repair activity on cancer cells, which might explain the underlying mechanisms why OCT4/ZEB1 axis could promote the resistance of human rectal cancer cell to radiation. Taken together, our results provided a novel mechanism for radio-resistance development in human rectal cancer cells and a new target to overcome this resistance.

Calcium/calmodulin-dependent protein kinase II regulation of IKs during sustained ß-adrenergic receptor stimulation.

BACKGROUND: Sustained ß-adrenergic receptor (ß-AR) stimulation causes pathophysiological changes during heart failure (HF), including inhibition of the slow component of the delayed rectifier potassium current (IKs). Aberrant calcium handling, including increased activation of calcium/calmodulin-dependent protein kinase II (CaMKII), contributes to arrhythmia development during HF. OBJECTIVE: The purpose of this study was to investigate CaMKII regulation of KCNQ1 (pore-forming subunit of IKs) during sustained ß-AR stimulation and associated functional implications on IKs. METHODS: KCNQ1 phosphorylation was assessed using liquid chromatography-tandem mass spectrometry after sustained ß-AR stimulation with isoproterenol (ISO). Peptide fragments corresponding to KCNQ1 residues were synthesized to identify CaMKII phosphorylation at the identified sites. Dephosphorylated (alanine) and phosphorylated (aspartic acid) mimics were introduced at identified residues. Whole-cell, voltage-clamp experiments were performed in human endothelial kidney 293 cells coexpressing wild-type or mutant KCNQ1 and KCNE1 (auxiliary subunit) during ISO treatment or lentiviral δCaMKII overexpression. RESULTS: Novel KCNQ1 carboxy-terminal sites were identified with enhanced phosphorylation during sustained ß-AR stimulation at T482 and S484. S484 peptides demonstrated the strongest δCaMKII phosphorylation. Sustained ß-AR stimulation reduced IKs activation (P = .02 vs control) similar to the phosphorylated mimic (P = .62 vs sustained ß-AR). Individual phosphorylated mimics at S484 (P = .04) but not at T482 (P = .17) reduced IKs function. Treatment with CN21 (CaMKII inhibitor) reversed the reductions in IKs vs CN21-Alanine control (P < .01). δCaMKII overexpression reduced IKs similar to ISO treatment in wild type (P < .01) but not in the dephosphorylated S484 mimic (P = .99). CONCLUSION: CaMKII regulates KCNQ1 at S484 during sustained ß-AR stimulation to inhibit IKs. The ability of CaMKII to inhibit IKs may contribute to arrhythmogenicity during HF.

The curative effects of radiotherapy-based therapies for human epidermal growth factor receptor 2-positive breast cancer: A meta-analysis.

AIM: This meta-analysis was designed to fully assess the curative effects of radiotherapy-based therapies for human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC). METHODS: English articles were retrieved through searching Cochrane library, PubMed, and Embase databases updated to February 2017. Studies were selected based on the inclusion and exclusion criteria. The curative effects of radiotherapy-based therapies forHER2+ BC patients were assessed using hazard rates (HRs) or odds ratios (ORs), as well as their 95% confidence intervals (CIs). In addition, Egger test was used to assess publication bias, followed by sensitivity analysis. All statistic methods were conducted using R 3.12 software. RESULTS: A total of 9 eligible studies were included into this meta-analysis, which involved 2236 HER2+ BC patients. Egger test showed that the eligible studies had no publication bias (t = 2.198, P = .05918). Sensitivity analysis demonstrated that the results were stable. HER2+ BC patients in radiotherapy group had lower locoregional recurrences than those in other groups. Moreover, meta-analysis showed that no significant difference was found between HER2+ BC patients in radiotherapy group and other groups on the 1-year overall survival (P = 0.5263, I = 65.4%), 3-year overall survival (P = 0.4591, I = 0), and 5-year overall survival (P = 0.06277, I = 0). CONCLUSION: Radiotherapy-based therapies might have certain advantages in treating HER2+ BC patients.

[Effects of Jianpi Qinghua Recipe on angiotensin II/NADPH oxidase pathway in 5/6 nephrectomized rats].

OBJECTIVE: To study the effect of Jianpi Qinghua Recipe ( JPQHR) on angiotensin II/NADPH oxidase pathway in 5/6 nephrectomized rat renal failure model and the underlying mechanisms. METHODS: The animals were divided into 4 groups: the sham-operated group, the renal failure group, the JPQHR-treated group and the losartan-treated group. After 60-days therapy, serum nitrogen and creatinine were measured. The expression of angiotensin II type 1 receptor (AT1) protein and the expression of p47phox mRNA in renal tissue was determined. SOD and MDA were also examined. RESULTS: Compared with the sham-operated group, the levels of SCr and serum BUN and the AT1 protein and p47phox mRNA expression in the renal failure group were significantly increased. The activities of SOD in renal tissue from the renal failure group was significantly down-regulated while MDA was up-regulated (P<0.05). Compared with the renal failure group, the levels of SCr and serum BUN and the AT1 protein and p47phox mRNA expression in both JPQHR-treated group and losartan-treated group were significantly decreased. The activities of SOD in renal tissue from JPQHR-treated group and losartan-treated group were significantly up-regulated whereas the content of MDA were down-regulated (P<0.05). Compared with the losartan-treated group, the activities of SOD in renal tissue from the JPQHR-treated group was obviously increased (P<0.05), the decrease in AT1 protein and p47phox mRNA was more evident but not statistically different (P>0.05). The level of SCr and serum BUN and the content of MDA were also not statistically different (P>0.05). CONCLUSION: Through decrease the expression of angiotensin II and NADPH oxidase, JPQHR can reduce the oxidative stress in chronic renal failure and delay the renal fibrosis progression.

[Effects of shenshuai II recipe on the protein expressions of Ang II and nNOS in chronic renal failure rats' nephridial tissue].

OBJECTIVE: To observe the effects of Shenshuai II Recipe (SSR) on the fibrosis of remnant nephridial tissue and expressions of Ang II and nNOS in the chronic renal failure (CRF) rats induced by 5/6 ablation/infarction (A/I), and to preliminarily investigate its mechanism of action. METHODS: Fifty-seven SD male rats were used to prepare the CRF rat model by means of 5/6 A/I. After modeling, they were randomly divided into the model group, the SSR group (2 mL SSR condensed decoction given by gastrogavage), and the Western medicine group (treated by 2 mL suspension of losartan potassium and fosinopril sodium given by gastrogavage), 15 rats in each group. Another 15 rats were recruited as the normal control group. Equal volume of pure water was given to rats in the normal control group and the model group. Relevant treatment was given to rats in each group once daily, for 60 successive days. The serum creatinine (SCr), blood urea nitrogen (BUN), and creatinine clearance rate (CCr) were detected. The expressions of angiotensin II (Ang II) and nervous system type nitric oxide synthase (nNOS) in the remnant renal cortex and the medulla were detected by Western blot. The pathomorphology of the nephridial tissue was observed. RESULTS: Compared with the normal control group, the levels of SCr and BUN increased (P<0.01) and the level of CCr decreased (P<0.01) in the model group, indicating a successful modeling. Compared with the same group before treatment, the levels of SCr and BUN decreased and the level of CCr increased in the SSR group and the Western medicine group (all P<0.01). Compared with the model group after treatment, the levels of SCr and BUN decreased, and the expression of Ang II in the medulla decreased in the SSR group and the Western medicine group (P<0.01, P<0.05). The levels of CCr and protein expressions of nNOS in the renal cortex and the medulla obviously increased in the SSR group and the Western medicine group (P<0.01, P<0.05). The pathology of the nephridial tissue showed that the pathological changes in the SSR group were obviously ameliorated, better than those of the model group. CONCLUSIONS: SSR could improve the renal function and relieve the renal interstitial fibrosis in the rats induced by 5/6 A/I. Its mechanism of action was possibly correlated with regulating the renal imbalanced Ang II and nNOS signal transduction pathway.

Targeting the insulin growth factor and the vascular endothelial growth factor pathways in ovarian cancer.

Antiangiogenic therapy is emerging as a highly promising strategy for the treatment of ovarian cancer, but the clinical benefits are usually transitory. The purpose of this study was to identify and target alternative angiogenic pathways that are upregulated in ovarian xenografts during treatment with bevacizumab. For this, angiogenesis-focused gene expression arrays were used to measure gene expression levels in SKOV3 and A2780 serous ovarian xenografts treated with bevacizumab or control. Reverse transcription-PCR was used for results validation. The insulin growth factor 1 (IGF-1) was found upregulated in tumor and stromal cells in the two ovarian xenograft models treated with bevacizumab. Cixutumumab was used to block IGF-1 signaling in vivo. Dual anti-VEGF and IGF blockade with bevacizumab and cixutumumab resulted in increased inhibition of tumor growth. Immunohistochemistry measured multivessel density, Akt activation, and cell proliferation, whereas terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) assay measured apoptosis in ovarian cancer xenografts. Bevacizumab and cixutumumab combination increased tumor cell apoptosis in vivo compared with therapy targeting either individual pathway. The combination blocked angiogenesis and cell proliferation but not more significantly than each antibody alone. In summary, IGF-1 activation represents an important mechanism of adaptive escape during anti-VEGF therapy in ovarian cancer. This study provides the rationale for designing bevacizumab-based combination regimens to enhance antitumor activity.

Changes of the transverse diameter and volume and dosimetry before the 25th fraction during the course of intensity-modulated radiation therapy (IMRT) for patients with nasopharyngeal carcinoma.

To quantify changes of the transverse diameter and volume and dosimetry, and to illustrate the inferiority of non-replanning during intensity-modulated radiotherapy (IMRT) for nasopharyngeal carcinoma (NPC) patients. Fifty-three NPC patients who received IMRT in 33 fractions were enrolled in this prospective trial. Before the 25th fraction, a new simulation computed tomography (CT) scan was acquired for all patients. The dose-volume histograms of the phantom plan were compared with the initial plan. Significant reduction of the transverse diameter of the nasopharyngeal, the neck, and 2 parotid glands volume was observed on second CT compared with the first CT (mean reduction 7.48 ± 4.45 mm, 6.80 ± 15.14 mm, 5.70 ± 6.26 mL, and 5.04 ± 5.85 mL, respectively; p < 0.01). The maximum dose and V-40 of the spinal cord, mean dose, and V30 of the left and right parotid, and V-50 of the brain stem were increased significantly in the phantom plan compared with the initial plan (mean increase 4.75 ± 5.55 Gy, 7.18 ± 10.07%, 4.51 ± 8.55 Gy, 6.59 ± 17.82%, 5.33 ± 8.55 Gy, 11.68 ± 17.11% and 1.48 ± 3.67%, respectively; p < 0.01). On the basis of dose constraint criterion in the RTOG0225 protocol, the dose of the normal critical structures for 52.83% (28/53) of the phantom plans were out of limit compared with 1.89% (1/53) of the initial plans (p < 0.0001). Because of the significant change in anatomy and dose before the 25th fraction during IMRT, replanning should be necessary during IMRT with NPC.

Targeting ovarian tumor cell adhesion mediated by tissue transglutaminase.

Tissue transglutaminase (TG2) is a transpeptidase involved in protein cross-linking through generation of ε-(γ-glutamyl)lysine isopeptide bonds. It also promotes cell adhesion through interaction with fibronectin and facilitates formation of fibronectin-integrin complexes. This interaction is involved in tumor cell adhesion to the matrix and in the process of tumor dissemination. Its inhibition by small molecules may therefore be useful in blocking metastasis. To that end, we screened more than 800,000 compounds following an in silico docking approach targeting two distinct cavities in the vicinity of the fibronectin-binding site on TG2. A total of 120 compounds were acquired and tested in cell culture-based assays for inhibition of ovarian tumor cell adhesion and proliferation. Seven compounds showed more than 50% inhibition of cell adhesion at a concentration of 25 µmol/L. A follow-up fluorescence polarization study revealed that one compound in particular (ITP-79) inhibited binding of a TG2 peptide to a 42-kDa fragment of fibronectin in a dose-dependent manner. This inhibition was confirmed in cancer cells by coimmunoprecipitation. A competition assay with surface plasmon resonance showed that ITP-79 modulated binding of TG2 to fibronectin. Direct binding of compounds that inhibited adhesion to TG2 were examined with differential scanning fluorimetry, which measures the effect of the compound on the melting temperature of the target. Two compounds, including ITP-79, reduced TG2 stabilization, mimicking the effects of GTP, a known negative allosteric regulator of TG2 enzymatic function. This suggests a potential allosteric mechanism for the compound in light of its distal target site.