Summary Background Endogenous or iatrogenic antitumour immune responses can improve the course of follicular lymphoma, but might be diminished by immune checkpoints in the tumour microenvironment. ...These checkpoints might include effects of programmed cell death 1 (PD1), a co-inhibitory receptor that impairs T-cell function and is highly expressed on intratumoral T cells. We did this phase 2 trial to investigate the activity of pidilizumab, a humanised anti-PD1 monoclonal antibody, with rituximab in patients with relapsed follicular lymphoma. Methods We did this open-label, non-randomised trial at the University of Texas MD Anderson Cancer Center (Houston, TX, USA). Adult (≥18 years) patients with rituximab-sensitive follicular lymphoma relapsing after one to four previous therapies were eligible. Pidilizumab was administered at 3 mg/kg intravenously every 4 weeks for four infusions, plus eight optional infusions every 4 weeks for patients with stable disease or better. Starting 17 days after the first infusion of pidilizumab, rituximab was given at 375 mg/m2 intravenously weekly for 4 weeks. The primary endpoint was the proportion of patients who achieved an objective response (complete response plus partial response according to Revised Response Criteria for Malignant Lymphoma). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov , number NCT00904722. Findings We enrolled 32 patients between Jan 13, 2010, and Jan 20, 2012. Median follow-up was 15·4 months (IQR 10·1–21·0). The combination of pidilizumab and rituximab was well tolerated, with no autoimmune or treatment-related adverse events of grade 3 or 4. The most common adverse events of grade 1 were anaemia (14 patients) and fatigue (13 patients), and the most common adverse event of grade 2 was respiratory infection (five patients). Of the 29 patients evaluable for activity, 19 (66%) achieved an objective response: complete responses were noted in 15 (52%) patients and partial responses in four (14%). Interpretation The combination of pidilizumab plus rituximab is well tolerated and active in patients with relapsed follicular lymphoma. Our results suggest that immune checkpoint blockade is worthy of further study in follicular lymphoma. Funding National Institutes of Health, Leukemia and Lymphoma Society, Cure Tech, and University of Texas MD Anderson Cancer Center.
Objectives To estimate the shifts in age at menarche from 1985 to 2010, compare the differences of average age at menarche between urban and rural groups, and determine the association of menarche ...with body mass index (BMI). Study design The data were obtained from 4 cross-sectional Chinese National Surveys on Students' Constitution and Health (1985, 1995, 2005, and 2010). In this representative sample of Chinese school-aged girls, the average age at menarche was determined using probit analysis and compared between urban and rural areas. Logistic regression was used to assess the association of BMI with the likelihood of having reached menarche. Results The age at menarche in Chinese girls dropped from 13.41 years to 12.47 years from 1985 to 2010. There was a significant difference in age at menarche between urban and rural girls over time, with urban girls having their menarche earlier than rural girls. Logistic regression showed that a higher BMI was strongly associated with an increased likelihood of having reached menarche, even after controlling for age, urban or rural residence, province, social economic status, and school. Conclusion The analysis suggests a drop of about 4.5 months per decade in the average age at menarche over the past 25 years, and a significant inverse association between BMI and having reached menarche. Considering that both early menarche and higher BMI are significant risk factors for chronic diseases, and may act together in later years to the detriment of a woman's health, greater attention should be paid to the health of girls with earlier menarche and higher BMI.
Objective To assess the trend of sex disparity in hemoglobin concentration and prevalence of anemia among Chinese school-aged children from 1995 to 2010. Study design Data were collected from 360 866 ...children aged 7, 9, 12, 14, and 17 years during 4 cross-sectional surveys (1995, 2000, 2005, and 2010) of the Chinese National Surveys on Students Constitution and Health. Shifts in hemoglobin concentration distributions were compared by sex. Average shifts and sex differences were calculated with quantile regression models. Logistic regression was used to estimate the prevalence odds ratio of sex for prevalence of anemia in different surveys. Results The mean hemoglobin concentration increased among Chinese children between 1995 and 2010, from 132.7 to 138.3 g/L in boys, and from 127.7 to 132.3 g/L in girls. The prevalence of anemia decreased from 18.8% in 1995 to 9.9% in 2010. It was higher in rural than urban children among all age groups. The prevalence odds ratios of girls versus boys for anemia increased in both urban and rural areas over time. Conclusion Hemoglobin concentration and prevalence of anemia improved among Chinese school-aged children over time. Hemoglobin concentration improved faster in boys than girls and as a result the relative prevalence of anemia in girls compared with boys increased. Sex-specific preventive guidelines and public health policies for childhood anemia are needed in China.
Basic fibroblast growth factor (bFGF) stimulates neoangiogenesis. The sustained release of bFGF by using biomaterials helped to enhance its angiogenic activity in vivo. In this study we investigated ...the effects of co-injection of bFGF with temperature-responsive chitosan hydrogel on myocardial performance in a rat model of infarction.
Myocardial infarction was induced in rats using coronary artery ligation. Temperature-responsive chitosan hydrogel was prepared and injected intramyocardially into the left ventricular wall of rat infarction models alone or together with bFGF. Detailed histologic analysis and echocardiography were used to determine the structural and functional consequences 4 weeks after injection.
Heart function improved significantly in the chitosan+bFGF group compared with the phosphate-buffered saline (PBS)+bFGF group with regard to left ventricular ejection fraction (LVEF) and LV fractional shortening (LVFS) 4 weeks after transplantation (p < 0.05, n = 8 per group). In addition, arteriole densities within the infarcted area improved significantly (p < 0.01) in the chitosan+bFGF group (259 +/- 22/mm(2)) compared with the PBS+bFGF group (95 +/- 18/mm(2); n = 8 per group) at 4 weeks after transplantation. Infarct size and fibrotic area decreased significantly (p < 0.05) in the chitosan+bFGF group (39.64 +/- 1.75% and 25.09 +/- 3.31%, respectively) compared with the PBS+bFGF group (48.91 +/- 1.39% and 48.0 +/- 3.83%, respectively; n = 8 per group). No significant difference (p > 0.05) was noted between the PBS and PBS+bFGF groups.
Co-injection of bFGF with temperature-responsive chitosan hydrogels enhanced the effects of bFGF on arteriogenesis, ventricular remodeling and cardiac function. Our findings suggest a new approach to improve infarcted repairs in the prevention of adverse remodeling after myocardial infarction.
Lung cancer remains one of the leading causes of cancer deaths around the world. Previous studies have shown that microRNAs have pivotal functions in tumorigenesis including lung cancer. It is ...reported that microRNA-195-5p acts as a tumor suppressor role in human cancers. However, the function and molecular mechanism of microRNA-195-5p in lung cancer progression is still unclear. In the present study, the results showed that the expression of microRNA-195-5p was downregulated both in lung cancer tissues and in lung cancer cell lines. Enhanced expression of microRNA-195-5p inhibited cell proliferation, migration, and invasion in lung cancer cells. Furthermore, Forkhead box k1 was identified as the direct target of microRNA-195-5p. Forkhead box k1 overexpression could restore the repressed cell proliferation and metastasis caused by microRNA-195-5p overexpression. Our results demonstrated that a functional mechanism of microRNA-195-5p in regulating lung cancer. It indicates that microRNA-195-5p may regulate lung cancer growth and metastasis through the regulation of Forkhead box k1, highlighting the potential application for the treatment of lung cancer in the future.
Objective Proanthocyanidins are abundantly found in grape seeds and have been suggested to inhibit the pathogenesis of systemic diseases. We investigated the antithrombotic effects of ...proanthocyanidins in a rat model of deep vein thrombosis (DVT) and examined the underlying mechanisms. Methods DVT was induced in rat model by inferior vena cava (IVC) ligation. Grape seed proanthocyanidins extract (GSPE, 400 mg/kg/d) dissolved in saline (2 mL) was orally administered to the experimental rats. Control rats were administrated saline (2 mL) only. The thrombi were harvested and weighed. The IVC was analyzed histologically and by transmission electron microscopy. The cytokines interleukin (IL)-6, IL-8, and tumor necrosis factor-α (TNF-α) were detected by enzyme-linked immunosorbent assay. Expression of cellular adhesion molecules (CAMs) in thrombi was examined by Western blot. Results GSPE significantly reduced thrombus length and weight ( P < .01) and protected the integrity of the endothelium. GSPE inhibited thrombogenesis-promoting factors P-selectin, von Willebrand factor, and CAMs, and promoted thrombogenesis-demoting factors CD34, vascular endothelial growth factor receptor-2, and ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type one motif, member 13). Compared with the control, GSPE significantly lowered the cytokines IL-6 (74.19 ± 13.86 vs 189.54 ± 43.76 pg/mL; P < .01), IL-8 (80.71 ± 21.42 vs 164.56 ± 39.54 pg/mL; P < .01), and TNF-α (43.11 ± 17.58 vs 231.84 ± 84.11 pg/mL; P < .01). Conclusions GSPE significantly inhibited the propagation of thrombus induced by IVC ligation in a rat model. The antithrombotic properties of proanthocyanidins are likely to be directly associated with endothelial protection and regeneration, platelet aggregation, and inhibition of inflammatory cell and thrombus adhesion. Thus, proanthocyanidins may have a clinical application in DVT treatment.
Pancreatic ductal adenocarcinoma is characterized by an extensive stromal response called desmoplasia. Within the tumor stroma, cancer-associated fibroblasts (CAFs) are the primary cell type. CAFs ...have been shown to play a role in pancreatic cancer progression; they secrete growth factors, inflammatory cytokines, and chemokines that stimulate signaling pathways in cancer cells and modulate the cancer biology toward increased aggressiveness. Therefore, targeting CAFs may serve as a powerful weapon against pancreatic cancer and improve therapeutic effects. However, a previous study aiming to deplete CAFs by inhibiting sonic Hedgehog signaling failed to show any benefit in survival time of pancreatic cancer patients. We reported that the natural product curcumin reeducated CAFs in pancreatic cancer treatment. A low concentration of curcumin reversed the activation of fibroblasts without exhibiting growth suppression effects. In addition, curcumin suppressed CAF-induced pancreatic cancer cell migration and invasion in vitro and lung metastasis in vivo. The results of our study suggest that active CAFs can be inactivated by certain natural products such as curcumin. Reeducation of CAFs back to their normal state, rather than their indiscriminate depletion, may broaden our view in the development of therapeutic options for the treatment of pancreatic cancer.
Background CASP7 plays a crucial role in cancer development and chemotherapy efficacy. We, therefore, explored whether single nucleotide polymorphisms (SNPs) of the CASP7 gene can modulate outcomes ...of patients with advanced non-small cell lung cancer (NSCLC) treated with first-line platinum-based chemotherapy. Methods We systematically genotyped 17 SNPs of CASP7 first in a discovery set of 279 patients with advanced NSCLC treated with platinum-based chemotherapy and then replicated the results in an independent set of 384 patients, in whom we evaluated associations with overall survival (OS) and progress-free survival (PFS) by Kaplan-Meier analysis and Cox hazards regression analysis. Results In both discovery and validation sets as well as in the pooled analysis, heterozygotes of CASP7 rs2227310 and rs4353229 as well as rs12415607 variant allele were strongly associated with a better OS of NSCLC (in the pooled sample: adjusted hazard ratio HR, 0.73; 95% CI = 0.59–0.90; P = .003; HR, 0.72; 95% CI = 0.59–0.89; P = .002; and HR, 0.76; 95% CI = 0.62–0.94; P = .009; respectively). In stratified analyses of the pooled data set, treated with paclitaxel, individuals carrying variant allele of rs2227310, rs4353229, and rs12415607 had significantly improved OS (HR, 0.60; 95% CI = 0.41–0.87; P = .008; HR, 0.58; 95% CI = 0.39–0.84; P = .004; and HR, 0.61; 95% CI = 0.42–0.89; P = .010; respectively). Conclusions This study provides evidence that genetic variations of CASP7 may modulate OS and PFS of patients with advanced NSCLC treated with platinum-based chemotherapy.
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