Targeted Delivery of Curcumin Rescues Endoplasmic Reticulum-Retained Mutant NOX2 Protein and Avoids Leukocyte Apoptosis.

Chronic granulomatous disease (CGD) is a primary immunodeficiency disease caused by defects in the leukocyte NADP oxidase. We previously reported that sarcoplasmic/endoplasmic reticulum calcium pump (SERCA) inhibitors could be used to rescue mutant H338Y-gp91phox protein of a particular type of CGD with a CybbC1024T mutation, leading to endoplasmic reticulum (ER) retention of the mutant protein. In this study, we developed a novel mouse model with the CybbC1024T mutation on a Cybb knockout background and investigated the therapeutic effects of ER-targeted delivery of the SERCA inhibitor, curcumin, with poly(lactic-coglycolic acid) (PLGA) nanoparticles (NPs). We found that PLGA encapsulation improved the efficacy of curcumin as a SERCA inhibitor to induce ER calcium release. ER-targeting curcumin-loaded PLGA NPs reduced and delayed extracellular calcium entry and protected the cells from mitochondrial damage and apoptosis. In vivo studies showed that ER-targeting curcumin-loaded PLGA NPs treatment enhanced neutrophil gp91phox expression, ROS production and peritoneal bacterial clearance ability of the CybbC1024T transgenic Cybb -/- mice. Our findings indicate that ER-targeted delivery of curcumin not only rescues ER-retained H338Y-gp91phox protein, and hence leukocyte function, but also enhances the bioavailability and reduces cytotoxicity. Modulation of ER function by using organelle-targeted NPs may be a promising strategy to improve the therapeutic potential of curcumin as a treatment for CGD.

Clinicopathological features and survival in young Taiwanese women with endometrial carcinoma.

OBJECTIVE: The aim of this study is to compare the clinicopathological features and survival of young women with endometrial cancer (aged <50 years) with those of older women with endometrial cancer (aged ≥50 years). METHODS: We conducted a retrospective cohort study of patients with histologically confirmed endometrial cancer treated at the Taipei Veterans General Hospital from 2001 to 2010. RESULTS: One hundred forty-six patients (28.5%) were aged younger than 50 years at diagnosis. The median follow-up was 36.5 months (range, 0.9-121.7 months). Low body mass index (P < 0.001), nulliparity (P < 0.001), less medical illness (P < 0.001), synchronous primary ovarian cancer (P = 0.001), endometrioid type (P = 0.005), low tumor grade (P < 0.001), no para-aortic lymph node involvement (P < 0.047), less myometrial invasion (P < 0.001), and no vascular space invasion (P = 0.001) were common among the younger women compared with the older women. There were significant differences in the disease-free survival (P = 0.006) and overall survival (P = 0.004) between the 2 groups. In the multivariate Cox model, advanced stage had an effect on both disease-free survival (P = 0.004) and overall survival (P = 0.050). CONCLUSIONS: Nulliparity, body mass index less than or equal to 23 kg/m, endometrioid type, low-grade tumor, synchronous primary ovarian cancer, and favorable survival were common among the younger women.

Primary fallopian tube carcinoma: a clinicopathologic analysis and literature review.

BACKGROUND: Primary fallopian tube carcinoma (PFTC) is a rare tumor, and it is very difficult to diagnose preoperatively. The aims of this study were to evaluate the clinicopathologic features of primary fallopian tube carcinoma (PFTC) and to review the current available literature on PFTC. METHODS: The medical records of 16 patients who were diagnosed with PFTC at Taipei Veterans General Hospital between January 2001 and December 2011 were analyzed retrospectively. RESULTS: The mean age at diagnosis was 63 years (range, 41-86 years), and the mean follow-up period was 39.8 months (range, 4.0-102.8 months). Fourteen (87.5%) patients were menopausal women. The most common clinical presentation was nonspecific pelvic pain (37.5%), followed by abnormal vaginal bleeding (31.2%), pelvic mass (18.8%), and gastrointestinal symptoms (12.5%). One patient was diagnosed with PFTC preoperatively; 11 (68.6%) patients were diagnosed as having adnexal mass of unknown origin, but primarily in the ovary. Other diagnoses included endometrial cancer, cervical cancer, colon cancer, and rectum cancer in one patient each. Three (18.8%) patients were in Stage I, two (12.5%) in Stage II, nine (56.2%) in Stage III, and two (12.5%) in Stage IV. The serous type was histologically predominant (75%), and six patients were of a high grade (37.5%). The 5-year disease-free survival rate was 73.3%. CONCLUSION: PFTC is infrequently diagnosed preoperatively or intraoperatively due to its rarity, and has a varied and nonspecific presentation. Only 6.3% of the patients had typical symptoms suggestive of tubal carcinoma. This report may benefit surgeons by providing additional information about the clinicopathologic behavior of PFTC so that patients can be appropriately counseled.