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Purpose Incidentally discovered diffusely infiltrating lower-grade gliomas (incidental LGGs, iLGGs) are defined as gliomas occasionally found in patients without tumor-related symptoms. At present, very few in-depth research studies on incidental LGGs were reported. We aimed to find out the inherent difference between iLGGs and LGGs with tumor-related symptoms. Patients and methods We enrolled 2486 all-grade gliomas and screened 1594 lower-grade gliomas for further analysis. Medical records were retrospectively reviewed for iLGGs. Clinical and mRNA sequencing data were collected for in-depth analysis. Results We found that with increasing grade, the proportion of incidental glioma patients decreased obviously. In 1594 patients who underwent craniotomy for LGG, 80 (5%) patients were discovered incidentally. Grade II patients (88%) and patients bearing 1p/19q co-deletion in their tumors (23%) were more likely to be diagnosed as iLGGs. Regular radiological screening (48%) and trauma (24%) were the main complaint for brain imaging for iLGGs. Kaplan-Meier survival analysis indicated that iLGGs patients lived a significantly longer survival and Cox regression analysis revealed that iLGGs were an independent indicator of better prognosis. Subsequent gene set enrichment analysis and differential expression analysis based on the gene expression profile revealed that mitochondrial aerobic respiration process was enriched in iLGGs. Moreover, we found that iLGGs tended to generate energy by unique mitochondrial aerobic respiration. Conclusion These results provided a primitive exploration of iLGGs, which may potentially assist clinical neurosurgeons with personalized management of iLGGs.

Phosphatidylinositol 3-kinase catalytic subunit type 3 (PIK3C3), the mammalian ortholog of yeast vesicular protein sorting 34 (Vps34), belongs to the phosphoinositide 3-kinase (PI3K) family. PIK3C3 can phosphorylate phosphatidylinositol (PtdIns) to generate phosphatidylinositol 3-phosphate (PI3P), a phospholipid central to autophagy. Inhibition of PIK3C3 successfully inhibits autophagy. Autophagy maintains cell survival when modifications occur in the cellular environment and helps tumor cells resist metabolic stress and cancer treatment. In addition, PIK3C3 could induce oncogenic transformation and enhance tumor cell proliferation, growth, and invasion through mechanisms independent of autophagy. This review addresses the structural and functional features, tissue distribution, and expression pattern of PIK3C3 in a variety of human tumors and highlights the underlying mechanisms involved in carcinogenesis. The implications in cancer biology, patient prognosis prediction, and cancer therapy are discussed. Altogether, the discovery of pharmacological inhibitors of PIK3C3 could reveal novel strategies for improving treatment outcomes for PIK3C3-mediated human diseases.

Background: In our preliminary screening, expression of miR-338-5p was found to be higher in primary colorectal cancer (CRC) with metastasis. The autophagy related gene- phosphatidylinositol 3-kinase, catalytic subunit type 3 (PIK3C3) appeared to be targeted by miR-338-5p. Here, we provide solid evidence in support of PIK3C3 involved in miR-338-5p related metastasis of CRC in vitro and in vivo. Methods: The potential clinical relevance of miR-338-5p and its target gene was analyzed on benign colorectal polyp and primary CRCs by QPCR. Mouse spleen xenograft experiment was performed to examine the importance of miR-338-5p for metastasis. Findings: PIK3C3 was one of target genes of miR-338-5p. In primary CRCs, expression of miR-338-5p is positively related to tumor staging, distant metastasis and poor patient survival. Patients with higher ratios of miR-338-5p/ PIK3C3 also had significantly poor overall survival, supporting their significance in the progression of CRC. Over-expression of miR-338-5p promotes CRC metastasis to the liver and lung in vivo, in which PIK3C3 was down-regulated in the metastatic tumors. In contrast, overexpression of PIK3C3 in miR-338-5p stable cells inhibited the growth of metastatic tumors. Both migration and invasion of CRC in vitro induced by miR-338-5p are mediated by suppression of PIK3C3. Using forward and reverse approaches, autophagy was proved to involve in CRC migration induced by miR-338-5p. Interpretation: MiR-338-5p induces migration, invasion and metastasis of CRC in part through PIK3C3-related autophagy pathway. The miR-338-5p/PIK3C3 ratio may become a prognostic biomarker for CRC patients. Funding Statement: This work was supported by research grants [NCKUH-10704015] from National Cheng Kung University Hospital (Tainan, Taiwan) and [MOST-105-2320-B-006 -029 -MY3] from the Ministry of Science and Technology, TAIWAN. Declaration of Interests: The authors declare that they have no competing financial interests. Ethics Approval Statement: This study was approved by the NCKUH Institutional Review Board (B-ER-103-031). Informed consent was signed by all patients.

Plastin 3 (PLS3) has been identified as a candidate gene for bone fragility in the Rotterdam study (RS) population. So far, however, whether PLS3 polymorphisms are genetic risk factors for osteoporosis in Asian population remains unclear. In order to investigate the association between genetic variants in PLS3 and the risk of fragility fracture and/or bone mineral density (BMD) in postmenopausal Chinese women, we conducted a case-control association study. A total of 1083 postmenopausal patients with osteoporotic fractures and 2578 unrelated non-fracture controls in Shanghai were enrolled. Seven SNPs, including six tagSNPs in PLS3 and one identified genetic risk factor (rs140121121) for osteoporosis in the RS population, were genotyped in all the participants. BMD at lumbar spine and hip sites were measured in 2578 controls. Association between SNPs and the risk of osteoporotic fractures and/or BMD were analyzed. The GC genotype of rs757124 and AC genotype of rs10521693 were associated with lumbar vertebral fracture (P = 0.020 and 0.046, respectively). The association between tagSNPs and BMD were analyzed only in 2546 controls to avoid biased conclusion. rs757124 was significantly associated with BMD at lumbar spine and hip sites. GG genotype had the highest BMD at lumbar spine (L1-4), while CC genotype had the highest BMD at hip sites. Our results suggest that polymorphisms in PLS3 are genetic loci for osteoporosis in postmenopausal Chinese women.

To investigate the clinical implications of identifying urothelial carcinoma (UC) with trophoblastic differentiation (UCTD).A prospective cohort study was performed from 2010 to 2016 to examine the incidence of UCTD in urinary tract cancer and association with clinicopathological indicators and patient outcome.UCTD was detected in 47 of 859 (5.5%) cases of UC of the bladder and 65 of 635 (10.2%) cases in the upper urinary tract. UCTD of the bladder was significantly associated with non-papillary, multiple, larger size (3 cm), muscle invasion, and nodal metastasis (P ≤ 0.0001, respectively). A higher risk of recurrence (P = 0.005), progression (P0.0001), and patient death (P0.0001) was observed for UCTD than those with traditional, high-grade UC of the bladder. Among four patterns of expression, focal expression of β-human chorionic gonadotropin was frequently detected in papillary tumor (P0.005) and UCs of smaller than 3 cm (P = 0.03). Significant indicators in predicting poor disease-specific overall survival in multivariate statistical model were tumor staging (P = 0.001), followed by non-focal β-hCG expression (P = 0.049).UCTD is more often identified in the upper urinary tract than in the bladder. UCTD of the bladder was significantly associated with higher risk of recurrence, progression, and patient death. Expression of β-hCG in non-focal patterns predicts a worse prognosis for patients with UCTD and deserves an individualized treatment planning.

Parkinson’s disease (PD) has an average onset age of 55 years old. Its incidence increases with age. Due to an aging demographic, PD poses an increasing burden on patients and health care resources. PD causes tremors, rigidity, abnormal gait, postural instability, and freezing of gait. These symptoms diminish patients’ quality of life. Continuous rehabilitation of PD patients is more effective in the long term than either pharmacotherapy or surgical treatment. Nevertheless, a patient's motivation for rehabilitation suffers from the difficulties associated with the need for frequent visits to a rehabilitation center. The purpose of this study is to develop a serious game based on augmented reality for the rehabilitation of patients with PD. The game was designed to allow patients with PD to ambulate while following virtual visual cues in a real environment as well as incorporated levels with increasing difficulty. We assess improvements in gait and a sense of balance after 3 weeks of training. The results show that all patients have had improvements in these two outcomes. The results of this study provide references for future study and develop more or methods of playing rehabilitation games.

Hui Chen,* Jing-Qiu Wei,* Yi-Wen Wang, Kun-Peng Zhou, Ying He, He Liu, Yue-Ying Zhang Department of Anesthesiology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu 221004, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yue-Ying Zhang Department of AnesthesiologyThe Affiliated Hospital of Xuzhou Medical University, Huaihai Western Road, Quanshan District, Xuzhou, Jiangsu 221004, People’s Republic of ChinaTel +86 138 1531 0789Email zyy0218@126.comPurpose: To investigate the effects of different doses of rocuronium on ischemia-reperfusion injury in skeletal muscle induced by tourniquet in patients undergoing elective unilateral total knee arthroplasty.Patients and Methods: A total of 90 patients undergoing elective unilateral knee arthroplasty under general anesthesia combined with femoral nerve block were randomly divided into 3 groups: normal saline group (group S), rocuronium 0.6 mg/kg group (group L), and rocuronium 1.2 mg/kg group (group H). The primary outcome was the expression of dystrophin in skeletal muscle at 60 min after ischemia. Secondary outcomes included the concentration of malondialdehyde (MDA) and neuronal nitric oxide synthase (nNOS) in blood at 5 min and 30 min after reperfusion. In addition, thigh girth at 24 h and 48 h after operation, the leaving bed time, the incidence of tourniquet-related hypertension and short-term (3 days after operation) complications (nausea and vomiting, swelling, blister, wound infection) and long-term (3 months after operation) complications (joint instability, stiffness, nerve paralysis, pain) were recorded.Main Results: The expression of dystrophin in the rocuronium group was higher than that in group S after ischemia (P < 0.05). The concentration of MDA in the rocuronium 1.2 mg/kg group was lower at 30 min after reperfusion (P < 0.05). There was no significant difference in nNOS among groups at each time point (P > 0.05). The change of thigh girth was the smallest in the rocuronium 1.2 mg/kg group after operation (P< 0.05). The leaving bed time was significantly earlier after operation in the rocuronium group than that in group S (P < 0.05).Conclusion: Rocuronium can protect skeletal muscle from ischemia-reperfusion injury induced by tourniquet. The mechanism may be related to the fact that rocuronium can reduce the loss of dystrophin in skeletal muscle and have the effects of anti-oxidation and anti-stress.Trial Registration: The study was registered at http://www.chictr.org.cn (ChiCTR1800019221, registered on 2018– 10-31).Keywords: ischemia-reperfusion injury, rocuronium, dystrophin, TKA

Objective This study aimed to investigate whether umbilical cord milking (UCM) prevents and controls anemia in preterm infants, as compared with immediate cord clamping (ICC). Study Design Pregnant women delivering at Results Neonates receiving UCM had significant higher levels of hemoglobin (Hb), hematocrit, and serum iron (p 0.05). Conclusion UCM is an effective intervention to help preterm infants experience less anemia with the potential to increase blood volume, as seen by higher Hb levels and more enhanced iron stores.

AIM To investigate the clinicopathological significance of progesterone receptor membrane component 1 (PGRMC1) and PGRMC2 in hepatocellular carcinoma (HCC). METHODS We performed immunohistochemical staining to evaluate the estrogen receptor (ER), progesterone receptor (PR), PGRMC1, and PGRMC2 in a clinical cohort consisting of 89 paired HCC and non-tumor liver samples. We also analyzed HCC data (n = 373) from The Cancer Genome Atlas (TCGA). We correlated the expression status of PGRMC1 and PGRMC2 with clinicopathological indicators and the clinical outcomes of the HCC patients. We knocked down or overexpressed PGRMC1 in HCC cell lines to evaluate its biological significance in HCC cell proliferation, differentiation, migration, and invasion. RESULTS We found that few HCC cases expressed ER (5.6%) and PR (4.5%). In contrast, most HCC cases expressed PGRMC1 (89.9%) and PGRMC2 (100%). PGRMC1 and PGRMC2 exhibited significantly lower expression in tumor tissue than in non-tumor tissue (P < 0.001). Lower PGRMC1 expression in HCC was significantly associated with higher serum alpha-fetoprotein expression (P = 0.004), poorer tumor differentiation (P = 0.045) and liver capsule penetration (P = 0.038). Low PGRMC1 expression was an independent predictor for worse disease-free survival (P = 0.002, HR = 2.384, CI: 1.377-4.128) in our cases, as well as in the TCGA cohort (P < 0.001, HR = 2.857, CI: 1.781-4.584). The expression of PGRMC2 did not relate to patient outcome. PGRMC1 knockdown promoted a poorly differentiated phenotype and proliferation of HCC cells in vitro, while PGRMC1 overexpression caused the opposite effects. CONCLUSION PGRMC1 is a non-classical hormonal receptor that negatively regulates hepatocarcinogenesis. PGRMC1 down-regulation is associated with progression of HCC and is a poor prognostic indicator.

Significant skin pigmentation changes occur when patients suffer deep burn injuries. These pigmentation disorders may cause not only cosmetic and psychological issues, but more importantly it increases the risk of skin cancer or photoaging. Severe burns significantly effect on the process of repigmentation as the pigmentation is tightly regulated by cell proliferation and differentiation of melanocytes and melanocyte stem cells which are housing in the epidermis and hair follicles of the skin. In the present review, we discuss the possible mechanisms to replenish the melanocytes from the healthy epidermis and hair follicles surrounding burn wounds. The molecular mechanisms of skin repigmentation following healing of burn injuries includes the differentiation of melanoblasts into melanocytes, the distribution and responses of melanocytes and melanocyte stem cells after burn injury, and the regulation of melanin production. We also reviewed advanced therapeutic strategies to treat pigmentation disorders, such as convectional surgery, laser, UV treatment and emerging concepts in skin tissue-engineering.

BACKGROUND MiR-101-3p can promote apoptosis and inhibit proliferation, invasion, and metastasis in breast cancer (BC) cells. However, its mechanisms in BC are not fully understood. Therefore, a comprehensive analysis of the target genes, pathways, and networks of miR-101-3p in BC is necessary. MATERIAL AND METHODS The miR-101 profiles for 781 patients with BC from The Cancer Genome Atlas (TCGA) were analyzed. Gene expression profiling of GSE31397 with miR-101-3p transfected MCF-7 cells and scramble control cells was downloaded from Gene Expression Omnibus (GEO), and the differentially expressed genes (DEGs) were identified. The potential genes targeted by miR-101-3p were also predicted. Gene Ontology (GO) and pathway and network analyses were constructed for the DEGs and predicted genes. RESULTS In the TCGA data, a low level of miR-101-2 expression might represent a diagnostic (AUC: 0.63) marker, and the miR-101-1 was a prognostic (HR=1.79) marker. MiR-101-1 was linked to the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), and miR-101-2 was associated with the tumor (T), lymph node (N), and metastasis (M) stages of BC. Moreover, 427 genes were selected from the 921 DEGs in GEO and the 7924 potential target genes from the prediction databases. These genes were related to transcription, metabolism, biosynthesis, and proliferation. The results were also significantly enriched in the VEGF, mTOR, focal adhesion, Wnt, and chemokine signaling pathways. CONCLUSIONS MiR-101-1 and miR-101-2 may be prospective biomarkers for the prognosis and diagnosis of BC, respectively, and are associated with diverse clinical parameters. The target genes of miR-101-3p regulate the development and progression of BC. These results provide insight into the pathogenic mechanism and potential therapies for BC.

Background: Exercise is one of the optimal and alternative treatments for type 2 diabetes (T2DM). Although the effect of a single bout of exercise on insulin sensitivity is reported to persist only for 2–3 days, effects remain unclear of a 12-week aerobic exercise training on insulin sensitivity, quality of life (QOL), and depression status over time as exercise training duration increases in patients with T2DM. Objectives: To investigate the effects over time in patients with T2DM of a 12-week aerobic exercise training on insulin sensitivity, QOL, and depression status. Materials and Methods: Purposive sampling was used to recruit 17 T2DM patients. Participants underwent a 12-week, supervised, moderate-intensity aerobic exercise training three times per week, 30 min per session. Outcome indicators including insulin sensitivity (measured by a 2-h oral glucose tolerance test [OGTT] and homeostatic model assessment-insulin resistance [HOMA-IR]), QOL (Medical Outcomes Study Short Form 36), and depression status (beck depression inventory scale) were evaluated at baseline and at 4-week intervals. Results: A final 13 eligible participants completed the study. For every 4-week increase in duration of exercise training, there was an increase over time in insulin sensitivity, including a decrease over time in OGTT glucose area under the curve of 66.92 min/mmol/L. Glucose concentrations decreased over time at 60, 90, and 120 min after an oral glucose challenge. Further, the HOMA-IR decreased over time as the duration of exercise training increased. QOL and depression status improved significantly during the training. Conclusions: Moderate-intensity exercise training improves insulin sensitivity, QOL, and depression status in T2DM patients, particularly over time within a 12-week exercise training course.

Sulfatase 2 (SULF2), an extracellular sulfatase that alters sulfation on heparan sulfate proteoglycans, is involved in the tumorigenesis and progression of several carcinomas. SULF2 expression has not been evaluated in squamous cell carcinoma of the head and neck (HNSCC). Here we report results of IHC of SULF2 expression in HNSCC tissue. SULF2 was detected in 57% of tumors (n = 40) with a significant increase in intensity and number of stained cells compared to adjacent cancer-free tissue (p-value < 0.01), increasing with cancer stage when comparing stages 1 and 2 to stages 3 and 4 (p-value 0.01). SULF2 was not detected in epithelial cells of cancer-free controls, and expression was independent of patient demographics, tumor location and etiological factors, smoking and HPV infection by p16 IHC analysis. Sandwich ELISA was performed on serum of HNSCC patients (n = 28) and controls (n = 35), and although SULF2 was detectable, no change was observed in HNSCC. Saliva, collected by mouthwash, from HNSCC patients (n = 8) and controls (n = 8) was also tested by ELISA in a preliminary investigation and an increase in SULF2 was observed in HNSCC (p-value 0.041). Overall, this study shows that SULF2 is increased in HNSCC independent of tissue location (oral cavity, oropharynx, larynx and hypopharynx), patient demographics and etiology. Although no change in SULF2 was detected in HNSCC serum, its detection in saliva makes it worthy of further investigation as a potential HNSCC biomarker.

Although Butylphthalide (BP) has protective effects that reduce ischemia-induced brain damage and neuronal cell death, little is known about the precise mechanisms occurring during cerebral ischemia/reperfusion (I/R). Therefore, the aim of this study was to investigate the neuroprotective mechanisms of BP against ischemic brain injury induced by cerebral I/R through inhibition of the c-Jun N-terminal kinase (JNK)-Caspase3 signaling pathway. BP in distilled non-genetically modified Soybean oil was administered intragastrically three times a day at a dosage of 15 mg/(kg day) beginning at 20 min after I/R in Sprague-Dawley rats. Immunohistochemical staining and Western blotting were performed to examine the expression of related proteins, and TUNEL-staining was used to detect the percentage of neuronal apoptosis in the hippocampal CA1 region. The results showed that BP could significantly protect neurons against cerebral I/R-induced damage. Furthermore, the expression of p-JNK, p-Bcl2, p-c-Jun, FasL, and cleaved-caspase3 was also decreased in the rats treated with BP. In summary, our results imply that BP could remarkably improve the survival of CA1 pyramidal neurons in I/R-induced brain injury and inhibit the JNK-Caspase3 signaling pathway.

Aims and objectives To explore triggers of and decision-making patterns for older adults with knee osteoarthritis to receive total knee arthroplasty. Background Older adults with knee osteoarthritis pain are often reluctant to undergo total knee arthroplasty until their physical health and psychological health have deteriorated. This delay may lead to poor long-term outcomes after the surgery. Thus, it is important to help these older adults decide to undergo total knee arthroplasty in an appropriate time frame. Design A qualitative descriptive study. Methods Older adult outpatients scheduled to receive total knee arthroplasty within 1 month (N = 79) were recruited by convenience from two medical centres and one regional hospital in northern Taiwan. Data were collected in individual interviews using a semistructured guide and analysed by thematic analysis. Results The main triggers for older adults to receive total knee arthroplasty were severe pain and inability to walk. We identified four decision-making patterns for undergoing total knee arthroplasty: tried everything to relieve pain and surgery was the last choice; previously received total knee arthroplasty; perceived oneself as still young and wanted to enjoy life; and adjusted work characteristics, but in vain. Conclusion Healthcare providers of older patients with knee osteoarthritis must carefully assess their characteristics, especially age, occupation and previous total knee arthroplasty, to guide them in deciding to undergo total knee arthroplasty. Clinicians also need to provide appropriate information about osteoarthritis care, pain medications, total knee arthroplasty, the relationship between knee osteoarthritis pain and quality of life, as well as the relationship between preoperative status and postoperative long-term outcomes for older adults to maintain their quality of life. Relevance to clinical practice Our findings provide evidence for healthcare providers to offer information and support to their older adult patients with knee-osteoarthritis pain who are deciding whether to undergo total knee arthroplasty.

Background To treat skin color disorders, such as vitiligo or burns, melanocytes are transplanted for tissue regeneration. However, melanocyte distribution in the human body varies with age and location, making it difficult to select the optimal donor skin to achieve a desired color match. Determining the correlations with the desired skin color measurement based on CIELAB color, epidermal melanocyte numbers, and melanin content of individual melanocytes is critical for clinical application. Method Fifteen foreskin samples from Asian young adults were analyzed for skin color, melanocyte ratio (melanocyte proportion in the epidermis), and melanin concentration. Furthermore, an equation was developed based on CIELAB color with melanocyte ratio, melanin concentration, and the product of melanocyte ratio and melanin concentration. The equation was validated by seeding different ratios of keratinocytes and melanocytes in tissue-engineered skin substitutes, and the degree of fitness in expected skin color was confirmed. Results Linear regression analysis revealed a significant strong negative correlation (r = − 0.847, R2 = 0.717) between CIELAB L* value and the product of the epidermal melanocyte ratio and cell-based melanin concentration. Furthermore, the results showed that an optimal skin color match was achieved by the formula. Discussion We found that L* value was correlated with the value obtained from multiplying the epidermal melanocyte ratio (R) and melanin content (M) and that this correlation was more significant than either L* vs M or L* vs R. This suggests that more accurate prediction of skin color can be achieved by considering both R and M. Therefore, precise skin color match in treating vitiligo or burn patients would be potentially achievable based on extensive collection of skin data from people of Asian descent.

A multicenter, open-label, noncomparative, randomized phase II study (PEPCOL) was conducted to evaluate the efficacy and safety of the irinotecan or PEP02 (MM-398, nanoliposomal irinotecan) with leucovorin (LV)/5-fluorouracil (5-FU) combination as second-line treatment in patients with metastatic colorectal cancer (mCRC). Patients with unresectable mCRC who had failed one prior oxaliplatin-based first-line therapy were randomized toirinotecan with LV/5-FU (FOLFIRI) or PEP02 with LV/5-FU (FUPEP; PEP02 80 mg/m(2) with LV 400 mg/m(2) on day 1 and 5-FU 2400 mg/m(2) on days 1-2). Bevacizumab (5 mg/kg, biweekly) was allowed in both arms. The primary endpoint was 2-month response rate (RR). Fifty-five patients were randomized (FOLFIRI, n = 27; FUPEP, n = 28). In the intent-to-treat population (n = 55), 2-month RR response rate was observed in two (7.4%) and three (10.7%) patients in the FOLFIRI and FUPEP arms, respectively. The most common grade 3-4 adverse events reported in the respective FOLFIRI and FUPEP arms were diarrhea (33% vs. 21%), neutropenia (30% vs. 11%), mucositis (11% vs. 11%), and grade 2 alopecia (26% vs. 25%). FUPEP has activity and acceptable safety profile in oxaliplatin-pretreated mCRC patients.

Justicidin A (JA) is one of the methanol extracts of Justicia procumbens and was reported to induce apoptosis and inhibit the proliferation of human colon cancer cells. Using bladder cancer as a paradigm, this study was designed to identify the novel molecular basis underlying the antiangiogenic activities of JA and its potential in cancer therapy. Human bladder cancer cell lines (TSGH8301 and RT4) and immortalized uroepithelial cell lines (E6 and E7) were chosen to investigate the efficacy of JA in cell proliferation, apoptosis, and angiogenesis in vitro. The biological effects of JA treatment in vivo were examined using a xenograft tumor model in SCID mice. JA showed a dose-dependent and time-dependent inhibition of cell proliferation on TSGH8301 cancer cells, with IC50 values determined to be 0.44 μmol/l. Of interest, TSGH8301 cancer cells were more sensitive to JA than E7 immortalized uroepithelial cells, especially at lower concentrations. We further showed that JA inhibited the autocrine production of angiogenic factors and matrix-degrading enzymes in vitro and microvessel density in SCID mice in vivo (P< 0.01). Both differential cytotoxicity and angiogenesis inhibition of JA were confirmed by SCID mice experiments. Together, JA showed antiangiogenesis in vitro and in vivo through pleiotropic positive and negative regulators of angiogenesis molecules. The current investigation supports the potential of JA as an alternative chemoprevention agent for human bladder cancer.

Muscle wasting is common and is associated with increased morbidity and mortality in patients with chronic kidney disease (CKD). However, factors associated with decreased muscle mass in CKD patients are seldom reported. We performed a cross-sectional study of 326 patients (age 65.8 ± 13.3 years) with stage 3–5 CKD who were not yet on dialysis. Muscle mass was determined using the Body Composition Monitor (BCM), a multifrequency bioimpedance spectroscopy device, and was expressed as the lean tissue index (LTI, lean tissue mass/height2). An LTI of less than 10% of the normal value (low LTI) indicates muscle wasting. Patients with low LTI (n = 40) tended to be diabetic, had significantly higher fat tissue index, urine protein creatinine ratio, and interleukin-6 and tumor necrosis factor-α levels, but had significantly lower serum albumin and hemoglobin levels compared with those with normal LTI. In multivariate linear regression analysis, age, sex, cardiovascular disease, and interleukin-6 were independently associated with LTI. Additionally, diabetes mellitus remained an independent predictor of muscle wasting according to low LTI by multivariate logistic regression analysis. We conclude that LTI has important clinical correlations. Determination of LTI may aid in clinical assessment by helping to identify muscle wasting among patients with stage 3–5 CKD.

Hypertrophic scarring is related to persistent activation of transforming growth factor-β (TGF-β)/Smad signaling. In the TGF-β/Smad signaling cascade, the TGF-β type I receptor (TGFBRI) phosphorylates Smad proteins to induce fibroblast proliferation and extracellular matrix deposition. In this study, we inhibited TGFBRI gene expression via TGFBRI small interfering RNA (siRNA) to reduce fibroblast proliferation and extracellular matrix deposition. Our results demonstrate that downregulating TGFBRI expression in cultured human hypertrophic scar fibroblasts significantly suppressed cell proliferation and reduced type I collagen, type III collagen, fibronectin, and connective tissue growth factor (CTGF) mRNA, and type I collagen and fibronectin protein expression. In addition, we applied TGFBRI siRNA to wound granulation tissue in a rabbit model of hypertrophic scarring. Downregulating TGFBRI expression reduced wound scarring, the extracellular matrix deposition of scar tissue, and decreased CTGF and α-smooth muscle actin mRNA expression in vivo. These results suggest that TGFBRI siRNA could be applied clinically to prevent hypertrophic scarring.

Background Chronic alcohol intake affects liver function and causes hepatic pathological changes. It has been shown that peroxisome proliferator-activated receptor α (PPARα)-null mice developed more pronounced hepatic changes than wild-type (WT) mice after chronic exposure to a diet containing 4% alcohol. The remarkable similarity between the histopathology of alcoholic liver disease (ALD) in Ppara-null model and in humans, and the fact that PPARα expression and activity in human liver are less than one-tenth of those in WT mouse liver make Ppara-null a good system to investigate ALD. Methods In this study, the Ppara-null model was used to elucidate the dynamic regulation of PPARα activity during chronic alcohol intake. Hepatic transcriptomic and metabolomic analyses were used to examine alterations of gene expression and metabolites associated with pathological changes. The changes triggered by alcohol consumption on gene expression and metabolites in Ppara-null mice were compared with those in WT mice. Results The results showed that in the presence of PPARα, 3 major metabolic pathways in mitochondria, namely the fatty acid β-oxidation, the tricarboxylic acid cycle, and the electron transfer chain, were induced in response to a 2-month alcohol feeding, while these responses were greatly reduced in the absence of PPARα. In line with the transcriptional modulations of these metabolic pathways, a progressive accumulation of triglycerides, a robust increase in hepatic cholic acid and its derivatives, and a strong induction of fibrogenesis genes were observed exclusively in alcohol-fed Ppara-null mice. Conclusions These observations indicate that PPARα plays a protective role to enhance mitochondrial function in response to chronic alcohol consumption by adaptive transcriptional activation and suggest that activation of this nuclear receptor may be of therapeutic value in the treatment for ALD.

// Min-Huey Chung 1 , Yi-Wen Wang 2 , Yung-Lung Chang 3 , Shih-Ming Huang 3 and Wei-Shiang Lin 4 1 Graduate Institute of Nursing, College of Nursing, Taipei Medical University, Taipei 110, Taiwan, Republic of China 2 Department of Biology and Anatomy, National Defense Medical Center, Taipei City 114, Taiwan, Republic of China 3 Department of Biochemistry, National Defense Medical Center, Taipei City 114, Taiwan, Republic of China 4 Department of Medicine, Division of Cardiology, Tri-Service General Hospital, National Defense Medical Center, Taipei City 114, Taiwan, Republic of China Correspondence to: Wei-Shiang Lin, email: wslin545@ms27.hinet.net Keywords: heart failure, digoxin, cancer, cell-based strategy, personalized medicine Received: February 18, 2017 Accepted: March 30, 2017 Published: April 25, 2017 ABSTRACT Heart failure (HF) is the leading cause of death in the world and digoxin remains one of the oldest therapies for HF. However, its safety and efficacy have been controversial since its initial use and there is uncertainty about its long-term efficacy and safety. Recently, the repositioning of cardiac glycosides is to function in anti-tumor activity via multiple working pathways. It is interesting to compare the potential effects of digoxin in clinical patients and cell lines. First, we analyze patient information retrieved from the National Health Insurance Research database of Taiwan between January 1, 2000 and December 31, 2000. This retrospective study included a study cohort (1,219 patients) and a comparison cohort. Our analytical data suggested that patients taking digoxin are at an increased risk of cancers, including breast, liver, and lung cancers, during the 10-year follow-up period. In contrast to the anti-tumor function of digoxin, we further examined the potential pathway of digoxin via the cell-based strategy using several breast cancer cell lines, including MCF-7, BT-474, MAD-MB-231, and ZR-75-1. Digoxin consistently exerted its cytotoxicity to these four cell lines with various range of concentration. However, the proliferation of ZR-75-1 cells was the only cell lines induced by digoxin and the others were dramatically suppressed by digoxin. The responsiveness of SRSF3 to digoxin might be involved with cell-type differences. In summary, we combined a cohort study for digoxin treatment for HF patients with a cell-based strategy that addresses the translation issue, which revealed the complexity of personalized medicine.

The epithelial membrane protein genes 1, 2, and 3 (EMP1, EMP2, and EMP3) belong to the peripheral myelin protein 22-kDa (PMP22) gene family, which consists of at least seven members: PMP22, EMP1, EMP2, EMP3, PERP, brain cell membrane protein 1, and MP20. This review addresses the structural and functional features of EMPs, detailing their tissue distribution and functions in the human body, their expression pattern in a variety of tumors, and highlighting the underlying mechanisms involved in carcinogenesis. The implications in cancer biology, patient prognosis prediction, and potential application in disease therapy are discussed. For example, EMP1 was reported to be a biomarker of gefitinib resistance in lung cancer and contributes to prednisolone resistance in acute lymphoblastic leukemia patients. EMP2 functions as an oncogene in human endometrial and ovarian cancers; however, characteristics of EMP2 in urothelial cancer fulfill the criteria of a suppressor gene. Of particular interest, EMP3 overexpression in breast cancer is significantly related to strong HER-2 expression. Co-expression of HER-2 and EMP3 is the most important indicator of progression-free and metastasis-free survival for patients with urothelial carcinoma of the upper urinary tract. Altogether, discovery of pharmacological inhibitors and/or regulators of EMP protein activity could open novel strategies for enhanced therapy against EMP-mediated human diseases.

weng l.-c., huang h.-l., wang y.-w., chang c.-l., tsai c.-h. & lee w.-c. (2011) Primary caregiver stress in caring for a living-related liver transplantation recipient during the postoperative stage. Journal of Advanced Nursing 67(8), 1749–1757. Abstract Aim. The aim of this study was to explore the stress experienced by the primary family caregiver of the living-related liver transplantation patient during the postoperative stage. Background. Living-related liver transplantation is a treatment choice for end-stage liver disease patients who face a shortage of available donated livers. Research suggests that the caregiver of the liver transplant recipient experiences tremendous stress because a family member is on the waiting list. Nevertheless, there are limited studies that investigate the caregiver experience of stress during this surgery. Method. This qualitative study used face-to-face semi-structured interviews to understand the subjective experiences of study participants. The study participants were drawn from a tertiary medical centre in northern Taiwan. During the data collection period (October 2007 to May 2008), 6 of the 12 caregivers agreed to participate in this study (N = 6), all of whom were female and, except for one participant, were the wives of the recipients. Results. Participant stress was caused by the gap between expectations and primary caregiving experiences. In particular, the five themes that were identified: (a) unstable sentiment towards liver transplantation; (b) entanglement of burden; (c) non-synchronized family interaction; (d) distance from the healthcare professional; and (e) concern about the protector role function. Conclusions. The stress of primary caregivers of living-related liver transplantation is related to the gap between expectations and primary caregiving experiences. The immediate postoperative stage is a critical one for health professionals to provide intervention and management.

Aims. The aim of this study was to evaluate the validity and reliability of the stress index for 10–18-years-old children or adolescents with Tourette syndrome. Background. Tourette syndrome is a chronic tic disorder, which occurs in childhood. Children with Tourette syndrome exhibit sudden and unexpected voices or movements that may have influence on their daily activities and cause interaction barriers for children with Tourette syndrome. Therefore, a self-report stress index is necessary for children with Tourette syndrome to quickly measure the stress they have. Design and methods. Eight experts rated appropriateness, comprehensiveness and relevance of the questionnaire to establish content validity. A total of 116 paediatric patients filled out the stress index for 10-–18-years-old children or adolescents with Tourette syndrome to evaluate its construct validity using exploratory factor analysis and internal consistency. Data from 90 pairs of paediatric patients and their caregivers were used to evaluate the inter-rater reliability. Result. The criterion validity index ranged from 80–98%. One item was deleted because of a small item-to-total correlation. Therefore, 26 items made up the final stress index for 10-–18-years-old children or adolescents with Tourette syndrome. In exploratory factor analysis, four factors (unfairly treated, psychological, symptom control and future concern) were achieved and accounted for 52·3% of the total variance. Cronbach’s alphas of the stress index for 10-–18-years-old children or adolescents with Tourette syndrome were 0·89. The inter-rater reliability of stress Index for 10-–18-years-old children or adolescents with Tourette syndrome (Pearson correlation coefficient between patients and their caregivers) was 0·56. Conclusion. The stress Index for 10-–18-years-old children or adolescents with Tourette syndrome is a self-administered tool to assess the stress of children or adolescents with Tourette syndrome. Validity (content and construct) and reliability (internal consistency and inter-rater reliability) of our Stress Index for 10-–18-years-old Children or Adolescents with Tourette syndrome was acceptable. Relevance to clinical practice. The Stress Index for Children or Adolescents with Tourette Syndrome appears to be an ideal instrument for evaluating the stress for children with Tourette syndrome in clinical setting and finding the direction in designing an appropriate intervention programme. We welcome other researchers to use stress index for 10–18-years-old children or adolescents with Tourette syndrome so that their findings can be compared using the same measurement.

Aims. The aim of this study was to examine the effect of self-efficacy on depression and to consider the mediating effect of self-care behaviour. Background. Depression is a problem for kidney transplant recipients and can compromise their quality of life. From other studies on chronic illnesses, self-efficacy and self-care behaviour have been considered to be potential determinants for depressive symptoms. However, none of these previous studies have investigated the relationships among these variables in kidney transplantation recipients. Design. A cross-sectional survey employing correlation design and purposive sampling was used. Methods. One hundred and seventy-seven persons who had received a kidney transplant participated. A self-administrated questionnaire and a medical record audit were used to collect data. The data were analysed using correlation and hierarchical linear regression methods. Results. The average score of depressive symptoms was 8·61 SD 7·64. Among the participants in the study, 32·8% had scores of depressive symptoms higher than 11 (indicating mild to severe symptoms of depression). Self-efficacy and self-care behaviour had direct negative effects on depressive symptoms. Self-care behaviour had partial mediating effect on the relationship between self-efficacy and depression. Total variance explained was 23%. Conclusion. Depressive symptoms are still a problem that need to be addressed among kidney transplantation patients. Patients who have higher self-efficacy and higher self-care behaviour will have lower depressive symptoms. Our results support that self-efficacy is the significant predictor of depressive symptoms. Relevance to clinical practice. Self-efficacy is a powerful and modifiable determinant of depressive symptoms. We should design interventions that focus not only on the skill aspects of self-care behaviour but also on those that have a strong connection with self-efficacy. We could incorporate the self-efficacy-enhanced strategies as proposed by social cognitive theory into the kidney transplantation care programme.

Background This study aims to compare the efficacy and safety of the Ahmed glaucoma valve (AGV) with the Baerveldt glaucoma implant (BGI) in glaucoma patients. Methods Databases were searched to identify studies that met pre-stated inclusion criteria, involving randomized controlled clinical trials (RCTs) and non-randomized controlled clinical trials. Treatment effect was analyzed using a random-effect model. Results Ten controlled clinical trials (1048 eyes) were analyzed, involving two RCTs and eight retrospective comparative studies. Short-term results (6–18 months) and long-term results (>18 months) were analyzed separately. There was no significant difference in the success rate for short-term follow-up between the AGV and BGI groups (5studies, 714 eyes, odds ratio [OR]: 0.97; 95 % confidence interval [CI]: 0.56, 1.66; P = 0.90). For long-term pooled results (7studies, 835 eyes), the success rate of AGVs was lower than that of BGIs (OR: 0.73; 95 % CI: 0.54, 0.99, P = 0.04), However, subgroup and sensitivity analyses did not show a significant difference in the success rate between the two groups (P ≥0.05). The AGV group had a higher mean intraocular pressure than the BGI group in short-term (6 studies, 685 eyes, weighted mean difference [WMD]: 2.12 mmHg; 95 % CI: 0.72–3.52; P

Background For preservation of integrity of appearance and function in a 66-year-old male with an extremely rare case of verrucous carcinoma developing from the subungium of his right thumb, intra-arterial infusion with methotrexate was used. Objective To evaluate the effectiveness of arterial infusion with methotrexate in this unusual nail bed cancer. Methods Right brachial arterial catheterization and infusion with methotrexate (50 mg) were used every 24 hours together with simultaneous intramuscular injection of 6 mg of leucovorin every 6 hours for 10 days. Results At 4 years, 8 months after therapy, the patient was in sustained complete remission with a functionally normal right thumb. Conclusion This case study suggests that intra-arterial infusion chemotherapy is a simple and effective method for thumb subungual verrucous carcinoma with the unique advantage of preservation of morphology and functional conditions. It can be considered an effective treatment option.

Aim: To investigate the fibrin(ogen)olytic character of FII a isolated from Agkistrodon acutus venom in vitro and in vivo . Methods: 125 I-labeled human plasma clot lysis was measured in vitro and rabbit carotid artery thrombosis was as an in vivo model. Results: In vitro , urokinase (UK) at 25, 35, 40, 45, 60 kU/L and FII a at 0.08, 0.23, 0.4, 0.5, and 0.7 g/L resulted an equivalent clot lysis (20%, 40%, 50%, 60%, and 80%). UK at 25-60 kU/L induced 27.3%plusminus3.6%, 35.2%plusminus2.3%, 39.3%plusminus2.4%, 44.2%plusminus4.6%, and 51.1%plusminus1.2% fibrinogen degradation. But FII a at 0.08–0.7 g/L induced 95.4%plusminus0.3%, >95.6%, >95.6%, >95.6%, >95.6% fibrinogen degradation respectively. In vivo , UK 40 kU/kg and FII a 1.0 mg/kg reduced the weight of residual thrombus to 9.0plusminus2.5 mg and 7.8plusminus3.5 mg compared with negative control group (30.0plusminus5.4 mg). But the fibrinogen degradation rate after UK 40 kU/kg and FII a 1.0 mg/kg treatment was 24.4%plusminus6.2% and 4.1%plusminus7.8%, respectively ( P the whole blood clots>platelet rich plasma (PRP) clots. The sequence for FII a 0.4 g/L was PRP>PPP>whole blood clots. Conclusion: At the same percentage of clot lysis, FIIa degraded more fibrinogen than UK did in vitro but less fibrinogen than UK did in vivo . The order of the lysis speed was PPP>whole blood clots>PRP clots for UK and PRP>PPP>whole blood clots for FII a .

Objectives Penile verrucous carcinoma is characterized by aggressive local growth and a low metastatic potential. Lower abdominal aortic infusion chemotherapy has the main advantage of delivering a very high concentration of an anticancer drug to the whole pelvic area, including the penis, and is especially suitable to treat penile verrucous carcinoma. Methods From 1991 to 2000, 4 cases of penile verrucous carcinoma were treated by continuous intra-aortic infusion with methotrexate (50 mg) every 24 hours, for an average of 10 days. Citrovorum factor (6 mg) was given intramuscularly every 6 hours during the period of methotrexate infusion. Results After treatment, 3 patients achieved complete remission. They were living disease free 10 years, 10 months, 6 years, 9 months, and 1 year, 8 months after therapy. Conclusions Intra-aortic infusion chemotherapy is a simple and effective method for penile verrucous carcinoma with the unique advantage of preserving cosmetic and functional integrity. It may be considered an effective alternative treatment for penile verrucous carcinoma. By using this simple method many unnecessary penectomies can be avoided.

In this study, we investigated the neuroprotective effect of sevoflurane against ischemic brain injury and its underlying molecular mechanisms. Transient global brain ischemia was induced by 4-vessel occlusion in adult male Sprague-Dawley rats. The rats were pretreated with sevoflurane alone or sevoflurane combined with LY294002/wortmannin (selective inhibitor of PI3K) before ischemia. Cresyl violet staining was used to examine the survival of hippocampal CA1 pyramidal neurons. Immunoblotting and immunoprecipitation were performed to measure the phosphorylation of Akt1, PRAS40, ASK1, and JNK3 and the expression of cleaved-caspase-3. The results demonstrated that a moderate dose of sevoflurane inhalation of 2 % for 2 h had significant neuroprotective effects against ischemia/reperfusion induced hippocampal neuron death. Sevoflurane significantly increased Akt and PRAS40 phosphorylation and decreased the phosphorylation of ASK1 at 6 h after reperfusion and the phosphorylation of JNK3 at 3 days after reperfusion following 15 min of transient global brain ischemia. Conversely, LY294002 and wortmannin significantly inhibited the effects of sevoflurane. Taken together, the results suggest that sevoflurane could suppress ischemic brain injury by downregulating the activation of the ASK1/JNK3 cascade via increasing the phosphorylation of Akt1 during ischemia/reperfusion.

Upper urinary tract (pyelocalyceal cavities and ureter) urothelial carcinoma is a relatively rare neoplastic disease. Although diagnosis and treatment of this tumor variant have improved significantly, accurate risk stratification remains a challenge. To identify the putative oncogene involved in urothelial carcinoma progression we performed bioinformatics guided experimental investigation targeting chromosome 19q13.We investigated the effects of EMP3 on cancer cell growth, migration and adhesion in transfection and siRNA experiments in vitro. Crosstalk of integrins or ErbB2 with EMP3 was examined by reverse transcriptase-polymerase chain reaction and immunoblot. The potential involvement of epigenetic alterations of EMP3 in vitro and in vivo was analyzed by methylation specific polymerase chain reaction. To validate clinical relevance we measured EMP3 expression at the mRNA and protein levels in a cohort of 77 patients with upper urinary tract urothelial carcinoma and compared prognostic significance in relation to that of ErbB2 expression.We noted functional crosstalk between ErbB2 and EMP3 in vitro. EMP3 over expression promoted cancer cell proliferation and migration but suppressed cell adhesion in vitro. EMP3 activated the ErbB2-PI3K-AKT pathway to increase cell growth in vitro. In the clinical cohort Kaplan-Meier survival estimates showed that ErbB2 and EMP3 co-expression was the most important indicator of progression-free and metastasis-free survival in patients with upper urinary tract urothelial carcinoma (log rank test p = 0.018 and 0.04, respectively).EMP3 is an important prognostic indicator for selecting patients with upper urinary tract urothelial carcinoma for more intensive therapy. EMP3 is an innovative co-targeting candidate for designing ErbB2 based cancer therapy.

Upper urinary tract urothelial carcinoma is a relatively uncommon disease and is diagnosed more frequently at advanced stages. The prognosis of these patients mainly has been related to tumor stage and grade. As a result, the definition of prognostic indicators enabling precise patient selection is mandatory for neoadjuvant or adjuvant therapies. The epithelial membrane protein (EMP2) was identified as one of the up-regulated genes by isoflavones. EMP2 overexpression suppressed foci formation, anchorage-independent growth in vitro, and tumorigenicity in severe combined immunodeficiency mice (all P < 0.05). In addition, a cross-talk between EMP2 and integrins αV and β3 was shown in the regulation of cell adhesion and migration. Higher EMP2 expression was associated with a better progression-free survival (P = 0.008) and cancer-related death (P < 0.001). EMP2 was identified as a tumor-suppressor gene in urinary tract urothelial carcinoma and may be an innovative co-targeting candidate for designing integrin-based cancer therapy.

BACKGROUND Living donor liver transplantation is an option for effective treatment for patients with liver disease or a liver tumor. One disadvantage, however, is the risk of complications or death in a healthy donor. Thus, promoting the donor's safety and well-being is a major goal of transplantation care. In this regard, more research on physical and psychological complications and adjustment among donors is needed. OBJECTIVES The aim of this study was to describe the experiences of living liver donors, focusing on their perceptions of living liver transplantation and corresponding coping strategies. METHODS The data were analyzed using content analysis in this qualitative design. RESULTS Seven of 12 donors, all men, agreed to participate in the study. The core theme that emerged in regard to adjustment was "maintaining peace of mind." In addition, there were 4 subthemes: (a) removing themselves from information, (b) viewing the surgery as common, (c) having overall confidence, and (d) assigning value to their decision. DISCUSSION Living donor liver transplantation is a treatment option that requires acceptance by both the donor and his or her family. The process is enormously stressful, and the living liver donor needs adjustment strategies to maintain his or her peace of mind throughout the process.

Traditional treatment for advanced penile verrucous carcinoma is penectomy. This mostly leads to remarkable psychosexual problems and greatly affects quality of life, especially in young patients. To preserve the penis we used intra-aortic infusion chemotherapy for advanced verrucous carcinoma.From 1991 to 2009 we treated 6 men with penile verrucous carcinoma with continuous intra-aortic infusion of 50 mg methotrexate every 24 hours (average 550 mg, range 400 to 800). Citrovorum factor (6 mg) was given intramuscularly every 6 hours during methotrexate infusion. After continuous methotrexate infusion no further anticancer drug was given to complete responders. Partial responders subsequently received long-term, intermittent, intra-aortic infusion of 50 mg methotrexate or 2 mg mitomycin C plus 250 mg 5-fluorouracil every 1 to 2 weeks until tumors disappeared and all wounds healed.After treatment 4 patients achieved a complete response and were disease-free 3 years 9 months to 17 years 10 months (median 11 years 3 months) after therapy. Two patients had a partial response. The patient with a shaft tumor subsequently underwent total penectomy due to unbearable penile pain 4 years after infusion with various drugs without an appreciable response. He has survived 12 years 5 months after initial treatment. The other patient with glans and prepuce tumors had progression with bilateral inguinal metastases despite 1 1/2 years of infusion therapy. Total penectomy was done. Histological examination of the glans mass revealed moderately differentiated squamous cell carcinoma. Patient condition progressed rapidly and he died 11 months after penectomy.Intra-aortic infusion chemotherapy is a simple, effective method to treat penile verrucous carcinoma with the uniqueness of preserving the anatomical structure and sexual function in complete responders. For penile verrucous carcinoma, especially in younger patients, intra-aortic infusion chemotherapy may be considered organ sparing treatment before penectomy.

Interleukin-1 (IL-1) has many roles in the brain in addition to mediating inflammatory processes in the glia, and has also been implicated in neurodegenerative disease. Traumatic brain injury (TBI) is one of the most prevalent causes of morbidity and mortality in young persons. We conducted a study to assess the effect of IL-1 on the TBI-induced death of hippocampal neurons. After TBI was induced in adult male Sprague-Dawley rats under anesthesia, we evaluated neuronal damage score through microscopic examination and Pulsinelli's grading system. Reverse transcription-polymerase chain reaction (RT-PCR) and Western blotting were used to measure the levels of IL-1alpha and IL- 1beta in brain tissue at different points after the induction of TBI. Over a 4-day period, the specific sites of release of IL-1alpha and IL-1beta in the brain were elucidated by immunocytochemistry with double- labeling. TBI to the hippocampus was followed by disruption of the blood-brain barrier and severe neuronal loss. Levels of IL-1alpha RNA and protein were significantly elevated at 3 h after TBI, peaked at 12 h, and remained elevated for 168 h. IL-1beta RNA and protein expression were also elevated at 3 h after TBI, but remained so only for 48 h. Our findings indicate that the observed TBI-induced increases in IL-1alpha and IL-1beta occur largely through release of these cytokines from neurons and astrocytes, respectively. Intraventricular administration of antibodies to IL-1alpha and IL-1beta before TBI significantly attenuated the TBI-induced loss of hippocampal neurons. These results show that IL-1alpha and IL-1beta play important roles in the TBI-induced loss of hippocampal neurons.

Traumatic brain injury (TBI) is one of the most prevalent causes of morbidity and mortality in youth. Interleukin-1 (IL-1) has many roles in the brain in addition to mediating glial inflammatory response; it has also been implicated in neurodegenerative diseases. We demonstrated the signal transduction pathway of IL-1 overproduction-induced cortical neuron loss during TBI. A calibrated weight-drop device (450 g weight and 2m height) was used to induce TBI in adult male Sprague-Dawley rats under general anesthesia (sodium pentobarbital: 40 mg/kg, i.p.). Expression of interleukin-1alpha (IL-1alpha), interleukin-1beta (IL-1beta), extracellular signal-regulated kinase (ERK), Jun, and p-38 were determined by Western blotting and RT-PCR. Neuronal damage was evaluated by microscopic examination. We found both mRNA and proteins of cortical IL-1alpha and IL-1beta increased three hours after TBI. Phosphorylation of ERK significantly increased but there were no significant effects on cortical expression of ERK, Jun and p-38. Administration of ERK inhibitor, PD98059, IL-1alpha antibody and IL-1beta antibody protected animals from TBI-induced neuronal damage. Our results suggest that TBI-induced cortical neuron death was mediated by the IL-1 receptor through ERK phosphorylation.

Background. For preservation of integrity of appearance and function in a 57-year-old male with a squamous cell carcinoma of his left big toe who had refused amputation, intra-arterial infusion with methotrexate was used. Objective. To evaluate the effectiveness of arterial infusion with methotrexate in this uncommon big toe cancer. Methods. Left external iliac arterial catheterization and infusion with methotrexate (50 mg) were used every 24 hours plus simultaneous intramuscular injection of 6 mg of leucovorin every 6 hours for 8 days. Results. At 7 years and 3 months after therapy, the patient was in sustained complete remission with a functionally normal left foot. Conclusion. This case study suggests that intra-arterial infusion chemotherapy is a simple and effective method for big toe squamous cell carcinoma with the unique advantage of preservation of organ and function. It can be considered as an effective alternative treatment.

613 Background: PEP02 (MM-398) is a nanoliposomal formulation of irinotecan (CPT-11) that has improved pharmacokinetics (PK) and tumor distribution of CPT-11 and its active metabolite, SN-38. PEP02 single agent q3w has shown preliminary efficacy and safety in Phase II pancreatic and gastric cancer studies. Since irinotecan is approved for metastatic colorectal cancer (mCRC) and biweekly regimens are widely used, the aims of this study are to determine the maximum tolerated dose (MTD), characterize the PK and pharmacogenetics (PGx), and explore the efficacy of PEP02 q2w in mCRC. Methods: Patients (pts) with disease progression after 1st-line oxaliplatin-based chemotherapy, ECOG PS 0-1, and without prior exposure to irinotecan were eligible. PEP02 was given on day 1 and 15 of each 28 day treatment cycle. The starting dose was 80 mg/m2 and escalated by 10 mg/m2 to the target dose of 100 mg/m2. PK was evaluated during the 1st cycle and the tumor response was assessed by RECIST. Results: A total of 18 pts (M/F 9/9; median age 57.5) were enrolled, with 6 at each dose level. Dose-limiting toxicity manifested as G3 diarrhea was observed in one pt per dose level. The target dose of 100 mg/m2 was determined to be the MTD. Nine pts had dose delayed (4, 3, 2 at 80, 90, 100 mg/m2), mostly because of neutropenia. The PK and PGx are being analysed. As of August 2011, there are 3 pts still on study treatment and 17 pts evaluable for tumor response. Four pts (2 at 80 mg/m2, 1 each at 90 and 100 mg/m2) showed partial response (3 after 2 cycles and 1 after 8 cycles) and 8 pts (3 each at 80 and 90 mg/m2, 2 at 100 mg/m2) maintained stable disease for at least 2 cycles, which resulted in a response rate (RR) of 23.5% and a disease control rate (DCR) of 70.6%. Current median progression-free survival (PFS) is 4 months and 8 pts (47%) had PFS ≥ 6 months. Conclusions: The MTD of biweekly PEP02 is 100 mg/m2. As a 2nd-line monotherapy after oxaliplatin-based chemotherapy, the efficacy results indicate the potential benefit of PEP02 for mCRC (FOLFIRI-1 achieved only 4% RR, 34% DCR, and 2.5 months PFS in FOLFOX pretreated pts). A randomized Phase II study evaluating PEP02 plus 5-FU/LV (FUPEP regimen) vs. FOLFIRI is currently ongoing in France.

Ppm1d (Wip1) is a member of the magnesium-dependent serine/threonine protein phosphatase family, and is considered to be an oncogene. Previous work from our lab showed that Ppm1d null mice were remarkably more resistant to oncogene driven mammary tumorigenesis. In human tumors, PPM1D amplification and overexpression are observed in multiple tumor types. In addition PPM1D amplification has often been associated with poorer prognosis than the counterpart with normal PPM1D level. Overexpression of Ppm1d in mouse embryo fibroblasts (MEFs) and in transgenic mice showed enhanced cell transformation and accelerated cancer progress. However it remains to be determined whether Ppm1d facilitates the metastasis processes. In order to address this question our lab generated a cross strain of Wip1 null and Grm1 trangenic mice. Grm1 Tg is a well-characterized mouse model for melanoma and the mice with the Grm1 transgene develop metastasis of melanoma with high frequency. Ppm1d deficiency dramatically reduced the metastasis in Grm1 Tg mice. We observed less migration efficiency in the melanoma cells with Ppm1d gene knock-down. We are investigating the known Ppm1d downstream pathways and also other signaling events to determine the potential mechanism(s). We are also extending the study to another tumor type system to determine if the pro-metastatic effect of Ppm1d is melanoma specific or not. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3387.

Background PEP02 (also known as MM-398, nal-IRI) is a novel nanoparticle formulation of irinotecan encapsulated in liposomes. The aims of this study were to investigate the dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and pharmacokinetics (PK) of PEP02 in combination with 5-FU and LV, in patients with advanced refractory solid tumors. Methods Patients were enrolled in cohorts to receive PEP02 from 60 to 120 mg/m2 (dose expressed as the irinotecan hydrochloride trihydrate salt) as a 90-min intravenous infusion on day 1, followed by 24 h infusion of 5-FU 2,000 mg/m2 and LV 200 mg/m2 on days 1 and 8, every 3 weeks. Results A total of 16 patients were assigned to four dose levels, 60 (three patients), 80 (six patients), 100 (five patients) and 120 mg/m2 (two patients). DLT was observed in four patients, two at the 100 mg/m2 dose level (one had grade III infection with hypotension and grade III hemorrhage; the other had grade III diarrhea and grade IV neutropenia), and two at the 120 mg/m2 dose level (one had grade III diarrhea and grade IV neutropenia; the other had grade III diarrhea). The MTD of PEP02 was determined as 80 mg/m2. The most common treatment-related adverse events were nausea (81%), diarrhea (75%) and vomiting (69%). Among the six patients who received the MTD, one patient exhibited partial response, four patients had stable disease and one showed progressive disease. Pharmacokinetic data showed that PEP02 had a lower peak plasma concentration, longer half-life, and increased area under the plasma concentration-time curve from zero to time t of SN-38 than irinotecan at similar dose level. Conclusions The MTD of PEP02 on day 1 in combination with 24-h infusion of 5-FU and LV on days 1 and 8, every 3 weeks was 80 mg/m2, which will be the recommended dose for future studies. Trial registration The trial was retrospectively registered (NCT02884128) with date of registration: August 12, 2016. Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2933-6) contains supplementary material, which is available to authorized users.