Monoclonal antibody against cadherin-17 as a potential treatment for liver cancer

This journal suppl. entitled: Abstracts of The International Liver Congress™ 2012 – 47th annual meeting of the European Association for the Study of the Liver / Poster AbstractsBACKGROUND AND AIMS: Hepatocellular carcinoma (HCC) is a major type of liver cancer associated with high mortality. Prognosis is poor in HCC patients largely because of late diagnosis and limitations in treatment options. Therefore, this study aims to identify alternative target for HCC in hope to offer new treatments to patients. Cadherin-17 (CDH17) has been identified as an oncofetal molecule of HCC and that a suppression of its expression by RNA interference (RNAi) leads to anti-tumorigenesis. To supplement the drawbacks associated with the use of RNAi approach in biotherapy, we developed specific antibody against CDH17 for achieving similar purpose. METHODS: Hybridoma cell clones capable of secreting antibodies ...postprin

Mortalin-p53 interaction in cancer cells is stress dependent and constitutes a novel target for liver cancer therapy

Poster AbstractsThis journal suppl. entitled: The International Liver Congress™ 2011 Abstract Book 46 annual meeting of the European Association for the Study of the LiverBACKGROUND AND AIMS: The mortality rate of HCC is high due to tumor recurrence and lack of effective treatment. By proteomics analysis of matched tumor and non-tumor tissues, mortalin was identified as a marker for hepatocellular carcinoma (HCC) metastasis and recurrence, suggesting its tight link in HCC development and recurrence. The aim of this study is to examine the role of mortalin in hepatocarcinogenesis. METHODS: The mortalin expression ...postprin

Hyperoxia resensitizes chemoresistant human glioblastoma cells to temozolomide

Temozolomide (TMZ) is standard chemotherapy for glioblastoma multiforme (GBM). Intratumoral hypoxia is common in GBM and may be associated with the development of TMZ resistance. Oxygen therapy has previously been reported to potentiate the effect of chemotherapy in cancer. In this study, we investigated whether hyperoxia can enhance the TMZ-induced cytotoxicity of human GBM cells, and whether and how it would resensitize TMZ-resistant GBM cells to TMZ. TMZ-sensitive human GBM cells (D54-S and U87-S) were treated with TMZ to develop isogenic subclones of TMZ-resistant cells (D54-R and U87-R). All cell lines were then exposed to different oxygen levels (1, 21, 40, or 80 %), with or without concomitant TMZ treatment, before assessment of cell cytotoxicity and morphology. Cell death and survival pathways elicited by TMZ and/or hyperoxia were elucidated by western blotting. Our results showed that TMZ sensitivity of both chemo-sensitive and resistant cells was enhanced significantly under hyperoxia. At the cell line-specific optimum oxygen concentration (D54-R, 80 %; U87-R, 40 %), resistant cells had the same response to TMZ as the parent chemosensitive cells under normoxia via the caspase-dependent pathway. Both TMZ and hyperoxia were associated with increased phosphorylation of ERK p44/42 MAPK (Erk1/2), but to a lesser extent in D54-R cells, suggesting that Erk1/2 activity may be involved in regulation of hyperoxia and TMZ-mediated cell death. Overall, hyperoxia enhanced TMZ toxicity in GBM cells by induction of apoptosis, possibly via MAPK-related pathways. Induced hyperoxia is a potentially promising approach for treatment of TMZ-resistant GBM.published_or_final_versio

Feasibility of Tomotherapy-Based Image-Guided Radiotherapy to Reduce Aspiration Risk in Patients with Non-Laryngeal and Non-Pharyngeal Head and Neck Cancer

PURPOSE: The study aims to assess the feasibility of Tomotherapy-based image-guided radiotherapy (IGRT) to reduce the aspiration risk in patients with non-laryngeal and non-hypopharyngeal cancer. A retrospective review of 48 patients undergoing radiation for non-laryngeal and non-hypopharyngeal head and neck cancers was conducted. All patients had a modified barium swallow (MBS) prior to treatment, which was repeated one month following radiotherapy. Mean middle and inferior pharyngeal dose was recorded and correlated with the MBS results to determine aspiration risk. RESULTS: Mean pharyngeal dose was 23.2 Gy for the whole group. Two patients (4.2%) developed trace aspiration following radiotherapy which resolved with swallowing therapy. At a median follow-up of 19 months (1-48 months), all patients were able to resume normal oral feeding without aspiration. CONCLUSION AND CLINICAL RELEVANCE: IGRT may reduce the aspiration risk by decreasing the mean pharyngeal dose in the presence of large cervical lymph nodes. Further prospective studies with IGRT should be performed in patients with non-laryngeal and non-hypopharyngeal head and neck cancers to verify this hypothesis

A survival analysis of ventricular access devices for delivery of cerliponase alfa

OBJECTIVE: Late infantile neuronal ceroid lipofuscinosis type 2 (CLN2) is a rare autosomal recessive disease caused by tripeptidyl peptidase 1 enzyme deficiency. At the authors' center, the medication cerliponase alfa is administered every 2 weeks via the intracerebroventricular (ICV) route. This requires the placement of a ventricular access device (VAD) or reservoir and frequent percutaneous punctures of this device over the child's lifetime. In this study, the authors audited the longevity and survival of these VADs and examined the causes of device failure. METHODS: A single-center survival analysis of VAD insertions and revisions (January 2014 through June 2020) was conducted. All children received cerliponase alfa infusions through a VAD. Patient characteristics and complications were determined from a prospectively maintained surgical database and patient records. For the VAD survival analysis, the defined endpoint was when the device was removed or changed. Reservoir survival was assessed using Kaplan-Meier curves and the log-rank (Cox-Mantel) test. RESULTS: A total of 17 patients had VADs inserted for drug delivery; median (range) age at first surgery was 4 years 4 months (1 year 8 months to 15 years). Twenty-six VAD operations (17 primary insertions and 9 revisions) were required among these 17 patients. Twelve VAD operations had an associated complication, including CSF infection (n = 6) with Propionibacterium and Staphylococcus species being the most prevalent organisms, significant surgical site swelling preventing infusion (n = 3), leakage/wound breakdown (n = 2), and catheter obstruction (n = 1). There were no complications or deaths associated with VAD insertion. The median (interquartile range) number of punctures was 59.5 (7.5-82.0) for unrevised VADs (n = 17) versus 2 (6-87.5) for revised VADs (n = 9) (p = 0.70). The median survival was 301 days for revisional reservoirs (n = 9) versus 2317 days for primary inserted reservoirs (n = 17) (p = 0.019). CONCLUSIONS: In the context of the current interest in intrathecal drug delivery for rare metabolic disorders, the need for VADs is likely to increase. Auditing the medium- to long-term outcomes associated with these devices will hopefully result in their wider application and may have potential implications on the development of new VAD technologies. These results could also be used to counsel parents prior to commencement of therapy and VAD implantation

Loss of Endometrial Plasticity in Recurrent Pregnancy Loss

© 2015 AlphaMed Press.Menstruation drives cyclic activation of endometrial progenitor cells, tissue regeneration, and maturation of stromal cells, which differentiate into specialized decidual cells prior to and during pregnancy. Aberrant responsiveness of human endometrial stromal cells (HESCs) to deciduogenic cues is strongly associated with recurrent pregnancy loss (RPL), suggesting a defect in cellular maturation. MeDIP-seq analysis of HESCs did not reveal gross perturbations in CpG methylation in RPL cultures, although quantitative differences were observed in or near genes that are frequently deregulated in vivo. However, RPL was associated with a marked reduction in methylation of defined CA-rich motifs located throughout the genome but enriched near telomeres. Non-CpG methylation is a hallmark of cellular multipotency. Congruently, we demonstrate that RPL is associated with a deficiency in endometrial clonogenic cell populations. Loss of epigenetic stemness features also correlated with intragenic CpG hypomethylation and reduced expression of HMGB2, coding high mobility group protein 2. We show that knockdown of this sequence-independent chromatin protein in HESCs promotes senescence and impairs decidualization, exemplified by blunted time-dependent secretome changes. Our findings indicate that stem cell deficiency and accelerated stromal senescence limit the differentiation capacity of the endometrium and predispose for pregnancy failure. Stem Cells 2016;34:346-356 Recurrent pregnancy loss is caused by endometrial stem cell deficiency, triggering heightened tissue senescence and impaired decidualization

The National Food Consumption Survey (NFCS): South Africa, 1999

Objective: The aim of the National Food Consumption Survey (NFCS) in South Africa was to determine the nutrient intakes and anthropometric status of children (1-9 years old), as well as factors that influence their dietary intake. Design: This was a cross-sectional survey of a nationally representative sample of all children aged 1-9 years in South Africa. A nationally representative sample with provincial representation was selected using 1996 Census information. Subjects: Of the 3120 children who were originally sampled data were obtained from 2894, a response rate of 93%. Methods: The sociodemographic status of each household was assessed by a questionnaire. Dietary intake was assessed by means of a 24-hour recall and a food-frequency questionnaire from the caregivers of the children. Food purchasing practices were determined by means of a food procurement questionnaire. Hunger was assessed by a modified hunger scale questionnaire. Nutritional status was determined by means of anthropometric measurements: height, weight, head circumference and arm circumference. Results: At the national level, stunting (height-for-age below minus two standard deviations (< -2SD) from the reference median) was by far the most common nutritional disorder, affecting nearly one in five children. The children least affected (17%) were those living in urban areas. Even with regard to the latter, however, children living in informal urban areas were more severely affected (20%) compared with those living in formal urban areas (16%). A similar pattern emerged for the prevalence of underweight (weight-for-age < -2SD), with one in 10 children being affected at the national level. Furthermore, one in 10 (13%) and one in four (26%) children aged 1-3 years had an energy intake less than half and less than two-thirds of their daily energy needs, respectively. For South African children as a whole, the intakes of energy, calcium, iron, zinc, selenium, vitamins A, D, C and E, riboflavin, niacin, vitamin B6 and folic acid were below two-thirds of the Recommended Dietary Allowances. At the national level, data from the 24-hour recalls indicated that the most commonly consumed food items were maize, sugar, tea, whole milk and brown bread. For South African children overall, one in two households (52%) experienced hunger, one in four (23%) were at risk of hunger and only one in four households (25%) appeared food-secure. Conclusion: The NFCS indicated that a large majority of households were food-insecure and that energy deficit and micronutrient deficiencies were common, resulting in a high prevalence of stunting. These results were used as motivation for the introduction of mandatory fortification in South Africa. © The Authors 2005.Conference Pape

Depressed Adolescents’ Pupillary Response to Peer Acceptance and Rejection: The Role of Rumination

Heightened emotional reactivity to peer feedback is predictive of adolescents’ depression risk. Examining variation in emotional reactivity within currently depressed adolescents may identify subgroups that struggle the most with these daily interactions. We tested whether trait rumination, which amplifies emotional reactions, explained variance in depressed adolescents’ physiological reactivity to peer feedback, hypothesizing that rumination would be associated with greater pupillary response to peer rejection and diminished response to peer acceptance. Twenty currently depressed adolescents (12–17) completed a virtual peer interaction paradigm where they received fictitious rejection and acceptance feedback. Pupillary response provided a time-sensitive index of physiological arousal. Rumination was associated with greater initial pupil dilation to both peer rejection and acceptance, and diminished late pupillary response to peer acceptance trials only. Results indicate that depressed adolescents high on trait rumination are more reactive to social feedback regardless of valence, but fail to sustain cognitive-affective load on positive feedback

Tumor necrosis factor-α-induced protein 1 and immunity to hepatitis B virus

Aim: To compare the gene expression profile in a pair of HBV-infected twins. Methods: The gene expression profile was compared in a pair of H BV-infected twins. Results: The twins displayed different disease outco mes. One acquired natural immunity against HBV, whereas the other became a chronic HBV carrier. Eighty-eight and forty-six genes were found to be up- or downregulated in their PBMCs, respectively. Tumor necrosis factor-alpha-induced protein 1 (TNF-αIP1) that expressed at a higher level in the HBV-immune twins was identified and four pairs of siblings with HBV immunity by RT-PCR. However, upon HBV core antigen stimulation, TNF-αIP1 was downregulated in PBMCs from subjects with immunity, whereas it was slightly upregulated in HBV carriers. Bioinformatics analysis revealed a K+ channel tetramerization domain in TNF-αIP1 that shares a significant homology with some human, mouse, and C elegan proteins. Conclusion: TNF-αIP1 may play a role in the innate immunity against HBV. © 2005 The WJG Press and Elsevier Inc. All rights reserved.published_or_final_versio