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DNMT1 is predictive of survival and associated with Ki-67 expression in R-CHOP-treated diffuse large B-cell lymphomas

Loo SK, Ch'ng ES, Lawrie CH, Muruzabal MA, Gaafar A, Pomposo MP, et al.

Pathology, 2017 Dec;49(7):731-739.
PMID: 29074044 DOI: 10.1016/j.pathol.2017.08.009

DNMT1 is a target of approved anti-cancer drugs including decitabine. However, the prognostic value of DNMT1 protein expression in R-CHOP-treated diffuse large B-cell lymphomas (DLBCLs) remains unexplored. Here we showed that DNMT1 was expressed in the majority of DLBCL cases (n = 209/230, 90.9%) with higher expression in germinal centre B-cell-like (GCB)-DLBCL subtype. Low and negative DNMT1 expression (20% cut-off, n = 33/230, 14.3%) was predictive of worse overall survival (OS; p < 0.001) and progression-free survival (PFS; p < 0.001). Nonetheless, of the 209 DNMT1 positive patients, 33% and 42% did not achieve 5-year OS and PFS, respectively, indicating that DNMT1 positive patients showed considerably heterogeneous outcomes. Moreover, DNMT1 was frequently expressed in mitotic cells and significantly correlated with Ki-67 or BCL6 expression (r = 0.60 or 0.44, respectively; p < 0.001). We demonstrate that DNMT1 is predictive of DLBCL patients' survival, and suggest that DNMT1 could be a DLBCL therapeutic target due to its significant association with Ki-67.

Matched MeSH terms: Disease-Free Survival
Fulltext Isolation and characterization of Acanthamoeba spp. from air-conditioners in Kuala Lumpur, Malaysia

Chan LL, Mak JW, Low YT, Koh TT, Ithoi I, Mohamed SM

Acta Trop, 2011 Jan;117(1):23-30.
PMID: 20858455 DOI: 10.1016/j.actatropica.2010.09.004

During a study on the quality of the indoor environment, Acanthamoeba spp. were detected in 20 out of 87 dust samples collected from air-conditioners installed in a four-story campus building located in Kuala Lumpur, Malaysia. Twenty-one cloned Acanthamoeba isolates designated as IMU1 to IMU21 were established from the positive primary cultures. Five species were identified from the 16 isolates according to the morphological criteria of Pussard and Pons; i.e. A. castellanii, A. culbertsoni, A. griffini, A. hatchetti and A. polyphaga. Species identities for the remaining five isolates (IMU4, IMU5, IMU15, IMU20 and IMU21), however, could not be determined morphologically. At genotypic characterization, these isolates were placed into T3 (IMU14); T5 (IMU16 and IMU17) and T4 (all the remaining isolates). To predict the potential pathogenicity of these Acanthamoeba isolates, thermo- and osmotolerance tests were employed; many isolates were predicted as potential human pathogens based on the outcome of these tests. This is the first time potentially pathogenic Acanthamoeba have been isolated from air-conditioners in Malaysia.

Matched MeSH terms: Cell Survival
Fulltext Upregulation of miR-101 during Influenza A Virus Infection Abrogates Viral Life Cycle by Targeting mTOR Pathway

Sharma S, Chatterjee A, Kumar P, Lal S, Kondabagil K

Viruses, 2020 04 15;12(4).
PMID: 32326380 DOI: 10.3390/v12040444

Micro RNAs (miRNAs) are a class of small non-coding single-stranded RNA, which play an important role in modulating host-Influenza A virus (IAV) crosstalk. The interplay between influenza and miRNA interaction is defined by a plethora of complex mechanisms, which are not fully understood yet. Here, we demonstrate that in IAV infected A549 cells, a synchronous increase was observed in the expression of mTOR up to 24 hpi and significant downregulation at 48 hpi. Additionally, NP of IAV interacts with mTOR and modulates the levels of mTOR mRNA and protein, thus regulating the translation of host cell. RNA sequencing and qPCR analysis of IAV-infected A549 cells and NP transfected cells revealed that miR-101 downregulates mTOR transcripts at later stages of infection. Ectopic expression of miR-101 mimic led to a decrease in expression of NP, a reduction in IAV titer and replication. Moreover, treatment of the cells with Everolimus, a potent inhibitor of mTOR, resulted in an increase of miR-101 transcript levels, which further suppressed the viral protein synthesis. Collectively, the data suggest a novel mechanism that IAV stimulates mTOR pathway at early stages of infection; however, at a later time-point, positive regulation of miR-101 restrains the mTOR expression, and hence, the viral propagation.

Matched MeSH terms: Cell Survival
Resistance against apoptosis by the cellular prion protein is dependent on its glycosylation status in oral HSC-2 and colon LS 174T cancer cells

Yap YH, Say YH

Cancer Lett, 2011 Jul 1;306(1):111-9.
PMID: 21439722 DOI: 10.1016/j.canlet.2011.02.040

Most studies have focused on the role of the cellular prion protein (PrP(C)) in neurodegenerative diseases, whereas the function of this ubiquitous protein outside the nervous system remains elusive. Therefore, the anti-apoptotic property of PrP(C) in oral squamous cell carcinoma (HSC-2) and colon adenocarcinoma (LS 174T) was evaluated in this study, by stable shRNA knockdown and overexpression, respectively. PrP(C) confers resistance against oxidative stress-apoptosis as indicated by MTT assay, Annexin V-FITC/PI and DCFH-DA staining, but this property is abolished upon N-glycosylation inhibition by tunicamycin. Our results indicate that the inhibition of glycosylation in cancer cells overexpressing PrP(C) could represent a potential therapeutic target.

Matched MeSH terms: Cell Survival
Etiology, outcome and prognostic indicators of childhood fulminant hepatic failure in the United kingdom

Lee WS, McKiernan P, Kelly DA

J Pediatr Gastroenterol Nutr, 2005 May;40(5):575-81.
PMID: 15861019

OBJECTIVE: To study the etiology, outcome and prognostic indicators in children with fulminant hepatic failure in the United Kingdom.
DESIGN: Retrospective review of all patients <17 years with fulminant hepatic failure from 1991 to 2000. Fulminant hepatic failure was defined as presence of coagulopathy (prothrombin time >24 seconds or International Normalized Ratio >2.0) with or without hepatic encephalopathy within 8 weeks of the onset of symptoms.
SETTING: Liver Unit, Birmingham Children's Hospital, United Kingdom.
RESULTS: Ninety-seven children (48 male, 49 female; median age, 27 months; range, 1 day-192.0 months) were identified with fulminant hepatic failure. The etiologies were: 22 metabolic, 53 infectious, 19 drug-induced, and 3 autoimmune hepatitis. The overall survival rate was 61%. 33% (32/97) recovered spontaneously with supportive management. Fifty-five children were assessed for liver transplantation. Four were unstable and were not listed for liver transplantation; 11 died while awaiting liver transplantation. Liver transplantation was contraindicated in 10 children. Of the 40 children who underwent liver transplantation, 27 survived. Children with autoimmune hepatitis, paracetamol overdose or hepatitis A were more likely to survive without liver transplantation. Children who had a delay between the first symptom of liver disease and the onset of hepatic encephalopathy (median, 10.5 days versus 3.5 days), higher plasma bilirubin (299 micromol/L versus 80 micromol/L), higher prothrombin time (62 seconds versus 40 seconds) or lower alanine aminotransferase (1288 IU/L versus 2929 IU/L) levels on admission were more likely to die of fulminant hepatic failure or require liver transplantation (P < 0.05). On multivariate analysis, the significant independent predictors for the eventual failure of conservative therapy were time to onset of hepatic encephalopathy >7 days, prothrombin time >55 seconds and alanine aminotransferase =2384 IU/L on admission.
CONCLUSIONS: Children with fulminant hepatic failure with severe coagulopathy, lower alanine aminotransferase on admission and prolonged duration of illness before the onset of hepatic encephalopathy are more likely to require liver transplantation. Early referral to a specialized center for consideration of liver transplantation is vital.

Matched MeSH terms: Survival Rate
Fulltext DNA methylation profiling revealed promoter hypermethylation-induced silencing of p16, DDAH2 and DUSP1 in primary oral squamous cell carcinoma

Khor GH, Froemming GR, Zain RB, Abraham MT, Omar E, Tan SK, et al.

Int J Med Sci, 2013;10(12):1727-39.
PMID: 24155659 DOI: 10.7150/ijms.6884

BACKGROUND: Hypermethylation in promoter regions of genes might lead to altered gene functions and result in malignant cellular transformation. Thus, biomarker identification for hypermethylated genes would be very useful for early diagnosis, prognosis, and therapeutic treatment of oral squamous cell carcinoma (OSCC). The objectives of this study were to screen and validate differentially hypermethylated genes in OSCC and correlate the hypermethylation-induced genes with demographic, clinocopathological characteristics and survival rate of OSCC.
METHODS: DNA methylation profiling was utilized to screen the differentially hypermethylated genes in OSCC. Three selected differentially-hypermethylated genes of p16, DDAH2 and DUSP1 were further validated for methylation status and protein expression. The correlation between demographic, clinicopathological characteristics, and survival rate of OSCC patients with hypermethylation of p16, DDAH2 and DUSP1 genes were analysed in the study.
RESULTS: Methylation profiling demonstrated 33 promoter hypermethylated genes in OSCC. The differentially-hypermethylated genes of p16, DDAH2 and DUSP1 revealed positivity of 78%, 80% and 88% in methylation-specific polymerase chain reaction and 24% and 22% of immunoreactivity in DDAH2 and DUSP1 genes, respectively. Promoter hypermethylation of p16 gene was found significantly associated with tumour site of buccal, gum, tongue and lip (P=0.001). In addition, DDAH2 methylation level was correlated significantly with patients' age (P=0.050). In this study, overall five-year survival rate was 38.1% for OSCC patients and was influenced by sex difference.
CONCLUSIONS: The study has identified 33 promoter hypermethylated genes that were significantly silenced in OSCC, which might be involved in an important mechanism in oral carcinogenesis. Our approaches revealed signature candidates of differentially hypermethylated genes of DDAH2 and DUSP1 which can be further developed as potential biomarkers for OSCC as diagnostic, prognostic and therapeutic targets in the future.

Matched MeSH terms: Survival Analysis
Ethnicity modifies the association between diabetes mellitus and ischaemic heart disease in Chinese, Malays and Asian Indians living in Singapore

Yeo KK, Tai BC, Heng D, Lee JM, Ma S, Hughes K, et al.

Diabetologia, 2006 Dec;49(12):2866-73.
PMID: 17021918 DOI: 10.1007/s00125-006-0469-z

AIMS/HYPOTHESIS: The aim of the study was to determine whether the risk of ischaemic heart disease (IHD) associated with diabetes mellitus differs between ethnic groups.

METHODS: Registry linkage was used to identify IHD events in 5707 Chinese, Malay and Asian Indian participants from three cross-sectional studies conducted in Singapore between the years 1984 and 1995. The study provided a median of 10.2 years of follow-up with 240 IHD events experienced. We assessed the interaction between diabetes mellitus and ethnicity in relation to the risk of IHD events using Cox proportional hazards regression.

RESULTS: Diabetes mellitus was more common in Asian Indians. Furthermore, diabetes mellitus was associated with a greater risk of IHD in Asian Indians. The hazard ratio when comparing diabetes mellitus with non-diabetes mellitus was 6.41 (95% CI 5.77-7.12) in Asian Indians and 3.07 (95% CI 1.86-5.06) in Chinese (p = 0.009 for interaction). Differences in the levels of established IHD risk factors among diabetics from the three ethnic groups did not appear to explain the differences in IHD risk.

CONCLUSIONS/INTERPRETATION: Asian Indians are more susceptible to the development of diabetes mellitus than Chinese and Malays. When Asian Indians do develop diabetes mellitus, the risk of IHD is higher than for Chinese and Malays. Consequently, the prevention of diabetes mellitus amongst this ethnic group is particularly important for the prevention of IHD in Asia, especially given the size of the population at risk. Elucidation of the reasons for these ethnic differences may help us understand the pathogenesis of IHD in those with diabetes mellitus.

Matched MeSH terms: Survival Analysis
Extranodal site of diffuse large B-cell lymphoma and the risk of R-CHOP chemotherapy resistance and early relapse

Ting CY, Gan GG, Bee-Lan Ong D, Tan SY, Bee PC

Int J Clin Pract, 2020 Oct;74(10):e13594.
PMID: 32583545 DOI: 10.1111/ijcp.13594

BACKGROUND: About 20%-30% of diffuse large B-cell lymphoma (DLBCL) patients experience early disease progression despite R-CHOP chemotherapy treatment. Revised international prognostic index (R-IPI) score could risk stratify DLBCL patients but does not identify exactly which patient will be resistant to R-CHOP therapy or experience early relapse.
AIMS OF THE STUDY: To analyse pre-treatment clinical features of DLBCL patients that are predictive of R-CHOP therapy resistance and early disease relapse after R-CHOP therapy treatment.
METHODS USED TO CONDUCT THE STUDY: A total of 698 lymphoma patients were screened and 134 R-CHOP-treated DLBCL patients were included. The Lugano 2014 criteria was applied for assessment of treatment response. DLBCL patients were divided into R-CHOP resistance/early relapse group and R-CHOP sensitive/late relapse group.
RESULTS OF THE STUDY: 81 of 134 (60%) were R-CHOP sensitive/late relapse, while 53 (40%) were R-CHOP resistance/early relapse. The median follow-up period was 59 months ± standard error 3.6. Five-year overall survival rate of R-CHOP resistance/early relapse group was 2.1%, while it was 89% for RCHOP sensitive/late relapse group. Having more than one extranodal site of DLBCL disease is an independent risk factor for R-CHOP resistance/early relapse [odds ratio = 5.268 (1.888-14.702), P = .002]. The commonest extranodal sites were head and neck, gastrointestinal tract, respiratory system, vertebra and bones. Advanced age (>60 years), advanced disease stage (lll-lV), raised pre-treatment lactate dehydrogenase level, bone marrow involvement of DLBCL disease high Eastern Cooperative Oncology Group status (2-4) and high R-IPI score (3-5) showed no significant association with R-CHOP therapy resistance/early disease relapse (multivariate analysis: P > .05).
CONCLUSION AND CLINICAL IMPLICATIONS: DLBCL patients with more than one extranodal site are 5.268 times more likely to be R-CHOP therapy resistance or experience early disease relapse after R-CHOP therapy. Therefore, correlative studies are warranted in DLBCL patients with more than one extranodal site of disease to explore possible underlying mechanisms of chemoresistance.

Matched MeSH terms: Survival Rate
Morphological changes of post-isolation of caprine pancreatic islet

Hani H, Allaudin ZN, Tengku Ibrahim TA, Mohd-Lila MA, Sarsaifi K, Camalxaman SN, et al.

In Vitro Cell Dev Biol Anim, 2015 Feb;51(2):113-20.
PMID: 25303943 DOI: 10.1007/s11626-014-9821-7

Pancreatic islet transplantation is commonly used to treat diabetes. Cell isolation and purification methods can affect the structure and function of the isolated islet cells. Thus, the development of cell isolation techniques that preserve the structure and function of pancreatic islet cells is essential for enabling successful transplantation procedures. The impact of purification procedures on cell function can be assessed by performing ultrastructure and in vivo studies. Thus, the aim of this study was to evaluate the effect of caprine islets purification procedure on islet cell ultrastructure and functional integrity prior to and post-isolation/purification. The islets were isolated from caprine pancreas by using an optimized collagenase XI-S concentration, and the cells were subsequently purified using Euro-Ficoll density gradient. In vitro viability of islets was determined by fluorescein diacetate and propidium iodide staining. Static incubation was used to assess functionality and insulin production by islet cells in culture media when exposed to various levels of glucose. Pancreatic tissues were examined by using light microscopy, fluorescence microscopy, scanning, and transmission electron microscopy. In vivo viability and functionality of caprine islets were assessed by evaluating the transplanted islets in diabetic mice. Insulin assay of glucose-stimulated insulin secretion test showed that the insulin levels increased with increasing concentration of glucose. Thus, purified islets stimulated with high glucose concentration (25 mM) secreted higher levels of insulin (0.542 ± 0.346 μg/L) than the insulin levels (0.361 ± 0.219, 0.303 ± 0.234 μg/L) secreted by exposure to low glucose concentrations (1.67 mM). Furthermore, insulin levels of recipient mice were significantly higher (p

Matched MeSH terms: Cell Survival
Fulltext Clinical Use of Programmed Cell Death-1 and Its Ligand Expression as Discriminatory and Predictive Markers in Ovarian Cancer

Chatterjee J, Dai W, Aziz NHA, Teo PY, Wahba J, Phelps DL, et al.

Clin Cancer Res, 2017 07 01;23(13):3453-3460.
PMID: 27986748 DOI: 10.1158/1078-0432.CCR-16-2366

Purpose: We aimed to establish whether programmed cell death-1 (PD-1) and programmed cell death ligand 1 (PD-L1) expression, in ovarian cancer tumor tissue and blood, could be used as biomarkers for discrimination of tumor histology and prognosis of ovarian cancer.Experimental Design: Immune cells were separated from blood, ascites, and tumor tissue obtained from women with suspected ovarian cancer and studied for the differential expression of possible immune biomarkers using flow cytometry. PD-L1 expression on tumor-associated inflammatory cells was assessed by immunohistochemistry and tissue microarray. Plasma soluble PD-L1 was measured using sandwich ELISA. The relationships among immune markers were explored using hierarchical cluster analyses.Results: Biomarkers from the discovery cohort that associated with PD-L1+ cells were found. PD-L1+ CD14+ cells and PD-L1+ CD11c+ cells in the monocyte gate showed a distinct expression pattern when comparing benign tumors and epithelial ovarian cancers (EOCs)-confirmed in the validation cohort. Receiver operating characteristic curves showed PD-L1+ and PD-L1+ CD14+ cells in the monocyte gate performed better than the well-established tumor marker CA-125 alone. Plasma soluble PD-L1 was elevated in patients with EOC compared with healthy women and patients with benign ovarian tumors. Low total PD-1+ expression on lymphocytes was associated with improved survival.Conclusions: Differential expression of immunological markers relating to the PD-1/PD-L1 pathway in blood can be used as potential diagnostic and prognostic markers in EOC. These data have implications for the development and trial of anti-PD-1/PD-L1 therapy in ovarian cancer. Clin Cancer Res; 23(13); 3453-60. ©2016 AACR.

Matched MeSH terms: Disease-Free Survival
Fulltext Small molecule grp94 inhibitors block dengue and Zika virus replication

Rothan HA, Zhong Y, Sanborn MA, Teoh TC, Ruan J, Yusof R, et al.

Antiviral Res, 2019 11;171:104590.
PMID: 31421166 DOI: 10.1016/j.antiviral.2019.104590

Two major flaviviruses, dengue virus (DENV) and Zika virus (ZIKV), cause severe health and economic burdens worldwide. Recently, genome-wide screenings have uncovered the importance of regulators of the Hrd1 ubiquitin ligase-mediated endoplasmic reticulum (ER)-associated degradation (ERAD) pathway for flavivirus replication in host cells. Here we report the identification of the compound Bardoxolone methyl (CDDO-me) as a potent inhibitor of the Hrd1 ubiquitin ligase-mediated ERAD, which possesses a broad-spectrum activity against both DENV and ZIKV. Cellular thermal shift assay (CETSA) suggested that CDDO-me binds to grp94, a key component of the Hrd1 pathway, at a low nanomolar concentration, whereas interaction was not detected with its paralog Hsp90. CDDO-me and the grp94 inhibitor PU-WS13 substantially suppressed DENV2 replication and the cytopathic effects caused by DENV and ZIKV infection. The antiviral activities of both compounds were demonstrated for all four DENV serotypes and four ZIKV strains in multiple human cell lines. This study defines grp94 as a crucial host factor for flavivirus replication and identified CDDO-me as a potent small molecule inhibitor of flavivirus infection. Inhibition of grp94 may contribute to the antiviral activity of CDDO-me. Further investigation of grp94 inhibitors may lead to a new class of broad-spectrum anti-flaviviral medications.

Matched MeSH terms: Cell Survival
Fulltext Suppression of Plasmodium berghei parasitemia by LiCl in an animal infection model

Nurul Aiezzah Z, Noor E, Hasidah MS

Trop Biomed, 2010 Dec;27(3):624-31.
PMID: 21399604 MyJurnal

Malaria, caused by the Plasmodium parasite is still a health problem worldwide due to resistance of the pathogen to current anti-malarials. The search for new anti-malarial agents has become more crucial with the emergence of chloroquine-resistant Plasmodium falciparum strains. Protein kinases such as mitogen-activated protein kinase (MAPK), MAPK kinase, cyclin-dependent kinase (CDK) and glycogen synthase kinase- 3(GSK-3) of parasitic protozoa are potential drug targets. GSK-3 is an enzyme that plays a vital role in multiple cellular processes, and has been linked to pathogenesis of several diseases such as type II diabetes and Alzheimer's disease. In the present study, the antiplasmodial property of LiCl, a known GSK-3 inhibitor, was evaluated in vivo for its antimalarial effect against mice infected with Plasmodium berghei. Infected ICR mice were intraperitoneally administered with LiCl for four consecutive days before (prophylactic test) and after (suppressive test) inoculation of P. berghei-parasitised erythrocytes. Results from the suppressive test (post-infection LiCl treatment) showed inhibition of erythrocytic parasitemia development by 62.06%, 85.67% and 85.18% as compared to nontreated controls for the 100 mg/kg, 300 mg/kg and 600 mg/kg dosages respectively. Both 300 mg/kg and 600 mg/kg LiCl showed similar significant (P<0.05) suppressive values to that obtained with chloroquine-treated mice (86% suppression). The prophylactic test indicated a significantly (P<0.05) high protective effect on mice pre-treated with LiCl with suppression levels relatively comparable to chloroquine (84.07% and 86.26% suppression for the 300 mg/kg and 600 mg/kg LiCl dosages respectively versus 92.86% suppression by chloroquine). In both the suppressive and prophylactic tests, LiCl-treated animals survived longer than their non-treated counterparts. Mortality of the non-treated mice was 100% within 6 to 7 days of parasite inoculation whereas mice administered with LiCl survived beyond 9 days. Healthy non-infected mice administered with 600 mg/ kg LiCl for four consecutive days also showed decreased mortality compared to animals receiving lower doses of LiCl; three of the seven mice intraperitoneally injected with the former dose of LiCl did not survive more than 24 h after administration of LiCl whereas animals given the lower LiCl doses survived beyond four days of LiCl administration. To date, no direct evidence of anti-malarial activity in vivo or in vitro has been reported for LiCl. Evidence of anti-plasmodial activity of lithium in a mouse infection model is presented in this study.

Matched MeSH terms: Survival Analysis
Characterization and biological properties of NanoCUR formulation and its effect on major human cytochrome P450 enzymes

Shamsi S, Chen Y, Lim LY

Int J Pharm, 2015 Nov 10;495(1):194-203.
PMID: 26319630 DOI: 10.1016/j.ijpharm.2015.08.066

Curcumin (CUR) has been formulated into a host of nano-sized formulations in a bid to improve its in vivo solubility, stability and bioavailability. The aim of this study was to investigate whether the encapsulation of CUR in nanocarriers would impede its biological interactivity, specifically its potential anti-cancer adjuvant activity via the modulation of CYP enzymes in vitro. NanoCUR, a micellar dispersion prepared via a thin film method using only Pluronic F127 as excipient, was amenable to lyophilization, and retained its nano-sized spherical dimensions (17-33 nm) upon reconstitution with water followed by dilution to 5 μM with HBSS or EMEM. NanoCUR was a weaker cytotoxic agent compared to CUR in solution (sCUR), affecting HepG2 cell viability only when the incubation time was prolonged from 4h to 48 h. Correlation with 2h uptake data suggests this was due to a lower cellular uptake rate of CUR from NanoCUR than from sCUR. The poorer CUR accessibility might also account for NanoCUR being a weaker inhibitor of CYP2C9 and CYP2D6 than sCUR. NanoCUR was, however, 1.76-fold more potent against the CYP3A4 (IC50 5.13 ± 0.91 μM) metabolic function. The higher activity against CYP3A4 might be attributed to the synergistic action of Pluronic F127, since the blank micellar dispersion also inhibited CYP3A4 activity. Both sCUR and NanoCUR had no effect on the CYP3A4 mRNA levels in the HepG2 cells. NanoCUR therefore, maintained most of the biological activities of CUR in vitro, albeit at a lower potency and response rate.

Matched MeSH terms: Cell Survival
Fulltext Multi-Target Approach to Metastatic Adrenal Cell Carcinoma

Wahab NA, Zainudin S, AbAziz A, Mustafa N, Sukor N, Kamaruddin NA

Arch Iran Med, 2016 Sep;19(9):671-3.
PMID: 27631184 DOI: 0161909/AIM.0012

Adrenal cell carcinoma is a rare tumor and more than 70% of patients present with advanced stages. Adrenal cell carcinoma is an aggressive tumor with a poor prognosis. Surgical intervention is the gold standard treatment and mitotane is the only drug approved for the treatment of adrenal cell carcinoma. Until recently in 2012, the etoposide, doxorubicin, cisplatin plus mitotane are approved as first-line therapy based on response rate and progression-free survival. This case illustrates a case of advanced adrenal cell carcinoma in a young girl who presented with huge adrenal mass with inferior vena cava thrombosis and pulmonary embolism. Multi-approach of therapy was used to control the tumor size and metastasis. Therefore, it may prolong her survival rate for up to 5 years and 4 months.

Matched MeSH terms: Disease-Free Survival
Conventional versus Doxorubicin-Eluting Beads Transarterial Chemoembolization for Unresectable Hepatocellular Carcinoma: a Tertiary Medical Centre Experience in Malaysia

Rahman FA, Naidu J, Ngiu CS, Yaakob Y, Mohamed Z, Othman H, et al.

Asian Pac J Cancer Prev, 2016;17(8):4037-41.
PMID: 27644658

BACKGROUND: Hepatocellular carcinoma (HCC) is a common cancer that is frequently diagnosed at an advanced stage. Transarterial chemoembolisation (TACE) is an effective palliative treatment for patients who are not eligible for curative treatment. The two main methods for performing TACE are conventional (c-TACE) or with drug eluting beads (DEB-TACE). We sought to compare survival rates and tumour response between patients undergoing c-TACE and DEB-TACE at our centre.
MATERIALS AND METHODS: A retrospective cohort study of patients undergoing either treatment was carried out from January 2009 to December 2014. Tumour response to the procedures was evaluated according to the modified Response Evaluation Criteria in Solid Tumors (mRECIST). Kaplan-Meier analysis was used to assess and compare the overall survival in the two groups.
RESULTS: A total of 79 patients were analysed (34 had c-TACE, 45 had DEB-TACE) with a median follow-up of 11.8 months. A total of 20 patients in the c-TACE group (80%) and 12 patients in the DEB-TACE group (44%) died during the follow up period. The median survival durations in the c-TACE and DEB-TACE groups were 4.9 ± 3.2 months and 8.3 ± 2.0 months respectively (p=0.008). There was no statistically significant difference noted among the two groups with respect to mRECIST criteria.
CONCLUSIONS: DEB-TACE demonstrated a significant improvement in overall survival rates for patients with unresectable HCC when compared to c-TACE. It is a safe and promising approach and should potentially be considered as a standard of care in the management of unresectable HCC.

Matched MeSH terms: Survival Rate
MSCs can be differentially isolated from maternal, middle and fetal segments of the human umbilical cord

Lim J, Razi ZR, Law J, Nawi AM, Idrus RB, Ng MH

Cytotherapy, 2016 12;18(12):1493-1502.
PMID: 27727016 DOI: 10.1016/j.jcyt.2016.08.003

BACKGROUND AIMS: Human Wharton's jelly-derived mesenchymal stromal cells (hWJMSCs) are possibly the most suitable allogeneic cell source for stromal cell therapy and tissue engineering applications because of their hypo-immunogenic and non-tumorigenic properties, easy availability and minimal ethical concerns. Furthermore, hWJMSCs possess unique properties of both adult mesenchymal stromal cells and embryonic stromal cells. The human umbilical cord (UC) is approximately 50-60 cm long and the existing studies in the literature have not provided information on which segment of the UC was studied. In this study, hWJMSCs derived from three anatomical segments of the UC are compared.
METHODS: Three segments of the whole UC, each 3 cm in length, were identified anatomically as the maternal, middle and fetal segments. The hWJMSCs from the different segments were analyzed via trypan blue exclusion assay to determine the growth kinetics and cell viability, flow cytometry for immunophenotyping and immunofluorescence and reverse transcriptase polymerase chain reaction (RT-PCR) for expression of stromal cell transcriptional factors. Furthermore, the trilineage differentiation potential (osteogenic, adipogenic and chondrogenic) of these cells was also assessed.
RESULTS: hWJMSCs isolated from the maternal and fetal segments displayed greater viability and possessed a significantly higher proliferation rate compared with cells from the middle segment. Immunophenotyping revealed that hWJMSCs derived from all three segments expressed the MSC markers CD105, CD73, CD90, CD44, CD13 and CD29, as well as HLA-ABC and HLA-DR, but were negative for hematopoietic markers CD14, CD34 and CD45. Analysis of the embryonic markers showed that all three segments expressed Nanog and Oct 3/4, but only the maternal and fetal segments expressed SSEA 4 and TRA-160. Cells from all three segments were able to differentiate into chondrogenic, osteogenic and adipogenic lineages with the middle segments showing much lower differentiation potential compared with the other two segments.
CONCLUSIONS: hWJMSCs derived from the maternal and fetal segments of the UC are a good source of MSCs compared with cells from the middle segment because of their higher proliferation rate and viability. Fetal and maternal segments are the preferred cell source for bone regeneration.

Matched MeSH terms: Cell Survival
Conversion to shockable rhythms during resuscitation and survival for out-of hospital cardiac arrest

Wah W, Wai KL, Pek PP, Ho AFW, Alsakaf O, Chia MYC, et al.

Am J Emerg Med, 2017 Feb;35(2):206-213.
PMID: 27810251 DOI: 10.1016/j.ajem.2016.10.042

BACKGROUND: In out of hospital cardiac arrest (OHCA), the prognostic influence of conversion to shockable rhythms during resuscitation for initially non-shockable rhythms remains unknown. This study aimed to assess the relationship between initial and subsequent shockable rhythm and post-arrest survival and neurological outcomes after OHCA.
METHODOLOGY: This was a retrospective analysis of all OHCA cases collected from the Pan-Asian Resuscitation Outcomes Study (PAROS) registry in 7 countries in Asia between 2009 and 2012. We included OHCA cases of presumed cardiac etiology, aged 18-years and above and resuscitation attempted by EMS. We performed multivariate logistic regression analyses to assess the relationship between initial and subsequent shockable rhythm and survival and neurological outcomes. 2-stage seemingly unrelated bivariate probit models were developed to jointly model the survival and neurological outcomes. We adjusted for the clustering effects of country variance in all models.
RESULTS: 40,160 OHCA cases met the inclusion criteria. There were 5356 OHCA cases (13.3%) with initial shockable rhythm and 33,974 (84.7%) with initial non-shockable rhythm. After adjustment of baseline and prehospital characteristics, OHCA with initial shockable rhythm (odds ratio/OR=6.10, 95% confidence interval/CI=5.06-7.34) and subsequent conversion to shockable rhythm (OR=2.00,95%CI=1.10-3.65) independently predicted better survival-to-hospital-discharge outcomes. Subsequent shockable rhythm conversion significantly improved survival-to-admission, discharge and post-arrest overall and cerebral performance outcomes in the multivariate logistic regression and 2-stage analyses.
CONCLUSION: Initial shockable rhythm was the strongest predictor for survival. However, conversion to subsequent shockable rhythm significantly improved post-arrest survival and neurological outcomes. This study suggests the importance of early resuscitation efforts even for initially non-shockable rhythms which has prognostic implications and selection of subsequent post-resuscitation therapy.

Matched MeSH terms: Survival Analysis
Systemic inflammatory response syndrome in acute-on-chronic liver failure: Relevance of 'golden window': A prospective study

Choudhury A, Kumar M, Sharma BC, Maiwall R, Pamecha V, Moreau R, et al.

J Gastroenterol Hepatol, 2017 Dec;32(12):1989-1997.
PMID: 28374414 DOI: 10.1111/jgh.13799

BACKGROUND AND AIM: Systemic inflammatory response syndrome (SIRS) is an early marker of sepsis and ongoing inflammation and has been reported in large proportion of acute-on-chronic liver failure (ACLF) patients. Whether sepsis is the cause or the result of liver failure is unclear and is vital to know. To address this, the study investigated the course and outcome of ACLF patients without SIRS/sepsis.
METHODS: Consecutive ACLF patients were monitored for the development of SIRS/sepsis and associated complications and followed till 90 days, liver transplant or death.
RESULTS: Of 561 patients, 201 (35.8%) had no SIRS and 360 (64.2%) had SIRS with or without infection. New onset SIRS and sepsis developed in 74.6% and 8% respectively in a median of 7 (range 4-15) days, at a rate of 11% per day. The cumulative incidence of new SIRS was 29%, 92.8%, and 100% by days 4, 7, and 15. Liver failure, that is, bilirubin > 12 mg/dL (odds ratio [OR] = 2.5 [95% confidence interval {CI} = 1.05-6.19], P = 0.04) at days 0 and 4, and renal failure at day 4 (OR = 6.74 [95%CI = 1.50-13.29], P = 0.01), independently predicted new onset SIRS. Absence of SIRS in the first week was associated with reduced incidence of organ failure (20% vs 39.4%, P = 0.003), as was the 28-day (17.6% vs 36%, P = 0.02) and 90-day (27.5% vs 51%,P = 0.002) mortality. The 90-day mortality was 61.6% in the total cohort and that for those having no SIRS and SIRS at presentation were 42.8% and 65%, respectively (P

Matched MeSH terms: Survival Rate
Nephrology in the Oceania-South East Asia region: perspectives and challenges

Kerr PG, Tran HTB, Ha Phan HA, Liew A, Hooi LS, Johnson DW, et al.

Kidney Int, 2018 09;94(3):465-470.
PMID: 30045813 DOI: 10.1016/j.kint.2018.05.014
Matched MeSH terms: Survival Rate
Development of an In Vitro Cardiac Ischemic Model Using Primary Human Cardiomyocytes

Hafez P, Chowdhury SR, Jose S, Law JX, Ruszymah BHI, Mohd Ramzisham AR, et al.

Cardiovasc Eng Technol, 2018 09;9(3):529-538.
PMID: 29948837 DOI: 10.1007/s13239-018-0368-8

Developing experimental models to study ischemic heart disease is necessary for understanding of biological mechanisms to improve the therapeutic approaches for restoring cardiomyocytes function following injury. The aim of this study was to develop an in vitro hypoxic/re-oxygenation model of ischemia using primary human cardiomyocytes (HCM) and define subsequent cytotoxic effects. HCM were cultured in serum and glucose free medium in hypoxic condition with 1% O2 ranging from 30 min to 12 h. The optimal hypoxic exposure time was determined using Hypoxia Inducible Factor 1α (HIF-1α) as the hypoxic marker. Subsequently, the cells were moved to normoxic condition for 3, 6 and 9 h to replicate the re-oxygenation phase. Optimal period of hypoxic/re-oxygenation was determined based on 50% mitochondrial injury via 3-(4,5-dimethylthiazol-2-Yl)-2,5-diphenyltetrazolium bromide assay and cytotoxicity via lactate dehydrogenase (LDH) assay. It was found that the number of cells expressing HIF-1α increased with hypoxic time and 3 h was sufficient to stimulate the expression of this marker in all the cells. Upon re-oxygenation, mitochondrial activity reduced significantly whereas the cytotoxicity increased significantly with time. Six hours of re-oxygenation was optimal to induce reversible cell injury. The injury became irreversible after 9 h as indicated by > 60% LDH leakage compared to the control group cultured in normal condition. Under optimized hypoxic reoxygenation experimental conditions, mesenchymal stem cells formed nanotube with ischemic HCM and facilitated transfer of mitochondria suggesting the feasibility of using this as a model system to study molecular mechanisms of myocardial injury and rescue.

Matched MeSH terms: Cell Survival

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