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1.  Broad targeting of resistance to apoptosis in cancer 
Seminars in cancer biology  2015;35(0):S78-S103.
Apoptosis or programmed cell death is natural way of removing aged cells from the body. Most of the anti-cancer therapies trigger apoptosis induction and related cell death networks to eliminate malignant cells. However, in cancer, de-regulated apoptotic signaling, particularly the activation of an anti-apoptotic systems, allows cancer cells to escape this program leading to uncontrolled proliferation resulting in tumor survival, therapeutic resistance and recurrence of cancer. This resistance is a complicated phenomenon that emanates from the interactions of various molecules and signaling pathways. In this comprehensive review we discuss the various factors contributing to apoptosis resistance in cancers. The key resistance targets that are discussed include (1) Bcl-2 and Mcl-1 proteins; (2) autophagy processes; (3) necrosis and necroptosis; (4) heat shock protein signaling; (5) the proteasome pathway; (6) epigenetic mechanisms; and (7) aberrant nuclear export signaling. The shortcomings of current therapeutic modalities are highlighted and a broad spectrum strategy using approaches including (a) gossypol; (b) epigallocatechin-3-gallate; (c) UMI-77 (d) triptolide and (e) selinexor that can be used to overcome cell death resistance is presented. This review provides a roadmap for the design of successful anti-cancer strategies that overcome resistance to apoptosis for better therapeutic outcome in patients with cancer.
PMCID: PMC4720504  PMID: 25936818
Apoptosis; Necrosis; Autophagy; Apoptosis evasion; Nuclear transporters; natural; chemopreventive agents
2.  A Broad-Spectrum Integrative Design for Cancer Prevention and Therapy 
Block, Keith I. | Gyllenhaal, Charlotte | Lowe, Leroy | Amedei, Amedeo | Amin, A.R.M. Ruhul | Amin, Amr | Aquilano, Katia | Arbiser, Jack | Arreola, Alexandra | Arzumanyan, Alla | Ashraf, S. Salman | Azmi, Asfar S. | Benencia, Fabian | Bhakta, Dipita | Bilsland, Alan | Bishayee, Anupam | Blain, Stacy W. | Block, Penny B. | Boosani, Chandra S. | Carey, Thomas E. | Carnero, Amancio | Carotenuto, Marianeve | Casey, Stephanie C. | Chakrabarti, Mrinmay | Chaturvedi, Rupesh | Chen, Georgia Zhuo | Chen, Helen | Chen, Sophie | Chen, Yi Charlie | Choi, Beom K. | Ciriolo, Maria Rosa | Coley, Helen M. | Collins, Andrew R. | Connell, Marisa | Crawford, Sarah | Curran, Colleen S. | Dabrosin, Charlotta | Damia, Giovanna | Dasgupta, Santanu | DeBerardinis, Ralph J. | Decker, William K. | Dhawan, Punita | Diehl, Anna Mae E. | Dong, Jin-Tang | Dou, Q. Ping | Drew, Janice E. | Elkord, Eyad | El-Rayes, Bassel | Feitelson, Mark A. | Felsher, Dean W. | Ferguson, Lynnette R | Fimognari, Carmela | Firestone, Gary L. | Frezza, Christian | Fujii, Hiromasa | Fuster, Mark M. | Generali, Daniele | Georgakilas, Alexandros G. | Gieseler, Frank | Gilbertson, Michael | Green, Michelle F. | Grue, Brendan | Guha, Gunjan | Halicka, Dorota | Helferich, William G. | Heneberg, Petr | Hentosh, Patricia | Hirschey, Matthew D. | Hofseth, Lorne J. | Holcombe, Randall F. | Honoki, Kanya | Hsu, Hsue-Yin | Huang, Gloria S. | Jensen, Lasse D. | Jiang, Wen G. | Jones, Lee W. | Karpowicz, Phillip A. | Keith, W Nicol | Kerkar, Sid P. | Khan, Gazala N. | Khatami, Mahin | Ko, Young H. | Kucuk, Omer | Kulathinal, Rob J. | Kumar, Nagi B. | Kumara, H.M.C. Shantha | Kwon, Byoung S. | Le, Anne | Lea, Michael A. | Lee, Ho-Young | Lichtor, Terry | Lin, Liang-Tzung | Locasale, Jason W. | Lokeshwar, Bal L. | Longo, Valter D. | Lyssiotis, Costas A. | MacKenzie, Karen L. | Malhotra, Meenakshi | Marino, Maria | Martinez-Chantar, Maria L. | Matheu, Ander | Maxwell, Christopher | McDonnell, Eoin | Meeker, Alan K. | Mehrmohamadi, Mahya | Mehta, Kapil | Michelotti, Gregory A. | Mohammad, Ramzi M. | Mohammed, Sulma I. | Morre, D. James | Muqbil, Irfana | Muralidhar, Vinayak | Murphy, Michael P. | Nagaraju, Ganji Purnachandra | Nahta, Rita | Niccolai, Elena | Nowsheen, Somaira | Panis, Carolina | Pantano, Francesco | Parslow, Virginia R. | Pawelec, Graham | Pedersen, Peter L. | Poore, Brad | Poudyal, Deepak | Prakash, Satya | Prince, Mark | Raffaghello, Lizzia | Rathmell, Jeffrey C. | Rathmell, W. Kimryn | Ray, Swapan K. | Reichrath, Jörg | Rezazadeh, Sarallah | Ribatti, Domenico | Ricciardiello, Luigi | Robey, R. Brooks | Rodier, Francis | Rupasinghe, H.P. Vasantha | Russo, Gian Luigi | Ryan, Elizabeth P. | Samadi, Abbas K. | Sanchez-Garcia, Isidro | Sanders, Andrew J. | Santini, Daniele | Sarkar, Malancha | Sasada, Tetsuro | Saxena, Neeraj K. | Shackelford, Rodney E | Sharma, Dipali | Shin, Dong M. | Sidransky, David | Siegelin, Markus David | Signori, Emanuela | Singh, Neetu | Sivanand, Sharanya | Sliva, Daniel | Smythe, Carl | Spagnuolo, Carmela | Stafforini, Diana M. | Stagg, John | Subbarayan, Pochi R. | Sundin, Tabetha | Talib, Wamidh H. | Thompson, Sarah K. | Tran, Phuoc T. | Ungefroren, Hendrik | Vander Heiden, Matthew G. | Venkateswaran, Vasundara | Vinay, Dass S. | Vlachostergios, Panagiotis J. | Wang, Zongwei | Wellen, Kathryn E. | Whelan, Richard L. | Yang, Eddy S. | Yang, Huanjie | Yang, Xujuan | Yaswen, Paul | Yedjou, Clement | Yin, Xin | Zhu, Jiyue | Zollo, Massimo
Seminars in cancer biology  2015;35(Suppl):S276-S304.
Targeted therapies and the consequent adoption of “personalized” oncology have achieved notable successes in some cancers; however, significant problems remain with this approach. Many targeted therapies are highly toxic, costs are extremely high, and most patients experience relapse after a few disease-free months. Relapses arise from genetic heterogeneity in tumors, which harbor therapy-resistant immortalized cells that have adopted alternate and compensatory pathways (i.e., pathways that are not reliant upon the same mechanisms as those which have been targeted). To address these limitations, an international task force of 180 scientists was assembled to explore the concept of a low-toxicity “broad-spectrum” therapeutic approach that could simultaneously target many key pathways and mechanisms. Using cancer hallmark phenotypes and the tumor microenvironment to account for the various aspects of relevant cancer biology, interdisciplinary teams reviewed each hallmark area and nominated a wide range of high-priority targets (74 in total) that could be modified to improve patient outcomes. For these targets, corresponding low-toxicity therapeutic approaches were then suggested; many of which were phytochemicals. Proposed actions on each target and all of the approaches were further reviewed for known effects on other hallmark areas and the tumor microenvironment. Potential contrary or procarcinogenic effects were found for 3.9% of the relationships between targets and hallmarks, and mixed evidence of complementary and contrary relationships was found for 7.1%. Approximately 67% of the relationships revealed potentially complementary effects, and the remainder had no known relationship. Among the approaches, 1.1% had contrary, 2.8% had mixed and 62.1% had complementary relationships. These results suggest that a broad-spectrum approach should be feasible from a safety standpoint. This novel approach has potential to help us address disease relapse, which is a substantial and longstanding problem, so a proposed agenda for future research is offered.
PMCID: PMC4819002  PMID: 26590477
Multi-targeted; cancer hallmarks; phytochemicals; targeted therapy; integrative medicine
3.  Anti-Human Platelet Antigen-1a Immunoglobulin G Preparation Intended to Prevent Fetal and Neonatal Alloimmune Thrombocytopenia 
PLoS ONE  2016;11(9):e0162973.
Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a severe disease that is caused by maternal alloantibodies generated during pregnancy or at delivery as a result of incompatibility between maternal and fetal human platelet antigens (HPAs) inherited from the father. Antibody-mediated immune suppression using anti-HPA-1a immunoglobulins is thought to be able to prevent FNAIT caused by HPA-1a. A fractionation process to prepare anti-HPA-1a immunoglobulin (Ig) G (IgG) from human plasma was therefore developed. Anti-HPA-1a plasma was obtained from volunteer mothers who underwent alloimmunization against HPA-1a during a previous pregnancy. Plasma was cryoprecipitated and the supernatant treated with caprylic acid and solvent/detergent (S/D), purified by chromatography, nanofiltered, concentrated, and sterile-filtered. The anti-HPA-1a immunoglobulin fraction was characterized for purity and safety. PAK12 and quantitative monoclonal antibody immobilization of platelet antigen (MAIPA) assays were used to detect anti-HPA-1a IgG. Hepatitis C virus (HCV) removal during nanofiltration was assessed by spiking experiments, using cell culture-derived reporter HCV and luciferase analysis. The caprylic acid treatment precipitated non-Ig proteins yielding a 90% pure Ig supernatant. S-HyperCel chromatography of the S/D-treated supernatant followed by HyperCel STAR AX provided high IgG recovery (>80%) and purity (>99.5%), and efficient IgA and IgM removal. Concentrations of complement factors C3 and C4 were < 0.5 and < 0.4 mg/dL, respectively. The final IgG could be nanofiltered on Planova 20N under conditions removing more than 3 log HCV infectivity to baseline mock infection level, and concentrated to ca. 30 g/L. Proteolytic activity and thrombin generation were low in the final fraction. The Pak12 and MAIPA assays showed good recovery of anti-HPA-1a throughout the process. Clinical-grade HPA-1a IgG can be prepared using a process compliant with current quality requirements opening perspectives for the prevention of FNAIT.
PMCID: PMC5023090  PMID: 27627660
4.  The Host Cell Receptors for Measles Virus and Their Interaction with the Viral Hemagglutinin (H) Protein 
Viruses  2016;8(9):250.
The hemagglutinin (H) protein of measles virus (MeV) interacts with a cellular receptor which constitutes the initial stage of infection. Binding of H to this host cell receptor subsequently triggers the F protein to activate fusion between virus and host plasma membranes. The search for MeV receptors began with vaccine/laboratory virus strains and evolved to more relevant receptors used by wild-type MeV. Vaccine or laboratory strains of measles virus have been adapted to grow in common cell lines such as Vero and HeLa cells, and were found to use membrane cofactor protein (CD46) as a receptor. CD46 is a regulator that normally prevents cells from complement-mediated self-destruction, and is found on the surface of all human cells, with the exception of erythrocytes. Mutations in the H protein, which occur during adaptation and allow the virus to use CD46 as a receptor, have been identified. Wild-type isolates of measles virus cannot use the CD46 receptor. However, both vaccine/laboratory and wild-type strains can use an immune cell receptor called signaling lymphocyte activation molecule family member 1 (SLAMF1; also called CD150) and a recently discovered epithelial receptor known as Nectin-4. SLAMF1 is found on activated B, T, dendritic, and monocyte cells, and is the initial target for infections by measles virus. Nectin-4 is an adherens junction protein found at the basal surfaces of many polarized epithelial cells, including those of the airways. It is also over-expressed on the apical and basal surfaces of many adenocarcinomas, and is a cancer marker for metastasis and tumor survival. Nectin-4 is a secondary exit receptor which allows measles virus to replicate and amplify in the airways, where the virus is expelled from the body in aerosol droplets. The amino acid residues of H protein that are involved in binding to each of the receptors have been identified through X-ray crystallography and site-specific mutagenesis. Recombinant measles “blind” to each of these receptors have been constructed, allowing the virus to selectively infect receptor specific cell lines. Finally, the observations that SLAMF1 is found on lymphomas and that Nectin-4 is expressed on the cell surfaces of many adenocarcinomas highlight the potential of measles virus for oncolytic therapy. Although CD46 is also upregulated on many tumors, it is less useful as a target for cancer therapy, since normal human cells express this protein on their surfaces.
PMCID: PMC5035964  PMID: 27657109
measles virus; membrane cofactor protein; CD46; signaling lymphocyte activation molecule family member 1; SLAMF1; SLAM; CD150; nectin-4; polio virus receptor like protein 4; PVRL4
5.  Association between hyperglycaemic crisis and long-term major adverse cardiovascular events: a nationwide population-based, propensity score-matched, cohort study 
BMJ Open  2016;6(8):e012233.
Hyperglycaemic crisis was associated with significant intrahospital morbidity and mortality. However, the association between hyperglycaemic crisis and long-term cardiovascular outcomes remained unknown. This study aimed to investigate the association between hyperglycaemic crisis and subsequent long-term major adverse cardiovascular events (MACEs).
Participants and methods
This population-based cohort study was conducted using data from Taiwan's National Health Insurance Research Database for the period of 1996–2012. A total of 2171 diabetic patients with hyperglycaemic crisis fit the inclusion criteria. Propensity score matching was used to match the baseline characteristics of the study cohort to construct a comparison cohort which comprised 8684 diabetic patients without hyperglycaemic crisis. The risk of long-term MACEs was compared between the two cohorts.
Six hundred and seventy-six MACEs occurred in the study cohort and the event rate was higher than that in the comparison cohort (31.1% vs 24.1%, p<0.001). Patients with hyperglycaemic crisis were associated with a higher risk of long-term MACEs even after adjusting for all baseline characteristics and medications (adjusted HR=1.76, 95% CI 1.62 to 1.92, p<0.001). Acute myocardial infarction had the highest adjusted HR (adjusted HR=2.19, 95% CI 1.75 to 2.75, p<0.001) in the four types of MACEs, followed by congestive heart failure (adjusted HR=1.97, 95% CI 1.70 to 2.28, p<0.001). Younger patients with hyperglycaemic crisis had a higher risk of MACEs than older patients (adjusted HR=2.69 for patients aged 20–39 years vs adjusted HR=1.58 for patients aged >65 years).
Hyperglycaemic crisis was significantly associated with long-term MACEs, especially in the young population. Further prospective longitudinal study should be conducted for validation.
PMCID: PMC5013487  PMID: 27554106
diabetic ketoacidosis; hyperglycemic crisis; hyperglycemic hyperosmolar status; major adverse cardiovascular event
6.  Murine tribbles homolog 2 deficiency affects erythroid progenitor development and confers macrocytic anemia on mice 
Scientific Reports  2016;6:31444.
Tribbles homolog 2 (Trib2) is a member of Tribbles protein pseudokinases and involves in apoptosis, autoimmunity, cancer, leukemia and erythropoiesis, however, the physiological function of Trib2 in hematopoietic system remains to be elucidated. Here, we report that Trib2 knockout (KO) mice manifest macrocytic anemia and increase of T lymphocytes. Although Trib2 deficient RBCs have similar half-life as the control RBCs, Trib2 KO mice are highly vulnerable to oxidant-induced hemolysis. Endogenous Trib2 mRNA is expressed in early hematopoietic progenitors, erythroid precursors, and lymphoid lineages, but not in mature RBCs, myeloid progenitors and granulocytes. Consistently, flow cytometric analysis and in vitro colony forming assay revealed that deletion of Trib2 mainly affected erythroid lineage development, and had no effect on either granulocyte or megakaryocyte lineages in bone marrow. Furthermore, a genetic approach using double knockout of Trib2 and C/ebpα genes in mice suggested that Trib2 promotes erythropoiesis independent of C/ebpα proteins in vivo. Finally, ectopic expression of human Trib2 in zebrafish embryos resulted in increased expression of erythropoiesis-related genes and of hemoglobin. Taking all data together, our results suggest that Trib2 positively promotes early erythrocyte differentiation and is essential for tolerance to hemolysis.
PMCID: PMC4994003  PMID: 27550848
7.  (4R,6S)-2-Dihydromenisdaurilide is a Butenolide that Efficiently Inhibits Hepatitis C Virus Entry 
Scientific Reports  2016;6:29969.
Without a vaccine, hepatitis C virus (HCV) remains a significant threat, putting 170–300 million carriers worldwide at risk of cirrhosis and hepatocellular carcinoma. Although the direct-acting antivirals targeting HCV replication have revolutionized the treatment of hepatitis C, several obstacles persist, including resistance development, potential side-effects, and the prohibitive cost that limits their availability. Furthermore, treatment of HCV re-infection in liver transplantation remains a significant challenge. Developing novel antivirals that target viral entry could help expand the scope of HCV therapeutics and treatment strategies. Herein, we report (4R,6S)-2-dihydromenisdaurilide (DHMD), a natural butenolide, as an efficient inhibitor of HCV entry. Specifically, DHMD potently inhibited HCV infection at non-cytotoxic concentration. Examination on the viral life cycle demonstrated that DHMD selectively targeted the early steps of infection while leaving viral replication/translation and assembly/release unaffected. Furthermore, DHMD did not induce an antiviral interferon response. Mechanistic dissection of HCV entry revealed that DHMD could inactivate cell-free virus, abrogate viral attachment, and inhibit viral entry/fusion, with the most pronounced effect observed against the viral adsorption phase as validated using ELISA and confocal microscopy. Due to its potency, DHMD may be of value for further development as an entry inhibitor against HCV, particularly for application in transplant setting.
PMCID: PMC4947960  PMID: 27426693
8.  Antibodies against Venom of the Snake Deinagkistrodon acutus 
Snake venom protein from Deinagkistrodon acutus (DA protein), one of the major venomous species in Taiwan, causes hemorrhagic symptoms that can lead to death. Although horse-derived antivenin is a major treatment, relatively strong and detrimental side effects are seen occasionally. In our study, yolk immunoglobulin (IgY) was purified from eggs, and DA protein was recognized using Western blotting and an enzyme-linked immunosorbent assay (ELISA), similar to therapeutic horse antivenin. The ELISA also indicated that specific IgY antibodies were elicited after the fifth booster, plateaued, and lasted for at least 3 months. To generate monoclonal single-chain variable fragment (scFv) antibodies, we used phage display technology to construct two libraries with short or long linkers, containing 6.24 × 108 and 5.28 × 108 transformants, respectively. After four rounds of biopanning, the eluted phage titer increased, and the phage-based ELISA indicated that the specific clones were enriched. Nucleotide sequences of 30 individual clones expressing scFv were analyzed and classified into four groups that all specifically recognized the DA venom protein. Furthermore, based on mass spectrometry, the scFv-bound protein was deduced to be snake venom metalloproteinase proteins. Most importantly, both IgY and mixed scFv inhibited the lethal effect in mice injected with the minimum lethal dosage of the DA protein. We suggest that together, these antibodies could be applied to the development of diagnostic agents or treatments for snakebite envenomation in the future.
PMCID: PMC4702639  PMID: 26475102
9.  Microglia retard dengue virus-induced acute viral encephalitis 
Scientific Reports  2016;6:27670.
Patients with dengue virus (DENV) infection may also present acute viral encephalitis through an unknown mechanism. Here, we report that encephalitic DENV-infected mice exhibited progressive hunchback posture, limbic seizures, limbic weakness, paralysis, and lethality 7 days post-infection. These symptoms were accompanied by CNS inflammation, neurotoxicity, and blood-brain barrier destruction. Microglial cells surrounding the blood vessels and injured hippocampus regions were activated by DENV infection. Pharmacologically depleting microglia unexpectedly increased viral replication, neuropathy, and mortality in DENV-infected mice. In microglia-depleted mice, the DENV infection-mediated expression of antiviral cytokines and the infiltration of CD8-positive cytotoxic T lymphocytes (CTLs) was abolished. DENV infection prompted the antigen-presenting cell-like differentiation of microglia, which in turn stimulated CTL proliferation and activation. These results suggest that microglial cells play a key role in facilitating antiviral immune responses against DENV infection and acute viral encephalitis.
PMCID: PMC4899773  PMID: 27279150
10.  Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: focus on the cancer hallmark of tumor angiogenesis 
Carcinogenesis  2015;36(Suppl 1):S184-S202.
Angiogenesis is an important ‘hallmark’ of cancer. We reviewed the various pathways controlling angiogenesis, summarized the possible role of specific environmental chemicals disrupting these pathways and listed assays for assessing the effects of low-dose exposures to chemicals in promoting tumor angiogenesis.
One of the important ‘hallmarks’ of cancer is angiogenesis, which is the process of formation of new blood vessels that are necessary for tumor expansion, invasion and metastasis. Under normal physiological conditions, angiogenesis is well balanced and controlled by endogenous proangiogenic factors and antiangiogenic factors. However, factors produced by cancer cells, cancer stem cells and other cell types in the tumor stroma can disrupt the balance so that the tumor microenvironment favors tumor angiogenesis. These factors include vascular endothelial growth factor, endothelial tissue factor and other membrane bound receptors that mediate multiple intracellular signaling pathways that contribute to tumor angiogenesis. Though environmental exposures to certain chemicals have been found to initiate and promote tumor development, the role of these exposures (particularly to low doses of multiple substances), is largely unknown in relation to tumor angiogenesis. This review summarizes the evidence of the role of environmental chemical bioactivity and exposure in tumor angiogenesis and carcinogenesis. We identify a number of ubiquitous (prototypical) chemicals with disruptive potential that may warrant further investigation given their selectivity for high-throughput screening assay targets associated with proangiogenic pathways. We also consider the cross-hallmark relationships of a number of important angiogenic pathway targets with other cancer hallmarks and we make recommendations for future research. Understanding of the role of low-dose exposure of chemicals with disruptive potential could help us refine our approach to cancer risk assessment, and may ultimately aid in preventing cancer by reducing or eliminating exposures to synergistic mixtures of chemicals with carcinogenic potential.
PMCID: PMC4492067  PMID: 26106137
11.  Effect of ketamine combined with butorphanol on emergence agitation of postoperative patients with gastric cancer 
This study aimed to investigate the effect of ketamine combined with butorphanol on emergence agitation (EA) in postoperative gastric cancer patients.
Materials and methods
A total of 150 patients with gastric cancer were included and divided into group B (1 mg butorphanol before anesthesia induction, n=50), group K (1 mg/kg ketamine, n=50), and group C (1 mg butorphanol combined with 1 mg/kg ketamine, n=50). Mean arterial pressure (MAP) and heart rate (HR) at the end of operation, just before extubation (T0) and at 0 minute (T1), 5 minutes (T2), and 30 minutes (T3) after extubation were compared. Statistical analysis of recovery time, extubation time, time in postanesthesia care unit, and EA incidence and adverse reactions were performed.
There were no differences among groups with respect to MAP and HR at T0 and T1 (P>0.05). Compared with patients in group C, significant reduction of MAP and HR were observed in groups K and B at T2 and T3 (P<0.05), while no differences were found between group K and group B (P>0.05). Recovery time, extubation time, time in postanesthesia care unit, and incidence of EA in group C were significantly less than those in groups K and B (P<0.05), but no differences were observed between group K and group B (P>0.05). Total incidence of adverse reactions were significantly increased in group K compared to those in groups C and B (P<0.05).
Injection of ketamine combined with butorphanol before anesthesia induction was more effective than injection of ketamine or butorphanol separately in the prevention of EA.
PMCID: PMC4863591  PMID: 27217761
emergence agitation; ketamine; butorphanol; gastric cancer
12.  A case of adrenal Cushing’s syndrome with bilateral adrenal masses 
A functional lesion in corticotrophin (ACTH)-independent Cushing’s syndrome is difficult to distinguish from lesions of bilateral adrenal masses. Methods for distinguishing these lesions include adrenal venous sampling and 131I-6β-iodomethyl-19-norcholesterol (131I-NP-59) scintigraphy. We present a case of a 29-year-old Han Chinese female patient with a history of hypercholesterolaemia and polycystic ovary syndrome. She presented with a 6month history of an 8kg body weight gain and gradual rounding of the face. Serial examinations revealed loss of circadian rhythm of cortisol, elevated urinary free-cortisol level and undetectable ACTH level (<5pg/mL). No suppression was observed in both the low- and high-dose dexamethasone suppression tests. Adrenal computed tomography revealed bilateral adrenal masses. Adrenal venous sampling was performed, and the right-to-left lateralisation ratio was 14.29. The finding from adrenal scintigraphy with NP-59 was consistent with right adrenal adenoma. The patient underwent laparoscopic right adrenalectomy, and the pathology report showed adrenocortical adenoma. Her postoperative cortisol level was 3.2μg/dL, and her Cushingoid appearance improved. In sum, both adrenal venous sampling and 131I-NP-59 scintigraphy are good diagnostic methods for Cushing’s syndrome presenting with bilateral adrenal masses.
Learning points
The clinical presentation of Cushing’ syndrome includes symptoms and signs of fat redistribution and protein-wasting features.The diagnosis of patients with ACTH-independent Cushing’s syndrome with bilateral adrenal masses is challenging for localisation of the lesion.Both adrenal venous sampling and 131I-NP-59 scintigraphy are good methods to use in these patients with Cushing’s syndrome presenting with bilateral adrenal masses.
PMCID: PMC4870494  PMID: 27252858
13.  Reelin promotes the adhesion and drug resistance of multiple myeloma cells via integrin β1 signaling and STAT3 
Oncotarget  2016;7(9):9844-9858.
Reelin is an extracellular matrix (ECM) protein that is essential for neuron migration and positioning. The expression of reelin in multiple myeloma (MM) cells and its association with cell adhesion and survival were investigated. Overexpression, siRNA knockdown, and the addition of recombinant protein of reelin were used to examine the function of reelin in MM cells. Clinically, high expression of reelin was negatively associated with progression-free survival and overall survival. Functionally, reelin promoted the adhesion of MM cells to fibronectin via activation of α5β1 integrin. The resulting phosphorylation of Focal Adhesion Kinase (FAK) led to the activation of Src/Syk/STAT3 and Akt, crucial signaling molecules involved in enhancing cell adhesion and protecting cells from drug-induced cell apoptosis. These findings indicate reelin's important role in the activation of integrin-β1 and STAT3/Akt pathways in multiple myeloma and highlight the therapeutic potential of targeting reelin/integrin/FAK axis.
PMCID: PMC4891088  PMID: 26848618
multiple myeloma; reelin; adhesion; integrin; STAT3
14.  Splicing factor mutations predict poor prognosis in patients with de novo acute myeloid leukemia 
Oncotarget  2016;7(8):9084-9101.
Mutations in splicing factor (SF) genes are frequently detected in myelodysplastic syndrome, but the prognostic relevance of these genes mutations in acute myeloid leukemia (AML) remains unclear. In this study, we investigated mutations of three SF genes, SF3B1, U2AF1 and SRSF2, by Sanger sequencing in 500 patients with de novo AML and analysed their clinical relevance. SF mutations were identified in 10.8% of total cohort and 13.2% of those with intermediate-risk cytogenetics. SF mutations were closely associated with RUNX1, ASXL1, IDH2 and TET2 mutations. SF-mutated AML patients had a significantly lower complete remission rate and shorter disease-free survival (DFS) and overall survival (OS) than those without the mutation. Multivariate analysis demonstrated that SFmutation was an independent poor prognostic factor for DFS and OS. A scoring system incorporating SF mutation and ten other prognostic factors was proved very useful to risk-stratify AML patients. Sequential study of paired samples showed that SF mutations were stable during AML evolution. In conclusion, SF mutations are associated with distinct clinic-biological features and poor prognosis in de novo AML patients and are rather stable during disease progression. These mutations may be potential targets for novel treatment and biomarkers for disease monitoring in AML.
PMCID: PMC4891028  PMID: 26812887
de novo AML; splicing factor mutations; prognosis; paired sample
15.  Long-term antipsychotic treatment in schizophrenia: systematic review and network meta-analysis of randomised controlled trials 
BJPsych open  2016;2(1):59-66.
For treatment of patients diagnosed with schizophrenia, comparative long-term effectiveness of antipsychotic drugs to reduce relapses when minimising adverse effects is of clinical interest, hence prompting this review.
To evaluate the comparative long-term effectiveness of antipsychotic drugs.
We systematically searched electronic databases for reports of randomised controlled trials (RCTs) of antipsychotic monotherapy aimed at reducing relapse risks in schizophrenia. We conducted network meta-analysis of 18 antipsychotics and placebo.
Studies of 10 177 patients in 56 reports were included; treatment duration averaged 48 weeks (range 4–156). Olanzapine was significantly more effective than chlorpromazine (odds ratio (OR) 0.35, 95% CI 0.14–0.88) or haloperidol (OR=0.50, 95% CI 0.30–0.82); and fluphenazine decanoate was more effective than chlorpromazine (OR=0.31, 95% CI 0.11–0.88) in relapse reduction. Fluphenazine decanoate, haloperidol, haloperidol decanoate and trifluoperazine produced more extrapyramidal adverse effects than olanzapine or quetiapine; and olanzapine was associated with more weight gain than other agents.
Except for apparent superiority of olanzapine and fluphenazine decanoate over chlorpromazine, most agents showed intermediate efficacy for relapse prevention and differences among them were minor. Typical antipsychotics yielded adverse neurological effects, and olanzapine was associated with weight gain. The findings may contribute to evidence-based treatment selection for patients with chronic psychotic disorders.
Declaration of interest
R.J.B. received grants from the Bruce J. Anderson Foundation and the McLean Private Donors Psychopharmacology Research Fund.
Copyright and usage
© The Royal College of Psychiatrists 2016. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) licence.
PMCID: PMC4995551  PMID: 27703755
16.  Typing Discrepancy Between Phenotypic and Molecular Characterization Revealing an Emerging Biovar 9 Variant of Smooth Phage-Resistant B. abortus Strain 8416 in China 
A newly isolated smooth colony morphology phage-resistant strain 8416 isolated from a 45-year-old cattle farm cleaner with clinical features of brucellosis in China was reported. The most unusual phenotype was its resistance to two Brucella phages Tbilisi and Weybridge, but sensitive to Berkeley 2, a pattern similar to that of Brucella melitensis biovar 1. VITEK 2 biochemical identification system found that both strain 8416 and B. melitensis strains shared positive ILATk, but negative in other B. abortus strains. However, routine biochemical and phenotypic characteristics of strain 8416 were most similar to that of B. abortus biovar 9 except CO2 requirement. In addition, multiple PCR molecular typing assays including AMOS-PCR, B. abortus special PCR (B-ab PCR) and a novel sub-biovar typing PCR, indicated that strain 8416 may belong to either biovar 3b or 9 of B. abortus. Surprisingly, further MLVA typing results showed that strain 8416 was most closely related to B. abortus biovar 3 in the Brucella MLVA database, primarily differing in 4 out of 16 screened loci. Therefore, due to the unusual discrepancy between phenotypic (biochemical reactions and particular phage lysis profile) and molecular typing characteristics, strain 8416 could not be exactly classified to any of the existing B. abortus biovars and might be a new variant of B. abortus biovar 9. The present study also indicates that the present phage typing scheme for Brucella sp. is subject to variation and the routine Brucella biovar typing needs further studies.
PMCID: PMC4672676  PMID: 26696984
B. abortus; smooth phage-resistant (SPR); MLVA typing; unusual biochemical reactions
17.  Zebrafish as a disease model for studying human hepatocellular carcinoma 
World Journal of Gastroenterology  2015;21(42):12042-12058.
Liver cancer is one of the world’s most common cancers and the second leading cause of cancer deaths. Hepatocellular carcinoma (HCC), a primary hepatic cancer, accounts for 90%-95% of liver cancer cases. The pathogenesis of HCC consists of a stepwise process of liver damage that extends over decades, due to hepatitis, fatty liver, fibrosis, and cirrhosis before developing fully into HCC. Multiple risk factors are highly correlated with HCC, including infection with the hepatitis B or C viruses, alcohol abuse, aflatoxin exposure, and metabolic diseases. Over the last decade, genetic alterations, which include the regulation of multiple oncogenes or tumor suppressor genes and the activation of tumorigenesis-related pathways, have also been identified as important factors in HCC. Recently, zebrafish have become an important living vertebrate model organism, especially for translational medical research. In studies focusing on the biology of cancer, carcinogen induced tumors in zebrafish were found to have many similarities to human tumors. Several zebrafish models have therefore been developed to provide insight into the pathogenesis of liver cancer and the related drug discovery and toxicology, and to enable the evaluation of novel small-molecule inhibitors. This review will focus on illustrative examples involving the application of zebrafish models to the study of human liver disease and HCC, through transgenesis, genome editing technology, xenografts, drug discovery, and drug-induced toxic liver injury.
PMCID: PMC4641123  PMID: 26576090
Cancer model; Hepatocellular carcinoma; Liver disease; Zebrafish; Drug screening
18.  sapFinder: an R/Bioconductor package for detection of variant peptides in shotgun proteomics experiments 
Bioinformatics  2014;30(21):3136-3138.
Summary: Single nucleotide variations (SNVs) located within a reading frame can result in single amino acid polymorphisms (SAPs), leading to alteration of the corresponding amino acid sequence as well as function of a protein. Accurate detection of SAPs is an important issue in proteomic analysis at the experimental and bioinformatic level. Herein, we present sapFinder, an R software package, for detection of the variant peptides based on tandem mass spectrometry (MS/MS)-based proteomics data. This package automates the construction of variation-associated databases from public SNV repositories or sample-specific next-generation sequencing (NGS) data and the identification of SAPs through database searching, post-processing and generation of HTML-based report with visualized interface.
Availability and implementation: sapFinder is implemented as a Bioconductor package in R. The package and the vignette can be downloaded at and are provided under a GPL-2 license.
Supplementary information: Supplementary data are available at Bioinformatics online.
PMCID: PMC4609003  PMID: 25053745
19.  The Ethanolic Extract of Taiwanofungus camphoratus (Antrodia camphorata) Induces Cell Cycle Arrest and Enhances Cytotoxicity of Cisplatin and Doxorubicin on Human Hepatocellular Carcinoma Cells 
BioMed Research International  2015;2015:415269.
Taiwanofungus camphoratus (synonym Antrodia camphorata) is a widely used medicinal fungus in the folk medicine of Taiwan with several pharmacological features such as anti-inflammatory, liver protection, antihypertensive, and antioxidative activities. The ethanolic extract of T. camphoratus (TCEE) which contains abundant bioactive compounds including triterpenoids and polysaccharides also has antitumor effects in various human cancer cell lines. The aims of this study are to clarify the antitumor effects of TCEE on human hepatocellular carcinoma cells and also evaluate the combination drug effects with conventional chemotherapy agents, cisplatin and doxorubicin. In the present study, the TCEE treatment induced cell cycle arrest and suppressed cell growth on both Hep3B and HepJ5 cells. Expression of cell cycle inhibitors, P21 and P27, and activation of apoptosis executer enzyme, caspase-3, were also induced by TCEE. In combination with the chemotherapy agents, TCEE treatment further enhanced the tumor suppression efficiency of cisplatin and doxorubicin. These results together suggested that TCEE is a potential ingredient for developing an integrated chemotherapy for human liver cancer.
PMCID: PMC4628761  PMID: 26557666
20.  Growth arrest DNA damage-inducible gene 45 gamma expression as a prognostic and predictive biomarker in hepatocellular carcinoma 
Oncotarget  2015;6(29):27953-27965.
Growth arrest DNA damage-inducible gene 45 (GADD45) family proteins play a crucial role in regulating cellular stress responses and apoptosis. The present study explored the prognostic and predictive role of GADD45γ in hepatocellular carcinoma (HCC) treatment. GADD45γ expression in HCC cells was examined using quantitative reverse transcription-PCR (qRT-PCR) and Western blotting. The control of GADD45γ transcription was examined using a luciferase reporter assay and chromatin immunoprecipitation. The in vivo induction of GADD45γ was performed using adenoviral transfer. The expression of GADD45γ in HCC tumor tissues from patients who had undergone curative resection was measured using qRT-PCR. Sorafenib induced expression of GADD45γ mRNA and protein, independent of its RAF kinase inhibitor activity. GADD45γ induction was more prominent in sorafenib-sensitive HCC cells (Huh-7 and HepG2, IC50 6–7 μM) than in sorafenib-resistant HCC cells (Hep3B, Huh-7R, and HepG2R, IC50 12–15 μM). Overexpression of GADD45γ reversed sorafenib resistance in vitro and in vivo, whereas GADD45γ expression knockdown by using siRNA partially abrogated the proapoptotic effects of sorafenib on sorafenib-sensitive cells. Overexpression of survivin in HCC cells abolished the antitumor enhancement between GADD45γ overexpression and sorafenib treatment, suggesting that survivin is a crucial mediator of antitumor effects of GADD45γ. GADD45γ expression decreased in tumors from patients with HCC who had undergone curative surgery, and low GADD45γ expression was an independent prognostic factor for poor survival, in addition to old age and vascular invasion. The preceding data indicate that GADD45γ suppression is a poor prognostic factor in patients with HCC and may help predict sorafenib efficacy in HCC.
PMCID: PMC4695037  PMID: 26172295
GADD45γ; hepatocellular carcinoma (HCC); sorafenib; CCAAT/enhancer binding protein (C/EBP); survivin
21.  Deoxyinosine repair in nuclear extracts of human cells 
Cell & Bioscience  2015;5:52.
Deamination of adenine can occur spontaneously under physiological conditions generating the highly mutagenic lesion, hypoxanthine. This process is enhanced by ROS from exposure of DNA to ionizing radiation, UV light, nitrous acid, or heat. Hypoxanthine in DNA can pair with cytosine which results in A:T to G:C transition mutations after DNA replication. In Escherichia coli, deoxyinosine (hypoxanthine deoxyribonucleotide, dI) is removed through an alternative excision repair pathway initiated by endonuclease V. However, the correction of dI in mammalian cells appears more complex and was not fully understood.
All four possible dI-containing heteroduplex DNAs, including A-I, C-I, G-I, and T-I were introduced to repair reactions containing extracts from human cells. The repair reaction requires magnesium, dNTPs, and ATP as cofactors. We found G-I was the best substrate followed by T-I, A-I and C-I, respectively. Moreover, judging from the repair requirements and sensitivity to specific polymerase inhibitors, there were overlapping repair activities in processing of dI in DNA. Indeed, a hereditable non-polyposis colorectal cancer cell line (HCT116) demonstrated lower dI repair activity that was partially attributed to lack of mismatch repair.
A plasmid-based convenient and non-radioisotopic method was created to study dI repair in human cells. Mutagenic dI lesions processed in vitro can be scored by restriction enzyme cleavage to evaluate the repair. The repair assay described in this study provides a good platform for further investigation of human repair pathways involved in dI processing and their biological significance in mutation prevention.
PMCID: PMC4563847  PMID: 26357532
Deoxyinosine repair; Mismatch repair; Human cell extracts; In vitro assay; DNA repair deficiency
22.  Clinical and Genetic Factors Associated With Thiazide-Induced Hyponatremia 
Medicine  2015;94(34):e1422.
Thiazide diuretics are associated with an increased risk of hyponatremia. The aim of this study was to investigate possible predictors of thiazide-induced hyponatremia.
A total of 48 patients admitted to the ward or to the emergency department due to severe thiazide-induced hyponatremia (Na < 125 mmol/L) were enrolled in our study as the case group. Another 211 hypertensive patients with normal sodium levels after treatment with thiazide diuretics were selected as the control group. Twelve tag single nucleotide polymorphism markers were selected from the Potassium Channel, Inwardly Rectifying Subfamily J, Member 1 (KCNJ1) gene: rs1231254, rs2238009, rs1148058, rs675482, rs673614, rs12795437, rs2855800, rs2509585, rs3016774, rs881333, rs4529890, and rs7116606. Clinical and genetic parameters between patients with thiazide-induced hyponatremia and the control group were compared. Logistic regression was used to analyze data.
The patients with thiazide-induced hyponatremia were older (P < 0.001), predominantly female (P = 0.008), had a lower mean body mass index (BMI) (P < 0.001), and more commonly used angiotensin II receptor antagonist (P < 0.001) and spironolactone (P = 0.007) compared with the control groups. Analysis with multivariate logistic regression revealed that age (odds ratio [OR], 1.13; 95% confidence interval [CI], 1.08–1.19, P < 0.001), female gender (OR, 4.49; 95% CI, 1.54–13.11, P = 0.006), BMI (OR, 0.80; 95% CI, 0.69–0.93, P = 0.003), and KCNJ1 rs2509585 C/T or T/T polymorphisms (OR, 5.75; 95% CI, 1.25–26.45, P = 0.03) were independent predictors for thiazide-induced hyponatremia.
Older female patients with lower BMIs and KCNJ1 rs2509585 C/T or T/T polymorphisms were more likely to develop thiazide-induced hyponatremia.
PMCID: PMC4602917  PMID: 26313793
23.  Direct Renin Inhibition with Aliskiren Improves Ischemia-Induced Neovasculogenesis in Diabetic Animals via the SDF-1 Related Mechanism 
PLoS ONE  2015;10(8):e0136627.
Aliskiren is a direct renin inhibitor which is suggested to modify proangiogenic cells in addition to lower blood pressure. Given that angiogenesis is impaired in the presence of diabetes mellitus, we would like to investigate whether and how aliskiren enhances endothelial progenitor cells (EPCs) and improves ischemic-induced neovasculogenesis by an effect independent of blood pressure reduction in diabetic animals.
Streptozotocin-induced diabetic mice were administered with either aliskiren (5 or 25 mg/kg/day) using an osmotic pump or hydralazine (2 or 10 mg/kg/day) given in drinking water for two weeks prior to a hind-limb ischemia surgery. Laser Doppler imaging and flow cytometry were used to evaluate the degree of neovasculogenesis and the circulating levels of EPCs, respectively.
In streptozotocin-induced diabetic mice, aliskiren enhanced the recovery of limb perfusion and capillary density, increased the number of circulating Sca-1+/Flk-1+ EPC-like cells, and elevated the levels of the plasma vascular endothelial growth factor (VEGF) and stromal cell-derived factor (SDF)-1α in a dose-dependent manner, whereas there were no such effects in hydralazine-treated mice. Intraperitoneal administration of anti-SDF-1 neutralizing monoclonal antibodies abolished the effects of aliskiren.
Independent of the reduction of blood pressure, aliskiren enhanced ischemia-induced neovasculogenesis in a dose-dependent manner via VEGF/SDF-1α related mechanisms in diabetic mice.
PMCID: PMC4549314  PMID: 26305217
24.  Migraine is associated with an increased risk for benign paroxysmal positional vertigo: a nationwide population-based study 
There is evidence suggesting that migraine may be associated with vertigo. The aim of this study was to assess the risk of benign paroxysmal positional vertigo (BPPV), the most common form of vertigo, in patients with migraine using a population-based dataset.
The National Health Insurance Research Database in Taiwan was searched for migraine patients and was also used to select an age- and sex-matched cohort of subjects without migraine. The analyses included 8266 migraine patients and 8266 controls. The incidence rates of BPPV in the two cohorts were compared. Cox proportional hazard models were used to identify risk factors for BPPV in migraine patients.
In the migraine cohort, 1.11 % of the patients developed BPPV compared to 0.5 % of the controls. The incidence rate ratio was 2.03 (95 % CI 1.41–2.97; p <0.001). Cox proportional hazards analysis showed that age ≥40 years (HR 2.20; 95 % CI 1.40–3.45; p = 0.001), coronary artery disease (HR 4.62; 95 % CI 1.12–19.01; p = 0.034), and the number of outpatient department visits to neurologists because of migraine (HR 2.93; 95 % CI 2.50–3.44; p >0.001) were associated with an increased risk for BPPV.
The results showed that patients with migraine had a 2.03-fold increased risk of developing BPPV compared with age- and sex-matched controls. Although BPPV may not be a common condition in migraine patients, migraine sufferers with vestibular symptoms should alert physicians to the possibility of BPPV, particularly if patients are aged ≥40 years, have a history of coronary artery disease, or have frequent visits to neurologists clinics because of migraine.
PMCID: PMC4491067  PMID: 26141381
Migraine; Benign paroxysmal positional vertigo; Risk factors; Incidence rate
25.  Assessing the carcinogenic potential of low-dose exposures to chemical mixtures in the environment: the challenge ahead 
Goodson, William H. | Lowe, Leroy | Carpenter, David O. | Gilbertson, Michael | Manaf Ali, Abdul | Lopez de Cerain Salsamendi, Adela | Lasfar, Ahmed | Carnero, Amancio | Azqueta, Amaya | Amedei, Amedeo | Charles, Amelia K. | Collins, Andrew R. | Ward, Andrew | Salzberg, Anna C. | Colacci, Annamaria | Olsen, Ann-Karin | Berg, Arthur | Barclay, Barry J. | Zhou, Binhua P. | Blanco-Aparicio, Carmen | Baglole, Carolyn J. | Dong, Chenfang | Mondello, Chiara | Hsu, Chia-Wen | Naus, Christian C. | Yedjou, Clement | Curran, Colleen S. | Laird, Dale W. | Koch, Daniel C. | Carlin, Danielle J. | Felsher, Dean W. | Roy, Debasish | Brown, Dustin G. | Ratovitski, Edward | Ryan, Elizabeth P. | Corsini, Emanuela | Rojas, Emilio | Moon, Eun-Yi | Laconi, Ezio | Marongiu, Fabio | Al-Mulla, Fahd | Chiaradonna, Ferdinando | Darroudi, Firouz | Martin, Francis L. | Van Schooten, Frederik J. | Goldberg, Gary S. | Wagemaker, Gerard | Nangami, Gladys | Calaf, Gloria M. | Williams, Graeme | Wolf, Gregory T. | Koppen, Gudrun | Brunborg, Gunnar | Kim Lyerly, H. | Krishnan, Harini | Ab Hamid, Hasiah | Yasaei, Hemad | Sone, Hideko | Kondoh, Hiroshi | Salem, Hosni K. | Hsu, Hsue-Yin | Park, Hyun Ho | Koturbash, Igor | Miousse, Isabelle R. | Scovassi, A.Ivana | Klaunig, James E. | Vondráček, Jan | Raju, Jayadev | Roman, Jesse | Wise, John Pierce | Whitfield, Jonathan R. | Woodrick, Jordan | Christopher, Joseph A. | Ochieng, Josiah | Martinez-Leal, Juan Fernando | Weisz, Judith | Kravchenko, Julia | Sun, Jun | Prudhomme, Kalan R. | Narayanan, Kannan Badri | Cohen-Solal, Karine A. | Moorwood, Kim | Gonzalez, Laetitia | Soucek, Laura | Jian, Le | D’Abronzo, Leandro S. | Lin, Liang-Tzung | Li, Lin | Gulliver, Linda | McCawley, Lisa J. | Memeo, Lorenzo | Vermeulen, Louis | Leyns, Luc | Zhang, Luoping | Valverde, Mahara | Khatami, Mahin | Romano, Maria Fiammetta | Chapellier, Marion | Williams, Marc A. | Wade, Mark | Manjili, Masoud H. | Lleonart, Matilde | Xia, Menghang | Gonzalez, Michael J. | Karamouzis, Michalis V. | Kirsch-Volders, Micheline | Vaccari, Monica | Kuemmerle, Nancy B. | Singh, Neetu | Cruickshanks, Nichola | Kleinstreuer, Nicole | van Larebeke, Nik | Ahmed, Nuzhat | Ogunkua, Olugbemiga | Krishnakumar, P.K. | Vadgama, Pankaj | Marignani, Paola A. | Ghosh, Paramita M. | Ostrosky-Wegman, Patricia | Thompson, Patricia | Dent, Paul | Heneberg, Petr | Darbre, Philippa | Sing Leung, Po | Nangia-Makker, Pratima | Cheng, Qiang (Shawn) | Robey, R.Brooks | Al-Temaimi, Rabeah | Roy, Rabindra | Andrade-Vieira, Rafaela | Sinha, Ranjeet K. | Mehta, Rekha | Vento, Renza | Di Fiore, Riccardo | Ponce-Cusi, Richard | Dornetshuber-Fleiss, Rita | Nahta, Rita | Castellino, Robert C. | Palorini, Roberta | Abd Hamid, Roslida | Langie, Sabine A.S. | Eltom, Sakina | Brooks, Samira A. | Ryeom, Sandra | Wise, Sandra S. | Bay, Sarah N. | Harris, Shelley A. | Papagerakis, Silvana | Romano, Simona | Pavanello, Sofia | Eriksson, Staffan | Forte, Stefano | Casey, Stephanie C. | Luanpitpong, Sudjit | Lee, Tae-Jin | Otsuki, Takemi | Chen, Tao | Massfelder, Thierry | Sanderson, Thomas | Guarnieri, Tiziana | Hultman, Tove | Dormoy, Valérian | Odero-Marah, Valerie | Sabbisetti, Venkata | Maguer-Satta, Veronique | Rathmell, W.Kimryn | Engström, Wilhelm | Decker, William K. | Bisson, William H. | Rojanasakul, Yon | Luqmani, Yunus | Chen, Zhenbang | Hu, Zhiwei
Carcinogenesis  2015;36(Suppl 1):S254-S296.
Low-dose exposures to common environmental chemicals that are deemed safe individually may be combining to instigate carcinogenesis, thereby contributing to the incidence of cancer. This risk may be overlooked by current regulatory practices and needs to be vigorously investigated.
Lifestyle factors are responsible for a considerable portion of cancer incidence worldwide, but credible estimates from the World Health Organization and the International Agency for Research on Cancer (IARC) suggest that the fraction of cancers attributable to toxic environmental exposures is between 7% and 19%. To explore the hypothesis that low-dose exposures to mixtures of chemicals in the environment may be combining to contribute to environmental carcinogenesis, we reviewed 11 hallmark phenotypes of cancer, multiple priority target sites for disruption in each area and prototypical chemical disruptors for all targets, this included dose-response characterizations, evidence of low-dose effects and cross-hallmark effects for all targets and chemicals. In total, 85 examples of chemicals were reviewed for actions on key pathways/mechanisms related to carcinogenesis. Only 15% (13/85) were found to have evidence of a dose-response threshold, whereas 59% (50/85) exerted low-dose effects. No dose-response information was found for the remaining 26% (22/85). Our analysis suggests that the cumulative effects of individual (non-carcinogenic) chemicals acting on different pathways, and a variety of related systems, organs, tissues and cells could plausibly conspire to produce carcinogenic synergies. Additional basic research on carcinogenesis and research focused on low-dose effects of chemical mixtures needs to be rigorously pursued before the merits of this hypothesis can be further advanced. However, the structure of the World Health Organization International Programme on Chemical Safety ‘Mode of Action’ framework should be revisited as it has inherent weaknesses that are not fully aligned with our current understanding of cancer biology.
PMCID: PMC4480130  PMID: 26106142

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