Amino Acid Substitution ; Drug Resistance, Multiple, Bacterial ; physiology ; Escherichia coli ; physiology ; Escherichia coli Proteins ; genetics ; metabolism ; Membrane Potentials ; physiology ; Models, Biological ; Multidrug Resistance-Associated Proteins ; genetics ; metabolism ; Mutation, Missense

INTRODUCTIONEnteric fever is a multisystemic infection which largely affects children. This study aimed to analyse the epidemiology, clinical presentation, treatment and outcome of paediatric enteric fever in Singapore.

MATERIALS AND METHODSA retrospective review of children diagnosed with enteric fever in a tertiary paediatric hospital in Singapore was conducted from January 2006 to January 2012. Patients with positive blood cultures for Salmonella typhi or paratyphi were identified from the microbiology laboratory information system. Data was extracted from their case records.

RESULTSOf 50 enteric fever cases, 86% were due to Salmonella typhi, with 16.3% being multidrug resistant (MDR) strains. Sixty-two percent of S. typhi isolates were of decreased ciprofloxacin susceptibility (DCS). Five cases were both MDR and DCS. The remaining 14% were Salmonella paratyphi A. There were only 3 indigenous cases. Ninety-four percent had travelled to typhoid-endemic countries, 70.2% to the Indian subcontinent and the rest to Indonesia and Malaysia. All patients infected with MDR strains had travelled to the Indian subcontinent. Anaemia was a significant finding in children with typhoid, as compared to paratyphoid fever (P = 0.04). Although all children were previously well, 14% suffered severe complications including shock, pericardial effusion and enterocolitis. None had typhoid vaccination prior to their travel to developing countries.

CONCLUSIONEnteric fever is largely an imported disease in Singapore and has contributed to significant morbidity in children. The use of typhoid vaccine, as well as education on food and water hygiene to children travelling to developing countries, needs to be emphasised.

Adolescent ; Anemia ; epidemiology ; Anti-Bacterial Agents ; therapeutic use ; Child ; Child, Preschool ; Drinking Water ; Drug Resistance, Multiple, Bacterial ; physiology ; Enterocolitis ; epidemiology ; Female ; Food Contamination ; Health Education ; Hospitals, Pediatric ; Humans ; India ; Indonesia ; Infant ; Malaysia ; Male ; Paratyphoid Fever ; drug therapy ; epidemiology ; microbiology ; Pericardial Effusion ; epidemiology ; Retrospective Studies ; Salmonella paratyphi A ; physiology ; Salmonella typhi ; physiology ; Shock ; epidemiology ; Singapore ; epidemiology ; Tertiary Care Centers ; Travel ; Typhoid Fever ; drug therapy ; epidemiology ; microbiology ; prevention & control ; Typhoid-Paratyphoid Vaccines ; therapeutic use

OBJECTIVETo investigate the role of RLIP76 in regulating multi-drug resistance in small cell lung cancer (SCLC), and to analyze the relationship between its expression and prognosis.

METHODSThe expressions of RLIP76 protein and gene were detected by Western blotting and real-time PCR (RT-PCR) in both the chemosensitive SCLC H69 cell line and chemoresistant H69AR cell line, respectively. siRNA was transfected into the H69AR cells to inhibit RLIP76 expression, and eGFP-RLIP76 was transfected into the H69 cells to enhance RLIP76 expression. The drug-sensitivity of cells to chemotherapeutic drugs (ADM, DDP, VP-16) were detected by CCK8 assay. The expression of RLIP76 in the SCLC tissues was detected by immunohistochemistry. The relationship of RLIP76 expression with clinicopathological features and prognosis of the patients was analyzed.

RESULTSThe expression of RLIP76 in H69AR cells was 13.675 ± 0.983, significantly higher than 1.074 ± 0.107 in the H69 cells (P < 0.01). The drug-sensitivities of H69AR cells to chemotherapeutic drugs were significantly increased when the expression of RLIP76 was down-regulated (P< 0.001). The sensitivities of H69 cells to chemotherapeutic drugs ADM, DDP and VP-16 were significantly decreased after transfection with eGFP-RLIP76 up-regulating the RLIP76 expression (P = 0.003). The positive expression rates were 61.3% and 9.4% in the SCLC tumor tissues and para-cancerous tissues, respectively (P < 0.01). The expression of RLIP76 was significantly correlated with clinical stage, chemosensitivity and overall survival of the SCLC patients (P < 0.05).

CONCLUSIONSOur results suggest that RLIP76 is involved in the regulation of small cell lung cancer multidrug resistance. RLIP76 may serve as a potential target gene to evaluate the chemosensitivity and clinical prognostic for small cell lung cancer.

ATP-Binding Cassette Transporters ; metabolism ; physiology ; Antineoplastic Agents ; pharmacology ; Cisplatin ; pharmacology ; Down-Regulation ; Drug Resistance, Multiple ; Drug Resistance, Neoplasm ; Etoposide ; pharmacology ; GTPase-Activating Proteins ; metabolism ; physiology ; Humans ; Lung Neoplasms ; drug therapy ; metabolism ; RNA, Small Interfering ; Real-Time Polymerase Chain Reaction ; Small Cell Lung Carcinoma ; drug therapy ; metabolism ; Transfection ; Up-Regulation

To give an overview of contemporary experimental research using Chinese medicine (CM) for the treatment of cancer. As an integral part of mainstream medicine in the People's Republic of China, CM emphasizes improvements in holistic physical condition instead of merely killing tumor cells, which is consistent with the current medical model that advocates patient-oriented treatment. Great progress has been made in experimental research, and the principle aspects include anti-tumor angiogenesis, inducing apoptosis and differentiation, reversing multidrug resistance, and improving immune function. As a current hot topic in cancer research, tumor microenvironment (TME) highlights the mutual and interdependent interaction between tumor cells and their surrounding tissues, and the CM treatment concept bears a striking resemblance to it. To date, primary points of TME include extracellular matrix remodeling, inflammation, hypoxia, and angiogenesis, but trials using CM with a focus on TME are rare. Despite considerable recent development, experimental research on CM for solving cancer issues appears insufficient. Greater efforts in this field are urgently needed.
Apoptosis ; drug effects ; Autophagy ; drug effects ; Cell Differentiation ; drug effects ; Cell Hypoxia ; drug effects ; Drug Resistance, Multiple ; drug effects ; Immunomodulation ; Inflammation Mediators ; pharmacology ; Medicine, Chinese Traditional ; Neoplasms, Experimental ; Research ; Tumor Microenvironment ; drug effects ; physiology

Hepatocellular carcinoma (HCC) is one of leading causes of death in the world. Although various treatments have been developed, the therapeutic side effects are far from desirable. Chinese medicines (CMs, including plants, animal parts and minerals) have drawn a great deal of attention in recent years for their potential in the treatment of HCC. Most studies have shown that CMs may be able to retard HCC progression with multiple actions, either alone or in combination with other conventional therapies to improve quality of life in HCC patients. Additionally, CMs are used for preventing HCC occurrence. The aim of this study is to review the potential prophylactic and curative effects of CMs on human HCC and the possible mechanisms that underlie these pharmacological actions. Publications were collected and reviewed from PubMed and China National Knowledge Infrastructure from 2000 to 2014. Keywords for literature searches include "Chinese medicine", "Chinese herb", "traditional Chinese Medicine", "hepatocellular carcinoma" and "liver cancer". CMs in forms of pure compounds, isolated fractions, and composite formulas are included. Combination therapies are also considered. Both in vitro and in vivo efficacies of CMs are being discussed and the translational potential to bedside is to be discussed with clinical cases, which show the actions of CMs on HCC may include tumor growth inhibition, antimetastatic activities, anti-inflammation, anti-liver cancer stem cells, reversal on multi-drug resistance and induction/reduction of oxidative stress. Multiple types of molecules are found to contribute in the above actions. The review paper indicated that CMs might have potential to both prevent HCC occurrence and retard HCC progression with several molecular targets involved.
Carcinoma, Hepatocellular ; drug therapy ; prevention & control ; Drug Resistance, Multiple ; Humans ; Liver Neoplasms ; drug therapy ; prevention & control ; Medicine, Chinese Traditional ; NF-E2-Related Factor 2 ; physiology ; Neoplastic Stem Cells ; drug effects ; Reactive Oxygen Species ; metabolism

OBJECTIVETo investigate the role of wild-type p53-induced gene 1 (WIG-1) on the regulation of multi-drug resistance in small cell lung cancer.

METHODSThe expressions of WIG-1 protein and gene were detected by Western blot and real-time PCR (RT-PCR) in both the drug-sensitive H69 and drug-resistant H69AR cell lines, respectively. Meanwhile, the differential expression of WIG-1 was also detected in peripheral blood samples of responders and non-responder patients. Furthermore, the WIG-1 expression was inhibited by siRNA in H69AR cells, then the drug-sensitivities of H69AR cells to chemotherapy agents such as ADM, DDP, VP-16 were detected by CCK8 assay, and apoptosis rate was detected by flow cytometry. The possible association of WIG-1 with clinical parameters was evaluated.

RESULTSThe expression of WIG-1 was significantly increased in H69AR cells (5.965 ± 0.890) than that in the H69 cells (1.023 ± 0.127) (P = 0.007). The expression of WIG-1 was significantly increased in the non-responder patients (4.169 ± 0. 970) than in the H69 cells and responders (1.673 ± 0.127) (P < 0.001). The drug-sensitivities of H69AR cells to chemotherapeutic drugs were increased when the expression of the WIG-1 was down-regulated. The apoptosis rate was significantly decreased in the H69AR cells (1.037 ± 0.049)% compared with that in the H69 cells [(7.963 ± 0.097)%, (P < 0.01)]. The apoptosis rate was increased in the H69AR-Si-WIG-1 cells (20.915 ± 0.890)% than that of (1.037 ± 0.049)% in the H69AR and H69AR-NC group (2.025 ± 0.097)% (P < 0.01). The expression of WIG-1 was not significantly associated with gender, and age (P > 0.05), but significantly correlated with chemosensitivity, overall survival and clinical stage (P < 0.001 for all).

CONCLUSIONSOur results suggest that WIG-1 is involved in the regulation of the multidrug resistance mechanism in small cell lung cancer. Selective silencing of the WIG-1 gene may reverse the multidrug resistance of SCLC via increasing cell apoptosis.

Antineoplastic Agents ; Apoptosis ; DNA-Binding Proteins ; metabolism ; Down-Regulation ; Drug Resistance, Multiple ; Drug Resistance, Neoplasm ; physiology ; Etoposide ; Humans ; Lung Neoplasms ; metabolism ; Nuclear Proteins ; metabolism ; RNA, Small Interfering ; Small Cell Lung Carcinoma ; metabolism

OBJECTIVETo investigate the role of SALL4 in regulating multi-drug resistance in small cell lung cancer (SCLC), and to evaluate its clinical significance.

METHODSThe expression of SALL4 protein and gene was detected by Western blot and real-time PCR (RT-PCR) in both H69 and H69AR cell lines, respectively. SALL4 expression in H69AR was blocked by the siRNA, and then the drug-sensitivities of H69AR cell lines to chemotherapeutic drugs such as cisplatin, doxorubicin, and etoposide were evaluated by cell counting kit assay. SALL4 expression was also examined by immunohistochemistry, and correlated with patients' clinicopathological features and prognosis.

RESULTSThe expression of SALL4 was significantly increased in H69AR cells than in the H69 cells (P < 0.01). Down-regulation of SALL4 increased the drug-sensitivities of H69AR cells to chemotherapeutic drugs (P = 0.02). The expression of SALL4 was significantly increased in SCLC than in para-carcinoma tissues (P < 0.01). SALL4 expression correlated with clinical stage, chemosensitivity and overall survival (P < 0.05), but not with patients' age and gender.

CONCLUSIONSALL4 is involved in the regulation of multidrug resistance in SCLC; SALL4 may be a potential target gene to evaluate the chemosensitivity and clinical prognosis for SCLC.

Antineoplastic Agents ; pharmacology ; Cisplatin ; pharmacology ; Down-Regulation ; Doxorubicin ; pharmacology ; Drug Resistance, Multiple ; physiology ; Drug Resistance, Neoplasm ; physiology ; Etoposide ; pharmacology ; Humans ; Lung Neoplasms ; drug therapy ; metabolism ; RNA, Small Interfering ; Real-Time Polymerase Chain Reaction ; Small Cell Lung Carcinoma ; drug therapy ; metabolism ; Transcription Factors ; genetics ; physiology

Necroptosis is a caspase-independent programmed cell death, its regulation, induction and blocking mechanism are a complex process involving in a series of molecular expression and regulation. The studies found that the necroptosis is not only involved in the physiological regulation mechanism, but also directly correlated to the occurrence, development and final outcome of some necrotic diseases, such as neurodegenerative diseases, ischemic disease, inflammation and viral infection. Moreover, the studies on multidrug-resistant tumor cell line demonstrated that necroptotic induction agents possess excellent "broad-spectrum" to escape the multidrug resistance. Therefore, exploration of the signaling pathways, physical characteristics, clinical relevance of necroptosis may provide new prospects for molecular target therapy and drug discovery of tumours. This review summarizes the research progress on possible regulation mechanism of necroptosis, physiologic characteristics and relation of necroptosis with clinical diseases and multi-drug resistance.
Apoptosis ; physiology ; Drug Resistance, Multiple ; Humans ; Necrosis ; Signal Transduction

Recently, a large number of tyrosine kinase inhibitors(TKIs) have been developed as anticancer agents. These TKIs can specifically and selectively inhibit tumor cell growth and metastasis by targeting various tyrosine kinases and thereby interfering with cellular signaling pathways. The therapeutic potential of TKIs has been hindered by multidrug resistance(MDR), which is commonly caused by overexpression of ATP-binding cassette(ABC) membrane transporters. Interestingly, some TKIs have also been found to reverse MDR by directly inhibiting the function of ABC transporters and enhancing the efficacy of conventional chemotherapeutic drugs. In this review, we discuss ABC transporter-mediated MDR to TKIs and MDR reversal by TKIs.
ATP-Binding Cassette Transporters ; antagonists & inhibitors ; physiology ; Antineoplastic Agents ; pharmacology ; Drug Resistance, Multiple ; drug effects ; Drug Resistance, Neoplasm ; drug effects ; Humans ; Neoplasms ; drug therapy ; Protein Kinase Inhibitors ; pharmacology ; Protein-Tyrosine Kinases ; antagonists & inhibitors

Multidrug resistance proteins (MRPs) are members of the C family of a group of proteins named ATP-binding cassette (ABC) transporters. These ABC transporters together form the largest branch of proteins within the human body. The MRP family comprises of 13 members, of which MRP1 to MRP9 are the major transporters indicated to cause multidrug resistance in tumor cells by extruding anticancer drugs out of the cell. They are mainly lipophilic anionic transporters and are reported to transport free or conjugates of glutathione (GSH), glucuronate, or sulphate. In addition, MRP1 to MRP3 can transport neutral organic drugs in free form in the presence of free GSH. Collectively, MRPs can transport drugs that differ structurally and mechanistically, including natural anticancer drugs, nucleoside analogs, antimetabolites, and tyrosine kinase inhibitors. Many of these MRPs transport physiologically important anions such as leukotriene C4, bilirubin glucuronide, and cyclic nucleotides. This review focuses mainly on the physiological functions, cellular resistance characteristics, and probable in vivo role of MRP1 to MRP9.
Antineoplastic Agents ; metabolism ; pharmacology ; Biological Transport ; Drug Resistance, Multiple ; Drug Resistance, Neoplasm ; Glutathione ; metabolism ; Humans ; Leukotriene C4 ; metabolism ; Multidrug Resistance-Associated Proteins ; metabolism ; physiology ; Neoplasms ; drug therapy ; metabolism ; Tissue Distribution