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2.
J Hosp Infect ; 136: 110-117, 2023 Jun.
Article in English | MEDLINE | ID: mdl-37105259

ABSTRACT

BACKGROUND: Healthcare workers treating SARS-CoV-2 patients are at risk of infection by respiratory exposure to patient-emitted, virus-laden aerosols. Source control devices such as ventilated patient isolation hoods have been shown to limit the dissemination of non-infectious airborne particles in laboratory tests, but data on their performance in mitigating the airborne transmission risk of infectious viruses are lacking. AIM: We used an infectious airborne virus to quantify the ability of a ventilated hood to reduce infectious virus exposure in indoor environments. METHODS: We nebulized 109 plaque forming units (pfu) of bacteriophage PhiX174 virus into a ∼30-m3 room when the hood was active or inactive. The airborne concentration of infectious virus was measured by BioSpot-VIVAS and settle plates using plaque assay quantification on the bacterial host Escherichia coli C. The airborne particle number concentration (PNC) was also monitored continuously using an optical particle sizer. FINDINGS: The median airborne viral concentration in the room reached 1.41 × 105 pfu/m3 with the hood inactive. When active, the hood reduced infectious virus concentration in air samples by 374-fold. The deposition of infectious virus on the surface of settle plates was reduced by 87-fold. This was associated with a 109-fold reduction in total airborne particle number escape rate. CONCLUSION: A personal ventilation hood significantly reduced airborne particle escape, considerably lowering infectious virus contamination in an indoor environment. Our findings support the further development of source control devices to mitigate nosocomial infection risk among healthcare workers exposed to airborne viruses in clinical settings.


Subject(s)
COVID-19 , SARS-CoV-2 , Humans , COVID-19/prevention & control , Viral Load , Respiration, Artificial , Respiratory Aerosols and Droplets
3.
Med J Malaysia ; 78(2): 241-249, 2023 03.
Article in English | MEDLINE | ID: mdl-36988537

ABSTRACT

INTRODUCTION: Time is the greatest challenge in stroke management. This study aimed to examine factors contributing to prehospital delay and decision delay among stroke patients. MATERIALS AND METHODS: A cross-sectional study involving acute stroke patients admitted to Seri Manjung Hospital was conducted between August 2019 and October 2020 via faceto- face interview. Prehospital delay was defined as more than 120 minutes taken from recognition of stroke symptoms till arrival in hospital, while decision delay was defined as more than 60 minutes taken from recognition of stroke symptoms till decision was made to seek treatment. RESULTS: The median prehospital delay of 102 enrolled patients was 364 minutes (IQR 151.5, 1134.3) while the median for decision delay was 120 minutes (IQR 30.0, 675.0). No history of stroke (adj. OR 4.15; 95% CI 1.21, 14.25; p=0.024) and unaware of thrombolysis service (adj. OR 17.12; 95% CI 1.28, 229.17; p=0.032) were associated with higher odds of prehospital delay, while Indian ethnicity (adj. OR 0.09; 95% CI 0.02, 0.52; p=0.007) was associated with lower odds of prehospital delay as compared to Malay ethnicity. On the other hand, higher National Institutes of Health Stroke Scale (NIHSS) score (adj. OR 0.86; 95% CI 0.78, 0.95; p=0.002) was associated with lower odds of decision delay. CONCLUSION: Public awareness is crucial to shorten prehosital delay and decision delay for better patients' outcomes in stroke. Various public health campaigns are needed to improve the awareness for stroke.


Subject(s)
Emergency Medical Services , Stroke , Humans , Malaysia , Hospitals, District , Cross-Sectional Studies , Time Factors , Stroke/diagnosis , Stroke/therapy
4.
Med J Malaysia ; 76(6): 820-827, 2021 Nov.
Article in English | MEDLINE | ID: mdl-34806667

ABSTRACT

INTRODUCTION: Despite the ever-growing number of community onset (CO) Pseudomonas aeruginosa (P. aeruginosa) bacteraemia, there is a dearth of district hospital-based research examining this significant infection, which is associated with high mortality. The objectives of this study were as following: (1) to determine the risk factors of CO P. aeruginosa bacteraemia, (2) to compare the 30-day mortality rate between P. aeruginosa and Escherichia coli bacteraemia and (3) to identify the predictors of 30-day mortality for CO gram negative bacteraemia. METHODS: This is a retrospective case control study in Hospital Seri Manjung and Hospital Teluk Intan, Perak, Malaysia. P. aeruginosa bacteraemia cases that occurred between 1st January 2015 to 31st December 2019 were included, whilst E. coli bacteraemia cases that occurred within the same period were recruited successively until 1:2 case control ratio was achieved. Subjects below 12-year-old and those with polymicrobial bacteraemia were excluded. Demographic, clinical and treatment data were collected using pre-tested data collection forms by trained investigators. RESULTS: A total of 61 patients with P. aeruginosa bacteraemia and 122 patients with E. coli bacteraemia were included. Recent admission in the earlier three months, regular haemodialysis, immunosuppressive therapy in the past 30 days, chronic wound/pressure sore at presentation and indwelling urinary catheter at presentation were identified as independent predictors of CO pseudomonal bacteraemia. Whilst older age was identified as a negative predictor of CO Pseudomonal bacteraemia (all p<0.05). The 30-day mortality rate was 34.4% in subjects with P. aeruginosa bacteraemia and 27.0% in those with E. coli bacteraemia (p=0.302). Predictors of 30-day mortality for community onset gram negative bacteraemia were as follow: older age, underlying solid tumours, neutropaenia at presentation, in-patient mechanical ventilation, and inpatient nasogastric tube insertion. Unexpectedly, receipt of inappropriate empirical antibiotics which was switched later (delayed and non-delayed switching) was identified as the negative predictors of mortality (all p<0.05). CONCLUSION: It is prudent to restrict the usage of empirical anti-pseudomonal antibiotics among individuals at risk as liberal usage of broad-spectrum antibiotics engenders emergence of drug resistant organism, particularly in district setting where community onset pseudomonal bacteraemia remains scarce. Subjects with elevated risk of mortality should receive early escalation of care as per sepsis management guidelines.


Subject(s)
Bacteremia , Pseudomonas aeruginosa , Anti-Bacterial Agents/therapeutic use , Bacteremia/drug therapy , Bacteremia/epidemiology , Case-Control Studies , Child , Escherichia coli , Hospitals, District , Humans , Retrospective Studies , Risk Factors
5.
Med J Malaysia ; 76(5): 630-636, 2021 09.
Article in English | MEDLINE | ID: mdl-34508367

ABSTRACT

INTRODUCTION: Pseudomonas aeruginosa is known to be the epitome of nosocomial infections associated with high morbidity and mortality. The dearth of local pseudomonal studies has prompted us to conduct this study with the following objectives: (1) to examine the local pseudomonal bacteraemia (PB) epidemiology and clinical characteristics, (2) to compare the 30-day mortality among PB of different onsets and (3) to determine the predictors of 30-day mortality outcome. METHODS: This retrospective study was conducted in Hospital Seri Manjung, Perak, Malaysia. All cases of blood culture proven PB that occurred between 1st January 2015 and 31st December 2019 were reviewed. Subjects below 12 year old and whose index blood cultures grew more than one organism were excluded. Demographic, clinical and treatment data were collected using pre-tested data collection forms and analysed using SPSS version 20.0. RESULTS: Among the 59 subjects included, healthcare associated (HCA) infections were the most prevalent, next to hospital onset (HO) and community onset (CO) infections. The commonest underlying comorbidities were cardiovascular disease, diabetes mellitus, and chronic kidney disease. Respiratory tract was the most frequently implicated source amongst all, while the urinary tract was more frequently implicated as the source of infection among HCA cases. Seventeen patients were admitted to ICU, and they were predominantly from the HO group. Despite having a higher rate of adequate empirical antibiotics administered, the HO group reported the lowest 30-day survival rate. Multiple logistic regression analysis demonstrated the following were independent predictors of 30-day mortality: requiring mechanical ventilator support, requiring central venous line insertion, not requiring surgery, and receiving inappropriate definite antibiotics. CONCLUSION: The incidence of community onset PB was appreciably low, as cases were predominantly HCA and HO in origin. Significant morbidities were observed among pseudomonal infections, with HO infections portending the worst prognosis. Lastly, prognostic factors for determining the mortality caused by PB depended more on the severity of sepsis than the timeliness of appropriate antibiotics.


Subject(s)
Bacteremia , Community-Acquired Infections , Anti-Bacterial Agents/therapeutic use , Bacteremia/drug therapy , Bacteremia/epidemiology , Child , Hospitals, District , Humans , Pseudomonas aeruginosa , Retrospective Studies , Risk Factors
6.
Malays J Pathol ; 43(1): 41-48, 2021 Apr.
Article in English | MEDLINE | ID: mdl-33903304

ABSTRACT

INTRODUCTION: The Malaysian Association of Clinical Biochemists (MACB) established a Task Force for Chronic Kidney Disease. A survey was undertaken by the Task Force on the reporting of estimated glomerular filtration rate (eGFR) and urine albumin by hospital laboratories in Malaysia in both the government and private sectors. MATERIALS AND METHODS: An e-mail invitation to participate in an online survey was sent to hospital laboratories in Malaysia (n=140). Questions regarding methods for measuring creatinine, equations for calculating eGFR, eGFR reporting, the terminology used in reporting urine albumin, types of samples and the cut-off values used for normal albuminuria. RESULTS: A total of 42/140 (30%) laboratories answered the questionnaire. The prevalent method used for serum creatinine measurement was the Jaffé method (88.1%) traceable to isotope-dilution mass spectrometry. eGFR was reported along with serum creatinine by 61.9% of laboratories while 33.3% of laboratories report eGFR on request. The formula used for eGFR reporting was mainly MDRD (64.3%) and results were reported as exact numbers even when the eGFR was <60 ml/min/1.73m2. The term microalbumin is still used by 83.3% of laboratories. There is a large heterogeneity among the labs regarding the type of sample recommended for measuring urine albumin, reference interval and reporting units. CONCLUSION: It is evident that the laboratory assessment of chronic kidney disease in Malaysia is not standardised. It is essential to provide a national framework for standardised reporting of eGFR and urine albumin. Recommendations developed by the MACB CKD Task Force, if adopted by all laboratories, will lead to a reduction in this variability.


Subject(s)
Renal Insufficiency, Chronic , Albumins , Creatinine , ErbB Receptors , Glomerular Filtration Rate , Humans , Proteinuria , Renal Insufficiency, Chronic/diagnosis
8.
Am J Physiol Lung Cell Mol Physiol ; 315(4): L467-L475, 2018 10 01.
Article in English | MEDLINE | ID: mdl-29847989

ABSTRACT

The electronic cigarette (e-cig) has been suggested as a safer alternative to tobacco cigarettes. However, the health effects of e-cigs on the airways have not been fully investigated. Nicotine, the primary chemical constituent of the e-cig aerosol, has been shown to stimulate vagal bronchopulmonary C-fiber sensory nerves, which upon activation can elicit vigorous pulmonary defense reflexes, including airway constriction. In this study, we investigated the bronchomotor response to e-cig inhalation challenge in anesthetized guinea pigs and the mechanisms involved in regulating these responses. Our results showed that delivery of a single puff of e-cig aerosol into the lung triggered immediately a transient bronchoconstriction that sustained for >2 min. The increase in airway resistance was almost completely abolished by a pretreatment with either intravenous injection of atropine or inhalation of aerosolized lidocaine, suggesting that the bronchoconstriction was elicited by cholinergic reflex mechanism and stimulation of airway sensory nerves was probably involved. Indeed, electrophysiological recording further confirmed that inhalation of e-cig aerosol exerted a pronounced stimulatory effect on vagal bronchopulmonary C-fibers. These effects on airway resistance and bronchopulmonary C-fiber activity were absent when the e-cig aerosol containing zero nicotine was inhaled, indicating a critical role of nicotine. Furthermore, a pretreatment with nicotinic acetylcholine receptor antagonists by inhalation completely prevented the airway constriction evoked by e-cig aerosol inhalation. In conclusion, inhalation of a single puff of e-cig aerosol caused a transient bronchoconstriction that was mediated through cholinergic reflex and triggered by a stimulatory effect of nicotine on vagal bronchopulmonary C-fiber afferents.


Subject(s)
Bronchi/pathology , Bronchoconstriction/drug effects , Electronic Nicotine Delivery Systems , Nerve Fibers, Unmyelinated/pathology , Nicotine/administration & dosage , Vagus Nerve/pathology , Administration, Inhalation , Aerosols , Airway Resistance , Animals , Bronchi/drug effects , Bronchi/metabolism , Guinea Pigs , Male , Nerve Fibers, Unmyelinated/drug effects , Reflex , Respiratory Mechanics , Vagus Nerve/drug effects
9.
J Appl Physiol (1985) ; 125(1): 117-123, 2018 07 01.
Article in English | MEDLINE | ID: mdl-29369741

ABSTRACT

Inhaled cigarette smoke stimulated vagal bronchopulmonary C fibers via an action of nicotine on neuronal nicotinic acetylcholine receptor (nAChR). Recent studies have reported that nicotine at high concentrations can also activate the transient receptor potential ankyrin 1 receptor (TRPA1) expressed in these sensory nerves. This study was performed to characterize the airway response to inhaled nicotine aerosol and to investigate the relative roles of nAChR and TRPA1 in this response. Guinea pigs were anesthetized and mechanically ventilated; one tidal volume of nicotine aerosol (2% solution) was diluted by an equal volume of air and delivered directly into the lung via a tracheal cannula in a single breath. Our results showed the following: 1) Inhalation of nicotine aerosol triggered an immediate and pronounced bronchoconstriction; the increase in total pulmonary resistance reached a peak of 588 ± 205% (mean ± SE) in 10-40 s, which gradually returned to baseline after 1-5 min. 2) Pretreatment with either atropine (iv) or mecamylamine (aerosol) almost completely abolished the nicotine-induced bronchoconstriction; the mecamylamine pretreatment did not block the bronchoconstriction and bradycardia evoked by electrical stimulation of the distal end of one sectioned vagus nerve, indicating its minimal systemic effects. 3) Pretreatment with HC-030031, a selective TRPA1 antagonist, abolished the bronchoconstriction induced by allyl isothiocyanate, a selective TRPA1 agonist, but did not attenuate the nicotine-evoked bronchoconstriction. In conclusion, inhalation of a single breath of nicotine aerosol evoked acute bronchoconstriction mediated through the cholinergic reflex pathway. This reflex response was triggered by activation of nAChR, but not TRPA1, located in airway sensory nerves. NEW & NOTEWORTHY Recent reports revealed that nicotine at high concentration activated transient receptor potential ankyrin 1 receptor (TRPA1) expressed in vagal bronchopulmonary sensory nerves. This study showed that inhalation of a single breath of nicotine aerosol consistently evoked acute bronchoconstriction that was mediated through the cholinergic reflex pathway and triggered by activation of nicotinic acetylcholine receptor, but not TRPA1, located in these nerves. This is new and important information considering the recent rapid and alarming rise in the prevalence of e-cigarette use for nicotine inhalation.


Subject(s)
Aerosols/administration & dosage , Bronchi/drug effects , Bronchoconstriction/drug effects , Nicotine/administration & dosage , Receptors, Nicotinic/metabolism , Reflex/drug effects , Administration, Inhalation , Animals , Atropine/administration & dosage , Bronchi/metabolism , Electronic Nicotine Delivery Systems/methods , Guinea Pigs , Lung/drug effects , Lung/metabolism , Male , Mecamylamine/administration & dosage , Nebulizers and Vaporizers , Nerve Fibers, Unmyelinated/metabolism , Smoke/adverse effects , Smoking/adverse effects , TRPA1 Cation Channel/metabolism , Vagus Nerve/drug effects , Vagus Nerve/metabolism
10.
Med J Malaysia ; 73(6): 427-429, 2018 12.
Article in English | MEDLINE | ID: mdl-30647223

ABSTRACT

The occurrence of Leptospirosis and Escherichia coli coinfection in the post-partum period is a novel case. This report illustrated a previously well woman from a suburban area presented with acute neurological deterioration following a two days history of fever during her puerperal period. Early interventions with fluids, broad spectrum antibiotics and intensive supportive care were given. Despite that, she deteriorated rapidly and developed pulmonary hemorrhage, disseminated intravascular coagulopathy, and multi-organ failure. She succumbed within 12 hours of admission. The knowledge about such fatal co-infections should be disseminated to medical practitioners encountering Leptospirosis infection and general public.


Subject(s)
Coinfection/microbiology , Escherichia coli Infections/complications , Leptospirosis/complications , Adult , Escherichia coli , Escherichia coli Infections/microbiology , Fatal Outcome , Female , Humans , Leptospira , Leptospirosis/microbiology , Postpartum Period
11.
Cell Death Differ ; 22(5): 875-84, 2015 May.
Article in English | MEDLINE | ID: mdl-25394489

ABSTRACT

The tumor suppressor phosphatase and tensin homolog (PTEN) dephosphorylates PIP3 and antagonizes the prosurvival PI3K-Akt pathway. Targeted deletion of PTEN in mice led to early embryonic lethality. To elucidate its role in embryonic epithelial morphogenesis and the underlying mechanisms, we used embryonic stem cell-derived embryoid body (EB), an epithelial cyst structurally similar to the periimplantation embryo. PTEN is upregulated during EB morphogenesis in parallel with apoptosis of core cells, which mediates EB cavitation. Genetic ablation of PTEN causes Akt overactivation, apoptosis resistance and cavitation blockade. However, rescue experiments using mutant PTEN and pharmacological inhibition of Akt suggest that the phosphatase activity of PTEN and Akt are not involved in apoptosis-mediated cavitation. Instead, hypoxia-induced upregulation of Bnip3, a proapoptotic BH3-only protein, mediates PTEN-dependent apoptosis and cavitation. PTEN inactivation inhibits hypoxia- and reactive oxygen species-induced Bnip3 elevation. Overexpression of Bnip3 in PTEN-null EBs rescues apoptosis of the core cells. Mechanistically, suppression of Bnip3 following PTEN loss is likely due to reduction of hypoxia-inducible factor-2α (HIF-2α) because forced expression of an oxygen-stable HIF-2α mutant rescues Bnip3 expression and apoptosis. Lastly, we show that HIF-2α is upregulated by PTEN at both transcriptional and posttranscriptional levels. Ablation of prolyl hydroxylase domain-containing protein 2 (PHD2) in normal EBs or inhibition of PHD activities in PTEN-null EBs stabilizes HIF-2α and induces Bnip3 and caspase-3 activation. Altogether, these results suggest that PTEN is required for apoptosis-mediated cavitation during epithelial morphogenesis by regulating the expression of HIF-2α and Bnip3.


Subject(s)
Apoptosis/physiology , Embryo, Mammalian/embryology , Epithelium/embryology , Gene Expression Regulation, Developmental/physiology , Membrane Proteins/biosynthesis , Mitochondrial Proteins/biosynthesis , PTEN Phosphohydrolase/metabolism , Transcription Factors/metabolism , Up-Regulation/physiology , Animals , Embryo, Mammalian/cytology , Membrane Proteins/genetics , Mice , Mice, Knockout , Mitochondrial Proteins/genetics , PTEN Phosphohydrolase/genetics , Proto-Oncogene Proteins c-akt/genetics , Proto-Oncogene Proteins c-akt/metabolism , Transcription Factors/genetics
12.
Singapore Med J ; 56(3): 157-63, 2015 Mar.
Article in English | MEDLINE | ID: mdl-25532516

ABSTRACT

INTRODUCTION: Teenage pregnancy is associated with poor neonatal outcomes, which may burden the young mothers and their families. The aim of this study was to determine the effect young maternal age and single motherhood has on neonatal outcomes. METHODS: We conducted a retrospective cohort study of 267 infants born to mothers aged ≤ 21 years in National University Hospital, Singapore, from January 2011 to December 2012. We compared the maternal demographics and neonatal outcomes of single mothers with those of married mothers. The neonatal outcomes of our study cohort were also compared to the hospital's birth cohort during the same period. RESULTS: Unsatisfactory antenatal care was more prevalent among the young single mothers than among the young married mothers (odds ratio [OR] 2.90, 95% confidence interval [CI] 1.71-4.92, p < 0.01). The infants of the young single mothers had a lower mean birth weight (p = 0.01), with a significant proportion weighing < 2.5 kg (OR 2.91, 95% CI 1.35-6.37, p < 0.01). Young maternal age was linked to a higher incidence of prematurity (OR 1.70, 95% CI 1.18-2.43, p < 0.01), major congenital defects (OR 4.68, 95% CI 2.10-10.13, p < 0.01), and a perinatal mortality of 18.7 per 1,000 births (OR 3.76, 95% CI 1.26-10.32, p = 0.02). CONCLUSION: Young single mothers were more likely to have unsatisfactory antenatal care and lighter infants. Young maternal age was associated with a higher risk of prematurity, major congenital malformations and perinatal mortality. More studies are needed to ascertain the cause of these adverse outcomes.


Subject(s)
Maternal Age , Pregnancy Outcome , Prenatal Care/statistics & numerical data , Adolescent , Female , Humans , Infant , Infant Mortality , Infant, Newborn , Infant, Premature , Mothers , Odds Ratio , Pregnancy , Premature Birth , Retrospective Studies , Risk Factors , Singapore , Single Parent , Treatment Outcome , Young Adult
13.
Transpl Infect Dis ; 16(3): 347-58, 2014 Jun.
Article in English | MEDLINE | ID: mdl-24750282

ABSTRACT

Diarrhea is a common complication after solid organ transplantation, and viruses are emerging as important but underestimated causative agents. Viral infections in solid organ transplant (SOT) recipients can result in severe and prolonged diarrhea with significant patient morbidity and graft complications. Cytomegalovirus remains the most common of the viruses to cause diarrhea, but other viruses are being increasingly recognized, including norovirus, rotavirus, and adenovirus. This article reviews the epidemiology, clinical presentation, diagnosis, management, and outcomes of these viral causes of diarrhea in SOT patients.


Subject(s)
Diarrhea/virology , Organ Transplantation/adverse effects , Virus Diseases/transmission , Diarrhea/pathology , Humans
14.
J Water Health ; 12(1): 196-209, 2014 Mar.
Article in English | MEDLINE | ID: mdl-24642445

ABSTRACT

This paper examines the impact of community-based water treatment systems on water quality in a peri-urban village in Yogyakarta, Indonesia. Water samples were taken from the wastewater treatment plants (WWTPs), irrigation canals, paddy fields and wells during the dry and wet seasons. The samples were tested for biological and chemical oxygen demand, nutrients (ammonia, nitrate, total nitrogen and total phosphorus) and Escherichia coli. Water quality in this village is affected by the presence of active septic tanks, WWTP effluent discharge, small-scale tempe industries and external sources. We found that the WWTPs remove oxygen-demanding wastes effectively but discharged nutrients, such as nitrate and ammonia, into irrigation canals. Irrigation canals had high levels of E. coli as well as oxygen-demanding wastes. Well samples had high E. coli, nitrate and total nitrogen levels. Rainfall tended to increase concentrations of biological and chemical oxygen demand and some nutrients. All our samples fell within the drinking water standards for nitrate but failed the international and Indonesian standards for E. coli. Water quality in this village can be improved by improving the WWTP treatment of nutrients, encouraging more villagers to be connected to WWTPs and controlling hotspot contamination areas in the village.


Subject(s)
Environmental Monitoring/methods , Waste Disposal, Fluid/methods , Wastewater/chemistry , Wastewater/microbiology , Water Pollutants, Chemical/chemistry , Water Pollutants, Chemical/isolation & purification , Water Purification/methods , Water Quality , Water Supply , Escherichia coli/isolation & purification , Indonesia
15.
BMJ Case Rep ; 20142014 Feb 20.
Article in English | MEDLINE | ID: mdl-24557479

ABSTRACT

A 42-year-old man who was being treated for pneumonia developed severe, sudden-onset abdominal pain with features of shock and peritonism. The clinical picture combined with radiological investigations raised suspicion of a bowel perforation necessitating urgent surgical review and emergency laparotomy. This diagnosed a jejunal perforation with abnormal lymph nodes. Histological examination confirmed diffuse large B-cell lymphoma. The patient was subsequently started on a course of chemotherapy. While gastrointestinal perforation secondary to antilymphoma treatment is a well-recognised complication, primary perforation caused by the lymphoma itself must always be considered.


Subject(s)
Intestinal Perforation/etiology , Jejunal Diseases/etiology , Lymphoma, B-Cell/complications , Lymphoma, B-Cell/diagnosis , Rare Diseases/etiology , Adult , Antibodies, Monoclonal, Murine-Derived/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cyclophosphamide/therapeutic use , Doxorubicin/therapeutic use , Humans , Intestinal Perforation/surgery , Jejunal Diseases/surgery , Lymphoma, B-Cell/drug therapy , Male , Prednisone/therapeutic use , Rare Diseases/surgery , Rituximab , Vincristine/therapeutic use
16.
Oncogene ; 33(18): 2385-94, 2014 May 01.
Article in English | MEDLINE | ID: mdl-23708659

ABSTRACT

Activation of the mitogen-activated protein kinase (MAPK) cascade in mammalian cell lines positively regulates the G2/M transition. The molecular mechanism underlying this biological phenomenon remains poorly understood. Ribosomal S6 kinase (RSK) is a key downstream element of the MAPK cascade. Our previous studies established roles of RSK2 in Cdc25C activation during progesterone-induced meiotic maturation of Xenopus oocytes. In this study we demonstrate that both recombinant RSK and endogenous RSK in Xenopus egg extracts phosphorylate all three isoforms of human Cdc25 at a conserved motif near the catalytic domain. In human HEK293 and PC-3mm2 cell lines, RSK preferentially phosphorylates Cdc25A and Cdc25B in mitotic cells. Phosphorylation of the RSK sites in these Cdc25 isoforms increases their M-phase-inducing activities. Inhibition of RSK-mediated phosphorylation of Cdc25 inhibits G2/M transition. Moreover, RSK is likely to be more active in mitotic cells than in interphase cells, as evidenced by the phosphorylation status of T359/S363 in RSK. Together, these findings indicate that RSK promotes G2/M transition in mammalian cells through activating phosphorylation of Cdc25A and Cdc25B.


Subject(s)
G2 Phase Cell Cycle Checkpoints , Ribosomal Protein S6 Kinases, 90-kDa/metabolism , cdc25 Phosphatases/metabolism , Amino Acid Sequence , Animals , HEK293 Cells , Humans , Molecular Sequence Data , Oocytes/enzymology , Phosphorylation , Ribosomal Protein S6 Kinases, 90-kDa/genetics , Xenopus , cdc25 Phosphatases/genetics
17.
Cancer Gene Ther ; 20(11): 606-15, 2013 Nov.
Article in English | MEDLINE | ID: mdl-24201869

ABSTRACT

Cancer stem cells are refractory to conventional therapy, which result to cancer metastasis and chemo-radioresistance. Grp78 is known to have important roles in cytoprotection and tumorigenesis in several cancers. We therefore examined whether Grp78 can serve as a therapeutic target for refractory stemness phenotype of head and neck cancer (HNC). Six HNC cell lines were used. Fluorescence-activated cell sorting (FACS) analysis was used to sort CD24(-)CD44(+) and Grp78(+) cells. The small interfering RNA (siRNA) knockdown and cDNA transfection were applied to examine the effects of Grp78 on cellular function. Western blot and confocol microscopy were used to determine the effects of downstream protein expressions. Xenografted mouse tumors and immunohistochemistry were used to validate the results. We found that Grp78 regulated the conversion of CD24(-)CD44(+) cells, a characteristic of HNC stem cells. The CD24(-)CD44(+)Grp78(+) cells showed superior chemo-radioresistance and invasion ability compared with CD24(-)CD44(+), Grp78(+) or the parental cells. Silencing Grp78 increased chemo-radiosensitivity, inhibited cell invasion, reverse epithelial-mesenchymal transition, suppressed cancer stemness, withdrew CD24(-)CD44(+) cell conversion and induced differentiated phenotype. Study in xenografted mice further showed that CD24(-)CD44(+)Grp78(+) cells exhibited highest tumorigenesis, compared with CD24(-)CD44(+) CD24(+)CD44(+) or the parental cells. Grp78 knockdown dramatically restrained tumor growth along with the inhibition of stem cell regulatory proteins Oct-4 and Slug. Grp78 may serve as a molecular target that can be further developed for eradication of refractory HNC with stemness phenotype.


Subject(s)
Head and Neck Neoplasms/therapy , Heat-Shock Proteins/genetics , Heat-Shock Proteins/metabolism , Neoplastic Stem Cells/pathology , Animals , CD24 Antigen/biosynthesis , Cell Differentiation/drug effects , Cell Differentiation/physiology , Cell Line, Tumor , Cisplatin/pharmacology , Endoplasmic Reticulum Chaperone BiP , Epithelial-Mesenchymal Transition , Head and Neck Neoplasms/genetics , Head and Neck Neoplasms/metabolism , Head and Neck Neoplasms/pathology , Heat-Shock Proteins/deficiency , Humans , Hyaluronan Receptors/biosynthesis , Mice , Molecular Targeted Therapy , Neoplastic Stem Cells/drug effects , Neoplastic Stem Cells/metabolism , Phenotype , RNA, Small Interfering/administration & dosage , RNA, Small Interfering/genetics , Random Allocation , Transfection , Xenograft Model Antitumor Assays
18.
Oncogene ; 32(24): 2973-83, 2013 Jun 13.
Article in English | MEDLINE | ID: mdl-22890325

ABSTRACT

Castration-resistant prostate cancer (PCa) is refractory to hormone therapy and new strategies for treatment are urgently needed. We found that androgen-insensitive (AI) PCa cells, LNCaP-AI, are reprogrammed to upregulate the mitotic kinase Plk1 (Polo-like kinase 1) and other M-phase cell-cycle proteins, which may underlie AI PCa growth. In androgen-depleted media, LNCaP-AI cells showed exquisite sensitivity to growth inhibition by subnanomolar concentrations of a small molecule inhibitor of Plk1, BI2536, suggesting that these cells are dependent on Plk1 for growth. In contrast, the androgen-responsive parental LNCaP cells showed negligible responses to BI2536 treatment under the same condition. BI2536 treatment of LNCaP-AI cells resulted in an increase in cell death marker PARP-1 (polymerase-1) but did not activate caspase-3, an apoptosis marker, suggesting that the observed cell death was caspase-independent. BI2536-treated LNCaP-AI cells formed multinucleated giant cells that contain clusters of nuclear vesicles indicative of mitotic catastrophe. Live-cell time-lapse imaging revealed that BI2536-treated giant LNCaP-AI cells underwent necroptosis, as evidenced by 'explosive' cell death and partial reversal of cell death by a necroptosis inhibitor. Our studies suggest that LNCaP-AI cells underwent reprogramming in both their cell growth and cell death pathways, rendering them highly sensitive to Plk1 inhibition that induces necroptosis. Harnessing necroptosis through Plk1 inhibition may be explored for therapeutic intervention of castration-resistant PCa.


Subject(s)
Androgens/metabolism , Cell Cycle Proteins/antagonists & inhibitors , Cell Cycle Proteins/metabolism , Prostatic Neoplasms/pathology , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins/antagonists & inhibitors , Proto-Oncogene Proteins/metabolism , Up-Regulation/drug effects , Aneuploidy , Autophagy/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Gene Expression Regulation, Neoplastic/drug effects , Humans , Male , Mitosis/drug effects , Necrosis/chemically induced , Necrosis/metabolism , Polo-Like Kinase 1
19.
Int J Clin Pract ; 66(4): 342-55, 2012 Apr.
Article in English | MEDLINE | ID: mdl-22420497

ABSTRACT

INTRODUCTION: Hepatitis C virus (HCV) affects approximately 3% of the world population. The current standard of care for treatment of HCV is a combination of pegylated interferon and ribavirin. Approximately 10% of patients will stop treatment and 30% of patients require dose reduction because of side effects. For genotype 1 HCV-infected patients, only 40% of patients will achieve undetectable viral load 26 weeks posttreatment. AIMS: The objectives of this review were to identify new treatments that are in clinical trials. These include boceprevir and telaprevir which are in routine clinical use and form part of the American Association for the Study of Liver Diseases (AASLD) 2011 guidelines as well as drugs based on observational studies, improving/modifying ribavirin or interferon-based therapies, modifying the host response and finally the use of direct-acting antiviral agents (DAA). MATERIALS AND METHODS: MEDLINE and EMBASE databases were searched from 2008 to 2011 for treatments for hepatitis C. Furthermore, abstracts and poster presentations for the annual European Association Study of the Liver, AASLD, Digestive Disease Week and Asian Pacific Association for the study of the Liver were searched for relevant material. RESULTS: All four classes of DAA; NS3/NS4a serine protease inhibitors, cyclophilin inhibitors, NS5b polymerase inhibitors and NS5a inhibitors, show good success rates. Trials have been performed without ribavirin or interferon and demonstrate good antiviral activity with a decreased side effect profile. Combinations of DAA are a promising area of research with a high success rate. CONCLUSIONS: Clinical trials show that future HCV therapy could be personalised, achieve higher success rates with decreased adverse incidents.


Subject(s)
Antiviral Agents/therapeutic use , Hepatitis C, Chronic/drug therapy , Biological Products/chemistry , Cyclophilins/antagonists & inhibitors , Drug Combinations , Drug Discovery , Hepacivirus/chemistry , Hepatitis C, Chronic/prevention & control , Humans , Immunologic Factors/therapeutic use , Matrix Metalloproteinase Inhibitors , Nucleotidyltransferases/antagonists & inhibitors , Randomized Controlled Trials as Topic , Serine Proteinase Inhibitors/therapeutic use , Viral Hepatitis Vaccines
20.
J Environ Sci (China) ; 24(9): 1559-68, 2012.
Article in English | MEDLINE | ID: mdl-23520862

ABSTRACT

The present work covers the preparation of carbon-based nanosorbents by ethylene decomposition on stainless steel mesh without the use of external catalyst for the treatment of water containing nickel ions (Ni2+). The reaction temperature was varied from 650 to 850 degrees C, while reaction time and ethylene to nitrogen flow ratio were maintained at 30 min and 1:1 cm3/min, respectively. Results show that nanosorbents synthesised at a reaction temperature of 650 degrees C had the smallest average diameter (75 nm), largest BET surface area (68.95 m2/g) and least amount of impurity (0.98 wt.% Fe). A series of batch-sorption tests were performed to evaluate the effects of initial pH, initial metal concentration and contact time on Ni2+ removal by the nanosorbents. The equilibrium data fitted well to Freundlich isotherm. The kinetic data were best correlated to a pseudo second-order model indicating that the process was of chemisorption type. Further analysis by the Boyd kinetic model revealed that boundary layer diffusion was the controlling step. This primary study suggests that the prepared material with Freundlich constants compared well with those in the literature, is a promising sorbent for the sequestration of Ni2+ in aqueous solutions.


Subject(s)
Ethylenes/chemistry , Nanotubes, Carbon/chemistry , Nickel/chemistry , Water/chemistry , Stainless Steel
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