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A case of iatrogenic Cushing syndrome and apparent mineralocorticoid excess presenting with accelerated hypertension and proteinuria

Kong WY, Leedman P, Irish A

Intern Med J, 2014 Sep;44(9):932-4.
PMID: 25201428 DOI: 10.1111/imj.12022
Fulltext The association between serum prolactin levels and interleukin-6 and systemic lupus erythematosus activity

Wan Asyraf WA, Mohd Shahrir MS, Asrul W, Norasyikin AW, Hanita O, Kong WY, et al.

Reumatismo, 2018 Dec 20;70(4):241-250.
PMID: 30570242 DOI: 10.4081/reumatismo.2018.1075

Based on the recent evidence of association between hyperprolactinemia and systemic lupus erythematosus disease activity (SLEDAI), a study was conducted to analyze the association of hyperprolactinemia with lupus nephritis disease activity. In this cross-sectional study, the analysis was conducted on SLE patients who visited the University Kebangsaan Malaysia Medical Centre (UKMMC) Nephrology Clinic from August 2015 till February 2016. The disease activity was measured using the SLEDAI score, with more than 4 indicating active lupus nephritis. Basal resting prolactin level was analyzed in 43 patients with lupus nephritis, in 27.9% of them had raised serum prolactin. The median of serum prolactin level at 0 minutes was 19.91 ng/mL (IQR: 15.95-22.65 ng/ mL) for active lupus nephritis, which was significantly higher compared to the median of serum prolactin level of 14.34 ng/mL (IQR: 11.09-18.70 ng/mL) for patients in remission (p=0.014). The serum prolactin level positively correlated with SLEDAI (rhos: 0.449, p=0.003) and the UPCI level in lupus nephritis patients (rhos: 0.241, p=0.032). The results were reproduced when the serum prolactin was repeated after 30 minutes. However, the serum prolactin levels at 0 minutes were higher than those taken after 30 minutes (p=0.001). An assessment of serum IL-6 levels found that the active lupus nephritis patients had a higher median level of 65.91 pg/ mL (IQR: 21.96-146.14 pg/mL) compared to the in-remission level of 15.84 pg/mL (IQR: 8.38-92.84 pg/mL), (p=0.039). Further correlation analysis revealed that there was no statistical correlation between the interleukin (IL)-6 levels with serum prolactin, SLEDAI and other lupus nephritis parameters. An ROC curve analysis of serum prolactin at 0 minutes and serum prolactin after 30 minutes and IL-6 levels for prediction of SLE disease activity provided the cutoff value of serum prolactin at 0 minutes, which was 14.63 ng/mL with a sensitivity of 91.7% and specificity of 58.1% and AUC of 0.74 (p=0.015). This study concurred with the previous findings that stated that hyperprolactinemia is prevalent in SLE patients and correlated with clinical disease activity and UPCI level. The baseline of the fasting serum prolactin level was found to be a sensitive biomarker for the evaluation of lupus nephritis disease activity.
The TRAIL to cancer therapy: Hindrances and potential solutions

Wong SHM, Kong WY, Fang CM, Loh HS, Chuah LH, Abdullah S, et al.

Crit Rev Oncol Hematol, 2019 Nov;143:81-94.
PMID: 31561055 DOI: 10.1016/j.critrevonc.2019.08.008

Apoptosis is an ordered and orchestrated cellular process that occurs in physiological and pathological conditions. Resistance to apoptosis is a hallmark of virtually all malignancies. Despite being a cause of pathological conditions, apoptosis could be a promising target in cancer treatment. Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), also known as Apo-2 ligand (Apo2L), is a member of TNF cytokine superfamily. It is a potent anti-cancer agent owing to its specific targeting towards cancerous cells, while sparing normal cells, to induce apoptosis. However, resistance occurs either intrinsically or after multiple treatments which may explain why cancer therapy fails. This review summarizes the apoptotic mechanisms via extrinsic and intrinsic apoptotic pathways, as well as the apoptotic resistance mechanisms. It also reviews the current clinically tested recombinant human TRAIL (rhTRAIL) and TRAIL receptor agonists (TRAs) against TRAIL-Receptors, TRAIL-R1 and TRAIL-R2, in which the outcomes of the clinical trials have not been satisfactory. Finally, this review discusses the current strategies in overcoming resistance to TRAIL-induced apoptosis in pre-clinical and clinical settings.
Anti-cancer Effects of Epigenetics Drugs Scriptaid and Zebularine in Human Breast Adenocarcinoma Cells

Yap ZH, Kong WY, Azeez AR, Fang CM, Ngai SC

Anticancer Agents Med Chem, 2021 Jun 07.
PMID: 34102995 DOI: 10.2174/1871520621666210608103251

BACKGROUND: High relapse and metastasis progression in breast cancer patients have prompted the need to explore alternative treatments. Epigenetic therapy has emerged as an attractive therapeutic strategy due to the reversibility of epigenome structures.
OBJECTIVE: This study investigated the anti-cancer effects of epigenetic drugs scriptaid and zebularine in human breast adenocarcinoma MDA-MB-231 and MCF-7 cells.
METHODS: First, the half maximal inhibitory concentration (IC50) of scriptaid, zebularine and the combination of both drugs on human breast adenocarcinoma MDA-MB-231 cells was determined. Next, MDA-MB-231 and MCF-7 cells were treated with scriptaid, zebularine and the combination of both. After treatments, the anti-cancer effects were evaluated via cell migration assay, cell cycle analysis and apoptotic studies, which included histochemical staining and reverse-transcriptase polymerase chain reaction (RT-PCR) of the apoptotic genes.
RESULTS: Both epigenetic drugs inhibited cell viability in a dose-dependent manner with 2 nM scriptaid, 8 µM zebularine and combination of 2 nM scriptaid and 2 µM zebularine. Both MDA-MB-231 and MCF-7 cells exhibited a reduction in cell migration after the treatments. In particular, MDA-MB-231 cells exhibited a significant reduction in cell migration (p < 0.05) after the treatments of zebularine and the combination of scriptaid and zebularine. Besides, cell cycle analysis demonstrated that scriptaid and the combination of both drugs could induce cell cycle arrest at the G0/G1 phase in both MDA-MB-231 and MCF-7 cells. Furthermore, histochemical staining allowed the observation of apoptotic features, such as nuclear chromatin condensation, cell shrinkage, membrane blebbing, nuclear chromatin fragmentation and cytoplasmic extension, in both MDA-MB-231 and MCF-7 cells after the treatments. Further apoptotic studies revealed that the upregulation of pro-apoptotic Bax, downregulation of anti-apoptotic Bcl-2 and elevation of Bax/Bcl-2 ratio were found in MDA-MB-231 cells treated with zebularine and MCF-7 cells treated with all drug regimens.
CONCLUSION: Collectively, these findings suggest that scriptaid and zebularine are potential anti-cancer drugs, either single or in combination, for the therapy of breast cancer. Further investigations of the gene regulatory pathways directed by scriptaid and zebularine are definitely warranted in the future.
Fulltext Community acquired multi drug resistant (MDR) Acinetobacter baumannii pneumonia in Malaysia - A case report

Mohd R, Nesam T, Kamaruzaman L, Cader RA, Mustafar R, Kong WY

Respir Med Case Rep, 2018;24:147-149.
PMID: 29977783 DOI: 10.1016/j.rmcr.2018.05.019

Acinetobacter baumannii is an aerobic Gram-negative coccobacillus that is associated with hospital acquired pneumonia. There is increased reporting of emergent cases of community acquired multidrug resistance (MDR) acinetobacter associated with a higher mortality due to antibiotic resistance. Community acquired MDR acinetobacter pneumonia has not been reported in Malaysia. Here we report a case of a 19-year-old army officer who presented with fever and respiratory symptoms for 5 days. He had no known medical illness before and no history of hospitalization. Upon arrival, he was in septicaemic shock, requiring invasive ventilator support and renal replacement therapy in intensive care unit. Chest radiograph showed bilateral lung consolidations and bronchoscopy revealed haemoserous and greenish bronchiole secretion. He was treated with broad spectrum antibiotics and oseltamivir. Unfortunately he died on day 3 of hospital admission. His bronchial lavage culture came back positive for MDR Acinetobacter baumannii. This case illustrates that clinicians need to be aware that MDR Acinetobacter baumannii can cause severe community acquired pneumonia. We may need to consider this diagnosis in patients who do not respond to standard therapy.
Fulltext Zebularine and trichostatin A sensitized human breast adenocarcinoma cells towards tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-induced apoptosis

Kong WY, Yee ZY, Mai CW, Fang CM, Abdullah S, Ngai SC

Heliyon, 2019 Sep;5(9):e02468.
PMID: 31687564 DOI: 10.1016/j.heliyon.2019.e02468

Tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) is a promising cancer therapeutic agent due to its selective killing on cancer cells while sparing the normal cells. Nevertheless, breast adenocarcinoma cells can develop TRAIL resistance. Therefore, this project investigated the anti-cancer effects of the combination of epigenetic drugs zebularine and trichostatin A (ZT) with TRAIL (TZT) on the human breast adenocarcinoma cells. This treatment regimen was compared with the natural anti-cancer compound curcumin (Cur) and standard chemotherapeutic drug doxorubicin (Dox). As compared to TRAIL treatment, TZT treatment hampered the cell viability of human breast adenocarcinoma cells MDA-MB-231 significantly but not MCF-7 and immortalized non-cancerous human breast epithelial cells MCF10A. Unlike TZT, Cur and Dox treatments reduced cell viability in both human breast adenocarcinoma and epithelial cells significantly. Nevertheless, there were no changes in cell cycle in both TRAIL and TZT treatments in breast adenocarcinoma and normal epithelial cells. Intriguingly, Cur and Dox treatment generally induced G2/M arrest in MDA-MB-231, MCF-7 and MCF10A but Cur induced S phase arrest in MCF10A. The features of apoptosis such as morphological changes, apoptotic activity and the expression of cleaved poly (ADP) ribose polymerase (PARP) protein were more prominent in TRAIL and TZT-treated MDA-MB-231 as compared to MCF10A at 24 h post-treatment. Compared to TZT treatment, Cur and Dox treatments exhibited lesser apoptotic features in MDA-MB-231. Collectively, the sensitization using Zeb and TSA to augment TRAIL-induced apoptosis might be an alternative therapy towards human breast adenocarcinoma cells, without harming the normal human breast epithelial cells.
Fulltext Breathlessness worsened by haemodialysis

Cader RA, Thoriappa K, Mohd R, Kong WY, Mustafar R, Kamaruzaman L

Respir Med Case Rep, 2019;26:6-8.
PMID: 30416956 DOI: 10.1016/j.rmcr.2018.10.022

A 54 year old lady with underlying chronic lung disease on long term oxygen therapy and end stage renal disease of unknown aetiology on regular haemodialysis for two years started developing progressive shortness of breath during her routine haemodialysis. She was unable to tolerate her haemodialysis sessions which had to be terminated prematurely in view of her symptoms despite adjustment of her dry weight and treatment of anaemia. She was not in chronic fluid overload and her symptoms always worsened after initiation of haemodialysis and improved after termination of haemodialysis. She was admitted to hospital for further investigations and initially treated for a lung infection but her symptoms did not improve. A computed tomography pulmonary angiography did not reveal any evidence of pulmonary embolism, and was consistent with chronic fibrotic changes. Her hypoxemia was concluded to be due to her underlying chronic lung disease, worsened by alveolar hypoventilation during haemodialysis. Her symptoms improved slightly with supplemental oxygen during her routine haemodialysis but we had to shorten her haemodialysis duration to 3 hours.
Clinical predictors of non-diabetic renal disease and role of renal biopsy in diabetic patients with renal involvement: a single centre review

Chong YB, Keng TC, Tan LP, Ng KP, Kong WY, Wong CM, et al.

Ren Fail, 2012;34(3):323-8.
PMID: 22250665 DOI: 10.3109/0886022X.2011.647302

BACKGROUND:
Type 2 diabetes mellitus (T2DM) is reportedly the leading cause of end-stage renal disease (ESRD) worldwide. However, non-diabetic renal diseases (NDRD) are not uncommon among T2DM patients with renal involvement. Our study aimed to examine the prevalence of NDRD in T2DM and clinical markers for diabetic nephropathy (DN) and NDRD and to determine the role of renal biopsy in T2DM patients and its impact on clinical practice.

METHODS:
We conducted a retrospective analysis of T2DM patients in whom renal biopsies were performed from January 2004 to March 2008 (n = 110).

RESULTS:
Biopsy results were divided into three groups: group I/pure DN (62.7%), group II/isolated NDRD (18.2%), and group III/mixed lesions (19.1%). The causes of NDRD in decreasing order of frequency were acute interstitial nephritis, glomerulonephritides, hypertensive renal disease, and acute tubular necrosis. Significant clinical markers for DN are presence of diabetic retinopathy and longer duration of diabetes. For NDRD, useful clinical markers include the presence of acute renal failure and microscopic hematuria. In the DN subgroup, Indians had significantly shorter duration of diabetes on biopsy compared with Malays and Chinese.

CONCLUSIONS:
NDRD is prevalent in T2DM patients, and given its potentially treatable nature, renal biopsy should be considered in T2DM patients with nephropathy, especially in those with atypical features.
Fulltext Role of febuxostat in retarding progression of diabetic kidney disease with asymptomatic hyperuricemia: A 6-months open-label, randomized controlled trial

Mukri MNA, Kong WY, Mustafar R, Shaharir SS, Shah SA, Abdul Gafor AH, et al.

EXCLI J, 2018;17:563-575.
PMID: 30108461 DOI: 10.17179/excli2018-1256

Introduction: Hyperuricemia is associated with chronic kidney disease (CKD) progression and poor cardiovascular outcomes. We studied the effect of febuxostat on estimated glomerular filtration rate (eGFR), proteinuria and monitored the safety profile of the medication.
Material and Methods: This is a prospective open-label, randomized study in CKD stage 3 and 4 patients with diabetic nephropathy and asymptomatic hyperuricemia. Patients were randomized into febuxostat 40 mg daily and no treatment group using block randomization method and were followed up for 6 months. Their usual care for diabetes mellitus, hypertension and dyslipidemia were continued in the study. Blood and urine investigations were monitored at baseline, 3 months and 6 months.
Results: The eGFR in febuxostat group was stabilized at 6 months with no significant reduction [26.2 (IQR 14.30) at baseline to 26.3 (IQR 15.2) ml/min/1.73 m2]. Whereas, there was a significant reduction of the eGFR in no treatment group from 28.2 (IQR 17.9) to 27.6 (IQR 19.3) ml/min/1.73 m2 (p value < 0.01). We found the HbA1c (glycosylated hemoglobin) was significantly increased in febuxostat group from 7.2 ± 0.5 % at baseline to 7.6 ± 1.4 at 6 months (p value 0.04) but no significant change of HbA1c in the no treatment group. Proteinuria level was unchanged in both groups. The commonest adverse event was joint pain.
Conclusions: Febuxostat was able to preserve eGFR in CKD patients with diabetic nephropathy and this effect was beyond glycemic control. Increment of HbA1c level in febuxostat group needs further larger trials.
Study site: Chronic kidney disease clinic, Hospital Canselor Tuanku Muhriz, Pusat Perubatan Universiti Kebangsaan Malaysia (PPUKM), Kuala Lumpur, Malaysia
Rapamycin synergizes cisplatin sensitivity in basal-like breast cancer cells through up-regulation of p73

Wong SW, Tiong KH, Kong WY, Yue YC, Chua CH, Lim JY, et al.

Breast Cancer Res Treat, 2011 Jul;128(2):301-13.
PMID: 20686837 DOI: 10.1007/s10549-010-1055-0

Recent gene expression profiling studies have identified five breast cancer subtypes, of which the basal-like subtype is the most aggressive. Basal-like breast cancer poses serious clinical challenges as there are currently no targeted therapies available to treat it. Although there is increasing evidence that these tumors possess specific sensitivity to cisplatin, its success is often compromised due to its dose-limiting nephrotoxicity and the development of drug resistance. To overcome this limitation, our goal was to maximize the benefits associated with cisplatin therapy through drug combination strategies. Using a validated kinase inhibitor library, we showed that inhibition of the mTOR, TGFβRI, NFκB, PI3K/AKT, and MAPK pathways sensitized basal-like MDA-MB-468 cells to cisplatin treatment. Further analysis demonstrated that the combination of the mTOR inhibitor rapamycin and cisplatin generated significant drug synergism in basal-like MDA-MB-468, MDA-MB-231, and HCC1937 cells but not in luminal-like T47D or MCF-7 cells. We further showed that the synergistic effect of rapamycin plus cisplatin on basal-like breast cancer cells was mediated through the induction of p73. Depletion of endogenous p73 in basal-like cells abolished these synergistic effects. In conclusion, combination therapy with mTOR inhibitors and cisplatin may be a useful therapeutic strategy in the treatment of basal-like breast cancers.

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