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Fulltext Cisplatin-Resistance in Oral Squamous Cell Carcinoma: Regulation by Tumor Cell-Derived Extracellular Vesicles

Khoo XH, Paterson IC, Goh BH, Lee WL

Cancers (Basel), 2019 Aug 14;11(8).
PMID: 31416147 DOI: 10.3390/cancers11081166

Drug resistance remains a severe problem in most chemotherapy regimes. Recently, it has been suggested that cancer cell-derived extracellular vesicles (EVs) could mediate drug resistance. In this study, the role of EVs in mediating the response of oral squamous cell carcinoma (OSCC) cells to cisplatin was investigated. We isolated and characterized EVs from OSCC cell lines showing differential sensitivities to cisplatin. Increased EV production was observed in both de novo (H314) and adaptive (H103/cisD2) resistant lines compared to sensitive H103 cells. The protein profiles of these EVs were then analyzed. Differences in the proteome of EVs secreted by H103 and H103/cisD2 indicated that adaptation to cisplatin treatment caused significant changes in the secreted nanovesicles. Intriguingly, both resistant H103/cisD2 and H314 cells shared a highly similar EV protein profile including downregulation of the metal ion transporter, ATP1B3, in the EVs implicating altered drug delivery. ICP-MS analysis revealed that less cisplatin accumulated in the resistant cells, but higher levels were detected in their EVs. Therefore, we inhibited EV secretion from the cells using a proton pump inhibitor and observed an increased drug sensitivity in cisplatin-resistant H314 cells. This finding suggests that control of EV secretion could be a potential strategy to enhance the efficacy of cancer treatment.
High Accuracy of a Simplified, Practical Algorithm in Differentiating Crohn's Disease from Intestinal Tuberculosis

Hilmi IN, Nik Muhamad Affendi NA, Shahrani S, Thalha AM, Leow AH, Khoo XH

Dig Dis, 2023;41(4):581-588.
PMID: 36702102 DOI: 10.1159/000529238

BACKGROUND: The differentiation between intestinal tuberculosis (ITB) and Crohn's disease (CD) remains a challenge, particularly in areas where tuberculosis is highly prevalent. Previous studies have identified features that favour one diagnosis over the other. The aim of the study was to determine the accuracy of a standardized protocol in the initial diagnosis of CD versus ITB.
METHODS: All patients with suspected ITB or CD were prospectively recruited. A standardized protocol was applied, and the diagnosis was made accordingly. The protocol consists of history and examination, ileocolonoscopy with biopsies, and tuberculosis workup. The diagnosis of probable ITB was made based on at least one positive finding. All other patients were diagnosed as probable CD. Patients were treated either with anti-tubercular therapy or steroids. Reassessment was then carried out clinically, biochemically, and endoscopically. In patients with suboptimal response, the treatment was either switched or escalated depending on the reassessment.
RESULTS: 164 patients were recruited with final diagnosis of 30 (18.3%) ITB and 134 (81.7%) CD. 1 (3.3%) out of 30 patients with ITB was initially treated as CD. 16 (11.9%) out of 134 patients with CD were initially treated as ITB. The initial overall accuracy for the protocol was 147/164 (89.6%). All patients received the correct diagnosis by 12 weeks after reassessment.
CONCLUSION: In our population, most patients had CD rather than ITB. The standardized protocol had a high accuracy in differentiating CD from ITB.
Fulltext Extracellular Vesicle-Mediated Chemoresistance in Oral Squamous Cell Carcinoma

Law ZJ, Khoo XH, Lim PT, Goh BH, Ming LC, Lee WL, et al.

Front Mol Biosci, 2021;8:629888.
PMID: 33768115 DOI: 10.3389/fmolb.2021.629888

Oral Squamous Cell Carcinoma (OSCC) remains a cancer with poor prognosis and high recurrence rate. Even with multimodal treatment options available for OSCC, tumor drug resistance is still a persistent problem, leading to increased tumor invasiveness among OSCC patients. An emerging trend of thought proposes that extracellular vesicles (EVs) play a role in facilitating tumor progression and chemoresistance via signaling between tumor cells. In particular, exosomes and microvesicles are heavily implicated in this process by various studies. Where primary studies into a particular EV-mediated chemoresistance mechanism in OSCC are limited, similar studies on other cancer cell types will be used in the discussion below to provide ideas for a new line of investigation into OSCC chemoresistance. By understanding how EVs are or may be involved in OSCC chemoresistance, novel targeted therapies such as EV inhibition may be an effective alternative to current treatment options in the near future. In this review, the current understandings on OSCC drug mechanisms under the novel context of exosomes and microvesicles were reviewed, including shuttling of miRNA content, drug efflux, alteration of vesicular pH, anti-apoptotic signaling, modulation of DNA damage repair, immunomodulation, epithelial-to-mesenchymal transition and maintenance of tumor by cancer stem cells.
A Systematic Review on the Increasing Incidence of Inflammatory Bowel Disease in Southeast Asia: Looking Beyond the Urbanization Phenomenon

Chew DCH, Khoo XH, Lee TS, Chin KY, Raja Ali RA, Muhammad Nawawi KN, et al.

Inflamm Bowel Dis, 2024 Sep 03;30(9):1566-1578.
PMID: 37935628 DOI: 10.1093/ibd/izad189

The incidence of inflammatory bowel disease (IBD) has been increasing in Southeast Asia (SEA) in tandem with its economic growth and urbanization over the past 2 decades. Specific characteristics of IBD in SEA are similar to East Asia and the West, such as the declining ratio of ulcerative colitis to Crohn's disease. However, exceptionally low familial aggregation is seen. Smoking is also not a common risk factor in patients with Crohn's disease. The incidence of perianal disease is higher in SEA than in Australia and is comparable to the West. In a multiracial population, such as Singapore and Malaysia, Indians have the highest incidence and prevalence rates, which are likely to be due to important putative mutations. For instance, a higher frequency of the NOD2 predisposing mutation SNP5 and IBD risk allele IGR2198a and IGR2092a were found in Indians. Although differences in the genetic constitution play an important role in the epidemiology and prognosis of IBD in SEA, the emergence of this disease offers a unique opportunity to identify potential exposomes that contribute to its pathogenesis.
The development of a novel, multilingual IBD knowledge questionnaire for Asian patients with inflammatory bowel disease

Razima Wan Ibrahim N, Danaee M, Khoo XH, Sithambaram S, Shahrani S, Hwong-Ruey Leow A, et al.

BMC Gastroenterol, 2023 May 25;23(1):185.
PMID: 37231353 DOI: 10.1186/s12876-023-02817-0

BACKGROUND: Inflammatory bowel disease is an uncommon disease in developing nations whereby patient's knowledge on the disease may be limited. The CCKNOW questionnaire, a widely known questionnaire to assess patient's knowledge on the disease, may be too complex to comprehend for patients in developing countries. The aim of this study is to develop a new tool known as AIBDKQ questionnaire to evaluate the local inflammatory bowel disease patient's knowledge.
METHODS: This was a prospective study carried out in four phases. In phase 1, three gastroenterologists with expertise in IBD generated a total of 21 questions related to the general knowledge of the disease in the English language. Phase 2 involved content and face validity whereby the questions were further validated by other gastroenterologists. In phase 3, the validated questions were translated into three languages namely Malay, Mandarin and Tamil which are commonly used in Malaysia. In phase 4 (statistical validity), administration of the questionnaires to patients and hospital staff were conducted to assess the construct validity, discriminative ability, predictive validity and reliability of the questionnaires.
RESULTS: A total of 21 questions were generated initially. Further evaluation indicated that 20 items had adequate kappa and content validity index for relevance (CVI: 0.714 to 1, Kapp: 0.645 to 1) and clarity (CVI: 0.714 to 1, Kapp: 0.645 to 1). The questionnaires in four languages were administered to 213 patients to assess the construct validity. Six items were removed (three for low communality, one for small loading factors, two for cross loading), resulting in 16 final questions. Assessment with 34 hospital staff involving nurses, doctors and clerks showed significant differences in knowledge between the groups (F = 14.007, p
The impact of diet and ethnicity on gut microbiota variation in irritable bowel syndrome: A multi-center study

Khoo XH, Chong CW, Talha AM, Philip K, Teh CS, Isa AM, et al.

J Gastroenterol Hepatol, 2023 Aug;38(8):1259-1268.
PMID: 36908030 DOI: 10.1111/jgh.16174

BACKGROUND AND AIM: The gut microbiota in irritable bowel syndrome (IBS) is known to vary with diet. We aim to (i) analyze the gut microbiota composition of IBS patients from a multi-ethnic population and (ii) explore the impact of a low FODMAP diet on gastrointestinal symptoms and gut microbiota composition among IBS patients.
METHODS: A multi-center study of multi-ethnic Asian patients with IBS was conducted in two phases: (i) an initial cross-sectional gut microbiota composition study of IBS patients and healthy controls, followed by (ii) a single-arm 6-week dietary interventional study of the IBS patients alone, exploring clinical and gut microbiota changes.
RESULTS: A total of 34 adult IBS patients (IBS sub-types of IBS-D 44.1%, IBS-C 32.4%, and IBS-M 23.5%) and 15 healthy controls were recruited. A greater abundance of Parabacteroides species with lower levels of bacterial fermenters and short-chain fatty acids producers were found among IBS patients compared with healthy controls. Age and ethnicity were found to be associated with gut microbiota composition. Following a low FODMAP dietary intervention, symptom and quality of life improvement were observed in 24 (70.6%) IBS patients. Symptom improvement was associated with adherence to the low FODMAP diet (46.7% poor adherence vs 92.9% good adherence, P = 0.014), and gut microbiota patterns, particularly with a greater abundance of Bifidobacterium longum, Anaerotignum propionicum, and Blautia species post-intervention.
CONCLUSION: Gut microbiota variation in multi-ethnic IBS patients may be related to dietary intake and may be helpful to identify patients who are likely to respond to a low FODMAP diet.
Ten missteps in the management of inflammatory bowel disease in Asia: An expert report by the Asian Pacific Association of Gastroenterology Working Group on Inflammatory Bowel Disease

Ahuja V, Hilmi I, Ye BD, Ling KL, Ng SC, Leong RW, et al.

J Gastroenterol Hepatol, 2024 May 09.
PMID: 38725188 DOI: 10.1111/jgh.16599

Inflammatory bowel disease (IBD) is rapidly emerging in the Asia Pacific region. However, there are many challenges in the diagnosis and management of this condition. The Asian Pacific Association of Gastroenterology (APAGE) Working Group on IBD conducted a round table meeting to identify 10 common mistakes in the management of IBD in Asia. To summarize, many physicians still over rely on a definitive histological diagnosis before starting treatment and do not fully establish disease extent such as perianal and proximal gastrointestinal involvement in Crohn's disease (CD) or extent of involvement in ulcerative colitis (UC). It is also essential to actively look for evidence of extra-intestinal manifestations, which may influence choice of therapy. In terms of conventional therapy, underuse of topical 5 aminosalicylates (5-ASAs) in UC and inappropriate dosing of corticosteroids are also important considerations. Acute severe UC remains a life-threatening condition and delay in starting rescue therapy after inadequate response to intravenous steroids is still common. Anti-tumor necrosis factors should be considered first line in all cases of complex perianal fistulizing CD. Most patients with IBD are on potent immunosuppressive therapy and should be screened for latent infections and offered vaccinations according to guidelines. Under-recognition and management of significant complications such as anemia, osteoporosis, malnutrition, and thromboembolism should also be addressed. Colonoscopy is still not properly performed for dysplasia/cancer surveillance and for evaluating post-op recurrence of CD. Another common misstep is inappropriate withdrawal of medications during pregnancy leading to increased complications for the mother and the newborn.