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Fulltext The prevalence and risk factors of occult stress urinary incontinence in women undergoing genitourinary prolapse surgery

Jibril AH, Norlelawati Ab Latip, Ng, PY, Jegasothy, R

Journal of Surgical Academia, 2016;6(1):10-17.
MyJurnal

De novo stress urinary incontinence (SUI) may occur in up to 80% of clinically continent women following genitourinary prolapse surgery. This had resulted in an increase in the rate of concurrent continence surgery during prolapse repair from 38% in 2001 to 47% in 2009 in the United States. To date, there is no local data available to estimate the prevalence of occult SUI (OSUI) among Malaysian women awaiting surgery. Therefore, this study was conducted to elicit the prevalence of occult SUI and its associated risks factors in patients awaiting prolapse surgery. We retrospectively studied the records of 296 consecutive women with significant pelvic organ prolapse awaiting reconstructive repair. All patients attended the Urogynaecology Unit in Hospital Kuala Lumpur Malaysia between October 2007 and September 2011. They had undergone standardized interviews, clinical examinations and urodynamic studies. During the urodynamic testings, all prolapses were reduced using ring pessaries to elicit OSUI. Primary outcome was the prevalence of OSUI with prolapse reduction to predict possibility of developing de novo SUI following prolapse surgery. Secondary outcome was the assessment of potential risk factors for OSUI. Among the 296 women studied, 121 (40.9%) were found to have OSUI. The risk factors associated with OSUI included age, BMI, numbers of SVD, recurrent UTI, reduction of urinary flow symptoms and grade 2 to 4 central compartment prolapses. We concluded that preoperative urodynamic testing with reduction of prolapse is useful to identify women with OSUI. This is important for preoperative counselling as well as planning for one step approach of prophylactic concomitant anti-incontinence procedures during prolapse surgery in order to avoid postoperative de novo SUI.
Fulltext Promising Druggable Target in Head and Neck Squamous Cell Carcinoma: Wnt Signaling

Aminuddin A, Ng PY

Front Pharmacol, 2016;7:244.
PMID: 27570510 DOI: 10.3389/fphar.2016.00244

Canonical Wnt signaling pathway, also known as Wnt/β-catenin signaling pathway, is a crucial mechanism for cellular maintenance and development. It regulates cell cycle progression, apoptosis, proliferation, migration, and differentiation. Dysregulation of this pathway correlates with oncogenesis in various tissues including breast, colon, pancreatic as well as head and neck cancers. Furthermore, the canonical Wnt signaling pathway has also been described as one of the critical signaling pathways for regulation of normal stem cells as well as cancer cells with stem cell-like features, termed cancer stem cells (CSC). In this review, we will briefly describe the basic mechanisms of Wnt signaling pathway and its crucial roles in the normal regulation of cellular processes as well as in the development of cancer. Next, we will highlight the roles of canonical Wnt signaling pathway in the regulation of CSC properties namely self-renewal, differentiation, metastasis, and drug resistance abilities, particularly in head and neck squamous cell carcinoma. Finally, we will examine the findings of several recent studies which explore druggable targets in the canonical Wnt signaling pathway which could be valuable to improve the treatment outcome for head and neck cancer.
Fulltext MinION: A Novel Tool for Predicting Drug Hypersensitivity?

Chua EW, Ng PY

Front Pharmacol, 2016;7:156.
PMID: 27378921 DOI: 10.3389/fphar.2016.00156

The launch of the MinION Access Program has caused much activity within the scientific community. MinION represents a keenly anticipated, novel addition to the current melange of commercial sequencers. Driven by the nanopore sequencing mechanism that requires minimal sample manipulation, the device is capable of generating long sequence reads in sizes (up to or exceeding 50 kb) that surpass those of all other platforms. One notable advantage of this feature is that long-range haplotypes can be more accurately resolved; such advantage is particularly pertinent to the genotyping of complex loci such as genes encoding the human leukocyte antigens, which are pivotal determinants of drug hypersensitivity. With this timely, albeit brief, review, we set out to examine the applications on which MinION has been tested thus far, the bioinformatics workflow tailored to the unique characteristics of its extended sequence reads, the device's potential utility in the detection of genetic markers for drug hypersensitivity, and how it may eventually evolve to become fit for diagnostic purposes in the clinical setting.
Manchester - Fothergill procedure for treatment of recurrence procidentia in young nulliparous woman: A case report

Ab Latip N, Ng PY, Jaili S, Mohd Noordin N

Med J Malaysia, 2018 02;73(1):41-43.
PMID: 29531201 MyJurnal

Procidentia is uncommon condition altering quality of life of young and nulliparous women. Its management poses significant dilemma and challenges as its associated body image, fertility and sexuality issues. Uterine preservation surgery described by Archibald Donald in 1888 known as Manchester -Fothergill procedure seems best option as alternative to vaginal hysterectomy. Despite its increasing popularity among surgeons and patients, robust clinical evidence is needed. We report a case of recurrent procidentia in a young nulliparous woman who had Manchester repair following vaginal sacrospinous hysteropexy. We concluded that Manchester repair is a useful and safe alternative for uterine-preserving technique.
Moringa oleifera standardised aqueous leaf extract-loaded hydrocolloid film dressing: in vivo dermal safety and wound healing evaluation in STZ/HFD diabetic rat model

Chin CY, Ng PY, Ng SF

Drug Deliv Transl Res, 2019 04;9(2):453-468.
PMID: 29560587 DOI: 10.1007/s13346-018-0510-z

Previously, Moringa oleifera leaf (MOL) standardised aqueous extract-loaded films were successfully developed and they showed potential wound healing activity in vitro. The objective of this study was to evaluate in vivo dermal safety as well as wound healing efficacy of these MOL film dressings (containing 0.1, 0.5 and 1% MOL) on diabetic rat model. The acute dermal toxicity was carried out on healthy rats, and signs of toxicity over 14 days were observed. For wound healing studies, excision and abrasion wounds were created out on the STZ/HFD-induced diabetic rat model and the wound healing was studied over 21 days. The wound healing evaluation determined by histology staining, hydroxyproline assay and ELISA assays on wound healing related-growth factors, cytokines and chemokines. MOL film formulations exhibited no signs of dermal toxicities. In excision wound model, 0.5% film significantly enhanced the wound closure by 77.67 ± 7.28% at day 7 compared to control group. While in abrasion wounds, 0.5% MOL films accelerated wound closure significantly at 81 ± 4.5% as compared to the control. The histology findings and hydroxyproline assay revealed that high collagen deposition and complete re-epithelialisation were observed for the wounds treated with 0.5 and 1% MOL films. All MOL film dressings had successfully tested non-toxic via in vivo safety dermal toxicity. It was concluded that the 0.5% MOL extract-loaded film had proven to be the most promising approach to accelerate diabetic wound healing process in both full-thickness excision and partial thickness abrasion wounds on the HFD/STZ-induced diabetic type II model.
Cytochrome P450 2W1 (CYP2W1) in Colorectal Cancers

Chung FF, Mai CW, Ng PY, Leong CO

Curr Cancer Drug Targets, 2016;16(1):71-8.
PMID: 26563883

Cytochrome P450, family 2, subfamily W, polypeptide 1 (CYP2W1) is a newly identified monooxygenase enzyme that is expressed specifically in tumor tissues and during fetal life. Particularly, high expression of CYP2W1 was observed in up to 60% of colorectal cancers and its expression correlated with poor survival. CYP2W1 has been shown to metabolize various endogenous substrates including lysophospholipids and several procarcinogens, such as polycyclic aromatic hydrocarbon. The specific substrate for CYP2W1, however, is currently unknown. Due to its tumor-specific expression and its unique catalytic activities in colorectal cancers, CYP2W1 was deemed as an interesting target in colorectal cancer therapy. This review sought to summarize the current understanding of the CYP2W1 biology and biochemistry, its genetic polymorphisms and cancer risk, and its implication as a tumor-specific diagnostic and therapeutic target.
Corrigendum to "Sulfur and nitrogen containing plasma polymers reduces bacterial attachment and growth" [Mater. Sci. Eng. C 107 (2020) 110225]

Siow KS, Rahman ASA, Ng PY, Majlis BY

Mater Sci Eng C Mater Biol Appl, 2021 Feb;121:111817.
PMID: 33579461 DOI: 10.1016/j.msec.2020.111817
Recent advances in tau-directed immunotherapy against Alzheimer's disease: an overview of pre-clinical and clinical development

Ng PY, Chang IS, Koh RY, Chye SM

Metab Brain Dis, 2020 10;35(7):1049-1066.
PMID: 32632666 DOI: 10.1007/s11011-020-00591-6

Alzheimer's disease (AD) has been a worldwide concern for many years now. This is due to the fact that AD is an irreversible and progressive neurodegenerative disease that affects quality of life. Failure of some Phase II/III clinical trials in AD targeting accumulation of β-amyloid in the brain has led to an increase in interest in studying alternative treatments against tubulin-associated unit (Tau) pathology. These alternative treatments include active and passive immunisation. Based on numerous studies, Tau is reported as a potential immunotherapeutic target for tauopathy-related diseases including AD. Accumulation and aggregation of hyperphosphorylated Tau as neuropil threads and neurofibrillary tangles (NFT) are pathological hallmarks of AD. Both active and passive immunisation targeting Tau protein have shown the capabilities to decrease or prevent Tau pathology and improve either motor or cognitive impairment in various animal models. In this review, we summarise recent advances in active and passive immunisation targeting pathological Tau protein, and will discuss with data obtained from both animal and human trials. Together, we give a brief overview about problems being encountered in these immunotherapies.
Fulltext Author Correction: Mitochondrial DNA alterations may influence the cisplatin responsiveness of oral squamous cell carcinoma

Aminuddin A, Ng PY, Leong CO, Chua EW

Sci Rep, 2021 Jul 05;11(1):14193.
PMID: 34226653 DOI: 10.1038/s41598-021-93444-w
Enhancing the biocompatibility of the polyurethane methacrylate and off-stoichiometry thiol-ene polymers by argon and nitrogen plasma treatment

Chen TF, Siow KS, Ng PY, Majlis BY

Mater Sci Eng C Mater Biol Appl, 2017 Oct 01;79:613-621.
PMID: 28629060 DOI: 10.1016/j.msec.2017.05.091

Our studies focused on improving the biocompatibility properties of two microfluidic prototyping substrates i.e. polyurethane methacrylate (PUMA) and off-stoichiometry thiol-ene (OSTE-80) polymer by Ar and N2plasma treatment. The contact angle (CA) measurement showed that both plasma treatments inserted oxygen and nitrogen moieties increased the surface energy and hydrophilicity of PUMA and OSTE-80 polymer which corresponded to an increase of nitrogen to carbon ratios (N/C), as measured by XPS, to provide a conducive environment for cell attachments and proliferation. Under the SEM observation, the surface topography of PUMA and OSTE-80 polymer showed minimal changes after the plasma treatments. Furthermore, ageing studies showed that plasma-treated PUMA and OSTE-80 polymer had stable hydrophilicity and nitrogen composition during storage in ambient air for 15days. After in vitro cell culture of human umbilical vein endothelial cells (HUVECs) on these surfaces for 24h and 72h, both trypan blue and alamar blue assays indicated that PUMA and OSTE-80 polymer treated with N2plasma had the highest viability and proliferation. The polar nitrogen moieties, specifically amide groups, encouraged the HUVECs adhesion on the plasma-treated PUMA and OSTE-80 surfaces. Interestingly, PUMA polymer treated with Ar and N2plasma showed different HUVECs morphology which was spindle and cobblestone-shaped respectively after 72h of incubation. On the contrary, a monolayer of well-spread HUVECs formed on the Ar and N2plasma-treated OSTE-80 polymers. These variable morphologies observed can be ascribed to the adherence HUVECs on the different elastic moduli of these surfaces whereby further investigation might be needed. Overall, Ar and N2plasma treatment had successfully altered the surface properties of PUMA and OSTE-80 polymer by increasing its surface energy, hydrophilicity and chemical functionalities to create a biocompatible surface for HUVECs adhesion and proliferation.
Sulfur and nitrogen containing plasma polymers reduces bacterial attachment and growth

Siow KS, Abdul Rahman AS, Ng PY, Majlis BY

Mater Sci Eng C Mater Biol Appl, 2020 Feb;107:110225.
PMID: 31761201 DOI: 10.1016/j.msec.2019.110225

Role of sulfur (S) and nitrogen (N) groups in promoting cell adhesion or commonly known as biocompatibility, is well established, but their role in reducing bacterial attachment and growth is less explored or not well-understood. Natural sulfur-based compounds, i.e. sulfide, sulfoxide and sulfinic groups, have shown to inhibit bacterial adhesion and biofilm formation. Hence, we mimicked these surfaces by plasma polymerizing thiophene (ppT) and air-plasma treating this ppT to achieve coatings with S of similar oxidation states as natural compounds (ppT-air). In addition, the effects of these N and S groups from ppT-air were also compared with the biocompatible amine-amide from n-heptylamine plasma polymer. Crystal violet assay and live and dead fluorescence staining of E. coli and S. aureus showed that all the N and S coated surfaces generated, including ppHA, ppT and ppT-air, produced similarly potent, growth reduction of both bacteria by approximately 65% at 72 h compared to untreated glass control. The ability of osteogenic differentiation in Wharton's jelly mesenchymal stem cells (WJ-MSCs) were also used to test the cell biocompatibility of these surfaces. Alkaline phosphatase assay and scanning electron microscopy imaging of these WJ-MSCs growths indicated that ppHA, and ppT-air were cell-friendly surfaces, with ppHA showing the highest osteogenic activity. In summary, the N and S containing surfaces could reduce bacteria growth while promoting mammalian cell growth, thus serve as potential candidate surfaces to be explored further for biomaterial applications.
Development and formulation of Moringa oleifera standardised leaf extract film dressing for wound healing application

Chin CY, Jalil J, Ng PY, Ng SF

J Ethnopharmacol, 2018 Feb 15;212:188-199.
PMID: 29080829 DOI: 10.1016/j.jep.2017.10.016

ETHNOPHARMACOLOGICAL RELEVANCE: M.oleifera is a medicinal plant traditionally used for skin sores, sore throat and eye infections. Recently, the wound healing property of the leaves of M. oleifera was has been well demonstrated experimentally in both in vivo and in vitro models. However, there is a lack of research which focuses on formulating M.oleifera into a functional wound dressing. In this study, the M.oleifera leaf standardized aqueous extract with highest potency in vitro migration was formulated into a film for wound healing application.
MATERIALS AND METHODS: Firstly, M. oleifera leaf were extracted in various solvents (aqueous, 50%, 70% and 100% ethanolic extracts) and standardized by reference standards using UHPLC technique. The extracts were then tested for cell migration and proliferation using HDF and HEK cell lines. M. oleifera leaf aqueous extract was then incorporated into alginate-pectin (SA-PC) based film dressing. The film dressings were characterized for the physicochemical properties and the bioactives release from the M. oleifera leaf extract loaded film dressing was also investigated using Franz diffusion cells.
RESULTS: All extracts were found to contain vicenin-2, chlorogenic acid, gallic acid, quercetin, kaempferol, rosmarinic acid and rutin. Among all M. oleifera extracts, aqueous standardized leaf extracts showed the highest human dermal fibroblast and human keratinocytes cells proliferation and migration properties. Among the film formulations, SA-PC (3% w/v) composite film dressing containing M. oleifera aqueous leaf extract was found to possess optimal physicochemical properties as wound dressing.
CONCLUSION: A potentially applicable wound dressing formulated as an alginate-pectin film containing aqueous extracts of M. oleifera has been developed. The dressing would be suitable for wounds with moderate exudates.
Fulltext Mitochondrial DNA alterations may influence the cisplatin responsiveness of oral squamous cell carcinoma

Aminuddin A, Ng PY, Leong CO, Chua EW

Sci Rep, 2020 May 12;10(1):7885.
PMID: 32398775 DOI: 10.1038/s41598-020-64664-3

Cisplatin is the first-line chemotherapeutic agent for the treatment of oral squamous cell carcinoma (OSCC). However, the intrinsic or acquired resistance against cisplatin remains a major obstacle to treatment efficacy in OSCC. Recently, mitochondrial DNA (mtDNA) alterations have been reported in a variety of cancers. However, the role of mtDNA alterations in OSCC has not been comprehensively studied. In this study, we evaluated the correlation between mtDNA alterations (mtDNA content, point mutations, large-scale deletions, and methylation status) and cisplatin sensitivity using two OSCC cell lines, namely SAS and H103, and stem cell-like tumour spheres derived from SAS. By microarray analysis, we found that the tumour spheres profited from aberrant lipid and glucose metabolism and became resistant to cisplatin. By qPCR analysis, we found that the cells with less mtDNA were less responsive to cisplatin (H103 and the tumour spheres). Based on the findings, we theorised that the metabolic changes in the tumour spheres probably resulted in mtDNA depletion, as the cells suppressed mitochondrial respiration and switched to an alternative mode of energy production, i.e. glycolysis. Then, to ascertain the origin of the variation in mtDNA content, we used MinION, a nanopore sequencer, to sequence the mitochondrial genomes of H103, SAS, and the tumour spheres. We found that the lower cisplatin sensitivity of H103 could have been caused by a constellation of genetic and epigenetic changes in its mitochondrial genome. Future work may look into how changes in mtDNA translate into an impact on cell function and therefore cisplatin response.
Urinary incontinence in primigravida: the neglected pregnancy predicament

Abdullah B, Ayub SH, Mohd Zahid AZ, Noorneza AR, Isa MR, Ng PY

Eur J Obstet Gynecol Reprod Biol, 2016 Mar;198:110-115.
PMID: 26808667 DOI: 10.1016/j.ejogrb.2016.01.006

OBJECTIVE: To determine the prevalence of urinary incontinence among primigravida in the third trimester, its risk factors and its effect to quality of life.
STUDY DESIGN: This is a cross sectional study involving primigravida in their third trimester of pregnancy, who attended the Patient Assessment Centre of a tertiary referral hospital in Klang Valley from July 2012 to June 2013. The participants were chosen randomly using convenience sampling. A face-to-face interview and a review of their antenatal record were done by trained interviewers. Data on sociodemographic and risk factors were obtained followed by the International Consultation on Incontinence Questionnaire - Short Form (ICIQ-SF). The data was analysed using Statistical Package for Social Science version 20.0.
RESULTS: A total of 306 women were involved. The prevalence of urinary incontinence during third trimester was 34.3% (95%CI: 29.0, 39.7). Stress incontinence (64.8%) is the commonest followed by mixed incontinence (24.8%) and urge incontinence (6.7%). Childhood enuresis (p=0.003) and previous history of urinary incontinence (p<0.001) were significantly associated with urinary incontinence. More than 50 percent of women with urinary incontinence in the third trimester felt that it did not affect their daily activities at all. Only 10% of women felt greatly affected by this problem.
CONCLUSION: Urinary incontinence is not uncommon among primigravida however many women did not feel that it affected their quality of life. Childhood enuresis and history of urinary incontinence were proven risk factors.
Insight into delivery of dermal fibroblast by non-biodegradable bacterial nanocellulose composite hydrogel on wound healing

Loh EYX, Fauzi MB, Ng MH, Ng PY, Ng SF, Mohd Amin MCI

Int J Biol Macromol, 2020 Sep 15;159:497-509.
PMID: 32387606 DOI: 10.1016/j.ijbiomac.2020.05.011

In skin tissue engineering, a biodegradable scaffold is usually used where cells grow, produce its own cytokines, growth factors, and extracellular matrix, until the regenerated tissue gradually replaces the scaffold upon its degradation. However, the role of non-biodegradable scaffold remains unexplored. This study investigates the potential of a non-biodegradable bacterial nanocellulose/acrylic acid (BNC/AA) hydrogel to transfer human dermal fibroblasts (HDF) to the wound and the resulting healing effects of transferred HDF in athymic mice. Results demonstrated that the fabricated hydrogel successfully transferred >50% of HDF onto the wound site within 24 h, with evidence of HDF detected on day 7. The gene and protein study unveiled faster wound healing in the hydrogel with HDF group and characterized more mature newly formed skin microstructure on day 7, despite no visible differences. These findings give a new perspective regarding the role of non-biodegradable materials in skin tissue engineering, in the presence of exogenous cells, mainly at the molecular level.
Fulltext CRISPR Gene-Editing Models Geared Toward Therapy for Hereditary and Developmental Neurological Disorders

Wong PK, Cheah FC, Syafruddin SE, Mohtar MA, Azmi N, Ng PY, et al.

Front Pediatr, 2021;9:592571.
PMID: 33791256 DOI: 10.3389/fped.2021.592571

Hereditary or developmental neurological disorders (HNDs or DNDs) affect the quality of life and contribute to the high mortality rates among neonates. Most HNDs are incurable, and the search for new and effective treatments is hampered by challenges peculiar to the human brain, which is guarded by the near-impervious blood-brain barrier. Clustered Regularly Interspaced Short Palindromic Repeat (CRISPR), a gene-editing tool repurposed from bacterial defense systems against viruses, has been touted by some as a panacea for genetic diseases. CRISPR has expedited the research into HNDs, enabling the generation of in vitro and in vivo models to simulate the changes in human physiology caused by genetic variation. In this review, we describe the basic principles and workings of CRISPR and the modifications that have been made to broaden its applications. Then, we review important CRISPR-based studies that have opened new doors to the treatment of HNDs such as fragile X syndrome and Down syndrome. We also discuss how CRISPR can be used to generate research models to examine the effects of genetic variation and caffeine therapy on the developing brain. Several drawbacks of CRISPR may preclude its use at the clinics, particularly the vulnerability of neuronal cells to the adverse effect of gene editing, and the inefficiency of CRISPR delivery into the brain. In concluding the review, we offer some suggestions for enhancing the gene-editing efficacy of CRISPR and how it may be morphed into safe and effective therapy for HNDs and other brain disorders.
Fulltext Melatonin Induces Autophagy via Reactive Oxygen Species-Mediated Endoplasmic Reticulum Stress Pathway in Colorectal Cancer Cells

Chok KC, Koh RY, Ng MG, Ng PY, Chye SM

Molecules, 2021 Aug 20;26(16).
PMID: 34443626 DOI: 10.3390/molecules26165038

Even though an increasing number of anticancer treatments have been discovered, the mortality rates of colorectal cancer (CRC) have still been high in the past few years. It has been discovered that melatonin has pro-apoptotic properties and counteracts inflammation, proliferation, angiogenesis, cell invasion, and cell migration. In previous studies, melatonin has been shown to have an anticancer effect in multiple tumors, including CRC, but the underlying mechanisms of melatonin action on CRC have not been fully explored. Thus, in this study, we investigated the role of autophagy pathways in CRC cells treated with melatonin. In vitro CRC cell models, HT-29, SW48, and Caco-2, were treated with melatonin. CRC cell death, oxidative stress, and autophagic vacuoles formation were induced by melatonin in a dose-dependent manner. Several autophagy pathways were examined, including the endoplasmic reticulum (ER) stress, 5'-adenosine monophosphate-activated protein kinase (AMPK), phosphoinositide 3-kinase (PI3K), serine/threonine-specific protein kinase (Akt), and mammalian target of rapamycin (mTOR) signaling pathways. Our results showed that melatonin significantly induced autophagy via the ER stress pathway in CRC cells. In conclusion, melatonin demonstrated a potential as an anticancer drug for CRC.
Plasma polymerized carvone as an antibacterial and biocompatible coating

Chan YW, Siow KS, Ng PY, Gires U, Yeop Majlis B

Mater Sci Eng C Mater Biol Appl, 2016 Nov 01;68:861-871.
PMID: 27524089 DOI: 10.1016/j.msec.2016.07.040

Antibacterial coating is important to prevent the colonization of medical devices by biofilm forming bacteria that would cause infection and sepsis in patients. Current coating techniques such as immobilization of antimicrobial compounds, time-releasing antibiotic agents and silver nanoparticles, require multiple processing steps, and they have low efficacy and low stability. We proposed a single-step plasma polymerization of an essential oil known as carvone to produce a moderately hydrophobic antibacterial coating (ppCar) with an average roughness of <1nm. ppCar had a static water contact angle of 78°, even after 10days of air aging and it maintained its stability throughout 24h of LB broth immersion. ppCar showed promising results in the live-dead fluorescence assay and crystal violet assay. The biofilm assay showed an effective reduction of E. coli and S. aureus bacteria by 86% and 84% respectively. ppCar is also shown to rupture the bacteria membrane for its bactericidal effects. The cytotoxicity test indicated that the coating is not cytotoxic to the human cell line. This study would be of interest to researcher keen on producing a bacteria-resistance and biocompatible coating on different substrates in a cost-effective manner.
HER2/neu-Based Peptide Vaccination-Pulsed with B-Cell Epitope Induced Efficient Prophylactic and Therapeutic Antitumor Activities in TUBO Breast Cancer Mice Model

Nordin ML, Mohamad Norpi AS, Ng PY, Yusoff K, Abu N, Lim KP, et al.

Cancers (Basel), 2021 Oct 01;13(19).
PMID: 34638441 DOI: 10.3390/cancers13194958

Breast cancer is the most common invasive cancer diagnosed among women. A cancer vaccine has been recognized as a form of immunotherapy with a prominent position in the prevention and treatment of breast cancer. The majority of current breast cancer vaccination strategies aim to stimulate antitumor T-cell responses of the HER2/neu oncogene, which is abnormally expressed in breast cancer cells. However, the role of the B-cell humoral response is often underappreciated in the cancer vaccine design. We have advanced this idea by elucidating the role of B-cells in cancer vaccination by designing a chimeric antigenic peptide possessing both cytotoxic T lymphocytes (GP2) and B-cell (P4) peptide epitopes derived from HER2/neu. The chimeric peptide (GP2-P4) was further conjugated to a carrier protein (KLH), forming a KLH-GP2-P4 conjugate. The immunogenicity of KLH-GP2-P4 was compared with KLH-GP2 (lacking the B-cell epitope) in BALB/c mice. Mice immunized with KLH-GP2-P4 elicited more potent antigen-specific neutralizing antibodies against syngeneic TUBO cells (cancer cell line overexpressing HER2/neu) that was governed by a balanced Th1/Th2 polarization in comparison to KLH-GP2. Subsequently, these immune responses led to greater inhibition of tumor growth and longer survival in TUBO tumor-bearing mice in both prophylactic and therapeutic challenge experiments. Overall, our data demonstrated that the B-cell epitope has a profound effect in orchestrating an efficacious antitumor immunity. Thus, a multi-epitope peptide vaccine encompassing cytotoxic T-lymphocytes, T-helper and B-cell epitopes represents a promising strategy in developing cancer vaccines with a preventive and therapeutic modality for the effective management of breast cancer.
Fulltext Sphingosine Kinase 1 Signaling in Breast Cancer: A Potential Target to Tackle Breast Cancer Stem Cells

Hii LW, Chung FF, Mai CW, Ng PY, Leong CO

Front Mol Biosci, 2021;8:748470.
PMID: 34820423 DOI: 10.3389/fmolb.2021.748470

Sphingosine kinases (SPHKs) are conserved lipid enzymes that catalyze the formation of sphingosine-1-phosphate (S1P) through ATP-dependent phosphorylation of sphingosine. Two distinct SPHK isoforms, namely SPHK1 and SPHK2, have been identified to date, and the former has been implicated for its oncogenic roles in cancer development and progression. While SPHK1 signaling axis has been extensively studied in non-stem breast cancer cells, recent evidence has emerged to suggest a role of SPHK1 in regulating cancer stem cells (CSCs). With the clinical implications of CSCs in disease relapse and metastasis, it is believed that therapeutic approaches that can eradicate both non-stem cancer cells and CSCs could be a key to cancer cure. In this review, we first explore the oncogenic functions of sphingosine kinase 1 in human cancers and summarize current research findings of SPHK1 signaling with a focus on breast cancer. We also discuss the therapeutic potentials and perspectives of targeting SPHK1 signaling in breast cancer and cancer stem cells. We aim to offer new insights and inspire future studies looking further into the regulatory functions of SPHK1 in CSC-driven tumorigenesis, uncovering novel therapeutic avenues of using SPHK1-targeted therapy in the treatment of CSC-enriched refractory cancers.

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