Peptide-Based Vaccine against Breast Cancer: Recent Advances and Prospects.

Breast cancer is considered the second-leading cancer after lung cancer and is the most prevalent cancer among women globally. Currently, cancer immunotherapy via vaccine has gained great attention due to specific and targeted immune cell activity that creates a potent immune response, thus providing long-lasting protection against the disease. Despite peptides being very susceptible to enzymatic degradation and poor immunogenicity, they can be easily customized with selected epitopes to induce a specific immune response and particulate with carriers to improve their delivery and thus overcome their weaknesses. With advances in nanotechnology, the peptide-based vaccine could incorporate other components, thereby modulating the immune system response against breast cancer. Considering that peptide-based vaccines seem to show remarkably promising outcomes against cancer, this review focuses on and provides a specific view of peptide-based vaccines used against breast cancer. Here, we discuss the benefits associated with a peptide-based vaccine, which can be a mainstay in the prevention and recurrence of breast cancer. Additionally, we also report the results of recent trials as well as plausible prospects for nanotechnology against breast cancer.

Comparing the performance of body mass index, waist circumference and waist-to-height ratio in predicting Malaysians with excess adiposity.

BACKGROUND: Body mass index (BMI) is a widely used surrogate tool to screen for obesity/adiposity, but it cannot differentiate between lean and fat mass. Thus, alternative tools to detect excess adiposity should be identified. AIM: This study aimed to compare the performance of BMI, waist circumference (WC) and waist-to-height ratio (WtHR) in predicting Malaysians with excess body fat defined by dual-energy X-ray absorptiometry (DXA). SUBJECTS AND METHODS: A total of 399 men and women aged ≥40 years were recruited from Klang Valley, Malaysia. The body composition of the subjects, including body fat percentage, was measured by DXA. The weight, height, WC and WHtR of the subjects were also determined. RESULTS: BMI [sensitivity = 55.7%, specificity = 86.1%, area under curve (AUC) = 0.709] and WC (sensitivity = 62.7%, specificity = 90.3%, AUC = 0.765) performed moderately in predicting excess adiposity. Their performance and sensitivity improved with lower cut-off values. The performance of WHtR (sensitivity = 96.6%, specificity = 36.1, AUC = 0.664) was optimal at the standard cut-off value and no modification was required. CONCLUSION: The performance of WC in identifying excess adiposity was greater than BMI and WHtR based on AUC values. Modification of cut-off values for BMI and WC could improve their performance and should be considered by healthcare providers in screening individuals with excess adiposity.

Mitochondrial DNA sequences and transcriptomic profiles for elucidating the genetic underpinnings of cisplatin responsiveness in oral squamous cell carcinoma.

OBJECTIVES: Functional genetic variation plays an important role in predicting patients' response to chemotherapeutic agents. A growing catalogue of mitochondrial DNA (mtDNA) alterations in various cancers point to their important roles in altering the drug responsiveness and survival of cancer cells. In this work, we report the mtDNA sequences, obtained using a nanopore sequencer that can directly sequence unamplified DNA, and the transcriptomes of oral squamous cell carcinoma (OSCC) cell lines with differing responses to cisplatin, to explore the interplay between mtDNA alterations, epigenetic regulation of gene expression, and cisplatin response in OSCC. DATA DESCRIPTION: Two human OSCC cell lines, namely H103 and SAS, and drug-resistant stem-like cells derived from SAS were used in this work. To validate our hypothesis that cisplatin sensitivity is linked to mtDNA changes, we sequenced their mtDNA using a nanopore sequencer, MinION. We also obtained the whole transcriptomic profiles of the cells from a microarray analysis. The mtDNA mutational and whole transcriptomic profiles that we provide can be used alongside other similar datasets to facilitate the identification of new markers of cisplatin sensitivity, and therefore the development of effective therapies for OSCC.

Effect of a Screening and Education Programme on Knowledge, Beliefs, and Practices Regarding Osteoporosis among Malaysians.

Background: Osteoporosis is an emerging geriatric condition with high morbidity and healthcare cost in developing nations experiencing rapid population ageing. Thus, identifying strategies to prevent osteoporosis is critical in safeguarding skeletal health. This study aimed to evaluate the effects of a bone health screening and education programme on knowledge, beliefs, and practice regarding osteoporosis among Malaysians aged 40 years and above. Methods: A longitudinal study was conducted from April 2018 to August 2019. During the first phase of the study, 400 Malaysians (190 men, 210 women) aged ≥ 40 years were recruited in Klang Valley, Malaysia. Information on subjects' demography, medical history, knowledge, and beliefs regarding osteoporosis, physical activity status, and dietary and lifestyle practices were obtained. Subjects also underwent body anthropometry measurement and bone mineral density scan (hip and lumbar spine) using a dual-energy X-ray absorptiometry device. Six months after the first screening, similar investigations were carried out on the subjects. Results: During the follow-up session, 72 subjects were lost to follow up. Most of them were younger subjects with a lower awareness of healthy practices. A significant increase in knowledge, beliefs (p < 0.05), calcium supplement intake (p < 0.001), and dietary calcium intake (p = 0.036) and a reduction in coffee intake (p < 0.001) were found among subjects who attended the follow-up. In this study, the percentage of successful referrals was 41.86%. Subjects with osteoporosis were mostly prescribed alendronate plus vitamin D3 by medical doctors, and they followed the prescribed treatment accordingly. Conclusions: The bone health screening and education programmes in this study are effective in changing knowledge, beliefs, and practice regarding osteoporosis. The information is pertinent to policymakers in planning strategies to prevent osteoporosis and its associated problems among the middle-aged and elderly population in Malaysia. Nevertheless, a more comprehensive bone health education program that includes long-term monitoring and consultation is needed to halt the progression of bone loss.

Surface-engineered liposomes for dual-drug delivery targeting strategy against methicillin-resistant Staphylococcus aureus (MRSA).

This study focused on the encapsulation of vancomycin (VAN) into liposomes coated with a red blood cell membrane with a targeting ligand, daptomycin-polyethylene glycol-1,2-distearoyl-sn-glycero-3-phosphoethanolamine, formed by conjugation of DAPT and N-hydroxysuccinimidyl-polyethylene glycol-1,2-distearoyl-sn-glycero-3-phosphoethanolamine. This formulation is capable of providing controlled and targeted drug delivery to the bacterial cytoplasm. We performed MALDI-TOF, NMR and FTIR analyses to confirm the conjugation of the targeting ligand via the formation of amide bonds. Approximately 45% of VAN could be loaded into the aqueous cores, whereas 90% DAPT was detected using UV-vis spectrophotometry. In comparison to free drugs, the formulations controlled the release of drugs for > 72 h. Additionally, as demonstrated using CLSM and flow cytometry, the resulting formulation was capable of evading detection by macrophage cells. In comparison to free drugs, red blood cell membrane-DAPT-VAN liposomes, DAPT liposomes, and VAN liposomes reduced the MIC and significantly increased bacterial permeability, resulting in > 80% bacterial death within 4 h. Cytotoxicity tests were performed in vitro and in vivo on mammalian cells, in addition to hemolytic activity tests in human erythrocytes, wherein drugs loaded into the liposomes and RBCDVL exhibited low toxicity. Thus, the findings of this study provide insight about a dual antibiotic targeting strategy that utilizes liposomes and red blood cell membranes to deliver targeted drugs against MRSA.

Perceived Symptoms of Depression, Anxiety and Stress amongst Staff in a Malaysian Public University: A Workers Survey.

Mental health conditions are a major part of workers' health that predisposes to poor self-motivation for sustaining productivity. This study was aimed to determine the prevalence of depression, anxiety, and stress among staff in a Malaysian public university and its associated factors. A cross-sectional study was conducted among 459 staff from the Universiti Kebangsaan Malaysia (UKM) between April and June 2019. A questionnaire that consisted of items on socio-demographic and socioeconomic characteristics, employment description, lifestyle risk behaviors, personal medical history, and symptoms of depression, anxiety, and stress was administered to participants. Descriptive and inferential statistics were conducted using SPSS version 22.0. The prevalence of perceived symptoms of depression, anxiety, and stress among the respondents was 28.7%, 50.1%, and 14.8%, respectively. Over one-quarter (26.5%) of the participants presented symptoms of two or more mental disorders. Women, those aged less than 40 years old, and non-academic professionals were more likely to exhibit depressive symptoms, while those with medical conditions that required hospitalizations sustained anxiety symptoms. Perceived stress was more likely to be prevalent among staff with secondary education or less and smokers. Proactive support for staff needs to be offered in sustaining their emotional well-being.

Extracellular ATP Induced S-Phase Cell Cycle Arrest via P2Y Receptor-Activated ERK Signaling in Poorly Differentiated Oral Squamous Cell Carcinoma SAS Cells.

Extracellular ATP in the tumor microenvironment exhibits either pro- or antitumor effect via interaction with P2Y receptors, but the intracellular signaling and functional roles of P2Y receptors in oral squamous cell carcinoma (OSCC) are unclear. We aimed to study the effect of ATP on OSCC cell lines and the potential mechanisms involved. Through GEPIA dataset analysis, high expression levels of mRNA encoding P2Y receptors, the ATP-induced G protein-coupled receptors, were associated with better overall patient survival in head and neck squamous cell carcinoma. qPCR analysis showed that the poorly differentiated OSCC SAS cell line, had higher P2RY1 expression level compared to the well-differentiated H103 and H376 cell lines. Western blotting and flow cytometry analyses revealed that ATP phosphorylated ERK and elevated intracellular calcium signaling in all tested cell lines. A significant S-phase cell cycle arrest was observed in SAS, and preincubation with the MEK inhibitor PD0325901 reversed the ATP-induced S-phase arrest. We further demonstrated that ATP induced a slight reduction in cell count and colony formation yet significant apoptosis in SAS. Overall, we postulate that the ATP-induced S-phase arrest effect in SAS cells may be regulated through P2Y receptor-mediated ERK signaling, thus suggesting a potential antitumor effect of ATP via interaction with its distinct profile of P2Y receptors.

Sphingosine Kinase 1 Signaling in Breast Cancer: A Potential Target to Tackle Breast Cancer Stem Cells.

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.

HER2/neu-Based Peptide Vaccination-Pulsed with B-Cell Epitope Induced Efficient Prophylactic and Therapeutic Antitumor Activities in TUBO Breast Cancer Mice Model.

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.

Factors Associated with Health-Related Quality of Life amongst Employees in a Malaysian Public University.

The current academic landscape has overwhelmed faculties and with demands to adopt tech-savvy teaching modes and accelerate scholarly works, administrative duties, and outreach programs. Such demands have deteriorated the health-related quality of life (HRQoL) among university employees. This study aimed to determine the factors associated with HRQoL among university employees in a Malaysian public university. This cross-sectional study was conducted among 397 employees from the Universiti Kebangsaan Malaysia (UKM) between April and June 2019. A self-administered questionnaire that consisted of socio-demographic items, risky health behaviors, health-related information, and validated scales for measuring employees' physical inactivity, psychological states, and HRQoL was utilized. Descriptive and inferential statistics were calculated using SPSS version 23.0. Hierarchical multiple linear regression models were yielded to determine the factors associated with different domains of HRQoL. Mediation analysis was conducted using PROCESS MACRO (Model 4). Statistical significance was set to p < 0.05. Physical HRQoL scored the highest, while environmental HRQoL had the lowest score among the employees. Physical HRQoL was influenced by age, service duration, comorbid conditions, BMI, chronic diseases, and anxiety. Factors associated with psychological HRQoL were age, service duration, depression, and stress. Age, service duration, and chronic diseases affected employees' social relationship HRQoL, while environmental HRQoL was associated with age, occupation type, chronic diseases, and depression. Socio-demographics, risky health behaviors, health profiles, and psychological attributes were significantly associated with employees' HRQoL. Age was the only positively correlated factor across all HRQoL domains, while other factors deteriorated employees' HRQoL.

Prevalence of metabolic syndrome and its associated risk factors among staffs in a Malaysian public university.

Public health systems are concerned with the commensurate rise of metabolic syndrome (MetS) incidence across populations worldwide, due to its tendency to amplify greater risk of diabetes and cardiovascular diseases within communities. This study aimed to determine the prevalence of MetS and its associated risk factors among staffs in a Malaysian public university. A cross-sectional study was conducted among 538 staffs from the Universiti Kebangsaan Malaysia (UKM) between April and June 2019. MetS was defined according to JIS "Harmonized" criteria. A questionnaire that consisted of items on socio-demographics, lifestyle risk behaviors and personal medical history information was administered to participants. Subsequently, a series of physical examination and biochemical assessment was conducted at the hall or foyer of selected faculties in the university. Descriptive and inferential statistics were conducted using SPSS version 22.0. Multivariate models were yielded to determine the risk factors associated with MetS. Statistical significance was set at P < 0.05. The overall prevalence of MetS was 20.6%, with men having greater prevalence than women (24.9% vs. 18.3%). Prevalence of MetS increased with age. Factors contributed to MetS in the overall sample were BMI, hypertension, diabetes and physical activity of moderate intensity. Diabetes and hypertension were significantly associated with MetS in men, whereas BMI, diabetes and hyperlipidemia were significantly associated with MetS in women. Lifestyle behaviors and cardio-metabolic risk factors were associated with MetS for the overall sample, and across genders.

CRISPR Gene-Editing Models Geared Toward Therapy for Hereditary and Developmental Neurological Disorders.

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.

Positive association between metabolic syndrome and bone mineral density among Malaysians.

Objectives: Metabolic syndrome (MetS) is a cluster of metabolic abnormalities that elevates the individual risk of cardiovascular diseases. These abnormalities are also known to alter bone remodelling. Therefore, MetS may be associated with osteoporosis. This study aims to determine the association between MetS and its components and bone mineral density (BMD) assessed by dual-energy X-ray absorptiometry (DXA) among Malaysians. Methods: 400 Malaysians aged ≥ 40 years (52.5% women) residing in Klang Valley, Malaysia, were recruited. Subjects' demographic and lifestyle details were collected using a questionnaire, and blood pressure and body anthropometry were measured. Subjects' lumbar spine and total hip BMD were measured by DXA. Their fasting blood was collected for blood glucose level and lipid profile analysis. Regression analysis was used to analyze the relationship between MetS or its components and BMD. Results: Subjects with MetS had higher BMD compared to subjects without MetS in models unadjusted for BMI (spine p=0.008; hip p<0.001). This difference was attenuated with BMI adjustment (spine p=0.625; hip p=0.478). Waist circumference was associated positively with BMD in models unadjusted for BMI (spine p=0.012; hip p<0.001), but the association became negative with BMI adjustment (spine p=0.044; hip p=0.021). Systolic blood pressure was associated positively with total hip BMD (p=0.019) but BMI adjustment attenuated the relationship (p=0.080). Triglyceride level was associated with osteoporosis in a fully adjusted model (p=0.001). Overall, MetS was associated with osteoporosis (p=0.019) but lifestyle (p=0.188) and BMI adjustment attenuated the relationship (p=0.904). Conclusion: MetS is positively associated with BMD, and this relationship is predominantly mediated by BMI. Although MetS is not a significant risk factor for osteoporosis, the inverse relationship between waist circumference, a marker of central obesity, and BMD highlights the need to prevent adiposity to improve metabolic and skeletal health.

Prevalence and factors of T-score discordance between hip and spine among middle-aged and elderly Malaysians.

T-score discordance between hip and spine is a common problem in the diagnosis of osteoporosis based on dual-energy X-ray absorptiometry. Not much information on the prevalence and risk factors of this problem is available in Malaysia. Our study found that factors like age, height, physical activity and menopausal status should be taken into account in the diagnosis of osteoporosis. INTRODUCTION AND OBJECTIVE: T-score discordance between hip and spine is a common problem in bone mineral density assessment. A difference ≥ 1 standard deviation (SD) (regardless of diagnostic class) is considered minor, and a difference more than one diagnostic class is considered major discordance. This study aimed to determine the prevalence and factors of hip and spine T-score discordance in a population aged ≥ 40 years in Klang Valley, Malaysia. SUBJECTS AND METHODS: In this cross-sectional study, subjects answered a demographic questionnaire and underwent body composition and bone health assessment using dual-energy X-ray absorptiometry. Chi-square and binary logistic regression analysis were used to assess the prevalence of T-score discordance among the subjects. RESULTS: A total of 786 Malaysians (382 men, 404 women) subjects were recruited. The prevalence of minor and major discordance was 30.3% and 2.3%, respectively. Overall, factors related to T-score discordance were advanced age, decreased height, and being physically active. Sub-analysis showed that decreased height and being physically active predicted T-score discordance in men, being menopausal and Indian (vs Chinese) were predictors in women. CONCLUSIONS: T-score discordance between hip and spine is common among Malaysian middle-aged and elderly population. Diagnosis of osteopenia/osteoporosis should be based on the T-score of more than one skeletal site as per the current recommendations.

Mitochondrial DNA alterations may influence the cisplatin responsiveness of oral squamous cell carcinoma.

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.

Insight into delivery of dermal fibroblast by non-biodegradable bacterial nanocellulose composite hydrogel on wound healing.

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.

Development of Osteoporosis Screening Algorithm for Population Aged 50 Years and above in Klang Valley, Malaysia.

Background: The current osteoporosis screening instruments are not optimized to be used among the Malaysian population. This study aimed to develop an osteoporosis screening algorithm based on risk factors for Malaysians. Methods: Malaysians aged ≥50 years (n = 607) from Klang Valley, Malaysia were interviewed and their bone health status was assessed using a dual-energy X-ray absorptiometry device. The algorithm was constructed based on osteoporosis risk factors using multivariate logistic regression and its performance was assessed using receiver operating characteristics analysis. Results: Increased age, reduced body weight and being less physically active significantly predicted osteoporosis in men, while in women, increased age, lower body weight and low-income status significantly predicted osteoporosis. These factors were included in the final algorithm and the optimal cut-offs to identify subjects with osteoporosis was 0.00120 for men [sensitivity 73.3% (95% confidence interval (CI) = 54.1%-87.7%), specificity 67.8% (95% CI = 62.7%-85.5%), area under curve (AUC) 0.705 (95% CI = 0.608-0.803), p < 0.001] and 0.161 for women [sensitivity 75.4% (95% CI = 61.9%-73.3%), specificity 74.5% (95% CI = 68.5%-79.8%), AUC 0.749 (95% CI = 0.679-0.820), p < 0.001]. Conclusion: The new algorithm performed satisfactorily in identifying the risk of osteoporosis among the Malaysian population ≥50 years. Further validation studies are required before applying this algorithm for screening of osteoporosis in public.