Hepatic and renal effects of oral stingless bee honey in a streptozotocin-induced diabetic rat model.

BACKGROUND: Diabetes is known damage the liver and kidney, leading to hepatic dysfunction and kidney failure. Honey is believed to help in lowering the blood glucose levels of diabetic patients and reducing diabetic complications. However, the effect of stingless bee honey (SBH) administration in relieving liver and kidney damage in diabetes has not been well-studied. AIM: To investigate the effect of SBH administration on the kidney and liver of streptozotocin-induced (STZ; 55 mg/kg) diabetic Sprague Dawley rats. METHODS: The rats were grouped as follows (n = 6 per group): non-diabetic (ND), untreated diabetic (UNT), metformin-treated (MET), and SBH+metformin-treated (SBME) groups. After successful diabetic induction, ND and UNT rats were given normal saline, whereas the treatment groups received SBH (2.0 g/kg and/or metformin (250 mg/kg) for 12 d. Serum biochemical parameters and histological changes using hematoxylin and eosin (H&E) and periodic acid-Schiff (PAS) staining were evaluated. RESULTS: On H&E and PAS staining, the ND group showed normal architecture and cellularity of Bowman's capsule and tubules, whereas the UNT and MET groups had an increased glomerular cellularity and thickened basement membrane. The SBH-treated group showed a decrease in hydropic changes and mild cellularity of the glomerulus vs the ND group based on H&E staining, but the two were similar on PAS staining. Likewise, the SBME-treated group had an increase in cellularity of the glomerulus on H&E staining, but it was comparable to the SBH and ND groups on PAS staining. UNT diabetic rats had tubular hydropic tubules, which were smaller than other groups. Reduced fatty vacuole formation and dilated blood sinusoids in liver tissue were seen in the SBH group. Conversely, the UNT group had high glucose levels, which subsequently increased MDA levels, ultimately leading to liver damage. SBH treatment reduced this damage, as evidenced by having the lowest fasting glucose, serum alanine transaminase, aspartate transaminase, and alkaline phosphatase levels compared to other groups, although the levels of liver enzymes were not statistically significant. CONCLUSION: The cellularity of the Bowman's capsule, as well as histological alteration of kidney tubules, glomerular membranes, and liver tissues in diabetic rats after oral SBH resembled those of ND rats. Therefore, SBH exhibited a protective hepatorenal effect in a diabetic rat model.

CD4+ Foxp3+ Regulatory T-cells in Modulating Inflammatory Microenvironment in Chronic Rhinosinusitis with Nasal Polyps: Progress and Future Prospect.

Chronic rhinosinusitis with nasal polyps (CRSwNP) is a subtype of chronic rhinosinusitis (CRS) characterized by the presence of nasal polyps (NP) in the paranasal mucosa. Despite the complex etiology, NP is believed to result from chronic inflammation. The long-term aftermath of the type 2 response is responsible for symptoms seen in NP patients, i.e. rhinorrhea, hyposmia, and nasal obstruction. Immune cellular tolerogenic mechanisms, particularly CD4 + Foxp3 + regulatory T cells (Tregs), are crucial to curtail inflammatory responses. Current evidence suggests impaired Treg activity is the main reason underlying the compromise of self-tolerance, contributing to the onset of CRSwNP. There is compelling evidence that tumor necrosis factor 2 (TNFR2) is preferentially expressed by Tregs, and TNFR2 is able to identify the most potent suppressive subset of Tregs. Tumor necrosis factor (TNF)-TNFR2 interaction plays a decisive role in the activation and expansion of Tregs. This review summarizes current understanding of Tregs biology, focusing on the discussion of the recent advances in the study of TNF-TNFR2 axis in the upregulation of Treg function as a negative feedback mechanism in the control of chronic inflammation. The role of dysregulation of Tregs in the immunopathogenesis of CRSwNP will be analyzed. The future perspective on the harnessing Tregs-mediated self-tolerant mechanism in the management of CRSwNP will be introduced.

Developing a Supplementary Diagnostic Tool for Breast Cancer Risk Estimation Using Ensemble Transfer Learning.

Breast cancer is the most prevalent cancer worldwide. Thus, it is necessary to improve the efficiency of the medical workflow of the disease. Therefore, this study aims to develop a supplementary diagnostic tool for radiologists using ensemble transfer learning and digital mammograms. The digital mammograms and their associated information were collected from the department of radiology and pathology at Hospital Universiti Sains Malaysia. Thirteen pre-trained networks were selected and tested in this study. ResNet101V2 and ResNet152 had the highest mean PR-AUC, MobileNetV3Small and ResNet152 had the highest mean precision, ResNet101 had the highest mean F1 score, and ResNet152 and ResNet152V2 had the highest mean Youden J index. Subsequently, three ensemble models were developed using the top three pre-trained networks whose ranking was based on PR-AUC values, precision, and F1 scores. The final ensemble model, which consisted of Resnet101, Resnet152, and ResNet50V2, had a mean precision value, F1 score, and Youden J index of 0.82, 0.68, and 0.12, respectively. Additionally, the final model demonstrated balanced performance across mammographic density. In conclusion, this study demonstrates the good performance of ensemble transfer learning and digital mammograms in breast cancer risk estimation. This model can be utilised as a supplementary diagnostic tool for radiologists, thus reducing their workloads and further improving the medical workflow in the screening and diagnosis of breast cancer.

Carcinosarcoma: A Rare and Aggressive Breast Tumor in a Young Lady.

Carcinosarcoma of the breast is a subtype of metaplastic breast carcinoma characterized by differentiation of the neoplastic epithelium toward mesenchymal-looking elements. It is a highly aggressive rare subtype of invasive breast neoplasm that exhibits a distinct histologic entity. Only a limited number of reports related to this type of disease have been reported. Here, we present a case of breast carcinosarcoma in a lady in her early 20s, which is relatively young among all cases published. It was challenging to achieve diagnosis preoperatively with histopathological evaluation of the ultrasound-guided tru-cut biopsy sample. With no evidence of distant metastasis clinically and radiologically, a surgical option was opted for. Left mastectomy and left chest wall reconstruction with deep inferior epigastric artery free flap were performed. Post-excision specimen was confirmed to be carcinosarcoma.

Comparing the Biology of Young versus Old Age Estrogen-Receptor-Positive Breast Cancer through Gene and Protein Expression Analyses.

Background: Breast cancer developed at a young age (≤45 years) is hypothesized to have unique biology; however, findings in this field are controversial. Methods: We compared the whole transcriptomic profile of young vs. old-age breast cancer using DNA microarray. RNA was extracted from 13 fresh estrogen receptor (ER)-positive primary breast cancer tissues of untreated patients (7 = young age ≤45 years and 6 = old age ≥55 years). In silico validation for the differentially expressed genes (DEGs) by young-age patients was conducted using The Cancer Genome Atlas (TCGA) database. Next, we analyzed the protein expression encoded by two of the significantly down-regulated genes by young-age patients, Glycine N-acyltransferase-like 1 (GLYATL-1) and Ran-binding protein 3 like (RANBP3L), using immunohistochemical analysis in an independent cohort of 56 and 74 ER-positive pre-therapeutic primary breast cancer tissues, respectively. Results: 12 genes were significantly differentially expressed by young-age breast cancers (fold change >2 or <2- with FDR p-value < 0.05). TCGA data confirmed the differential expression of six genes. Protein expression analysis of GLYATL-1 and RANBP3L did not show heterogeneous expression between young and old-age breast cancer tissues. Loss of expression of GLYATL-1 was significantly (p-value 0.005) associated with positive lymph node status. Higher expression of RANBP3L was significantly associated with breast cancers with lower histopathological grades (p-value 0.038). Conclusions: At the transcriptomic level, breast cancer developed in young and old age patients seems homogenous. The variation in the transcriptomic profiles can be attributed to the other clinicopathological characteristics rather than the age of the patient.

Over-the-Counter Breast Cancer Classification Using Machine Learning and Patient Registration Records.

This study aims to determine the feasibility of machine learning (ML) and patient registration record to be utilised to develop an over-the-counter (OTC) screening model for breast cancer risk estimation. Data were retrospectively collected from women who came to the Hospital Universiti Sains Malaysia, Malaysia for breast-related problems. Eight ML models were used: k-nearest neighbour (kNN), elastic-net logistic regression, multivariate adaptive regression splines, artificial neural network, partial least square, random forest, support vector machine (SVM), and extreme gradient boosting. Features utilised for the development of the screening models were limited to information in the patient registration form. The final model was evaluated in terms of performance across a mammographic density. Additionally, the feature importance of the final model was assessed using the model agnostic approach. kNN had the highest Youden J index, precision, and PR-AUC, while SVM had the highest F2 score. The kNN model was selected as the final model. The model had a balanced performance in terms of sensitivity, specificity, and PR-AUC across the mammographic density groups. The most important feature was the age at examination. In conclusion, this study showed that ML and patient registration information are feasible to be used as the OTC screening model for breast cancer.

The Effects of Tamoxifen on Tolerogenic Cells in Cancer.

Tamoxifen (TAM) is the most prescribed selective estrogen receptor modulator (SERM) to treat hormone-receptor-positive breast cancer patients and has been used for more than 20 years. Its role as a hormone therapy is well established; however, the potential role in modulating tolerogenic cells needs to be better clarified. Infiltrating tumor-microenvironment-regulatory T cells (TME-Tregs) are important as they serve a suppressive function through the transcription factor Forkhead box P3 (Foxp3). Abundant studies have suggested that Foxp3 regulates the expression of several genes (CTLA-4, PD-1, LAG-3, TIM-3, TIGIT, TNFR2) involved in carcinogenesis to utilize its tumor suppressor function through knockout models. TAM is indirectly concomitant via the Cre/loxP system by allowing nuclear translocation of the fusion protein, excision of the floxed STOP cassette and heritable expression of encoding fluorescent protein in a cohort of cells that express Foxp3. Moreover, TAM administration in breast cancer treatment has shown its effects directly through MDSCs by the enrichment of its leukocyte populations, such as NK and NKT cells, while it impairs the differentiation and activation of DCs. However, the fundamental mechanisms of the reduction of this pool by TAM are unknown. Here, we review the vital effects of TAM on Tregs for a precise mechanistic understanding of cancer immunotherapies.

High-Dose Vitamin C for Cancer Therapy.

In recent years, the idea that Vitamin C (Vit-C) could be utilized as a form of anti-cancer therapy has generated many contradictory arguments. Recent insights into the physiological characteristics of Vit-C, its pharmacokinetics, and results from preclinical reports, however, suggest that high-dose Vit-C could be effectively utilized in the management of various tumor types. Studies have shown that the pharmacological action of Vit-C can attack various processes that cancerous cells use for their growth and development. Here, we discuss the anti-cancer functions of Vit-C, but also the potential for the use of Vit-C as an epigenetic regulator and immunotherapy enhancer. We also provide a short overview of the current state of systems for scavenging reactive oxygen species (ROS), especially in the context of their influencing high-dose Vit-C toxicity for the inhibition of cancer growth. Even though the mechanisms of Vit-C action are promising, they need to be supported with robust randomized and controlled clinical trials. Moreover, upcoming studies should focus on how to define the most suitable cancer patient populations for high-dose Vit-C treatments and develop effective strategies that combine Vit-C with various concurrent cancer treatment regimens.

Advanced Nasopharyngeal Carcinoma with Generalized Lymphadenopathy Masquerade as Lymphoma.

Introduction: Nasopharyngeal carcinoma (NPC) is a nasopharyngeal epithelial neoplasm that has distinct aetiological, epidemiological and biological characteristics compared to other head and neck malignancies. Patients usually present late due to non-specific symptoms and deep location of the tumour in the nasopharynx. Case Report: We would like to highlight a case of advanced NPC presenting with generalised lymphadenopathy, without the presence of an obvious nasopharyngeal mass that masqueraded as lymphoma in the initial stage. Conclusions: NPC may share clinical features with other sinonasal pathologies or other malignant lymphoproliferative disorders that lead to a delay in diagnosis. NPC should be one of the differential diagnoses for any cases presenting with cervical lymphadenopathy, especially in adult male patients originating from East or Southeast Asia. Early diagnosis and treatment are crucial because early-stage NPC has an excellent chemoradiotherapy response and high survival rate.

"Ultraviolet C phototherapy as an adjunct wound therapy in full-thickness wound of a rat model".

Ultraviolet C (UVC) phototherapy is a potential modality to improve wound healing due to its well-known antimicrobial properties, and it promotes the expression of certain growth factors. However, limited data exist to show the clinical effect of UVC in wound healing compared with other advanced modern dressings. This animal preclinical study involved 56 Sprague-Dawley female rats aged 3 months old, weighing between 250 and 300 g, which were acclimatized for one week. Following the creation of a 2 × 2-cm-square full-thickness wound over the dorsum of each rat, they were divided into four treatment groups, namely, the control, UVC, hydrofiber silver, and UVC/hydrofiber silver groups. On Days 2, 4, 7, 10, 14, 21, and 28 postwounding, two rats from each group underwent wound assessment via wound measurement (mm2), calculation of the percentage of wound contracture and percentage of epithelization. Wound specimens were obtained for histological examination of inflammatory cells (neutrophils, lymphocytes and macrophages) and fibroblast cell counts. There was a relationship between wound size reduction and time to heal (P<0.05, R2=0.70) among the four treatment groups. The UVC/hydrofiber silver group had a significantly smaller wound size given the time to heal compared with the control group (P = 0.01) and UVC group (P = 0.02). There were no significant differences in terms of wound contracture and epithelization percentage among the four treatment groups. Histopathological examination revealed a significantly lower mean fibroblast count in the UVC/hydrofiber silver group than in the other groups (P = 0.025). These data suggested that UVC phototherapy did not increase the rate of healing but maintained the integrity of the wound by providing antimicrobial properties and preventing overproduction of fibroblasts. UVC was also safe, as no overt inflammatory response was discovered.

Factors Influencing Mammographic Density in Asian Women: A Retrospective Cohort Study in the Northeast Region of Peninsular Malaysia.

Mammographic density is a significant risk factor for breast cancer. In this study, we identified the risk factors of mammographic density in Asian women and quantified the impact of breast density on the severity of breast cancer. We collected data from Hospital Universiti Sains Malaysia, a research- and university-based hospital located in Kelantan, Malaysia. Multivariable logistic regression was performed to analyse the data. Five significant factors were found to be associated with mammographic density: age (OR: 0.94; 95% CI: 0.92, 0.96), number of children (OR: 0.88; 95% CI: 0.81, 0.96), body mass index (OR: 0.88; 95% CI: 0.85, 0.92), menopause status (yes vs. no, OR: 0.59; 95% CI: 0.42, 0.82), and BI-RADS classification (2 vs. 1, OR: 1.87; 95% CI: 1.22, 2.84; 3 vs. 1, OR: 3.25; 95% CI: 1.86, 5.66; 4 vs. 1, OR: 3.75; 95% CI: 1.88, 7.46; 5 vs. 1, OR: 2.46; 95% CI: 1.21, 5.02; 6 vs. 1, OR: 2.50; 95% CI: 0.65, 9.56). Similarly, the average predicted probabilities were higher among BI-RADS 3 and 4 classified women. Understanding mammographic density and its influencing factors aids in accurately assessing and screening dense breast women.

The Enigma of Giant Phyllodes Tumour.

Phyllodes tumours are an uncommon type of biphasic fibroepithelial neoplasm of the breast. We present a case of a 28-year-old, para one lady with no risk of breast cancer presented with painless left breast swelling for three months. Over one month, the swelling suddenly increased in size and became painful with skin changes associated with pus discharge. On physical examination, a huge swelling measuring about 25cm x 30cm occupies the central and lateral aspect of the left breast with surrounding erythema. We proceeded for a tru-cut biopsy, and the histopathological examination (HPE) showed a stromal proliferation with myxoid changes consistent with phyllodes tumour of benign type. The patient underwent a left simple mastectomy, and the histopathological examination (HPE) confirmed the diagnosis of borderline phyllodes tumour with clear margins without lymph nodes involvement. The patient was subsequently referred to the oncology team and was subjected to 40 Gy in 15 fractions of radiotherapy. Given the rarity of the disease and based on current studies, simple mastectomy with negative margins is recommended for giant benign phyllodes tumours.

Rapamycin as a potent and selective inhibitor of vascular endothelial growth factor receptor in breast carcinoma.

Angiogenesis is the process of new vascular formation, which is derived from various factors. For suppressing cancer cell growth, targeting angiogenesis is one of the therapeutic approaches. Vascular endothelial growth factor family receptors, including Flt-1, Flk-1 and Flt-4, have been found to play an essential role in regulating angiogenesis. Rapamycin is a macrolide compound with anti-proliferative properties, while platelet factor-4 (PF-4) is an antiangiogenic ELR-negative chemokine. Rapamycin inhibits mTOR ligands activation, thus suppressing cell proliferation, while PF-4 inhibits cell proliferation through several mechanisms. In the present study, we evaluated the effects of rapamycin and platelet factor-4 toward breast carcinoma at the proteomic and genomic levels. A total of 60 N-Methyl-N-Nitrosourea-induced rat breast carcinomas were treated with rapamycin, platelet factor-4 and rapamycin+platelet factor-4. The tumours were subsequently subjected to immunohistochemical protein analysis and polymerase chain reaction gene analysis. Protein analysis was performed using a semiquantitative scoring method, while the mRNA expression levels were analysed based on the relative expression ratio. There was a significant difference in the protein and mRNA expression levels for the selected markers. In the rapamycin+platelet factor-4-treated group, the Flt-4 marker was downregulated, whereas there were no differences in the expression levels of other markers, such as Flt-1 and Flk-1. On the other hand, platelet factor-4 did not exhibit a superior angiogenic inhibiting ability in this study. Rapamycin is a potent antiangiogenic drug; however, platelet factor-4 proved to be a less effective drug of anti-angiogenesis on rat breast carcinoma model.

A rare case of sinonasal solitary fibrous tumour in a patient with concurrent papillary thyroid carcinoma: A case report.

INTRODUCTION AND IMPORTANCE: A solitary fibrous tumour (SFT) is a rare neoplasm that commonly arises in the pleura and can occur in other extrathoracic sites. Extrapleural SFT, particularly in the sinonasal cavity, is extremely rare. There are no definite diagnostic criteria for sinonasal SFT as it is rare. Histologic analysis with immunohistochemistry plays an important role in diagnosing SFT. CASE PRESENTATION: We report herein a case of SFT of the sinonasal cavity, which later spread to the oral cavity in a 67-year-old male with underlying papillary thyroid carcinoma (PTC) stage IV. He complained of recurrent epistaxis from a mass in his left nasal cavity for two weeks. The mass grew bigger, and spread to the oral cavity, causing dysphagia and upper airway obstruction. Tracheostomy was done under local anaesthesia and a biopsy of the mass was taken to rule out metastasis from the PTC. However, histopathological examination revealed a mesenchymal tumour of fibroblastic type, consistent with an SFT. He was planned for surgical resection of the tumour. However, he refused the operation and was lost to follow-up. CLINICAL DISCUSSION: We describe the clinical presentation of this rare tumour of the sinonasal and oral cavity, including upper airway obstruction, and the importance of immunohistochemical markers such as CD34 and BCL-2 in diagnosing SFT. Complete resection of the tumour is the definitive treatment for SFT. CONCLUSION: SFT of the sinonasal and oral cavity is extremely rare. Upper airway obstruction may occur due to the location of the tumour in the airway region. Immunohistochemistry is crucial to distinguish this tumour from other mesenchymal tumours.

The Unique Biology behind the Early Onset of Breast Cancer.

Breast cancer commonly affects women of older age; however, in developing countries, up to 20% of breast cancer cases present in young women (younger than 40 years as defined by oncology literature). Breast cancer in young women is often defined to be aggressive in nature, usually of high histological grade at the time of diagnosis and negative for endocrine receptors with poor overall survival rate. Several researchers have attributed this aggressive nature to a hidden unique biology. However, findings in this aspect remain controversial. Thus, in this article, we aimed to review published work addressing somatic mutations, chromosome copy number variants, single nucleotide polymorphisms, differential gene expression, microRNAs and gene methylation profile of early-onset breast cancer, as well as its altered pathways resulting from those aberrations. Distinct biology behind early-onset of breast cancer was clear among estrogen receptor-positive and sporadic cases. However, further research is needed to determine and validate specific novel markers, which may help in customizing therapy for this group of patients.

Triple Negative Breast Cancer: A Review of Present and Future Diagnostic Modalities.

Triple-negative breast cancer (TNBC) is an aggressive breast type of cancer with no expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER2). It is a highly metastasized, heterogeneous disease that accounts for 10-15% of total breast cancer cases with a poor prognosis and high relapse rate within five years after treatment compared to non-TNBC cases. The diagnostic and subtyping of TNBC tumors are essential to determine the treatment alternatives and establish personalized, targeted medications for every TNBC individual. Currently, TNBC is diagnosed via a two-step procedure of imaging and immunohistochemistry (IHC), which are operator-dependent and potentially time-consuming. Therefore, there is a crucial need for the development of rapid and advanced technologies to enhance the diagnostic efficiency of TNBC. This review discusses the overview of breast cancer with emphasis on TNBC subtypes and the current diagnostic approaches of TNBC along with its challenges. Most importantly, we have presented several promising strategies that can be utilized as future TNBC diagnostic modalities and simultaneously enhance the efficacy of TNBC diagnostic.

Evaluation of NMU-Induced Breast Cancer Treated with Sirolimus and Sunitinib on Breast Cancer Growth.

OBJECTIVE: To analyze the effect of sirolimus and sunitinib in blocking the tumor growth and to evaluate the expressions of estrogen receptor (ER), progesterone receptor (PgR), and human epidermal growth factor receptor-2 (HER2/neu) after treated with sirolimus and sunitinib. METHODS: Thirty-two female Sprague Dawley rats at age 21-days old were administered intraperitoneally with N-Methyl-N-Nitroso Urea (NMU), dosed at 70mg/kg body weight. The rats were divided into 4 groups; Group 1 (Control, n=8), Group 2 (Sirolimus, n=8), Group 3 (Sunitinib, n=8) and Group 4 (Sirolimus+Sunitinib, n=8), being treated twice when the tumor reached the size of 14.5±0.5 mm and subsequently sacrificed after 5 days. The protein expressions of ER, PgR and HER2/neu of the tumor tissues were evaluated by using immunohistochemistry analysis. RESULTS: Treatment with sirolimus alone lowered expressions of ER and PgR of breast cancer and reduced tumor size. There was no significant difference of ER and PgR expressions between control and sunitinib treated tumor. Sunitinib treated tumors reduce in diameter after the first treatment, however the diameter increases after the second treatment. Histologically, sunitinib treated tumor did not show any aggressive invasive carcinoma of no special type (NST) histological subtypes. In addition, all NMU-induced tumors are HER2/neu-negative scoring. CONCLUSION: Sirolimus is neither synergistic nor additive with sunitinib for breast cancer treatment.
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Sustainable Medical Teaching and Learning During the COVID-19 Pandemic: Surviving the New Normal.

During the first phase of the Movement Control Order, many medical lecturers had difficulty adapting to the online teaching and learning methods that were made compulsory by the institutional directives. Some of these lecturers are clinicians who need to juggle between clinical work and teaching, and consider a two-week adaptation during this period to be not enough. Furthermore, converting traditional face-to-face learning to online formats for undergraduate and postgraduate clinical programmes would reduce the learning outcomes, especially those related to clinical applications and the acquisition of new skills. This editorial discusses the impact that movement restrictions have had on medical teaching and learning, the alternatives and challenges and the way forward.

Mesenchymal chondrosarcoma of maxilla in paediatric patient.

Chondrosarcoma (CS) is a malignant tumour of long and flat bone characterised by the formation of cartilage. Mesenchymal chondrosarcoma (MCS) is a rare subtype of CS that is more aggressive and may lead to erroneous diagnosis in a limited biopsy. The diagnosis is mainly based on the histopathological appearance of biphasic pattern of undifferentiated small round cells separated by islands of well-differentiated hyaline cartilage. We report a case of 13-year-old boy who initially presented with gum swelling and the biopsy result suggested a benign fibrous lesion. Following an extensive lesion shown in radiologic findings, the tumour excision was done and finally was diagnosed as an MCS of the maxilla. The patient was given postoperative chemotherapy (EURO-EWING 99 regimen), and now on regular follow-up for monitoring of local recurrence or tumour metastasis.