Nanoparticulate strategies for the delivery of miRNA mimics and inhibitors in anticancer therapy and its potential utility in oral submucous fibrosis

MicroRNAs (miRNAs) are naturally occurring noncoding RNAs with multiple functionalities. They are dysregulated in several conditions and can serve as disease biomarkers, therapeutic targets and therapeutic agents. Translation of miRNA therapeutics to the clinic poses several challenges related to the safe and effective delivery of these agents to the site of action. Nanoparticulate carriers hold promise in this area by enhancing targeting efficiency and reducing off-target effects. This paper reviews recent advances in the delivery strategies of miRNAs in anticancer therapy, with a focus on lipid-based, polymeric, inorganic platforms, cell membrane-derived vesicles and bacterial minicells. Additionally, this review explores the potentiality of miRNAs in the treatment of oral submucous fibrosis, a potentially premalignant condition of the oral cavity with no definitive treatment to date.

Immunohistochemical Analysis of Myofibroblasts Using α- SMA in Oral Submucous Fibrosis Turning into Malignancy- A Case Report and Review

Oral submucous fibrosis is a premalignant condition, characterized by fibrosis in oral mucosa causing stiffness of mucosa and leading to reduced mouth opening. The malignant transformation of oral submucous fibrosis is very high among the rest of the premalignant conditions. Chronic chewing of arecanut causes production of myofibroblasts. These myofibroblasts plays an important role in neoangiogenesis as well as disintegration of the basement membrane at the tumor invasive front leading to carcinoma. Here, we are doing an Immunohistochemical study using alpha SMA for proper microscopic visulizations of myofibroblastic activity in an OSF patient, encompassing the pathogenesis and malignant potentiality of the disease.

Malignancy Rate of Bethesda Class III Thyroid Nodules Based on the Presence of Chronic Lymphocytic Thyroiditis in Surgical Patients

BackgroundHashimoto’s thyroiditis (HT), also known as chronic lymphocytic thyroiditis (CLT), may interfere with the accurate cytological diagnosis of thyroid nodules. Recently, HT has been considered a premalignant condition for thyroid cancer development. The diagnosis of atypia of undetermined significance/follicular lesions of undetermined significance (AUS/FLUS) thyroid nodules is challenging and evidence for the malignancy risk of AUS/FLUS thyroid nodules coexisting with CLT is scarce. Therefore, we assessed the malignancy risk of AUS/FLUS thyroid nodules according to the presence of background CLT.MethodsThis study included 357 surgically resected thyroid nodules with AUS/FLUS cytology. Cases with concomitant malignant nodules were excluded. CLT was defined based on the pathologic report after thyroid surgery.ResultsAmong 357 tumors, 130 tumors (36%) were confirmed to have coexisting CLT, and 170 tumors (48%) were determined to be malignant after thyroidectomy. Malignancy rates were similar in both groups (48% in each) regardless of background CLT (62/130 with CLT vs. 108/227 without CLT). In the group with CLT, thyroiditis was more frequent in the final pathology (12% with CLT vs. 1% without CLT, P = 0.003). In multivariate analysis, positive BRAFV600E mutation, highly suspicious sonographic features (K-TIRADS 5), and smaller thyroid nodules were significant factors for thyroid malignancies.ConclusionThe malignancy rate of thyroid nodules with AUS/FLUS cytology was comparable irrespective of the presence of underlying CLT.

Oral Submucous Fibrosis - A Review

A common oral disease named as oral submucous fibrosis (OSMF) has the tendency to usually affect many areas of the oral cavity as well as involving the area of pharynx. The characteristic feature of oral submucous fibrosis is the fibrosis in submucosal area which involves maximum part of oral cavity leading to advanced lock jaw as a result of rigidity in cheeks, pharynx, lips and upper third part of the oesophageal canal progressing to dysphagia. It has been reported that OSMF occurs mainly in persons who are habituated to chew areca nut or products containing areca nut along with other ingredients. In recent years with the introduction of commercially available Gutka and other areca nut products, the incidence of OSMF is increasing especially in the younger generations. OSMF is irreversible and persists even after cessation of chewing habit and the severity increases along with the duration of habit. In 2007, the categorization of oral submucous fibrosis was done as a premalignant condition by WHO and it has higher chances of malignant transformation. Early diagnosis and application of proper treatment modality is mandatory to reduce morbidity and mortality rate. There are many classification systems that have been proposed in literature for oral submucous fibrosis, among which many are based on clinical features, some of them on functional aspects and others are based on histopathological aspects. Here is an attempt to enlighten the facts and recent updates of clinical, functional, histopathological features as well as pathogenesis and management of oral submucous fibrosis. The complete knowledge of oral submucous fibrosis is a useful to the clinicians as well as academicians and researchers for timely detection and proper management of the disease. KEY WORDS Oral Submucous Fibrosis, Precancerous Lesions, Precancerous Conditions, Sclerosing Stomatitis

Varied presentations of a mineralized styloid process in oral submucous fibrosis patients visualized on digital panoramic radiographs

Oral Submucous Fibrosis (OSMF) is a widely prevalent, premalignant condition which adversely affects the quality of life of an individual and can warrant stringent surgical regimen for its treatment. An Elongated Styloid Process (ESP), if coexisting, can invariably impair the post-surgical mandatory physiotherapy necessary to maintain the mouth-opening achieved intraoperatively. To evaluate digital Orthopantomograms (OPGs) of patients having OSMF and to observe presentations of various combinations of calcification types and patterns of ESP in them. Patients with clinically diagnosed OSMF (Grade III and IV according to Khanna and Andrade 1995) were advised a digital OPG to measure and observe the ESP using the C.S. Imaging Software 7.0.3.The digitized OPGs were converted into KODAK large format prints and then ESP was measured starting from the point where it is visualized to leave the tympanic plate extending upto its tip and its myriad of combinations of calcification patterns were recorded by a single observer.The presence of unilateral and bilateral elongation along with the type and pattern of calcification was effectively noted using the C.S. Imaging Software 7.0.3. Visualization of various unique, varying patterns of ESP was noted. Sixteen such different radiological presentations were shown, captured through digital OPGs. An undetected ESP can prove to be detrimental for a patient who is recently treated for OSMF as it hinders efficient postoperative mouth opening exercises. This can easily be prevented by a simple maneuver of identifying the ESP on a digital OPG using computer aided software. The presence of assorted radiographic patterns in patients having OSMF indicate that extensive research should be directed to identify and categorize such patterns which do not conform to the past methods of classification. This study hints towards the existence of a scope to study the factors responsible for the occurrence of the varied combinations of calcification and thickness of the ESP and their clinical relevance.

Hypoxia Inducible Factor-1α (HIF-1α): A Biomarker for Detection of Malignant Transformation in Oral Submucous Fibrosis

Oral submucous fibrosis (OSMF) is a premalignant condition, which involves the oral cavity as well as pharynx and upper third of the esophagus. It is a predominant disease of South and South-East Asian population. OSMF has the highest rate of malignant transformation among the other oral premalignant disorders (OPMD) that is 7-30% with a prevalence of about 0.03% to 6.42%. OSMF is described by extensive fibrosis of submucosa and reduced vascularity, which results in compromised blood supply guiding to hypoxia of tissue. This tissue hypoxia brings about the transcription of a set of genes associated with angiogenesis, breakdown of iron/glucose, cell division and cell stability. Hypoxia Inducible Factor-1α (HIF-1α) is the main biomarker intervening in this reaction. The alteration of cells to hypoxia emerges to be mediated through hypoxia inducible factor, which is said to be linked with malignant transformation of epithelium. Research-based studies covered on the probable mechanism of HIF-1α were explored using PubMed and Google Scholar. In this review, we analyzed over 40 articles from the years 2004-2021, which were published regarding the structure and function of HIF-1α, and its association with OSMF. Research articles in which HIF-1α is used separately or in combination with other biomarkers in oral submucous fibrosis have been selected. Keywords: Biomarker; Oral Submucous Fibrosis; Esophagus; Hypoxia.

Development of EndoScreen Chip, a Microfluidic Pre-Endoscopy Triage Test for Esophageal Adenocarcinoma

The current endoscopy and biopsy diagnosis of esophageal adenocarcinoma (EAC) and its premalignant condition Barrett’s esophagus (BE) is not cost-effective. To enable EAC screening and patient triaging for endoscopy, we developed a microfluidic lectin immunoassay, the EndoScreen Chip, which allows sensitive multiplex serum biomarker measurements. Here, we report the proof-of-concept deployment for the EAC biomarker Jacalin lectin binding complement C9 (JAC-C9), which we previously discovered and validated by mass spectrometry. A monoclonal C9 antibody (m26 3C9) was generated and validated in microplate ELISA, and then deployed for JAC-C9 measurement on EndoScreen Chip. Cohort evaluation (n = 46) confirmed the expected elevation of serum JAC-C9 in EAC, along with elevated total serum C9 level. Next, we asked if the small panel of serum biomarkers improves detection of EAC in this cohort when used in conjunction with patient risk factors (age, body mass index and heartburn history). Using logistic regression modeling, we found that serum C9 and JAC-C9 significantly improved EAC prediction from AUROC of 0.838 to 0.931, with JAC-C9 strongly predictive of EAC (vs. BE OR = 4.6, 95% CI: 1.6–15.6, p = 0.014; vs. Healthy OR = 4.1, 95% CI: 1.2–13.7, p = 0.024). This proof-of-concept study confirms the microfluidic EndoScreen Chip technology and supports the potential utility of blood biomarkers in improving triaging for diagnostic endoscopy. Future work will expand the number of markers on EndoScreen Chip from our list of validated EAC biomarkers.

Small Molecule “Silmitasertib” Repurposed as Inhibitor of Transforming Growth Factor Beta 1 for the Development of Therapeutics for Oral Submucous Fibrosis

Oral submucous fibrosis (OSMF) is considered a premalignant condition characterized by aggressive fibrosis of the submucosal tissues of the oral cavity reflecting its malignant transformation potential. Activation of transforming growth factor beta (TGF-β) signaling has been reported to lead increased collagen production and fibrosis. Recently, significant upregulation of TGF-β1 has been reported in OSMF as compared to normal tissues. Therefore, inhibition of the TGF-β1 may pave for the development of therapeutics of OSMF. Based on the structure-assisted drug designing, we found “silmitasertib” as potent inhibitor of TGF-β1. We suggest that this molecule can be validated and implemented for the treatment of OSMF.

Treg and Oligoclonal Expansion of Terminal Effector CD8+ T Cell as Key Players in Multiple Myeloma

The classical paradigm of host-tumor interaction, i.e. elimination, equilibrium, and escape (EEE), is reflected in the clinical behavior of myeloma which progresses from the premalignant condition, Monoclonal Gammopathy of Unknown Significance (MGUS). Despite the role of other immune cells, CD4+ regulatory T cells (Treg) and cytotoxic CD8+ T cells have emerged as the dominant effectors of host control of the myeloma clone. Progression from MGUS to myeloma is associated with alterations in Tregs and terminal effector CD8+ T cells (TTE). These changes involve CD39 and CD69 expression, affecting the adenosine pathway and residency in the bone marrow (BM) microenvironment, together with oligoclonal expansion within CD8+ TTE cells. In this mini-review article, in the context of earlier data, we summarize our recent understanding of Treg involvement in the adenosine pathway, the significance of oligoclonal expansion within CD8+ TTE cells and BM-residency of CD8+ TTE cells in MGUS and newly diagnosed multiple myeloma patients.