Epidermal growth factor receptor inhibition potentiates chemotherapeutics-mediated sensitization of metastatic breast cancer stem cells.

BACKGROUND: Metastasis has been a cause of the poor prognosis and cancer relapse of triple-negative breast cancer (TNBC) patients. The metastatic nature of TNBC is contributed by the breast cancer stem cells (CSCs) which have been implicated in tumorigenesis. Higher expression of epidermal growth factor receptor (EGFR) in breast CSCs has been used as a molecular target for breast cancer therapeutics. Thus, it necessitates the design and generation of efficacious EGFR inhibitors to target the downstream signaling associated with the cellular proliferation and tumorigenesis of breast cancer. AIM: To generate efficacious EGFR inhibitors that can potentiate the chemotherapeutic-mediated mitigation of breast cancer tumorigenesis. METHODS AND RESULTS: We identified small molecule EGFR inhibitors using molecular docking studies. In-vitro screening of the compounds was undertaken to identify the cytotoxicity profile of the small-molecule EGFR inhibitors followed by evaluation of the non-cytotoxic compounds in modulating the doxorubicin-induced migration, in-vitro tumorigenesis potential, and their effect on the pro-apoptotic genes' and protein markers' expression in TNBC cells. Compound 1e potentiated the doxorubicin-mediated inhibitory effect on proliferation, migration, in-vitro tumorigenesis capacity, and induction of apoptosis in MDA-MB-231 cells, and in the sorted CD24+-breast cancer cells and CD24-/CD44+-breast CSC populations. Orthotopic xenotransplantation of the breast CSCs-induced tumors in C57BL/6J mice was significantly inhibited by the low dose of Doxorubicin in the presence of compound 1e as depicted by molecular and immunohistochemical analysis. CONCLUSION: Thus, the study suggests that EGFR inhibition-mediated sensitization of the aggressive and metastatic breast CSCs in TNBCs toward chemotherapeutics may reduce the relapse of the disease.

Effect of long chain fatty acids on the memory switching behavior of tetraindolyl derivatives.

Non-volatile memory devices using organic materials have attracted much attention due to their excellent scalability, fast switching speed, low power consumption, low cost etc. Here, we report both volatile as well as non-volatile resistive switching behavior of p-di[3,3'-bis(2-methylindolyl)methane]benzene (Indole2) and its mixture with stearic acid (SA). Previously, we have reported the bipolar resistive switching (BRS) behavior using 1,4-bis(di(1H-indol-3-yl)methyl)benzene (Indole1) molecules under ambient conditions [Langmuir 37 (2021) 4449-4459] and complementary resistive switching (CRS) behavior when the device was exposed to 353 K or higher temperature [Langmuir 38 (2022) 9229-9238]. However, the present study revealed that when the H of -NH group of Indole1 is replaced by -CH3, the resultant Indole2 molecule-based device showed volatile threshold switching behaviour. On the other hand, when Indole2 is mixed with SA at a particular mole fraction, dynamic evolution of an Au/Indole2-SA/ITO device from volatile to non-volatile switching occurred with very good device stability (>285 days), memory window (6.69 × 102), endurance (210 times), data retention (6.8 × 104 s) and device yield of the order of 78.5%. Trap controlled SCLC as well as electric field driven conduction was the key behind the observed switching behaviour of the devices. In the active layer, trap centers due to the SA network may be responsible for non-volatile characteristics of the device. Observed non-volatile switching may be a potential candidate for write once read many (WORM) memory applications in future.

Evaluation of Cephalometric Changes and Its Relation to Changes in Patients' Quality of Life After Mandibular Setback Surgery.

Purpose: To find out if a relationship exists between the different cephalometric changes and the perception of patients before and after Bilateral Sagittal Split Osteotomy (BSSO) setback surgery. Patients and Methods: Sample consisted of 28 patients (mean age 23.78 ± 1.36 years), Male:Female = 1:1.3, with a median follow-up of 10 ± 1.8 months, with skeletal class III malocclusion treated with BSSO setback surgery. Pre- and post-surgery lateral cephalograms were analysed. The Oral Health Impact Profile (OHIP) questionnaire was used to assess the patients' quality of life after surgery. Cephalometric data were then correlated with the questionnaire results. Results: The psychological and social aspects of OHIP questionnaire were most affected. The most significant correlation between OHIP score change and cephalometric parameters was found with reduction of 'lower lip protrusion'; and significantly positive correlations were with increase in ANB angle and reduction in values of SND angle, N-B distance, lower lip length, lower facial height, mentolabial angle and angle of facial convexity. Conclusions: A significant relationship exists between the subjective and objective parameters which should be considered while planning for orthognathic surgery. Results of this study could be beneficial, helping the clinicians, to emphasise on specific cephalometric variable with the patient-specific expectations.

"Gigantic aggressive angiomyxoma" of the jaws: A rare case report.

Angiomyxomas are a group of rare myxoid benign mesenchymal tumors prone to local recurrences. Two types of angiomyxomas are well recognized in the literature: superficial and aggressive angiomyxoma. Aggressive angiomyxomas are relatively uncommon, poorly circumscribed, locally infiltrative myofibroblastic tumors with a specific predilection for the perineal regions and exceedingly rare in the head and neck region. To the best of our knowledge, we report the first case of a gigantic aggressive angiomyxoma occurring in both the maxilla and mandible in a 30-year-old male patient. Clinicians should carefully evaluate the clinical, radiological and histological data to derive the correct diagnosis of this myxoid intraoral soft-tissue neoplasm.

Effect of Diagnosis by Two-Dimensional Radiography Versus CBCT on Surgical Aspects of Transmigrated Impacted Mandibular Canines.

PURPOSE: The transmigration of mandibular canines is a rare clinical finding. The present study aimed to compare the effect of diagnosis by two-dimensional radiography and cone beam computed tomography on surgical aspects of transmigrated impacted mandibular canines. PATIENTS AND METHODS: A total of 20 patients (mean age 20.18 ± 3.36 years; male/female = 1.5:1), reporting to the Department of Oral and Maxillofacial Surgery with transmigrated impacted mandibular canines and planned for surgical removal, were randomly divided into two groups of ten patients each. Group A patients were diagnosed using 2D radiographs (orthopantomograms and occlusal view radiographs), and Group B patients were diagnosed using CBCT scans. The effects of the diagnosis on surgical aspects were compared in both the groups using various intraoperative and post-operative parameters. RESULTS: The operating surgeons experienced lesser operating time and more accuracy in terms of prediction of surgical approach in Group B patients than in Group A. Post-operative complications, including post-operative vitality of the adjacent tooth and lower lip paraesthesia, were seen to be more in Group A patients than in Group B. CONCLUSION: Increased precision in localization of transmigrated impacted mandibular canines was seen by using CBCT, leading to better surgical experience and lesser post-operative complications.

Intraoperative Image-Guided Retrieval of Foreign Body from Infratemporal Fossa: A Rare Case Report.

Entrapped foreign bodies in the head and neck region pose a challenge for surgeons, especially when present in areas like infratemporal space. In this case report, a bomb splinter entered through skin below the right infraorbital rim, traversed the maxillary antrum and got entrapped in the infratemporal fossa of the patient, which was initially localized using preoperative two-dimensional and three-dimensional radiographs. The foreign body was exposed via Alkayat Bramley approach and finally retrieved with the help of intraoperative C-arm fluoroscopy.

Rhinoplasty in secondary nasal deformities: Subjective and objective outcome evaluation.

INTRODUCTION: Secondary nasal deformities are associated with trauma and secondary cleft nose (after primary cleft nose surgery). Nasal deformities affect esthetic, function, and psychological status of the patient. The goal of the secondary rhinoplasty is to correct both form and function, so that this positively impacts on their facial appearance. AIMS: The study aimed to evaluate the patient satisfaction (subjective outcome) by rhinoplasty outcome evaluation questionnaire (ROEQ) preoperatively and postoperatively and esthetic outcome (objective outcome) by surgical team in patients with secondary nasal deformities. MATERIALS AND METHODS: Secondary rhinoplasty was done in 13 patients of traumatic and unilateral secondary cleft nose through the external approach. Objective outcome was assessed by surgical team with clinical measurement, radiograph (lateral cephalometric), and photographic documentation pre- and postoperatively. Clinical measurements include nasolabial and nasofrontal angle. The patients completed the ROEQ for the subjective outcome evaluation. RESULTS: There was significant improvement of subjective outcome (83.30%) based on the ROEQ and objective outcome based on the clinical measurement. CONCLUSION: Our study suggests that secondary rhinoplasty in trauma and cleft patients leads to both subjective and objective improvement of the facial appearance.

Discovery of novel potential selective HDAC8 inhibitors by combine ligand-based, structure-based virtual screening and in-vitro biological evaluation.

Neuroblastoma is the most common extracranial solid tumor found in children and survival rate is extremely meager. HDAC8, a class I zinc-dependent enzyme, is a potential drug target for treatment of neuroblastoma and T cell lymphoma. Most of the HDAC8 inhibitors discovered till date contains a hydroxamic acid group which acts as a zinc binding group. The high binding affinity to the zinc and other ions results in adverse effects. Also, the non-selective inhibition of HDACs cause a variety of side effects. The objective of this is to identify structurally diverse, non-hydroxamate, novel, potential and selective HDAC8 inhibitors. A number of five featured pharmacophore hypotheses were generated using 32 known selective HDAC8 inhibitors. The hypotheses ADDRR.4 were selected for building 3D QSAR model. This model has an excellent correlation coefficient and good predictive ability, which was employed for virtual screening of Phase database containing 4.3 × 106 molecules. The resultant hits with fitness score >1.0 were optimized using in-silico ADMET (absorption, distribution, metabolism,  excretion, and toxicity) and XP glide docking studies. On the basis of pharmacophore matching, interacting amino acid residues, XP glide score, more affinity towards HDAC8 and less affinity towards other HDACs, and ADME results five hits- SD-01, SD-02, SD-03, SD-04 and SD-05 with new structural scaffolds,  non-hydroxamate were selected for in vitro activity study. SD-01 and SD-02 were found to be active in the nanomolar (nM) range. SD-01 had considerably good selectivity for HDAC8 over HDAC6 and SD-02 had marginal selectivity for HDAC6 over HDAC8. The compounds SD-01 and SD-02 were found to inhibit HDAC8 at concentrations (IC50) 9.0 nM and 2.7 nM, respectively.

Enediynyl peptides and iso-coumarinyl methyl sulfones as inhibitors of proprotein convertases PCSK8/SKI-1/S1P and PCSK4/PC4: Design, synthesis and biological evaluations.

The proprotein convertases PCSK8 and PCSK4 are, respectively, the 8th and 4th members of Ca(+2)-dependent serine endoprotease of Proprotein Convertase Subtilisin Kexin (PCSK) super family structurally related to the bacterial subtilisin and yeast kexin. The membrane bound PCSK8 (also called SKI-1 or S1P) is implicated in sterol regulation and lipid synthesis via its role in the maturation of human (h) SREBP-2. It also plays role in cartilage formation, bone mineralization, as well as viral pathogenesis. On the other hand, PCSK4 has been linked to mammalian fertilization and placenta growth. Owing to these findings, interest has grown to develop specific inhibitors against these enzymes for potential biochemical and therapeutic applications. In this study we developed two types of small molecule inhibitors of PCSK8 and PCSK4 and demonstrated their anti-proteolytic activities in vitro cell-free and in vitro cell culture systems. These are isocoumarinyl methyl sulfone derivatives and enediyne amino acid containing peptides. Our in vitro data suggested that one of the 7 sulfone derivatives (methyl phenyl sulfone) inhibited PCSK8 with inhibition constant Ki ∼255µM. It also blocked PCSK8-mediated processing of hSREBP-2 in HepG2 cell in a concentration-dependent manner. However all 7 iso-coumarinyl methyl sulfones inhibited htrypsin with IC50 ranging from 2 to 165µM. In contrast, all our designed enediynyl peptides inhibited PCSK8 and PCSK4 activity with Ki and IC50 in low µM or high nM ranges. All compounds exhibited competitive inhibition as indicated by their enzyme kinetic plots and observed dependence of IC50 value on substrate concentration. Our study confirmed that incorporation at the substrate cleavage site of 'Enediyne amino acid' generates potent inhibitors of PCSK8 and PCSK4. This represents a novel approach for future development of inhibitors of PCSK or other enzymes.

Management of pseudoaneurysm of internal maxillary artery resulting from trauma.

Pseudoaneurysm of internal maxillary artery following trauma is a rare clinical entity. A rapidly growing swelling in the facial region following fracture of the mandibular subcondylar region is an indication of a developing aneurysm. A case of pseudoaneurysm of the internal maxillary artery following condylar fracture of mandible is reported. The case was treated successfully by surgery.

Basal cell adenoma-clinicopathological, immunohistochemical analysis and surgical considerations of a rare salivary gland tumor with review of literature.

INTRODUCTION: Basal cell adenoma (BCA) of the salivary glands is a rare benign salivary gland tumour. Differentiation of BCA from varied entities involving maxillofacial area is mandatory. AIM: To analyze the clinicopathological, histopathologic features, immunohistochemcal analysis and surgical considerations of this rare entity. MATERIALS AND METHODS: This study included 12 cases of BCA from archives of department reported over the period of 13 years. All the pertaining clinicopathologic features such as incidence, age, sex and site of lesions were assessed. Tissue sections were stained by using panel of immunohistochemical markers, i.e. Pan CK, CK 5/6 and S100, Calponin, p63, CD 117 and smooth muscle actin. RESULTS: BCA was observed in 26-52 years age group (mean age, 38.75 years) with female propensity of 7:5 male to female ratio. It is seen more commonly in parotid gland, followed by upper lip, buccal mucosa and palate. Solid type is the most common histopathologic type followed by tubular, membranous and trabecular. Only one case of membranous type of BCA showed recurrence. Pan CK, CK 5/6 showed strong immunoreactivity, calponin showed moderate staining, p63 and Ki-67 mild staining, whereas CD 117 and SMA showed negative immunostaining. CONCLUSION: Vigilant comprehensive analysis of all the pertaining clinicopathologic and histopathologic features and immunohistochemical analysis are required for differentiating from other lesions with basaloid differentiation having varying prognosis.

In vitro assay for protease activity of proprotein convertase subtilisin kexins (PCSKs): an overall review of existing and new methodologies.

The mammalian proprotein convertase subtilisin kexins (PCSKs) previously called proprotein or prohormone convertases (PCs) are a family of Ca(+2)-dependent endoproteases in the subtilisin family. These proteolytic enzymes exert their many crucial physiological and biological functions in vivo via their ability to cleave larger inactive precursor proteins into their biologically active mature forms. This event takes place in a highly efficient and selective manner. Such actions of PCSKs either alone or in combination to cleave specific protein bonds are the hallmark events that not only define the normal functions and metabolism of the body but also may lead to a variety of diseases or disorders with associated conditions. These include among others, diabetes, obesity, cancer, cardiovascular diseases, reproduction abnormalities as well as viral bacterial infections. These conditions were the direct consequences of an enhanced level of enzymatic activity of one or more PCSKs except only PCSK9, whose protease activity in relation to its physiological substrate has yet to be characterized. Owing to this finding, a large number of research studies have been exclusively devoted to develop rapid, efficient and reliable in vitro methods for examining the protease activity of these enzymes. Several assays have been developed to monitor PCSK activity and these are widely used in chemical, biochemical, cellular and animal studies. This review will cover various methodologies and protocols that are currently available in the literature for PCSK activity assays. These include liquid phase methods using fluorogenic, chromogenic and intramolecularly quenched fluorescent substrates as well as a newly developed novel solid phase fluorescence method. This review will also highlight the usefulness of these methodologies and finally a comparative analysis has been made to examine their merits and demerits with some key examples.

Bilateral hamartoma of tonsils bearing ectopic teeth: a case report.

Ectopic teeth presenting in bath the tonsils with hatnartomatous lesion has not been reported earlier. We present here a case of benign hamartoma of both the tonsils bearing 7 teeth in a 13 year old girl and also discuss about unusual Ectopic sites of tooth eruption as well as benign lesions of tonsil.