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.

Water-SDS-[BMIm]Br composite system for one-pot multicomponent synthesis of pyrano[2,3-c]pyrazole derivatives and their structural assessment by NMR, X-ray, and DFT studies.

Here, we report a simple, efficient, and green protocol for the one-pot synthesis of pyrano[2,3-c]pyrazole derivatives via a sequential three-component strategy using aromatic aldehydes, malononitrile and pyrazolin-5-one in a water-SDS-ionic liquid system. This is a base and volatile organic solvent-free approach that could be applicable to a wide substrate scope. The key advantages of the method over other established protocols are very high yield, eco-friendly conditions, chromatography-free purification and recyclability of the reaction medium. Our study revealed that the N-substituent present in pyrazolinone controls the selectivity of the process. N-unsubstituted pyrazolinone favours the formation of 2,4-dihydro pyrano[2,3-c]pyrazoles whereas under identical conditions N-phenyl substituent pyrazolinone favours the formation 1,4-dihydro pyrano[2,3-c]pyrazoles. Structures of the synthesized products were established by NMR and X-ray diffraction techniques. Energy optimized structures and energy gaps between the HOMO-LUMO of some selected compounds were estimated using density functional theory to explain the extra stability of the 2,4-dihydro pyrano[2,3-c]pyrazoles over 1,4-dihydro pyrano[2,3-c]pyrazoles.

Expedient approach for trans-esterification of ß-keto esters under solvent free conditions using silica supported boric acid (SiO2-H3BO3) as a recyclable catalyst.

A highly efficient trans-esterification of ß-keto methyl/ethyl esters with primary, secondary, allylic, benzylic and chiral alcohols has been carried out in excellent yields under solvent-free conditions using silica supported boric acid as a heterogeneous catalyst. The surface morphology of the silica-boric acid catalyst (fresh and recycled) has been characterized by SEM and EDX techniques. This sustainable protocol resulted in a remarkable enhancement in the synthetic efficiency (87-95% yield) with high purity and eliminating the use of an environmentally toxic solvent. The work up procedure is very simple and the catalyst has been successfully recovered and recycled. The present methodology is also applicable for trans-esterification with chiral alcohols on a multi-gram scale without compromising the yield. Noteworthy features of this protocol are simple operational procedure, minimizing production of chemical waste, mild reaction conditions, easy preparation of the catalyst and its recyclability up to five cycles without any appreciable loss of catalytic activity.

Complementary Resistive Switching Behavior in Tetraindolyl Derivative-Based Memory Devices.

Complementary resistive switching (CRS) devices are more advantageous compared to bipolar resistive switching (BRS) devices for memory applications as they can minimize the sneak path problem observed in the case of BRS having a crossbar array structure. Here, we report the CRS behavior of 1,4-bis(di(1H-indol-3-yl)methyl)benzene (Indole1) molecules. Our earlier study revealed that Au/Indole1/Indium tin oxide (ITO) devices showed BRS under ambient conditions. However, the present investigations revealed that when the device is exposed to 353 K or higher temperatures, dynamic evolution of the Au/Indole1/ITO device from BRS to CRS occurred with a very good memory window (∼103), data retention (5.1 × 103 s), stability (50 days), and device yield (∼ 60%). This work explores the application possibility of indole derivatives toward future ultradense resistive random access memory.

Nontraditional Redox Active Aliphatic Luminescent Polymer for Ratiometric pH Sensing and Sensing-Removal-Reduction of Cu(II): Strategic Optimization of Composition.

Here, redox active aliphatic luminescent polymers (ALPs) are synthesized via polymerization of N,N-dimethyl-2-propenamide (DMPA) and 2-methyl-2-propenoic acid (MPA). The structures and properties of the optimum ALP3, ALP3-aggregate and Cu(I)-ALP3, ratiometric pH sensing, redox activity, aggregation enhanced emission (AEE), Stokes shift, and oxygen-donor selective coordination-reduction of Cu(II) to Cu(I) are explored via spectroscopic, microscopic, density functional theory-reduced density gradient (DFT-RDG), fluorescence quenching, adsorption isotherm-thermodynamics, and electrochemical methods. The intense blue and green fluorescence of ALP3 emerges at pH = 7.0 and 9.0, respectively, due to alteration of fluorophores from -C(═O)N(CH3 )2 / -C(═O)OH to -C(O- )═N+ (CH3 )2 / -C(═O)O- , inferred from binding energies at 401.32 eV (-C(O- )═N+ (CH3 )2 ) and 533.08 eV (-C(═O)O- ), significant red shifting in absorption and emission spectra, and peak at 2154 cm-1 . The n-π* communications in ALP3-aggregate, hydrogen bondings within 2.34-2.93 Å (intramolecular) in ALP3 and within 1.66-2.89 Å (intermolecular) in ALP3-aggregate, respectively, contribute significantly in fluorescence, confirmed from NMR titration, ratiometric pH sensing, AEE, excitation dependent emission, and Stokes shift and DFT-RDG analyses. For ALP3, Stokes shift, excellent limit of detection, adsorption capacity, and redox potentials are 13561 cm-1 /1.68 eV, 0.137 ppb, 122.93 mg g-1 , and 0.33/-1.04 V at pH 7.0, respectively.

Design, synthesis and docking study of Vortioxetine derivatives as a SARS-CoV-2 main protease inhibitor.

PURPOSE: Vortioxetine an anti-depressant FDA-drug recently reported showing better in vitro efficacy against SARS-CoV-2. METHODS: In this study, we have synthesized ten new derivatives having alkenes, alkynes, benzyl, aryl, and mixed carbamate at the N-terminal of vortioxetine. Then the binding energy and interactions with the crucial amino acid residues in the binding pocket of main protease (Mpro) of SARS-CoV-2, of reported and ten newly synthesized vortioxetine derivatives (total thirty-one) in comparison with remdesivir are analyzed and presented in this paper. RESULTS: Based on the docking scores predicted by ADV and AD, most vortioxetine derivatives showed better binding efficiency towards Mpro of SARS-CoV-2 in comparison with remdesivir (an EUA approved drug against SARS-CoV-2 Mpro) and vortioxetine. CONCLUSION: This study shows that some vortioxetine derivatives can be developed into promising drugs for COVID-19 treatment.

Ratiometric pH Sensing, Photophysics, and Cell Imaging of Nonaromatic Light-Emitting Polymers.

Here, four nontraditional fluorescent polymers (NTFPs) of varying N,N-dimethyl-2-propenamide (DMPA) and butyl prop-2-enoate (BPE) mole ratios, i.e., 2:1 (NTFP1), 4:1 (NTFP2), 8:1 (NTFP3), and 16:1 (NTFP4), are prepared via random polymerization in water. The maximum fluorescence enhancement of NTFP3 makes it suitable for ratiometric pH sensing, Cu(II) sensing, and pH-dependent cell imaging of Madin-Darby canine kidney (MDCK) cells. The oxygen donor functionalities of NTFP3 involved in binding and sensing with Cu(II) ions are studied by absorption, emission, electron paramagnetic resonance, Fourier transform infrared (FTIR), and O1s/Cu2p X-ray photoelectron spectroscopies (XPS). The spectral responses of the ratiometric pH sensor within 1.5-11.5 confirm 22 and 44 nm red shifts in absorption and ratiometric emission, respectively. The striking color changes from blue (436 nm) to green (480 nm) via an increase in pH are thought to be the stabilization of the charged canonical form of tertiary amide, i.e., -C(O-)═N+(CH3)2, realized from the changes in the absorption/fluorescence spectra and XPS/FTIR analyses. The through-space n-π* interactions in the NTFP3 aggregate, N-branching-associated rigidity, and nonconventional intramolecular hydrogen bondings of adjacent NTFP3 moieties in the NTFP3 aggregate contribute to aggregation-enhanced emissions (AEEs). Here, structures of NTFP3, NTFP3 aggregate, and Cu(II)-NTFP3; absorption; n-π* interactions; hydrogen bondings; AEEs; and binding with Cu(II) are ascertained by density functional theory, time-dependent density functional theory, and reduced density gradient calculations. The excellent limits of detection and Stern-Volmer constants of NTFP3 are 2.24 nM/0.14234 ppb and 4.26 × 103 M-1 at pH = 6.5 and 0.95 nM/0.06037 ppb and 4.90 × 103 M-1 at pH = 8.0, respectively. Additionally, the Stokes shift and binding energy of NTFP3 are 13,636 cm-1/1.69 eV and -4.64 eV, respectively. The pH-dependent MDCK cell imaging ability of noncytotoxic NTFP3 is supported via fluorescence imaging and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay.

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.

Resistive Switching of the Tetraindolyl Derivative in Ultrathin Films: A Potential Candidate for Nonvolatile Memory Applications.

Bipolar resistive switching using organic molecule is very promising for memory applications owing to their advantages, such as simple device structure, low manufacturing cost, stability, and flexibility. Herein we report Langmuir-Blodgett (LB) and spin-coated-film-based bipolar resistive switching devices using organic material 1,4-bis(di(1H-indol-3-yl)methyl)benzene (Indole1). The pressure-area per molecule isotherm (π-A), Brewster angle microscopy (BAM), atomic force microscopy (AFM), and scanning electron microscopy (SEM) were used to formulate an idea about the organization and morphology of the organic material onto thin films. On the basis of the device structure and measurement protocol, it is observed that the device made up of Indole1 shows nonvolatile resistive random access memory (RRAM) behavior with a very high memory window (∼106), data sustainability (5400 s), device yield (86.7%), and repeatability. The oxidation-reduction process and electric-field-driven conduction are the keys behind such switching behavior. Because of very good data retention, repeatability, stability, and a high device yield, the switching device designed using compound Indole1 may be a potential candidate for memory applications.

Bis-indolylation of aldehydes and ketones using silica-supported FeCl3: molecular docking studies of bisindoles by targeting SARS-CoV-2 main protease binding sites.

We report herein an operationally simple, efficient and versatile procedure for the synthesis of bis-indolylmethanes via the reaction of indoles with aldehydes or ketones in the presence of silica-supported ferric chloride under grindstone conditions. The prepared supported catalyst was characterized by SEM and EDX spectroscopy. The present protocol has several advantages such as shorter reaction time, high yield, avoidance of using harmful organic solvents during the reaction and tolerance of a wide range of functional groups. Molecular docking studies targeted toward the binding site of SARS-CoV-2 main protease (3CLpro or Mpro) enzymes were investigated with the synthesized bis-indoles. Our study revealed that some of the synthesized compounds have potentiality to inhibit the SARS-CoV-2 Mpro enzyme by interacting with key amino acid residues of the active sites via hydrophobic as well as hydrogen bonding interactions.

7-Alkoxy-appended coumarin derivatives: synthesis, photo-physical properties, aggregation behaviours and current-voltage (I-V) characteristic studies on thin films.

In this study, we designed and synthesised a series of coumarin derivatives appended with a long alkoxy chain on the seventh position of the coumarin-3-carboxylate/carboxylic acid core to make thin film materials. Synthesised compounds were characterized by their UV and fluorescence spectra in solutions as well as their films prepared by both LB and spin-coated methods. The surface morphology and electrical behaviour of thin films were judged by AFM, SEM and I-V characteristic mapping respectively. Isotherm, UV-Vis absorption and fluorescence spectroscopic investigations revealed the formation of aggregates on thin films. The result of SEM and AFM images provides the information about the length and height of aggregates on the thin films of coumarin derivatives. From I-V characteristics, it was found that at room temperature, the spin-coated films of coumarin derivatives containing an ester functional group exhibited a threshold switching behaviour, whereas derivatives containing the carboxylic acid functional group showed both threshold and bipolar switching behaviours. We also noticed that the I-V characteristic features of synthesized materials depended on the length of the alkyl chain of individual series.

Metal-Free Indole-Phenacyl Bromide Cyclization: A Regioselective Synthesis of 3,5-Diarylcarbazoles.

A metal-free, simultaneous triple C-C coupling cyclization reaction between phenacyl bromides and indoles is discovered in a highly regioselective fashion to furnish 3,5-diarylcarbazoles. DMAP is utilized as the only reagent for the unusual and rapid cyclization reaction to furnish all new carbazole compounds through installation of a great diversity of substituents. A plausible radical mechanism for the new reaction is predicted by conducting various control experiments, competitive reactions, furoindole formation, and ESI-MS analyses of the ongoing cyclization reaction.

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.

Study of Compression-Induced Supramolecular Nanostructures of an Imidazole Derivative by Langmuir-Blodgett Technique.

In this communication, we report the design and synthesis as well as the supramolecular assembly behavior of a 2,4,5-triaryl imidazole derivative (compound 1) at the air-water interface and in thin films using Langmuir-Blodgett (LB) technique. The main idea for such a chemical structure is that the long alkyl chain and N-H of the imidazole core may help to form supramolecular architecture through the hydrophobic-hydrophobic interaction and hydrogen bonding, respectively. Accordingly, the interfacial behavior as well as morphology of 1 in thin films were studied through a series of characterization methods such as surface pressure-area (π-A) isotherm, hysteresis analysis, ultraviolet-visible (UV-vis) absorption and steady-state fluorescence spectroscopies, Fourier transform infrared, X-ray diffraction, Brewster angle microscopy (BAM), and atomic force microscopy (AFM) measurements, and so forth. Pressure-area isotherm is an indication toward the formation of supramolecular nanostructures instead of an ideal monolayer at the air-water interface. This has been confirmed by the hysteresis analysis and BAM measurement at the air-water interface. AFM images of 1 in the LB monolayer exhibits the formation of supramolecular nanowires as well as nanorods. By controlling different film-forming parameters, it becomes possible to manipulate these nanostructures. With the passage of time, the nanowires come close to each other and become straight. Similarly, nanorods come close to each other and form bundles of several rods in the LB films. H-bonding, J-aggregation, as well as compression during film formation might play a key role in the formation of such nanostructures. Electrical switching behavior of compound 1 was also observed because of the presence of an electron donor-acceptor system in 1. This type of organic switching behavior may be promising for next-generation organic electronics.

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.