A novel approach to investigate the combinatorial effects of TLK1 (Tousled-Like Kinase1) inhibitors with Temozolomide for glioblastoma therapy.

Glioblastoma multiforme (GBM) is an aggressive, incurable brain tumor with poor prognosis and limited treatment options. Temozolomide (TMZ) is the standard chemotherapeutic treatment for GBM, but its efficacy has drawn strong criticism from clinicians due to short survival gains and frequent relapses. One critical limitation of TMZ therapy is the hyperactivation of DNA repair pathways, which over time neutralizes the cytotoxic effects of TMZ, thus highlighting the urgent need for new treatment approaches. Addressing this, our study explores the therapeutic potential of in-house-designed phenothiazine-based Tousled-like kinase-1 (TLK1) inhibitors for GBM treatment. TLK1, overexpressed in GBM, plays a role in DNA repair. Phenothiazines are known to cross the blood-brain barrier (BBB). Among all molecules, J54 was identified as a potential lead molecule with improved cytotoxicity. In the context of O6-methylguanine-DNA methyltransferase (MGMT)-deficient GBM cells, the combined administration of phenothiazines and TMZ exhibited a collective reduction in clonogenic growth, coupled with anti-migratory and anti-invasion effects. Conversely, in MGMT-proficient cells, phenothiazine monotherapy alone showed reduced clonogenic growth, along with anti-migratory and anti-invasion effects. Notably, a synergistic increase in γH2AX levels and concurrent attenuation of DNA repair upon combinatorial exposure to TMZ and J54 were observed, implying increased cytotoxicity due to sustained DNA strand breaks. Overall, this study provides new insights into TLK1 inhibition for GBM therapy. Collectively, these findings indicate that TLK1 is one of the upregulated kinases in GBM and phenothiazine-based TLK1 inhibitors could be a promising treatment option for GBM patients.

Adenomatoid odontogenic tumor: A histopathologic profile of 43 cases with evidence supporting a mixed odontogenic origin.

BACKGROUND: Adenomatoid Odontogenic Tumor (AOT) accounts for 3% of all odontogenic tumors. It has been classified by WHO as an odontogenic tumor of purely epithelial origin. The current study attempts to establish the origin of the tumor along with detailed histopathological and clinicoradiographic analysis of 43 cases of AOT. MATERIAL AND METHODS: Forty-three cases were reviewed from the departmental archives for demographic data, radiographic features and histological features. Further, histopathological slides were stained with Picrosirius Red (PSR) and observed under polarised light. RESULTS: A majority of the cases were seen in the anterior jaws (76.7%), and were less than 3 cms (76.7%) in greatest dimension. Equal number of cases were of follicular and extra-follicular location while one was peripheral. Predominantly solid histological pattern was noted in 53.5%. Varied sub-patterns were observed with most cases exhibiting solid nodules and strands of tumor cells. Few cases showed melanin pigmentation. Over a third of cases (37.2%) showed dentigerous cyst like areas and one case each showed features of ossifying fibroma and focal cemento-osseous dysplasia. Tumor droplets, hyaline rings within duct-like structures, dentinoid material and osteodentin showed reddish yellow birefringence when observed under polarised microscopy post PSR staining. CONCLUSION: This study highlights the diverse histopathological variation of AOT with evidence to reclassify it as a mixed odontogenic tumor based on the polarising microscopic findings with PSR staining.

Versatility of Titanium Mesh in Comminuted Maxillofacial Fractures. A Retrospective Study.

Background: Titanium mesh provides three-dimensional stability, it is easier and quick in placement, highly malleable and adaptable hence, proved to be worth in restoring the function and form in cases of comminuted maxillofacial fractures. Materials and Methods: A total of 12 patients were included in this retrospective study at Department of Oral and maxillofacial surgery, Sri Rajiv Gandhi College of Dental Science and Hospital, from December 2015 to June 2020. Out of 12 patients, 7 reported with frontal bone fracture and 5 reported with mandibular fracture. Patients were followed up for upto 18 months to evaluate efficacy of titanium mesh on postoperative long-term healing, aesthetic outcomes and return to normal function were evaluated. Results: The results have shown that titanium mesh has low complication rates and the ability to maintain occlusion and chewing postoperatively. Union occurred without complication in 90% of fractures, and patients treated for frontal bone fracture had excellent cosmetic results. Conclusion: The semi rigid nature of the titanium mesh fixation allows micro movement at the healing bone ends, reduces stress shielding effect which may improve functional bone healing. Bony continuity of the mandible can be restored providing three-dimensional morphology and stability. The versatile placement of screws is the principal advantage.

2-Hydroxypyridine-based Ligands as Promoter in Ruthenium(II) Catalyzed C-H Bond Activation/Arylation Reactions.

A class of 2-hydroxypyridine based ligands are explored to achieve enhanced catalytic activity for ortho-C-H bond activation/arylation reaction over [(η6 -p-cymene)RuCl2 ]2 catalyst in water. Extensive studies using a series of substituted 2-hydroxypyridine based ligands (L1-L6) inferred that 5-trifluoromethyl-2-hydroxypyridine (L6) exhibited favorable effects to enhance the catalytic activity of Ru(II) catalyst for ortho C-H bond arylation of 2-phenylpyridine by 8 folds compared to those performed without ligands. The (η6 -p-cymene)Ru - L6 system also exhibited enhanced catalytic activity for ortho C-H bond arylation of 2-phenylpyridine using a variety of aryl halides. NMR and mass investigations inferred the presence of several ligand coordinated Ru(II) species, suggesting the involvement of these species in C-H bond activation reaction. Further in concurrence with the experimental findings, the density functional theory (DFT) calculations also evidenced the prominent role of 2-hydroxypyridine based ligands in Ru(II) catalyzed C-H bond arylation of 2-phenylpyridine with lower energy barrier for the C-H activation step.

Targeting ATM and ATR for cancer therapeutics: Inhibitors in clinic.

The DNA Damage and Response (DDR) pathway ensures accurate information transfer from one generation to the next. Alterations in DDR functions have been connected to cancer predisposition, progression, and response to therapy. DNA double-strand break (DSB) is one of the most detrimental DNA defects, causing major chromosomal abnormalities such as translocations and deletions. ATR and ATM kinases recognize this damage and activate proteins involved in cell cycle checkpoint, DNA repair, and apoptosis. Cancer cells have a high DSB burden, and therefore rely on DSB repair for survival. Therefore, targeting DSB repair can sensitize cancer cells to DNA-damaging agents. This review focuses on ATM and ATR, their roles in DNA damage and repair pathways, challenges in targeting them, and inhibitors that are in current clinical trials.

Cysticercosis: Unearthing the worm.

Cysticercosis, a helminthic disease caused by T. Solium, is a major health concern in developing and underdeveloped nations of the world. If left untreated, it may lead to severe neurological and ophthalmic complications. The diagnosis of oral cysticercosis depends on the identification of the larva in the biopsied tissue. However, an accurate diagnosis can be challenging, if the larva is dead because of which it cannot be identified. In such a scenario, step by step approach to unearth the worm is discussed here.

Exploring SPK98 for the Selective Sensitization of ATM- or P53-Deficient Cancer Cells.

Frequent mutation in the ATM/P53 signaling pathway has been documented in many human cancers. Reportedly, cancer cells with deficient P53/ATM pathways depend on functional Ataxia-telangiectasia and Rad3-related (ATR) protein for survival. This has prompted research in developing ATR inhibitors for the selective sensitization of cancer cells that are P53/ATM-deficient, but no clinical success has been attained thus far. This study explores the therapeutic potential of SPK98, an analogue of Torin2 in P53- and ATM-deficient cancer cells. Furthermore, the prospect of improving the therapeutic outcome of the genotoxic agent was also explored. SPK98 was shown to inhibit full-length human ATR protein purified from HEK293T cells. Cellular investigation using SPK98 demonstrated that it selectively sensitizes P53- and ATM-deficient cells at low concentrations compared to P53-/ATM-proficient cells. Furthermore, SPK98 drives the cancer cells toward cell death by promoting the formation of DNA double-strand breaks. Taken together, our findings suggest that SPK98 is a promising therapeutic molecule for P53- or ATM-deficient malignancy that merits additional preclinical investigation.

iMnet: Intelligent RAT Selection Framework for 5G Enabled IoMT Network.

The COVID-19 outburst has encouraged the adoption of Internet of Medical Things (IoMT) network to empower the antiquated healthcare system and alleviate the health care costs. To realise the functionalities of the IoMT network, 5G heterogeneous networks emerged as an exemplary connectivity solution as it facilitates diversified service provisioning in the service delivery model at more convenient care. However, the crucial challenge for 5G heterogeneous wireless connectivity solution is to facilitate agile differentiated service provisioning. Lately, considerable research endeavour has been noted in this direction but multiservice consideration and battery optimisation have not been addressed. Motivated by the gaps in the existing literature, an intelligent radio access technology selection approach has been proposed to ensure Quality of Service provisioning in a multiservice scenario on the premise of battery optimisation. In particular, the proposed approach leverages the concept of Double Deep Reinforcement Learning to attain an optimal network selection policy. Eventually, the proposed approach corroborated by the rigorous simulations demonstrated a substantial improvement in the overall system utility. Subsequently, the performance evaluation underlines the efficacy of the proposed scheme in terms of convergence and complexity.

5GhNet: an intelligent QoE aware RAT selection framework for 5G-enabled healthcare network.

The COVID-19 outbreak has stimulated the digital transformation of antiquated healthcare system to a smart hospital, enabling the personalised and remote healthcare services. To augment the functionalities of these intelligent healthcare systems, 5G & B5G heterogeneous network has emerged as a robust and reliable solution. But the pivotal challenge for 5G & B5G connectivity solutions is to ensure flexible and agile service orchestration with acknowledged Quality of Experience (QoE). However, the existing radio access technology (RAT) selection strategies are incapacitated in terms of QoE provisioning and Quality of Service (QoS) maintenance. Therefore, an intelligent QoE aware RAT selection architecture based on software-defined wireless networking (SDWN) and edge computing has been proposed for 5G-enabled healthcare network. The proposed model leverages the principles of invalid action masking and multi-agent reinforcement learning to allow faster convergence to QoE optimised RAT selection policy. The analytical evaluation validates that the proposed scheme outperforms the other existing schemes in terms of enhancing personalised user-experience with efficient resource utilisation.

Tagging the pre-metastatic node in oral cancer: A cross-sectional study.

INTRODUCTION: Lymph node involvement is the first indication of spread of oral squamous cell carcinoma (OSCC) and it is also a most significant prognostic factor. Lymph nodes show various tumor-induced histological changes preceding actual metastasis, viz. increased vascularity, follicular hyperplasia and desmoplasia which leads to pre-metastatic niche formation. This pre-metastatic niche primarily provides a favorable microenvironment to for the survival and subsequent growth of cancer cells within the lymph node. AIM: A retrospective study to evaluate carcinoma-induced changes in lymph nodes harvested from radical neck dissection in OSCC patients. OBJECTIVES: 1) To evaluate cancer-induced histological changes in positive and negative lymph nodes in OSCC patients. 2) To look for common histopathological changes in both pre-metastatic and metastatic lymph nodes. MATERIALS AND METHODS: Forty lymph nodes harvested from seven OSCC patients were sectioned and stained (Hematoxylin-Eosin) for documentation of histologically evident morphological and functional alterations. The Chi-square test was applied between the non-metastatic and metastatic lymph nodes findings and a statistically significant difference was seen. RESULTS: Sections from 28 negative nodes showed changes associated with pre-metastatic niche conditioning whereas, 12 sections exhibit frank metastases. CONCLUSION: The modified immunological responses and remodeling of the vasculature are the most common histologic tumor-induced pre-metastatic changes. This study reviewed and categorized these histological changes that point to pre-metastatic niche conditioning of lymph nodes.

Fluorescent molecular probe-based activity and inhibition monitoring of histone deacetylases.

Extensive studies in recent decades have revealed that gene expression regulation is not limited to genetic mutations but also to processes that do not alter the genetic sequence. Post-translational histone modification is one of these processes in addition to DNA or RNA modifications. Histone modifications are essential in controlling histone functions and play a vital role in cellular gene expression. The reversible histone acetylation, regulated by histone acetyltransferases (HATs) and histone deacetylases (HDACs), is an example of such modifications. HDACs are involved in the deacetylation of histones and lead to the termination of gene expression. Although this cellular process is essential, upregulation of HDACs is found in numerous cancers. Therefore, research related to the activity and inhibition monitoring of HDACs is necessary to gain profound knowledge of these enzymes and evaluate the success of the therapeutic approach. In this perspective, methodology derived from fluorescent molecular probes is one of the preferable methods. Herein, we describe fluorescent probes developed to target HDACs by considering their activity and inhibition characteristics.

Xanthene-based Fluorescence Turn-on Probe for Highly Acidic pH Range in Aqueous Solution.

A xanthene-based probe, Xanth-NPr, is developed as a molecular system that exhibits sensitivity for the highly acidic environments with fluorescence turn-on behavior. Xanth-NPr is designed on the principle of photoinduced electron transfer (PET), which controls the fluorescence profile of the probe. The structure of Xanth-NPr contains the dipropylaniline group as a PET promoting unit. Xanth-NPr exhibited quenched fluorescence as long as it is present in neutral or moderately acidic conditions. However, in the highly acidic pH range, it displayed a strong red-colored fluorescence at 592 nm as the protonation of dipropylaniline moiety inhibits the PET process. A model probe Xanth-M without any PET promoting unit was also synthesized. The model probe along with theoretical calculations was employed to explain the role of the PET process in regulating the fluorescence behavior of Xanth-NPr. Xanth-NPr showed linear fluorescence response as a function of pH in the range of 1 to 4.1 with the pKa value of 2.72. Likewise, its fluorescence profile is not altered by the presence of biologically relevant cations.

Characterization of SPK 98, a Torin2 analog, as ATR and mTOR dual kinase inhibitor.

A series of Torin2, a second-generation ATP-competitive inhibitor, analogues were biologically characterized to identify their potential for ATR and mTOR kinase inhibition. Compound SPK 98 was observed to inhibit ATR/mTOR kinase selectively over ATM kinase in HCT 116 cell line. In addition to that, SPK 98 on 30 min incubation with human, mice and rat liver microsomes showed improved properties with an increased half-life (a maximum T ½ of 157 min) and internal clearance in mouse as compared to Torin2. Further, SPK 98 was also noticed to indulge in inducing premature chromatin condensation as a result of ATR/mTOR kinase inhibition at 50 nM. In a nutshell, our work presents the identification and characterization of SPK 98, a small molecule inhibitor, which exhibits improved specific inhibition for ATR at a lower concentration than Torin2.

Adsorptional photocatalytic mineralization of oxytetracycline and ampicillin antibiotics using Bi2O3/BiOCl supported on graphene sand composite and chitosan.

In present study, heterojunctioned Bi2O3/BiOCl (BO/BOC) was synthesized via in situ chemical reduction and oxidation of BiOCl nanoplates. BiOCl was reduced to metallic Bi in KHB4 solution followed by oxidation in H2O2 solution to produce BO/BOC. The BO/BOC was supported over graphene sand composite and also on chitosan using wet impregnation method to report BO/BOC/GSC and BO/BOC/CT nanocomposite. The morphology and compositional characteristics of BO/BOC/GSC and BO/BOC/CT were investigated by FESEM, TEM, HRTEM, FTIR, XRD, EDX, RAMAN, BET and UV-visible diffuse reflectance spectral analysis. The photocatalytic activity of BO/BOC/GSC and BO/BOC/CT was performed for mineralization of ampicillin (AMP) and oxytetracycline (OTC) antibiotics under solar light. The adsorption process had significant effect on photodegradation of AMP and OTC. The adsorption of both OTC and AMP onto BO/BOC/GSC and BO/BOC/CT followed pseudo second order kinetics. Simultaneous adsorption and degradation process (A+P) resulted in higher degradation rate of investigated antibiotics. The applicability of power law model indicates the intricacies of mineralization process. During A+P process, OTC and AMP were mineralized to CO2·H2O, NO3(-) and SO4(2-) ions. Both BO/BOC/GSC and BO/BOC/CT exhibited significant recycle efficiency.

Microwave induced synthesis of graft copolymer of binary vinyl monomer mixtures onto delignified Grewia optiva fiber: application in dye removal.

Grafting method, through microwave radiation technique is very effective in terms of time consumption, cost effectiveness and environmental friendliness. Via this method, delignified Grewia optiva identified as a waste biomass, was graft copolymerized with methylmethacrylate (MMA) as an principal monomer in a binary mixture of ethyl methacrylate (EMA) and ethyl acrylate (EA) under microwave irradiation (MWR) using ascorbic acid/H2O2 as an initiator system. The concentration of the comonomer was optimized to maximize the graft yield with respect to the primary monomer. Maximum graft yield (86.32%) was found for dGo-poly(MMA-co-EA) binary mixture as compared to other synthesized copolymer. The experimental results inferred that the optimal concentrations for the comonomers to the optimized primary monomer was observed to be 3.19 mol/L × 10(-1) for EMA and 2.76 mol/L × 10(-1) for EA. Delignified and graft copolymerized fiber were subjected to evaluation of physicochemical properties such as swelling behavior and chemical resistance. The synthesized graft copolymers were characterized with Fourier transform infrared spectroscopy (FTIR), scanning electron microscopy (SEM), thermogravimetric analysis (TGA) and X-ray diffraction techniques. Thermal stability of dGo-poly(MMA-co-EA) was found to be more as compared to the delignified Grewia optiva fiber and other graft copolymers. Although the grafting technique was found to decrease percentage crystallinity and crystallinity index among the graft copolymers but there was significant increase in their acid/base and thermal resistance properties. The grafted samples have been explored for the adsorption of hazardous methylene dye from aqueous system.

Synthesis, characterization and antibacterial activity of biodegradable starch/PVA composite films reinforced with cellulosic fibre.

Cellulosic fibres reinforced composite blend films of starch/poly(vinyl alcohol) (PVA) were prepared by using citric acid as plasticizer and glutaraldehyde as the cross-linker. The mechanical properties of cellulosic fibres reinforced composite blend were compared with starch/PVA crossed linked blend films. The increase in the tensile strength, elongation percentage, degree of swelling and biodegradability of blend films was evaluated as compared to starch/PVA crosslinked blend films. The value of different evaluated parameters such as citric acid, glutaraldehyde and reinforced fibre to starch/PVA (5:5) was found to be 25 wt.%, 0.100 wt.% and 20 wt.%, respectively. The blend films were characterized using Fourier transform-infrared spectrophotometry (FTIR), scanning electron microscopy (SEM) and thermogravimetric analysis (TGA/DTA/DTG). Scanning electron microscopy illustrated a good adhesion between starch/PVA blend and fibres. The blend films were also explored for antimicrobial activities against pathogenic bacteria like Staphylococcus aureus and Escherichia coli. The results confirmed that the blended films may be used as exceptional material for food packaging.