To be Wild or Mutant: Role of Isocitrate Dehydrogenase 1 (IDH1) and 2-Hydroxy Glutarate (2-HG) in Gliomagenesis and Treatment Outcome in Glioma.

Molecular and clinical research based on isocitrate dehydrogenase (IDH) mutations is much sought after in glioma research since a decade of its discovery in 2008. IDH enzyme normally catalyzes isocitrate to α-keto-glutarate (α-KG), but once the gene is mutated it produces an 'oncometabolite', 2-hydroxyglutarate (2-HG). 2-HG is proposed to inhibit α-KG-dependent dioxygenases and also blocks cellular differentiation. Here, we discuss the role of the IDH1 mutation in gliomagenesis. The review also focuses on the effect of 2-HG on glioma epigenetics, the cellular signaling involved in IDH1 mutant glioma cells and the therapeutic response seen in mutant IDH1(mIDH1) harboring glioma patients in comparison to the patients with wild-type IDH1. The review encompasses the debatable impacts of the mutation on immune microenvironment a propos of various mIDH1 inhibitors in practice or in trials. Recent studies revealing the relation of IDH mutation with the immune microenvironment and inflammatory status in untreated versus treated glioblastoma patients are highlighted with respect to prospective therapeutic targets. Also at the molecular level, the association of mIDH1/2-HG with the intracellular components such as mitochondria and other neighboring cells is discussed.

A Real-Time Health 4.0 Framework with Novel Feature Extraction and Classification for Brain-Controlled IoT-Enabled Environments.

In this letter, we propose two novel methods for four-class motor imagery (MI) classification using electroencephalography (EEG). Also, we developed a real-time health 4.0 (H4.0) architecture for brain-controlled internet of things (IoT) enabled environments (BCE), which uses the classified MI task to assist disabled persons in controlling IoT-enabled environments such as lighting and heating, ventilation, and air-conditioning (HVAC). The first method for classification involves a simple and low-complex classification framework using a combination of regularized Riemannian mean (RRM) and linear SVM. Although this method performs better compared to state-of-the-art techniques, it still suffers from a nonnegligible misclassification rate. Hence, to overcome this, the second method offers a persistent decision engine (PDE) for the MI classification, which improves classification accuracy (CA) significantly. The proposed methods are validated using an in-house recorded four-class MI data set (data set I, collected over 14 subjects), and a four-class MI data set 2a of BCI competition IV (data set II, collected over 9 subjects). The proposed RRM architecture obtained average CAs of 74.30% and 67.60% when validated using datasets I and II, respectively. When analyzed along with the proposed PDE classification framework, an average CA of 92.25% on 12 subjects of data set I and 82.54% on 7 subjects of data set II is obtained. The results show that the PDE algorithm is more reliable for the classification of four-class MI and is also feasible for BCE applications. The proposed low-complex BCE architecture is implemented in real time using Raspberry Pi 3 Model B+ along with the Virgo EEG data acquisition system. The hardware implementation results show that the proposed system architecture is well suited for body-wearable devices in the scenario of Health 4.0. We strongly feel that this study can aid in driving the future scope of BCE research.

Surgical treatment of Langerhans cell histiocytosis of cervical spine: case report and review of literature.

INTRODUCTION: Langerhans cell histiocytosis (LCH) is a rare condition, and even rare is cervical spine involvement. CASE REPORT: A 9-year-old girl had neck pain, neck tilt and left upper limb weakness, occasional fever and positive family history of tuberculosis. Imaging showed C5 vertebral body collapse with epidural and prevertebral soft tissue collection causing cord and nerve root compression. The patient underwent C5 corpectomy and fusion. Histopathological was suggestive of LCH. She underwent radiotherapy and was asymptomatic at 1-year follow-up. CONCLUSION: Despite the rarity of the condition, the possibility of LCH should be considered in such cases. When neurologic deficits are present, operative treatment should be considered.

A lipo-polymeric hybrid nanosystem with metal enhanced fluorescence for targeted imaging of metastatic breast cancer.

Cancer metastasis plays a major role in failure of therapeutic avenues against cancer. Owing to metastasis, nearly 70-80% of stage IV breast cancer patients lose their lives. Nanodrug delivery systems are playing a critical role in the therapy of metastatic cancer in the recent times. This paper reports the enhanced permeation and retention (EPR) based targeting of metastatic breast cancer using a novel nano lipo-polymeric system (PIR-Au NPs). The PIR-Au NPs demonstrated an increase in fluorescence by virtue of surface coating with gold, owing to the metal enhanced fluorescence phenomenon as reported in our earlier reports. Enhanced fluorescence of PIR-Au NPs was observed in murine mammary carcinoma cell line (4T1), as compared to free IR780 or IR780 loaded nanosystems (P-IR NPs), when incubated for same time at same concentrations, indicating its potential application for imaging and an enhanced bioavailability of IR780. Significant cell death was noted with photothermal mediated cytotoxicity in-vitro against breast cancer cells (MCF-7 and 4T1). An enhanced fluorescence was observed in the zebra fish embryos incubated with PIR-Au NPs. The enhanced permeation and retention (EPR) effect was seen with PIR-Au NPs in-vivo. A strong fluorescent signal was recorded in mice injected with PIR-Au NPs. The tumor tissue collected after 72 h, clearly showed a greater fluorescence as compared to other groups, indicating the plasmon enhanced fluorescence. We also demonstrated the EPR-based targeting of the PIR-Au NPs in-vivo by means of photothermal heat. This lipo-polymeric hybrid nanosystem could therefore be successfully applied for image-guided, passive-targeting to achieve maximum therapeutic benefits.

Uniform trehalose nanogels for glucagon stabilization.

Glucagon is a peptide hormone that acts via receptor-mediated signaling predominantly in the liver to raise glucose levels by hepatic glycogen breakdown or conversion of noncarbohydrate, 3 carbon precursors to glucose by gluconeogenesis. Glucagon is administered to reverse severe hypoglycemia, a clinical complication associated with type 1 diabetes. However, due to low stability and solubility at neutral pH, there are limitations in the current formulations of glucagon. Trehalose methacrylate-based nanoparticles were utilized as the stabilizing and solubilizing moiety in the system reported herein. Glucagon was site-selectively modified to contain a cysteine at amino acid number 24 to covalently attach to the methacrylate-based polymer containing pyridyl disulfide side chains. PEG2000 dithiol was employed as the crosslinker to form uniform nanoparticles. Glucagon nanogels were monitored in Dulbecco's phosphate-buffered saline (DPBS) pH 7.4 at various temperatures to determine its long-term stability in solution. Glucagon nanogels were stable up to at least 5 months by size uniformity when stored at -20 °C and 4 °C, up to 5 days at 25 °C, and less than 12 hours at 37 °C. When glucagon stability was studied by either HPLC or thioflavin T assays, the glucagon was intact for at least 5 months at -20 °C and 4 °C within the nanoparticles at -20 °C and 4 °C and up to 2 days at 25 °C. Additionally, the glucagon nanogels were studied for toxicity and efficacy using various assays in vitro. The findings indicate that the nanogels were nontoxic to fibroblast cells and nonhemolytic to red blood cells. The glucagon in the nanogels was as active as glucagon alone. These results demonstrate the utility of trehalose nanogels towards a glucagon formulation with improved stability and solubility in aqueous solutions, particularly useful for storage at cold temperatures.

Supramolecular architectures of N-acetyl-L-proline monohydrate and N-benzyl-L-proline.

The title compounds, N-acetyl-L-proline monohydrate, C7H11NO3·H2O, (I), and N-benzyl-L-proline, C12H15NO2, (II), crystallize in the monoclinic space group P21 with Z' = 1 and Z' = 2, respectively. The conformation of C(γ) with respect to the carboxylic acid group in (I) is C(γ)-exo or UP pucker, with the pyrrolidine ring twisted, while in (II), it is C(γ)-endo or DOWN, with the pyrrolidine ring assuming an envelope conformation. The crystal packing interactions in (I) are composed of two substructures, one characterized by an R6(6)(24) motif through O-H...O hydrogen bonds and the other by an R4(4)(23) ring through C-H...O interactions. In (II), the crystal packing interactions consist of N-H...O and C-H...O hydrogen bonds. Proline (Pro) exists in its neutral form in (I) and is zwitterionic in (II). This difference in the ionization states of Pro is manifested through the absence of N-H...O and presence of O-H...O interactions in (I), and the presence of N-H...O and absence of O-H...O hydrogen bonds in (II). While C-H...O interactions are present in both (I) and (II), the geometry of the synthons formed by them and their mode of participation in intermolecular interactions is different. Though the title compounds differ significantly in terms of modifications in the Pro skeleton, the differences in their supramolecular structures may also be viewed as a result of the molecular recognition facilitated by the presence of a solvent water molecule in (I) and the zwitterionic state of the amino acid in (II).

4-Cyano-N-ethyl-spiro-[chromene-2,4'-piperidine]-1'-carboxamide.

The title compound, C17H19N3O2, crystallizes with two independent mol-ecules (A and B) in the asymmetric unit. In both mol-ecules, the pyran ring has a twisted conformation ((5)S4), with Q = 0.301 (3) Å, θ = 116.7 (6) and ϕ= 213.6 (7)° for mol-ecule A, and Q = 0.364 (2) Å, θ = 113.7 (3) and ϕ = 213.0 (4)° for mol-ecule B. In mol-ecule B, the terminal ethyl group is disordered over two orientations with an occupancy ratio of 0.55 (1):0.45 (1). In the crystal, mol-ecules A and B form very similar but separate R1(2)(7) motifs through N-H⋯O and C-H⋯O hydrogen bonds. The resulting chains along [001] are inter-linked by weaker C-H⋯O and C-H⋯π inter-actions, forming layers parallel to the bc plane.

N-But-oxy-carbonyl-5-oxo-l-proline ethyl ester.

The mol-ecular structure of the title compound, C12H19NO5, may be visualized as made up of two nearly perpendicular planes [dihedral angle = 87.39 (12)°] and its crystal structure is a good example of C-H⋯O inter-actions assuming significance in optimizing supra-molecular aggregation in crystals in a mol-ecule which is severely imbalanced in terms of donors to acceptor atoms. The pyrrolidine ring adopts a ((3) T 2) twist conformation with puckering parameters Q = 0.2630 (4) Šand ϕ = 59 (9)°. The crystal structure features R 2 (4)(10) and R 3 (4)(26) ring motifs formed by four weak C-H⋯O inter-actions, leading to supra-molecular sheets lying parallel to the bc plane.

N-tert-But-oxy-carbonyl-α-(2-fluoro-benzyl)-l-proline.

In the title compound, C17H22FNO4, the pyrrolidine ring adopts an envelope conformation with the disordered com-ponents of the methylene C atom, with site occupancies of 0.896 (7) and 0.104 (7), being the flap on either side of the mean plane involving the other atoms of the ring. The carb-oxy-lic acid group forms dihedral angles of 72.06 (11) and 45.44 (5)° with the N-tert-but-oxy-carbonyl group and the 2-fluoro-benzyl group, respectively. In the crystal, two-dimensional layers of mol-ecules parallel to (001) are built through an R 4 (4)(23) motif generated via O-H⋯O, C-H⋯O and C-H⋯F inter-actions, and an R 2 (2)(11) motif generated by C-H⋯O and C-H⋯F inter-actions.

Identification of Kaempferol as Viral Entry Inhibitor and DL-Arginine as Viral Replication Inhibitor from Selected Plants of Indian Traditional Medicine against COVID-19: An in silico Guided in vitro Approach.

BACKGROUND: Indian traditional medicinal plants are known for their great potential in combating viral diseases. Previously, we reported a systematic review approach of seven plausible traditional Indian medicinal plants against SARS-CoV-2. METHODS: Molecular docking was conducted with Biovia Discovery Studio. Three binding domains for spike glycoprotein (PDB IDs: 6LZG, 6M17, 6M0J) and one binding domain of RdRp (PDB ID: 7BTF) were used. Among 100 phytoconstituents listed from seven plants by the IMPPAT database used for virtual screening, the best six compounds were again filtered using Swiss ADME prediction and Lipinski's rule. Additionally, a pseudovirion assay was performed to study the interaction of SARS-CoV-2 S1-protein with the ACE 2 receptor to further confirm the effect. RESULTS: Chebulagic acid (52.06 Kcal/mol) and kaempferol (48.84 Kcal/mol) showed increased interaction energy compared to umifenovir (33.68 Kcal/mol) for the 6LZG binding domain of spike glycoprotein. Epicatechin gallate (36.95 Kcal/mol) and arachidic acid (26.09 Kcal/mol) showed equally comparable interaction energy compared to umifenovir (38.20 Kcal/mol) for the 6M17 binding domain of spike glycoprotein. Trihydroxychalcone (35.23 Kcal/mol) and kaempferol (36.96 Kcal/mol) showed equally comparable interaction energy with umifenovir (36.60 Kcal/mol) for 6M0J binding domain of spike glycoprotein. Upon analyzing the phytoconstituents against RdRp binding domain, DL-arginine (41.78 Kcal/mol) showed comparable results with the positive control remdesivir (47.61 Kcal/mol). ADME analysis performed using Swiss ADME revealed that kaempferol and DL arginine showed drug-like properties with appropriate pharmacokinetic parameters. Further in vitro analysis of kaempferol by pseudovirion assay confirmed an acceptable decrease of the lentiviral particles in transfected HEK293T-hACE2 cells. CONCLUSION: The study highlights that kaempferol and DL-arginine could be the significant molecules to exhibit potent action against SARS-CoV-2 and its variants.

Supramolecular sheets in (4H-chromeno[4,3-c]isoxazol-3-yl)methanol and its hydrated 8-methyl-substituted analogue at 100 K.

The title compounds, (4H-chromeno[4,3-c]isoxazol-3-yl)methanol, C(11)H(9)NO(3), (I), and (8-methyl-4H-chromeno[4,3-c]isoxazol-3-yl)methanol monohydrate, C(12)H(11)NO(3)·H(2)O, (II), crystallize in the monoclinic space groups P2(1)/c and C2/c, respectively. The simple addition of a methyl substituent in (II) results in a change in the structure type and substantially alters the intermolecular interaction patterns, while retaining the point-group symmetry 2/m. Compound (II) crystallizes as a hydrate and the resulting hydrogen-bonding interactions involving the water molecule are the cause of differences in the hydrogen-bonded supramolecular motifs present in (I) and (II). The water molecule in (II) is disordered over two positions having very similar orientations, with occupancies of 0.571 (18) and 0.429 (18), although the pattern of hydrogen-bonding interactions for the two disordered water molecules remains essentially the same. In both compounds, the primary donor hydroxy group adopts a trans conformation with respect to the isoxazole O atom, with a torsion angle of 170.65 (8)° for (I) and 179.56 (10)° for (II), the small difference being due to differences in the hydrogen-bonding environment of the hydroxy group. In (I), molecules are linked through two independent O-H···N and C-H···O hydrogen bonds and form sheets of centrosymmetric R(4)(4)(18) and R(4)(4)(14) rings extending parallel to the (100) plane. The supramolecular motifs in (II) generate two-dimensional sheets parallel to the (100) plane through a combination of O-H···X (X = N, O) and C-H···O hydrogen bonds, leading to water-assisted noncentrosymmetric R(2)(2)(8) and R(6)(6)(20) motifs. The present work is an example of how the simple replacement of a substituent in the main molecular scaffold may transform the structure type, paving the way for a variety of supramolecular motifs and consequently altering the complexity of the intermolecular interaction patterns.

Supramolecular networks in (9-fluoro-4H-chromeno[4,3-c]isoxazol-3-yl)methanol and its 9-chloro analogue at 100 K.

The title compounds, (9-fluoro-4H-chromeno[4,3-c]isoxazol-3-yl)methanol, C(11)H(8)FNO(3), (I), and (9-chloro-4H-chromeno[4,3-c]isoxazol-3-yl)methanol, C(11)H(8)ClNO(3), (II), crystallize in the orthorhombic space group Pbca with Z' = 1 and the triclinic space group P-1 with Z' = 6, respectively. The simple replacement of F by Cl in the main molecular scaffold of (I) and (II) results in significant differences in the intermolecular interaction patterns and a corresponding change in the point-group symmetry from D(2h) to C(i) = S(2). These striking differences are manifested through the presence of C-H···F and the absence of O-H···O and C-H···O interactions in (I), and the absence of C-H···Cl and the presence of O-H···O and C-H···O interactions in (II). However, the geometry of the synthons formed by the O-H···N and O-H···X (X = F or Cl) interactions observed in the constitution of the supramolecular networks of both (I) and (II) remains similar. Also, C-H···O interactions are not preferred in the presence of F in (I), while they are much preferred in the presence of Cl in (II).

1'-Benzylspiro-[chromene-2,4'-piperi-dine]-4-carbonitrile.

In the title compound, C(21)H(20)N(2)O, the piperidine ring adopts a chair conformation while the pyran ring adopts a screw-boat conformation. The piperidine ring forms dihedral angles of 65.75 (3) and 67.79 (5)° with the chroman and methyl-substituted benzene rings, respectively. The crystal structure features weak C-H⋯π and π-π [centroid-centroid distance = 3.8098 (8) Å] inter-actions.

Chitosan IR806 dye-based polyelectrolyte complex nanoparticles with mitoxantrone combination for effective chemo-photothermal therapy of metastatic triple-negative breast cancer.

Chemo-photothermal therapy is one of the emerging therapies for treating triple-negative breast cancer. In this study, we have used ionotropic gelation method to fabricate chitosan and IR806 dye-based polyelectrolyte complex (CIR-PEx) nanoparticles. These nano-complexes were in size range of 125 ± 20 nm. The complexation of IR 806 dye with chitosan improved photostability, photothermal transduction, and showed excellent biocompatibility. Cancer cells treated with CIR-PEx NPs enhanced intracellular uptake within 5 h of incubation and also displayed mitochondrial localization. With the combination of CIR-PEx NPs and a chemotherapeutic agent (i.e., mitoxantrone, MTX), a significant decline in cancer cell viability was observed in both 2D and 3D cell culture models. The chemo-photothermal effect of CIR-PEx NPs + MTX augmented apoptosis in cancer cells when irradiated with NIR light. Furthermore, when tested in the 4 T1-tumor model, the chemo-photothermal therapy showed a drastic decline in tumor volume and inhibited metastatic lung nodules. The localized hyperthermia caused by photothermal therapy reduced the primary tumor burden, and the chemotherapeutic activity of mitoxantrone further complemented by inhibiting the spread of cancer cells. The proposed chemo-photothermal therapy combination could be a promising strategy for treating triple-negative metastatic breast cancer.

Distribution and characterization of plastic debris pollution along the Poompuhar Beach, Tamil Nadu, Southern India.

The present study was carried out to determine the characteristics, distribution, and abundance of plastic debris in 25 sediment samples collected from the Poompuhar beach, southeast coast of India. The result reveals that the mean plastic debris abundance was 42 ± 27 particles/m2 dry weight (dw) (1 SD, n = 25) with higher concentrations in the river mouth. The dominant shapes in the study area were fragment (70.7%), followed by fiber (20.7%), and pellet-shaped (8.6%). The dominant colors of the plastic debris were: white-colored (47%) followed by blue (28%) and green (14%). The study further reveals that the dominant polymer type was polyethylene (PE, 63.4%), followed by nylon (PA, 16.9), polyvinyl chloride (PVC, 15.5%), polypropylene (PP, 3.1%), and polystyrene (PS, 1.1%). In the study area, the main source of plastic debris was from land-based fishing and tourism activities, and rainwater runoff from the Cauvery River.

Iontophoresis mediated localized delivery of liposomal gold nanoparticles for photothermal and photodynamic therapy of acne.

Acne is one of the common dermatological skin inflammatory conditions. The current therapeutic modalities for the treatment of acne include the administration of antibiotics and anti-inflammatory agents. The rising instance of antibiotic resistance in acne strains has led to the exploration of alternative therapeutic modalities. In the current study, we have employed a liposomal gold nanoparticle entrapping curcumin (Au Lipos Cur NPs) for dual light-mediated therapy for the treatment of acne. These nanoparticles exerted a positive zeta potential that enabled their localized follicular delivery by iontophoresis. The localized deposition of Au Lipos NPs leads to photothermal transduction causing destruction of sebaceous glands. Furthermore, when the nanoparticles were assessed in vitro by sequential irradiation with NIR and blue light, it resulted in significant inhibition of bacterial growth. Thus the dual light-mediated therapy by Au Lipos Cur NPs can form a potential therapeutic modality for the efficient treatment of recurrent acne.

MutT Homolog1 has multifaceted role in glioma and is under the apparent orchestration by Hypoxia Inducible factor1 alpha.

AIMS: The study focused on the expression and role of a recent potential cancer therapeutic target protein, MutT Homolog1 (MTH1). MTH1 gets activated in an increased reactive oxygen species (ROS) environment and removes the oxidized nucleotides from the cell. The study aimed to check the role of MTH1 in DNA damage and apoptosis, migration and angiogenesis and also to examine its regulation in glioma. MAIN METHODS: The experiments were carried out in human glioma tissue samples and brain tissues of epilepsy patients (non-tumor control). We used two human glioblastomas cell lines, U87MG and U251MG cells. In order to study the role of MTH1 in glioma and to analyze the relation of MTH1 with Hif1α, we have used MTH1 siRNA and Hif1α siRNA respectively. KEY FINDINGS: We found an increased expression of MTH1 in glioma tissues compared to the non-tumor brain tissues. Correlation analysis revealed that those samples showing reduced expression of MTH1 also had high levels of DNA damage and apoptotic markers, while diminished expression of angiogenesis regulators and levels of migration. MTH1 knockdown in vitro by siRNA in tumor cell lines corroborates the above observation. This justifies the emergence of MTH1 inhibitors as potential first-in-class drugs. Mechanistically, our observations suggest that Hif1α may modulate MTH1 expression. SIGNIFICANCE: We found elevated MTH1 expression in glioma irrespective of their grades, while its inhibition affects multiple tumor progression pathways, and that targeting Hif1α could simulate the same.

NIR-dye based mucoadhesive nanosystem for photothermal therapy in breast cancer cells.

Breast cancer is one of the leading causes of mortality in women, worldwide. The average survival rate of patients suffering from advanced breast cancer is about 27% for five years. Photothermal therapy employing biodegradable nanoparticle are extensively researched for enhanced anticancer therapy in breast cancer treatment. In the current study, we report a chitosan based mucoadherant and biodegradable niosome nanoparticle entrapping near infrared (NIR) dye (IR 806) for the treatment of breast cancer. Niosome entrapping IR 806 (NioIR) showed encapsulation efficacy of about 56 ± 2%. The prepared nanoparticles (NioIR) were further coated with chitosan (NioIR-C) to impart mucoadhesive property to the nanosystem. NioIR-C showed minimal degradation following NIR laser irradiation, thus enhancing its photothermal stability. They also exhibited efficient photothermal transduction, when compared with IR 806 dye. NioIR-C were biocompatible when treated with normal cell lines (NIH 3T3 and L929) and showed cytotoxicity towards breast cancer cell lines (MCF-7 and MDA-MB 231). When triggered with NIR laser, NioIR-C showed photothermal cell death (approximately 93%). The presence of chitosan coating on NioIR led to mucoadherence potential that further enhances the therapeutic effect on breast cancer cells when compared with IR 806 dye and NioIR. Thus NioIR-C can be a promising nanosystem for effective treatment of breast cancer using photothermal therapy.

A Novel Feature Extraction Framework for Four Class Motor Imagery Classification using Log Determinant Regularized Riemannian Manifold.

Brain-Computer Interface (BCI) systems allow the person in communicating with the external world using Electroencephalography (EEG). Motor Imagery (MI) based BCI systems play a vital role in interacting with the external environment. In this paper, we propose a novel robust feature extraction and classification framework for four class MI classification to improve the classification accuracy. The proposed architecture is developed using log-determinant (log-det) based Regularized Riemannian mean (LDRRM) and linear SVM. The robustness of features extracted from the four class MI data is improved to the outliers and noise by using the proposed LDRRM framework. We evaluated the performance of the proposed LDRRM classification framework on publicly available four class MI dataset 2a of BCI competition IV. The performance results show that the proposed LDRRM classification architecture obtained a mean classification accuracy of 69.12%, also achieved 1.54% higher classification accuracy when compared with the existing studies.