Multi-scale signaling and tumor evolution in high-grade gliomas.

Although genomic anomalies in glioblastoma (GBM) have been well studied for over a decade, its 5-year survival rate remains lower than 5%. We seek to expand the molecular landscape of high-grade glioma, composed of IDH-wildtype GBM and IDH-mutant grade 4 astrocytoma, by integrating proteomic, metabolomic, lipidomic, and post-translational modifications (PTMs) with genomic and transcriptomic measurements to uncover multi-scale regulatory interactions governing tumor development and evolution. Applying 14 proteogenomic and metabolomic platforms to 228 tumors (212 GBM and 16 grade 4 IDH-mutant astrocytoma), including 28 at recurrence, plus 18 normal brain samples and 14 brain metastases as comparators, reveals heterogeneous upstream alterations converging on common downstream events at the proteomic and metabolomic levels and changes in protein-protein interactions and glycosylation site occupancy at recurrence. Recurrent genetic alterations and phosphorylation events on PTPN11 map to important regulatory domains in three dimensions, suggesting a central role for PTPN11 signaling across high-grade gliomas.

Vulvar Complex Apocrine Carcinoma in a Horse (Equus caballus): A Case Report and Review of Literature.

A 6-year-old Marwari mare presented with recurrent vulvar growth. The growth was surgically excised, fixed and processed routinely. Microscopically, neoplasm showed proliferation of epithelial and myoepithelial cells with tubulopapillary pattern. On immunohistochemistry, myoepithelial cells showed strong immunoreactivity with smooth muscle actin alpha and p63. On basis of histopathology and immunohistochemistry, tumour was diagnosed as complex apocrine carcinoma. This case report describes first confirm vulvar complex apocrine carcinoma in equines.

Primary hepatic lymphoma- A diagnostic dilemma.

Primary non-Hodgkin lymphoma of liver is a very rare malignancy. Here we report the case of a 50 year old female who presented with dull ache in the right hypochondrium and decreased appetite since 1 month. CT scan of abdomen and pelvis showed an enlarged liver with an ill- defined soft tissue lesion arising from left lobe measuring 13 × 9 cm suggestive of primary hepatic neoplasm. CT scan of chest, abdomen, and pelvis and whole body positron emission tomography showed no involvement of bone marrow, lymph nodes, spleen, or any other organ. Her liver function tests, alpha fetoprotein and carcinoembryonic antigen levels were normal. Serology was negative for viruses. Pathological examination favored diagnosis of Burkitt's lymphoma. Cytogenetic studies for MYC translocation t (8;14) is suggested for confirming the diagnosis since Ki 67 index is > 70% and not nearly 100% which is characteristic of Burkitt's lymphoma.

Efficacy of Sagittal Split Fix Plates with Adjustable Slider for Intra-operative Identification and Correction of Condylar Sag in Sagittal Split Osteotomy-a Pilot Study.

Aim: To assess the efficacy of sagittal split plate with adjustable slider for intra-operative correction of condylar sag after bilateral sagittal split osteotomy. Subjects and Methods: Patients reporting for correction of mandibular skeletal deformities for correction with sagittal split osteotomy (SSRO) were enrolled in the study. Simple randomization method was followed for patient allocation. Patients in group A had undergone fixation sagittal split fix plates; in group B, miniplate fixation with monocortical screws was used. Occlusion was the key indicator of condylar sage that was checked at different time frames (intra-operatively T0, immediate T1, 6 months postoperatively T2). Preoperative, immediate and late postoperative (at 6 months and 1-year interval) and lateral cephalometric assessment was used to assess their stability. Results: Thirty-three patients were enrolled and 20 patients were included in the study. One patient of group A presented with central condylar sag that was identified intra-operatively and addressed immediately. All the patients in group B presented with type 2 peripheral condylar sag that was addressed by inter-maxillary elastics and orthodontics. Two patients in group A presented with mild degree of relapse at 6 months, which was comparable to the control group indicating good stability. Conclusion: Sagittal split plates appear to be efficacious for intra-operative identification and correction of condylar sag is associated with SSRO. Supplementary Information: The online version contains supplementary material available at 10.1007/s12663-022-01782-7.

Fate, cytotoxicity and cellular metabolomic impact of ingested nanoscale carbon dots using simulated digestion and a triculture small intestinal epithelial model.

Carbon dots (CDs) are a promising material currently being explored in many industrial applications in the biomedical and agri-food areas; however, studies supporting the environmental health risk assessment of CDs are needed. This study focuses on various CD forms including iron (FeCD) and copper (CuCD) doped CDs synthesized using hydrothermal method, their fate in gastrointestinal tract, and their cytotoxicity and potential changes to cellular metabolome in a triculture small intestinal epithelial model. Physicochemical characterization revealed that 75% of Fe in FeCD and 95% of Cu in CuCD were dissolved during digestion. No significant toxic effects were observed for pristine CDs and FeCDs. However, CuCD induced significant dose-dependent toxic effects including decreases in TEER and cell viability, increases in cytotoxicity and ROS production, and alterations in important metabolites, including D-glucose, L-cysteine, uridine, citric acid and multiple fatty acids. These results support the current understanding that pristine CDs are relatively non-toxic and the cytotoxicity is dependent on the doping molecules.

Auto-deconvolution and molecular networking of gas chromatography-mass spectrometry data.

We engineered a machine learning approach, MSHub, to enable auto-deconvolution of gas chromatography-mass spectrometry (GC-MS) data. We then designed workflows to enable the community to store, process, share, annotate, compare and perform molecular networking of GC-MS data within the Global Natural Product Social (GNPS) Molecular Networking analysis platform. MSHub/GNPS performs auto-deconvolution of compound fragmentation patterns via unsupervised non-negative matrix factorization and quantifies the reproducibility of fragmentation patterns across samples.

Coagulopathy in the nephrotic syndrome.

Coagulopathy in the nephrotic syndrome (NS) is very rare. Simultaneous prolongation of both prothrombin time and activated partial thromboplastin time suggests common coagulation pathway abnormality such as liver dysfunction, Vitamin K deficiency, disseminated intravascular coagulation, or primary fibrinolysis. This results in difficulty in proceeding with renal biopsy and tissue diagnosis. We report one such case of NS with coagulopathy and refractoriness to correction with blood products, which led us to make a diagnosis of AL amyloidosis, which was confirmed with abdominal fat pad biopsy and other work-up.

Multi-Targeted Design and Development of Dihydroisoquinolines as Potent Antimalarials.

BACKGROUND: Malaria is a serious parasitic infection with greater morbidity and motility in recent decades. Cysteine protease and DHODH enzyme serve as a potential target for antimalarial agents which inhibit parasite multiplication in the erythrocyte stage. Development of new leads which specifically target cysteine protease and DHODH enzyme can reduce the side effects and overcome multidrug resistance. OBJECTIVES: Representing the design and development of antimalarial agents by targeting cysteine protease and DHODH (Dihydroorotate dehydrogenase) enzyme by structure-based drug design. METHODS: In present work, the rational development of antimalarial agents by targeting cysteine protease and DHODH has been made by integrating binding confirmation from virtual analysis and synthetic procedures. RESULTS: A novel series of dihydroisoquinolines was designed by structure-based drug design. Compounds from the dataset were screened for interaction at the target site by performing molecular docking study and subsequently, all molecules were screened for drug-like properties and toxicity, prior to synthesis molecules subjected to virtual filters. Designed molecules which exceed these virtual filters were synthesized, characterized and finally screened for antimalarial activity. CONCLUSION: In this work, it has been observed that compound A1, A5, A6 and A9 showed desirable biological activity towards targets and also specific hydrogen bonding interaction with the targets. Further optimization in leads yields a drug-like candidate and may overcome multidrug resistance.

Development of 'S', 'N' Heterocycles as Antimycobacterials Targeting Fatty Acid Biosynthesis.

BACKGROUND: Mycobacterium tuberculosis is a causative organism of tuberculosis, which is the most deadly disease after cancer in the current decade. The development of multidrug and broadly drug- resistant strains makes the tuberculosis problem more and more critical. In the last 40 years, only one molecule is added to the treatment regimen. Generally, drug design and development programs are targeted proteins whose function is known to be essential to the bacterial cell. OBJECTIVES: Here are the development of 'S', 'N' heterocycles as antimycobacterials targeting fatty acid biosynthesis are reported. MATERIALS AND METHODS: In the present communication, rational development of anti-mycobacterial agent's targeting fatty acid biosynthesis has been done by integrating the pocket modeling and virtual analysis. RESULTS: The identified potential 33 lead compounds were synthesized, characterized by physicochemical and spectroscopic methods like IR, NMR spectroscopy and further screened for antimycobacterial activity using isoniazid as standard. All the designed compounds have shown profound antimycobacterial activity. CONCLUSION: In this present communication, we found that 3c, 3f, 3l and 4k molecules had expressive desirable biological activity and specific interactions with fatty acids. Further optimization of these leads is necessary for the development of potential antimycobacterial drug candidates having fewer side effects.

Role of Adjuvant Chemotherapy in Extranodal Follicular Dendritic Cell Sarcoma.

Extranodal follicular dendritic cell sarcomas (FDCSs) are an uncommon entity, commonly misdiagnosed because of the morphologic similarities with other neoplasias. Previously, FDCSs were not considered a differential diagnosis because of the limited use of immunohistochemistry. Surgical excision is the treatment of choice for localized FDCS. The role of chemotherapy has not been determined for this rare disease. We report 2 cases of metastatic extranodal intra-abdominal FDCS, initially misdiagnosed as gastrointestinal stromal tumor, their clinicopathological features, literature review, and the role of adjuvant chemotherapy.

A natural anticancer pigment,Pheophytin a,from a seagrass acts as a high affinity human mitochondrial translocator protein (TSPO) ligand, in silico, to reduce mitochondrial membrane Potential (∆ψmit) in adenocarcinomic A549 cells.

BACKGROUND: The present investigation looks at the most likely possibilities of usage of a naturally occurring photosynthetic pigment, Pheophytin a, from the seagrass, Syringodium isoetifolium, for plausible use as human TSPO ligand. METHODS: Pheophytin a isolated in our laboratory previously was administered to A549 cell lines in vitro to examine its effects on cell migrations, DNA, cell cycle, Mitochondrial Membrane Potential and gene expressions. In silico tools were used to predict the nature of the compound and target binding. RESULTS: Pheophytin a hadIC50 values of 22.9 ±â€¯5.8 µM for cancerous A549 cell lines, whilst not targeting non-cancerous vero cells [IC50: 183.6 ±â€¯1.92 µM]. Pheophytin a hindered cellular migration, fragmented DNA, arrested cell cycle precisely at S phase, reduced ∆ψmit and directed mRNA expressions toward apoptosis. In silico tools indicate that the compound binds to TSPO with high effectiveness to collapse ∆ψmit(which is proved using wet lab experiments) to promote mitophagy. CONCLUSION: Hence Pheophytin a could be seen as a possible TSPO ligand for targeting metastatic alveolar cancers like A549 via intrinsic apoptotic pathway. GENERAL SIGNIFICANCE: Given the inherent non-toxic nature of the compound and easy extractability from almost all autotrophic eukaryotes, one could be confident to testing in animal models.

Solitary Bone Cyst of Posterior Maxilla: A Rare Presentation.

Solitary bone cyst (SBC) is an uncommon, nonneoplastic osseous lesion that mainly affects metaphysis of long bones and rarely presents in jaws. Due to the lack of true epithelial lining, it is considered as a pseudocyst. It is generally asymptomatic and often discovered incidentally during routine radiographic examination as well-defined unilocular or multilocular radiolucent lesion in the posterior mandible mainly in the first two decades of life. Here, we report a very rare case of a 15-year-old female patient having a lesion in the posterior maxilla with clinical, radiological, and histopathological presentations of SBC.

New mass spectrometry technologies contributing towards comprehensive and high throughput omics analyses of single cells.

Mass-spectrometry based omics technologies - namely proteomics, metabolomics and lipidomics - have enabled the molecular level systems biology investigation of organisms in unprecedented detail. There has been increasing interest for gaining a thorough, functional understanding of the biological consequences associated with cellular heterogeneity in a wide variety of research areas such as developmental biology, precision medicine, cancer research and microbiome science. Recent advances in mass spectrometry (MS) instrumentation and sample handling strategies are quickly making comprehensive omics analyses of single cells feasible, but key breakthroughs are still required to push through remaining bottlenecks. In this review, we discuss the challenges faced by single cell MS-based omics analyses and highlight recent technological advances that collectively can contribute to comprehensive and high throughput omics analyses in single cells. We provide a vision of the potential of integrating pioneering technologies such as Structures for Lossless Ion Manipulations (SLIM) for improved sensitivity and resolution, novel peptide identification tactics and standards free metabolomics approaches for future applications in single cell analysis.

Identification of novel heterozygous Apex 1 gene variant (Glu87Gln) in patients with head and neck cancer of Indian origin.

Gene polymorphism among humans is one of the factors governing individual's susceptibility and resistance to various diseases including cancer. DNA repair enzymes play an important role in protecting our genome from various mutagens and preventing cancer. The role of DNA repair enzyme Apurinic/Apyrimidinic endodeoxyribonuclease 1 (Apex 1) in cancer has been very well documented. Using genomic DNA, Apex 1 coding region of 76 patients (n = 76) with head and neck cancer were amplified and sequenced to detect variations in the sequence. Of 76 patients, 1 patient with heterozygous novel Apex 1 variant (Glu87Gln) was identified. A comparative analysis of wild type and variant protein using in silico approach was performed to understand the difference in the structure and the function. This further revealed that the variant had a slight impact on the structure, which affected the stability and function of the protein. Using the state-of-the-art Molecular dynamic simulation analysis, we observed a loss in number of hydrogen bonds and salt bridge with a substitution of Gln for Glu at Position 87. This could be a possible reason behind the loss of stability/function of the protein. This study revealed a new variant of the Apex 1 gene; further studies will lead to the novel roles played by the variant Apex 1 protein in cause, disease progression, and response to the treatment in patients with cancer with Glu87Gln variant.

Impact of missense mutations in survival motor neuron protein (SMN1) leading to Spinal Muscular Atrophy (SMA): A computational approach.

Spinal muscular atrophy (SMA) is a neuromuscular disorder caused by the mutations in survival motor neuron 1 gene (SMN1). The molecular pathology of missense mutations in SMN1 is not thoroughly investigated so far. Therefore, we collected all missense mutations in the SMN1 protein, using all possible search terms, from three databases (PubMed, PMC and Google Scholar). All missense mutations were subjected to in silico pathogenicity, conservation, and stability analysis tools. We used statistical analysis as a QC measure for validating the specificity and accuracy of these tools. PolyPhen-2 demonstrated the highest specificity and accuracy. While PolyPhen-1 showed the highest sensitivity; overall, PolyPhen2 showed better measures in comparison to other in silico tools. Three mutations (D44V, Y272C, and Y277C) were identified as the most pathogenic and destabilizing. Further, we compared the physiochemical properties of the native and the mutant amino acids and observed loss of H-bonds and aromatic stacking upon the cysteine to tyrosine substitution, which led to the loss of aromatic rings and may reduce protein stability. The three mutations were further subjected to Molecular Dynamics Simulation (MDS) analysis using GROMACS to understand the structural changes. The Y272C and Y277C mutants exhibited maximum deviation pattern from the native protein as compared to D44V mutant. Further MDS analysis predicted changes in the stability that may have been contributed due to the loss of hydrogen bonds as observed in intramolecular hydrogen bond analysis and physiochemical analysis. A loss of function/structural impact was found to be severe in the case of Y272C and Y277C mutants in comparison to D44V mutation. Correlating the results from in silico predictions, physiochemical analysis, and MDS, we were able to observe a loss of stability in all the three mutants. This combinatorial approach could serve as a platform for variant interpretation and drug design for spinal muscular dystrophy resulting from missense mutations.

Investigating the Influence of Hotspot Mutations in Protein-Protein Interaction of IDH1 Homodimer Protein: A Computational Approach.

Protein-protein interaction (PPI) helps in maintaining the cellular homeostasis. In particular, the homodimeric proteins play a crucial role as cell regulators. Studying the critical functions of each PPI on the living system is very challenging. The mutations in the PPIs have given birth to various diseases including many types of cancers and it has soon become the target for drug discovery. The mutations in IDH1, an asymmetric homodimer in the cytoplasm, leads to various diseases including gliomas. In this study, we have used extensive computational approaches to identify the impact of missense mutations (R132C, R132G, R132H, R132L, R132S, and V178I) occurring in the interacting region of the IDH1 homodimer. By in silico pathogenicity analysis, all the mutations occurring at the positions 132 and 178 were found to be pathogenic and neutral respectively. Furthermore, the mutants R132C and R132G were found to be responsible for increasing the stability, whereas the mutants R132H, R132L, and R132S were found to be responsible for the decrease in stability by stability analysis. R132H, R132L, and R132S mutants exhibited higher destabilization when compared to the structures of R132C and R132G mutants by molecular docking and molecular dynamics analysis.

A profound computational study to prioritize the disease-causing mutations in PRPS1 gene.

Charcot-Marie-Tooth disease (CMT) is one of the most commonly inherited congenital neurological disorders, affecting approximately 1 in 2500 in the US. About 80 genes were found to be in association with CMT. The phosphoribosyl pyrophosphate synthetase 1 (PRPS1) is an essential enzyme in the primary stage of de novo and salvage nucleotide synthesis. The mutations in the PRPS1 gene leads to X-linked Charcot-Marie-Tooth neuropathy type 5 (CMTX5), PRS super activity, Arts syndrome, X-linked deafness-1, breast cancer, and colorectal cancer. In the present study, we obtained 20 missense mutations from UniProt and dbSNP databases and applied series of comprehensive in silico prediction methods to assess the degree of pathogenicity and stability. In silico tools predicted four missense mutations (D52H, M115 T, L152P, and D203H) to be potential disease causing mutations. We further subjected the four mutations along with native protein to 50 ns molecular dynamics simulation (MDS) using Gromacs package. The resulting trajectory files were analyzed to understand the stability differences caused by the mutations. We used the Root Mean Square Deviation (RMSD), Radius of Gyration (Rg), solvent accessibility surface area (SASA), Covariance matrix, Principal Component Analysis (PCA), Free Energy Landscape (FEL), and secondary structure analysis to assess the structural changes in the protein upon mutation. Our study suggests that the four mutations might affect the PRPS1 protein function and stability of the structure. The proposed study may serve as a platform for drug repositioning and personalized medicine for diseases that are caused by the PRPS1 deficiency.

Effect of UV radiation and its implications on carotenoid pathway in Bixa orellana L.

The current study was undertaken to analyse the effect of short-term UV-B and UV-C radiations in provoking carotenoid biosynthesis in Bixa orellana. Seeds of B. orellana were germinated and exposed to the short term UV pre-treatment under controlled environmental condition for 5days. The UV treated young seedlings response in pigment contents; antioxidant enzyme activity and mRNA gene expression level were analysed. The pigment content such as chlorophyll was increased in both UV-B and UV-C treated seedlings, but the total carotenoid level was decreased when compared to the control seedlings this can be attributed to the plant adaptability to survive in a stressed condition. The ß-carotene level was increased in UV-B, and UV-C treated young seedlings. No significant changes have occurred in the secondary pigment such as bixin and ABA. The activity of the antioxidant enzymes such as catalase, peroxidase, and superoxide dismutase was significantly increased in UV-B treated seedlings when compared to the UV-C treated seedlings and control. The mRNA expression of the genes involved in bixin biosynthesis pathways such as DXS, PSY, PDS, LCY-ß, LCY-ε, CMT, LCD, ADH and CCD genes showed different expression pattern in UV-B and UV-C treated young seedlings. Further we analysed the gene co-expression network to identify the genes which are mainly involved in carotenoid/bixin biosynthesis pathway. Form our findings the CCD, LCY, PDS, ZDS and PSY showed a close interaction. The result of our study shows that the short term UV-B and UV-C radiations induce pigment content, antioxidant enzyme activity and different gene expression pattern allowing the plant to survive in the oxidative stress condition.

Neocondyle distraction osteogenesis in the management of temporomandibular joint ankylosis: Report of five cases with review of literature.

INTRODUCTION AND OBJECTIVES: Management of temporomandibular joint (TMJ) ankylosis is a challenging and rather daunting task owing to complex abnormal anatomy and its sequel to craniofacial structures. Various autogenous grafts and alloplastic materials have been tried with variable success for creation of a near-normal joint. In recent years, neocondyle distraction has added a new dimension to the management of TMJ ankylosis. The aim of this paper is to describe the role of neocondyle distraction in TMJ ankylosis. MATERIALS AND METHODS: Neocondyle distraction was carried out in five patients with TMJ ankylosis following gap arthroplasty. Computed tomogram scans were taken before surgery and 1-year postdistraction for surgical planning and postoperative assessment, respectively. The intraoral distractors (KLS Martin, Jacksonville, FL, USA) were used in this study. RESULTS: All five patients reported with adequate mouth opening and functional jaw movements. The procedure was well tolerated by all the patients. None of the patients underwent reankylosis following neocondyle distraction. CONCLUSION: With proper surgical planning and distraction protocol, neocondyle distraction is an effective and safe technique for TMJ reconstruction and preventing reankylosis.