Robotic hernia repair with the novel HUGO robot system - An initial experience from a tertiary centre.

BACKGROUND: Hernia repair using robotic platforms has been on the rise in the last decade. The HUGO robotic-assisted surgery (RAS) system, introduced in 2021, is a new addition to the field. In this study, we share our experience with this innovative system for the management of ventral and groin hernias. PATIENTS AND METHODS: The aim of our study was to evaluate the feasibility and safety of using the HUGO robotic platform for hernia surgeries. We conducted a retrospective analysis of all hernia surgeries performed with the HUGO system over a 1-year study period. The study assessed various aspects, including the technical manoeuvres of the robotic system, duration of surgery, length of hospital stay, post-operative pain levels and 30-day morbidity rates. RESULTS AND CONCLUSIONS: A total of seven hernia surgeries were performed using the HUGO system, including five ventral hernias and two groin hernias. The average duration of surgery was 128 min, with a docking duration of 22.8 min. Notably, there were no intraoperative or post-operative adverse events reported during these procedures. The HUGO system features an open console that provides a panoramic view of the operating room. In addition, the individual arm carts can be easily manoeuvred around the operating table, facilitating improved access to multiple quadrants during surgery. In our case series, Robotic hernia repair using the HUGO system has demonstrated feasibility, with post-operative outcomes comparable to traditional approaches. This innovative system serves as an additional tool in the armamentarium of hernia surgery and shows potential for improving surgical outcomes. However, further investigation through large-scale prospective studies is necessary to comprehensively evaluate its efficacy and benefits.

Multi-Layered PLGA-PEI Nanoparticles Functionalized with TKD Peptide for Targeted Delivery of Pep5 to Breast Tumor Cells and Spheroids.

Purpose: Peptide-based therapy is a promising strategy for cancer treatment because of its low drug resistance. However, the major challenge is their inability to target cancer cells specifically. So, a targeted nano-delivery system that could deliver therapeutic peptides selectively to cancer cells to stimulate their action is highly desirable. This study aims to deliver the antitumor peptide, Pep5, to breast tumor cells selectively using a targeting peptide functionalised multi-layered PLGA-PEI nanoparticles. Methods: In this study, Pep5 entrapped PLGA-PEI (Pep5-PPN) dual layered nanoparticles were developed. These nanoparticles were decorated with TKD (Pep5-TPPN) on their surface for site-specific delivery of Pep5 to breast tumor cells. The particles were then characterized using various instrumental analyses. In vitro cytotoxicity of the particles was evaluated in estrogen receptor positive (ER+ve) and triple negative breast cancer (TNBC) cells. An ex vivo tumor spheroid model was used to analyze the antitumor activity of the particles. Results: Uniformly round Pep5-TPPN particles were synthesized with an average diameter of 420.8 ± 14.72 nm. The conjugation of PEI over Pep5-PLGA nanoparticles shifted the zeta potential from -11.6 ± 2.16 mV to +20.01 ± 2.97 mV. In vitro cytotoxicity analysis proved that TKD conjugation to nanoparticles enhanced the antitumor activity of Pep5 in tested breast cancer cells. Pep5-TPPN induced cytoskeletal damage and apoptosis in the tested cells, which showed that the mechanism of action of Pep5 is conserved but potentiated. Active targeting of Pep5 suppressed the tumor growth in ex vivo spheroid models. Conclusion: A multi-layered nanoparticle functionalized with dual peptide was fabricated for active tumor targeting, which stimulated Pep5 activity to reduce the tumor growth in vitro and ex vivo.

Stress and Strain Created Around Miniscrews during En Masse Retraction - A Finite Element Method.

Background: En masse retraction of the anterior teeth may create anchorage problems. The effective means of obtaining anchorage in en masse retraction is by the usage of temporary anchorage devices. Aims and Objectives: The purpose of this study is focused on stress and strain created around miniscrew during en masse retraction using the cone beam computed tomography (CBCT) data obtained at two intervals and by the finite element analysis done using the CBCT data obtained. This will show us the stress and strain created around miniscrews and the withstanding capacity of miniscrews. Conclusion: Stress and strain was higher in TADs as compared to cortical and alveolar bone.

Delivery of Small Molecules by Syndiotactic Peptides for Breast Cancer Therapy.

The utilization of peptide-based drug delivery systems has been suboptimal due to their poor proteolytic susceptibility, poor cell permeability, and limited tumor homing capabilities. Earlier attempts in using d-enantiomers in peptide sequences increased proteolytic stability but have compromised the overall penetration capability. We designed a series of peptides (STRAPs) with a syndiotactic polypeptide backbone that can potentially form a spatial array of cationic groups, an important feature that facilitates cellular uptake. The peptides penetrate cell membranes through a combination of active and passive modes. Furthermore, the cellular uptake of the peptides was unaffected by the presence of or treatment with bovine serum and human plasma. The designed peptides successfully delivered methotrexate, an anticancer drug, to the in vitro and in vivo models of breast cancer, with the best performing peptide STRAP-4-MTX conjugate having an EC50 value of 1.34 µM. Peptide drug delivery in mouse xenograft models showed a greater reduction of primary tumor and metastasis of breast cancer, in comparison to methotrexate of the same dose. The in vivo biodistribution assay of the STRAP-4 peptide suggests that the peptide accumulates at the tumor site after 2 h of treatment, and in the absence of tumors, the peptide gets metabolized and excreted from the system.

Molecular hybridization combining tumor homing and penetrating peptide domains for cellular targeting.

A complete peptide-based drug delivery unit has been designed with a tumor homing domain chemically linked to a syndiotactic cell-penetrating domain. The designed peptides were synthesized, characterized, and tested in vitro for cellular uptake and cytotoxicity evaluation. The differential uptake, cellular internalization, negligible hemotoxicity, selective toxicity to MDA-MB-231 breast cancer cells, and the superior penetration in three-dimensional MDA-MB-231 tumorospheres confirm their utility as a promising delivery vector.

Universality of plastic instability and mechanical yield in metallic glasses.

The generic response of a wide range of amorphous solids is the average increase of stress upon external loading until the yielding transition point, after which elasto-plastic steady state sets in. The stress-strain response comprises of a series of elastic branches interspersed with plastic drops. The ubiquitousness of these phenomena indicates universality, independent of material property, but the literature predominantly deals with specific materials. In pursuit of generality among different amorphous systems, we undertake a careful investigation in the mechanical response of metallic glasses using computer simulation. By comparing our results of multi-body metallic glass potentials to those obtained from pairwise Lennard-Jones glasses, we show that the mechanism of plastic instabilities is universal and independent of the details of the underlying potential. We also investigate the yielding transition in terms of the overlap parameterQ12, which has been successfully used Lennard-Jones glasses. The yielding is unambiguously identified as a first-order phase transition. These observations conform the nature of plastic instabilities and mechanical yield as universal and independent of microscopic interactions.

Transitional dynamics of cancer stem cells in invasion and metastasis.

At the onset, few cancer cells amidst the tumor bulk, identified as cancer stem cells (CSCs) or early disseminated cancer cells (eDCCs) are capable of survival post conventional therapy and persist as minimal residual disease (MRD). Metastatic subclones emerge both early and late in the life of primary tumor ensuing an ongoing regional clonal evolution of progenitor cells in metastatic and primary tumors. In the last decade, multiple studies proposed various identities of stem-like cells that undergo transitions to adapt to the changing microenvironment as the disease progresses. This review advocates with substantial evidence the dynamic model of tumor propagation by exploring the specific cell types, reversible phenotypic plasticity between the tumorigenic leader seeds and the supporting follower cancer cells both in circulation and in solid tissue to accurately decipher tumor promoting clones and its role in metastatic dissemination and tumor re-growth. (142 words).

Association of Papillary Thyroid Carcinoma with GIST-a Case Series.

Gastrointestinal stromal tumours (GIST) are the most common gastrointestinal mesenchymal tumours of the gastrointestinal tract. They are diagnosed by the expression of markers like CD 117, CD 34, DOG-1 and PDGFRA. The identification of these mutations has resulted in a better understanding of their oncogenic mechanisms. Few studies have shown the high incidence of a second malignancy including papillary thyroid cancer (PTC) in known patients of GIST. Literature review on pathogenesis of GIST and PTC showed that PTC targeting Protein Kinase C theta (PKCθ) plays role in both PTC and GIST. Further studies have also shown that, apart from somatic and familial gastrointestinal stromal tumours, PDGFRA is associated with many other malignancies including PTC. These studies explain the common genetic pathway involved in the development of GIST and PTC in same patient. In spite of common genetic association between GIST and other malignancies, none of the standard protocols recommends screening for second malignancy. In this article, we present the details of four patients who had associated GIST and PTC at the same time or developed during follow-up.

Peptide-based delivery vectors with pre-defined geometrical locks.

Design of peptide-based targeted delivery vectors with attributes of specificity and selective cellular targeting by fixing their topology and resulting electrostatic fingerprint is the objective of this study. We formulated our peptide design platform by utilizing the possibilities of side-chain induced geometric restrictions in a typical peptide molecule. Conceptually, we locked the conformation of the RGD/NGR motif of tumor homing peptides (THPs) by mutating glycine in these motifs with d-proline and tailed the peptides with a syndiotactic amphipathic segment for cellular penetration. The designed peptides were synthesized, characterized, and tested in vitro on various cell lines, including breast cancer (MDA-MB-231), cervical cancer (HeLa), osteosarcoma (U2-OS) and non-cancer mammary epithelial cells (MCF-10A), by flow cytometry and confocal microscopy. The results showed differential cellular uptake in different cell types, as a result of the distinct electrostatic fingerprint encoded in their design. The uptake of serum pre-treated peptides by cells reveals the retention of peptide activity even after the incubation with serum. In addition, peptide-methotrexate (MTX) conjugates compared to the methotrexate drug showed enhanced apoptotic cell death in MTX-resistant MDA-MB-231 cells, indicating the increase in MTX bioavailability.

Untargeted metabolomics reveals alterations in metabolites of lipid metabolism and immune pathways in the serum of rats after long-term oral administration of Amalaki rasayana.

Amalaki rasayana, a traditional preparation, is widely used by Ayurvedic physicians for the treatment of inflammatory conditions, cardiovascular diseases, and cancer. Metabolic alterations induced by Amalaki rasayana intervention are unknown. We investigated the modulations in serum metabolomic profiles in Wistar rats following long-term oral administration of Amalaki rasayana. Global metabolic profiling was performed of the serum of rats administered with either Amalaki rasayana (AR) or ghee + honey (GH) for 18 months and control animals which were left untreated. Amalaki rasayana components were confirmed from AR extract using HR-LCMS analysis. Significant reductions in prostaglandin J2, 11-dehydrothromboxane B2, and higher levels of reduced glutathione and glycitein metabolites were observed in the serum of AR administered rats compared to the control groups. Eleven different metabolites classified as phospholipids, glycerophospholipids, glucoside derivatives, organic acids, and glycosphingolipid were exclusively observed in the AR administered rats. Pathway analysis suggests that altered metabolites in AR administered rats are those associated with different biochemical pathways of arachidonic acid metabolism, fatty acid metabolism, leukotriene metabolism, G-protein mediated events, phospholipid metabolism, and the immune system. Targeted metabolomics confirmed the presence of gallic acid, ellagic acid, and arachidonic acid components in the AR extract. The known activities of these components can be correlated with the altered metabolic profile following long-term AR administration. AR also activates IGF1R-Akt-Foxo3 signaling axis in heart tissues of rats administered with AR. Our study identifies AR components that induce alterations in lipid metabolism and immune pathways in animals which consume AR for an extended period.

Does the Anatomy of the Transected Pancreatic Neck Influence Post Whipple's Operation Pancreatic Fistula?

Few studies correlate anatomical parameters of the transected pancreatic neck to occurrence of the dangerous complication-post Whipple's pancreaticoduodenectomy pancreatic fistula. To evaluate the correlation between anatomical details of the transected neck of the pancreas and post-operative pancreatic fistula (POPF) following Whipple's pancreaticoduodenectomy. Observational study. The study included 66 patients undergoing Whipple's pancreaticoduodenectomy with pancreaticojejunostomy at tertiary care centre between December 2009 and December 2014. Student's t test, Fisher's exact test, Pearson's chi-squared test and forward stepwise. Clinically relevant POPF (grade B and C) was noted in 12 patients. Morbidity/mortality was 30.30% and 4.54% respectively. Among the fistula v/s no fistula groups, (a) mean thickness of the pancreatic stump was 12.17 ± 1.40 mm v/s 14.94 ± 1.87 mm (P = 0.000), (b) mean width of the pancreatic stump was 24.33 ± 4.14 mm v/s 25.87 ± 4.02 mm (P = 0.238) and (c) mean pancreatic duct (PD) diameter was 2.92 ± 0.79 mm v/s 4.27 ± 1.39 mm (P = 0.001). Mean distances of PD from anterior, posterior, superior and inferior pancreatic borders in the fistula group v/s no fistula group were 6.08 ± 1.62 mm, 3.17 ± 0.72 mm, 9.92 ± 2.15 mm, and 11.42 ± 3.45 mm v/s 5.93 ± 1.71 mm, 4.83 ± 1.26 mm, 11.83 ± 2.79 mm and 9.96 ± 3.25 mm respectively. Eleven of 38 patients (28.9%) with soft pancreas developed POPF. Pancreatic duct < 3 mm diameter, < 3 mm from posterior border, < 12 mm from superior border, pancreatic neck thickness < 12 mm and soft pancreas consistency were significantly associated with POPF.

Novel flourescent spiroborate esters: potential therapeutic agents in in vitro cancer models.

The current treatment system in cancer therapy, which includes chemotherapy/radiotherapy is expensive and often deleterious to surrounding healthy tissue. Presently, several medicinal plants and their constituents are in use to manage the development and progression of these diseases.They have been found effective, safe, and less expensive. In the present study, we are proposing the utility of a new class of curcumin derivative, Rubrocurcumin, the spiroborate ester of curcumin with boric acid and oxalic acid (1:1:1), which have enhanced biostability for therapeutic applications. In vitro cytocompatibility of this drug complex was analysed using MTT assay, neutral red assay, lactate dehydrogenase assay in 3T3L1 adipocytes. Anti tumour activity of this drug complex on MCF7 and A431 human cancer cell line was studied by morphological analysis using phase contrast microscopy, Hoechst staining and cell cycle analysis by FACS. To explore the chemotherapeutic effect, the cytotoxic effect of this compound was also carried out. Rubrocurcumin is more biostable than natural curcumin in physiological medium. Our results prove that this curcumin derivative drug complex possess more efficacy and anti-cancer activity compared with curcumin. The findings out of this study suggests this novel compound as potential candidate for site targeted drug delivery.

Synthesis of Bioactive 3,4-Dihydro-2 H-naphtho[2,3- b][1,4]oxazine-5,10-dione and 2,3,4,5-Tetrahydro-1 H-naphtho[2,3- b]azepine-6,11-dione Derivatives via the Copper-Catalyzed Intramolecular Coupling Reaction.

A convenient synthesis of 3,4-dihydro-2 H-naphtho[2,3- b][1,4]oxazine-5,10-diones and 2,3,4,5-tetrahydro-1 H-naphtho[2,3- b]azepine-6,11-diones via the copper-catalyzed intramolecular C-O/C-C coupling reaction is described. This method showed a good tolerance for functional groups and was applied to the synthesis of natural product core structures. Some coupling products exhibited moderate activities against lung cancer A549 cells.

Ecotropic viral integration site 1 promotes metastasis independent of epithelial mesenchymal transition in colon cancer cells.

The most indecipherable component of solid cancer is the development of metastasis which accounts for more than 90% of cancer-related mortalities. A developmental program termed epithelial-mesenchymal transition (EMT) has also been shown to play a critical role in promoting metastasis in epithelium-derived solid tumors. By analyzing publicly available microarray datasets, we observed that ecotropic viral integration site 1 (EVI1) correlates negatively with SLUG, a master regulator of EMT. This correlation was found to be relevant as we demonstrated that EVI1 binds to SLUG promoter element directly through the distal set of zinc fingers and downregulates its expression. Many studies have shown that the primary role of SLUG during EMT and EMT-like processes is the regulation of cell motility in most of the cancer cells. Knockdown of EVI1 in metastatic colon cancer cell and subsequent passage through matrigel not only increased the invading capacity but also induced an EMT-like morphological feature of the cells, such as spindle-shaped appearance and led to a significant reduction in the expression of the epithelial marker, E-CADHERIN and increase in the expression of the mesenchymal marker, N-CADHERIN. The cells, when injected into immunocompromised mice, failed to show any metastatic foci in distant organs however the ones with EVI1, metastasized in the intraperitoneal layer and also showed multiple micro metastatic foci in the lungs and spleen. These findings suggest that in colon cancer EVI1 is dispensable for epithelial-mesenchymal transition, however, is required for metastasis.

Selective Aza Diels-Alder and Domino [4+2]/[2+2] Cycloaddition Reactions of Arynes with N-Sulfonyl Ketimines.

Transition-metal-free inverse electron-demand aza Diels-Alder and domino [4+2]/[2+2] cycloaddition reaction of arynes and N-sulfonyl ketimines has been demonstrated. This novel, mild, and efficient protocol allows rapid access to isothiazole dioxide-fused dihydroquinoline or dihydrocyclobutaquinoline derivatives selectively by simply varying the equivalents of aryne precursors. The application of this method has been amply illustrated in the synthesis of 2,4-diarylquinolines.

Synthesis of Dihydrophenanthridines and Oxoimidazolidines from Anilines and Ethylglyoxylate via Aza Diels-Alder Reaction of Arynes and KF-Induced Annulation.

The transition-metal-free multicomponent coupling of arynes, anilines, and ethylglyoxylate, proceeding via an inverse electron-demand aza Diels-Alder cycloaddition and N-arylation, has been demonstrated. This protocol allows rapid access to N-aryl dihydrophenanthridine derivatives in moderate to high yields at room temperature from readily available starting materials. In addition, an unprecedented fluoride induced annulation of ethyl(arylimino)acetates led to the formation of highly functionalized oxoimidazolidine derivatives in good yields under mild conditions.

Hesperetin and Naringenin sensitize HER2 positive cancer cells to death by serving as HER2 Tyrosine Kinase inhibitors.

AIM: Aberrant human epidermal growth factor receptor-2 (HER2) expression and constitutive mutant activation of its tyrosine kinase domain account for tumor aggression and therapy resistance in many types of cancers with major share in breast cancer cases. HER2 specific treatment modalities still face challenges owing to the side effects and acquired resistance of available therapeutics. Recently, the anti-proliferative and pro-apoptotic potential of phytochemicals, especially of flavonoids have become increasingly appreciated as powerful chemo preventive agents. Consequently, the major goal of our study is to identify flavonoids capable of inhibiting HER2 Tyrosine Kinase (HER2-TK) activity and validate their anti-tumor activity against HER2 positive tumors. MAIN METHODS: Molecular docking studies for identifying flavonoids binding at HER2 kinase domain, ADP-Glo™ Kinase Assay for determining kinase activity, MTT assay to measure growth inhibition, various apoptotic assays and cell cycle analysis by FACS were performed. KEY FINDINGS: Among the flavonoids screened, Naringenin (NG) and Hesperetin (HP) possessed high glide scores from molecular docking studies of enzyme-inhibitor mode. The interaction analysis revealed their ability to establish stable and strong interaction at the ATP binding site of HER2-TK. These compounds also inhibited in vitro HER2-TK activity suggesting their role as HER2 inhibitors. The study also unraveled the anti-proliferative, pro-apoptotic and anti-cancerous activity of these flavonoids against HER2 positive breast cancer cell line. SIGNIFICANCE: The study identified two citrus fruit flavonoids, NG and HP as HER2-TK inhibitors and this is the first report on their potential to target preferentially and sensitize HER2 positive cancer cells to cell death.

Synthesis of Carbazolequinones by Formal [3 + 2] Cycloaddition of Arynes and 2-Aminoquinones.

A formal cycloaddition reaction for the synthesis of biologically and pharmaceutically important carbazolequinones via the annulation of aminoquinones with arynes has been developed. This practical and metal-free cascade reaction proceeds through successive C-C/C-N bond formations. Moreover, this novel method has been utilized for the concise synthesis of bioactive murrayaquinone A and koeniginequinone B and their analogues.