Robot-Assisted Pelvic Dissection for Enlarged Lymph Nodes in Melanoma Improves Recovery with Equivalent Oncological Outcomes to Open Pelvic Dissection.

BACKGROUND: Robot-assisted pelvic lymph node dissection (rPLND) has been reported in heterogenous groups of patients with melanoma, including macroscopic or at-high-risk-for microscopic metastasis. With changing indications for surgery in melanoma, and availability of effective systemic therapies, pelvic dissection is now performed for clinically detected bulky lymph node metastasis followed by adjuvant drug therapy. rPLND has not been compared with open pelvic lymph node dissection (oPLND) for modern practice. METHODS: All patients undergoing pelvic node dissection for macroscopic melanoma at a single institution were reviewed as a cohort, observational study. RESULTS: Twenty-two pelvic lymph node dissections were identified (8 oPLND; 14 rPLND). The number of pelvic lymph nodes removed was similar (median oPLND 6.5 (interquartile range [IQR] 6.0-12.5] versus rPLND 6.0 [3.75-9.0]), with frequent matted nodes (11/22, 50.0%). Operative time (median oPLND 130 min [IQR 95.5-182] versus rPLND 126 min [IQR 97.8-160]) and complications (Clavien-Dindo scale) were similar. Length of hospital stay (median 5.34 days (IQR 3.77-6.94) versus 1.98 days (IQR 1.39-3.50) and time to postoperative adjuvant therapy (median 11.6 weeks [IQR 10.6-18.5] versus 7.71 weeks [IQR 6.29-10.4]) were shorter in the rPLND group. No differences in pelvic lymph node recurrence (p = 0.984), distant metastatic recurrence (p = 0.678), or melanoma-specific survival (p = 0.655) were seen (median follow-up 21.1 months [rPLND] and 25.7 months [oPLND]). CONCLUSIONS: rPLND is an effective way to remove bulky pelvic lymph nodes in melanoma, with a shorter recovery and reduced interval to initiating adjuvant therapy compared with oPLND. This group of patients may especially benefit from neoadjuvant systemic approaches to management.

Breaking Barriers: Current Advances and Future Directions in Mpox Therapy.

BACKGROUND: Mpox, a newly discovered zoonotic infection, can be transmitted from animal to human and between humans. Serological and genomic studies are used to identify the virus. OBJECTIVE: Currently, there are no proven effective treatments for Mpox. Also, the safety and efficacy of intravenous vaccinia immune globulin, oral Tecovirimat (an inhibitor of intracellular viral release), and oral Brincidofovir (a DNA polymerase inhibitor) against the Mpox virus are uncertain, highlighting the need for more effective and safe treatments. As a result, drug repurposing has emerged as a promising strategy to identify previously licensed drugs that can be repurposed to treat Mpox. RESULTS: Various approaches have been employed to identify previously approved drugs that can target specific Mpox virus proteins, including thymidylate kinase, D9 decapping enzyme, E8 protein, Topoisomerase1, p37, envelope proteins (D13, A26, and H3), F13 protein, virus's main cysteine proteases, and DNA polymerase. CONCLUSION: In this summary, we provide an overview of potential drugs that could be used to treat Mpox and discuss the underlying biological processes of their actions.

Interleukin-1ß converting enzyme (ICE): A comprehensive review on discovery and development of caspase-1 inhibitors.

Caspase-1 is a critical mediator of the inflammatory process by activating various pro-inflammatory cytokines such as pro-IL-1ß, IL-18 and IL-33. Uncontrolled activation of caspase-1 leads to various cytokines-mediated diseases. Thus, inhibition of Caspase-1 is considered therapeutically beneficial to halt the progression of such diseases. Currently, rilonacept, canakinumab and anakinra are in use for caspase-1-mediated autoinflammatory diseases. However, the poor pharmacokinetic profile of these peptides limits their use as therapeutic agents. Therefore, several peptidomimetic inhibitors have been developed, but only a few compounds (VX-740, VX-765) have advanced to clinical trials; because of their toxic profile. Several small molecule inhibitors have also been progressing based on the three-dimensional structure of caspase-1. However there is no successful candidate available clinically. In this perspective, we highlight the mechanism of caspase-1 activation, its therapeutic potential as a disease target and potential therapeutic strategies targeting caspase-1 with their limitations.

The C. elegans deglutamylase CCPP-6 does not operate redundantly with CCPP-1 in gross cilia integrity.

Tubulin glutamylation is a reversible modification of the microtubules that regulates cilia stability and function. The addition of glutamates to the microtubule is catalyzed by members of the TTLL family of enzymes, while the removal is carried out by a family of cytosolic carboxypeptidase (CCP) enzymes. C. elegans has two deglutamylating enzymes, CCPP-1 and CCPP-6 . CCPP-1 is required for ciliary stability and function in the worm, however CCPP-6 is dispensable for cilia integrity. To investigate redundancy between the two deglutamylating enzymes we made a ccpp-1 ( ok1821 ); ccpp-6 ( ok382 ) double mutant. The double mutant shows normal viability, and the dye-filling phenotypes are not worse than the ccpp-1 single mutant, suggesting that CCPP-1 and CCPP-6 do not function redundantly in C. elegans cilia .

A case report on implant retained auricular prosthesis: Bringing back hope and smile.

Long-term success of a facial prosthesis mainly depends on retention. Most articles relate tissue health to long-term success, not retention. Anatomic undercuts, skin adhesives and implants are important factors to provide sufficient retention. Extra oral implant retained prosthesis have been proven to be a predictable treatment option for maxillofacial rehabilitation. This case report describes the clinical and laboratory procedures for fabricating implant-retained auricular prosthesis using magnets for retention. It describes how an initial planning for implant placement with Hader-bar retentive system was opted out due to intra-surgical situation. The use of craniofacial implants for retention of extra oral prosthesis, such as ears, offers excellent support and retentive abilities and improves a patient's appearance and quality of life. It has been shown in clinical and biomechanical studies that two implants are sufficient to retain an auricular prosthesis. Judicial treatment planning and implant placement according to the available remaining structures is prudent for a successful prosthesis.

Exploring the mechanism of action bitter melon in the treatment of breast cancer by network pharmacology.

BACKGROUND: Bitter melon has been used to stop the growth of breast cancer (BRCA) cells. However, the underlying mechanism is still unclear. AIM: To predict the therapeutic effect of bitter melon against BRCA using network pharmacology and to explore the underlying pharmacological mechanisms. METHODS: The active ingredients of bitter melon and the related protein targets were taken from the Indian Medicinal Plants, Phytochemistry and Therapeutics and SuperPred databases, respectively. The GeneCards database has been searched for BRCA-related targets. Through an intersection of the drug's targets and the disease's objectives, prospective bitter melon anti-BRCA targets were discovered. Gene ontology and kyoto encyclopedia of genes and genomes enrichment analyses were carried out to comprehend the biological roles of the target proteins. The binding relationship between bitter melon's active ingredients and the suggested target proteins was verified using molecular docking techniques. RESULTS: Three key substances, momordicoside K, kaempferol, and quercetin, were identified as being important in mediating the putative anti-BRCA effects of bitter melon through the active ingredient-anti-BRCA target network study. Heat shock protein 90 AA, proto-oncogene tyrosine-protein kinase, and signal transducer and activator of transcription 3 were found to be the top three proteins in the protein-protein interaction network study. The several pathways implicated in the anti-BRCA strategy for an active component include phosphatidylinositol 3-kinase/protein kinase B signaling, transcriptional dysregulation, axon guidance, calcium signaling, focal adhesion, janus kinase-signal transducer and activator of transcription signaling, cyclic adenosine monophosphate signaling, mammalian target of rapamycin signaling, and phospholipase D signaling. CONCLUSION: Overall, the integration of network pharmacology, molecular docking, and functional enrichment analyses shed light on potential mechanisms underlying bitter melon's ability to fight BRCA, implicating active ingredients and protein targets, as well as highlighting the major signaling pathways that may be altered by this natural product for therapeutic benefit.

A ccpp-6 deletion mutation does not impair gross cilia integrity in C. elegans.

Tubulin glutamylation is a reversible modification that regulates microtubule function in cilia. The removal of glutamylation from microtubules is carried out by a family of cytosolic carboxypeptidase (CCP) enzymes. C. elegans has two deglutamylating enzymes, CCPP-1 and CCPP-6, homologs of mammalian CCP1 and CCP5 respectively. CCPP-1 is required for ciliary stability and function. To determine whether CCPP-6 is similarly required for cilia integrity in C. elegans we analyzed the ccpp-6(ok382) deletion mutant. We find that both dye-filling and male mating are normal, suggesting that CCPP-6 is not required for ciliary integrity in C. elegans.

Insights into the structural requirements of triazole derivatives as promising DPP IV inhibitors: computational investigations.

Diabetes is one of the leading causes of death globally as per World Health Organization 2019. To cope up with side effects of current diabetes therapy, researchers have found several novel targets for the treatment of diabetes. Currently, dipeptidyl peptidase IV (DPP IV) has emerged as a target in modulating the diabetes physiology. In the present work, various 3D-Quantitative structure activity relationship (QSAR) techniques namely comparative molecular field analysis (CoMFA), comparative molecular similarity indices analysis, topomer CoMFA and molecular hologram QSAR are used to explore the structural requirements of triazole derivatives as DPP IV inhibitors. Different models generated by 3D QSAR studies had acceptable statistical values for further prediction of molecules. From the contour maps of QSAR results, important structural features are deduced. Substitutions on N1 and N2 of triazole ring with H-bond donor group enhances the biological activity. Aliphatic side chain, less bulky group, H-bond donor group and -COOH group on N3 of triazole ring are vital for the DPP IV inhibition. Moreover, electron withdrawing side chain on the triazole ring improves the biological activity. Further, novel triazole derivatives were designed and docking results of these compounds proved the efficiency of the developed 3D QSAR model. In future, results of this study may provide promising DPP IV inhibitors for the treatment of diabetes. Communicated by Ramaswamy H. Sarma.

Pharmacophore- based virtual screening, 3D- QSAR, molecular docking approach for identification of potential dipeptidyl peptidase IV inhibitors.

Pharmacophore modeling, molecular docking, and in silico ADME studies have been carried out to determine the binding mode and drug likeliness profile of Pyrrolidine derivatives as Dipeptidyl peptidase IV inhibitors. A five point pharmacophore model (AAADH_1) was generated using 96 compounds with IC50 values ranging from 1.8 to 13000 nM. A statistically significant 3D-QSAR model was generated from the pharmacophore hypothesis. The model had a high correlation coefficient (R2 - 0.92), cross validation coefficient (Q2 - 0.776) and F value (F - 144) at 6 component Partial least square factor. Pearson r of 0.7124 indicated greater degree of confidence on the model. The accuracy and predictability of the generated model were checked by Enrichment factor, Receiver operating characteristic curves, area under curve, Boltzmann-enhanced discrimination of Receiver operating characteristic and the Robust initial enhancement. To identify novel and potent Dipeptidyl peptidase IV inhibitors, virtual screening was performed using the ligand and database screening. Considering the potent hit molecules on the basis of pharmacophore virtual screening, we have designed new molecules and further subjected to see the interaction with protein. The catalytic domain of Dipeptidyl peptidase IV enzyme in complex with Vildagliptin (PDB Code: 6B1E) was obtained from protein data bank with resolution 1.77 A°. Compound 75 showed the better binding (dock score -7.966) with protein than standard drug vildagliptin (Dock Score -6.554). The hits obtained on virtual screening of the database have provided new chemical starting points for design and development of novel Dipeptidyl peptidase IV inhibitory agents.Communicated by Ramaswamy H. Sarma.

Recent Medicinal Chemistry Approach for the Development of Dipeptidyl Peptidase IV Inhibitors.

BACKGROUND: Diabetes, a metabolic disease, occurs due to a decreased or no effect of insulin on the blood glucose level. The current oral medications stimulate insulin release, increase glucose absorption and its utilization, and decrease hepatic glucose output. Two major incretin hormones like Glucose-dependent insulinotropic polypeptide (GIP) and glucagonlike peptide - 1 (GLP-1) stimulate insulin release after a meal, but their action is inhibited by enzyme dipeptidyl peptidase- IV. OBJECTIVE: The activity of endogenous GLP-1 and GIP prolongs and extends with DPP IV inhibitors, which are responsible for the stimulation of insulin secretion and regulation of blood glucose level. DPP IV inhibitors have shown effectiveness and endurability with a neutral effect on weight as well as less chances of hypoglycemia in the management of type 2 diabetes. These journeys started from Sitagliptin (marketed in 2006) to Evogliptin (marketed in 2015, Korea). CONCLUSION: Treatment of type 2 diabetes includes lifestyle changes, oral medications, and insulin. Newer and superior therapies are needed more than currently prescribed drugs. Various heterocyclic derivatives have been tried, but due to masking of DASH proteins, CYP enzymes, and hERG channel, they showed side effects. Based on these, the study has been focused on the development of safe, influential, selective, and long-lasting inhibitors of DPP IV.

In silico studies on therapeutic agents for COVID-19: Drug repurposing approach.

AIMS: The severe acute respiratory syndrome coronavirus 2, better known as COVID-19 has become the current health concern to the entire world. Initially appeared in Wuhan, China around December 2019, it had spread to almost 187 countries due to its high contagious nature. Precautionary measures remain the sole obliging tactic to cease the person to person transmissions till any effective method of treatment or vaccine is developed. Amidst the pandemic, research and development of new molecule is labour-intensive and tedious process. Drug repurposing is the concept of identifying therapeutically potent molecule from the library of pre-existing molecules. MATERIALS AND METHODS: In the present study, 61 molecules that are already being used in clinics or under clinical scrutiny as antiviral agents are surveyed via docking study. Docking study was performed using Maestro interface (Schrödinger Suite, LLC, NY). KEY FINDINGS: Out of these 61 molecules, 37 molecules were found to interact with >2 protein structures of COVID-19. The docking results indicate that amongst the reported molecules, HIV protease inhibitors and RNA-dependent RNA polymerase inhibitors showed promising features of binding to COVID-19 enzyme. Along with these, Methisazone an inhibitor of protein synthesis, CGP42112A an angiotensin AT2 receptor agonist and ABT450 an inhibitor of the non-structural protein 3-4A might become convenient treatment option as well against COVID-19. SIGNIFICANCE: The drug repurposing approach provide an insight about the therapeutics that might be helpful in treating corona virus disease.

Percutaneous Peritoneal Dialysis Catheter Placement in Patients with Complex Abdomen.

Peritoneal dialysis (PD) is an effective treatment for end-stage renal disease. There are several techniques of percutaneous PD catheter placement including trocar or Seldinger techniques. Placement can be performed with fluoroscopy and/or sonography or as a blind percutaneous procedure. Historically, percutaneous PD catheters have been placed in patients even if they had prior abdominal surgeries. The outcomes of percutaneous PD catheter placement in patients with complex abdomen (patients with two or more abdominal surgeries or known adhesions) are unknown. This study was carried out to determine the outcomes of percutaneous PD catheter placements using Seldinger technique with sonography and fluoroscopy in patients with complex abdomen. Preprocedure sonography was also used to identify site of adhesions and blood vessels. The goal was to see if ultrasound and fluoroscopy would support placement of PD catheters in patients with complex abdomens. There were total of 10 catheter placements in 10 patients with complex abdomen. The initial success rate was 100%. The patients had an average of 2.8 abdominal surgeries. The mean BMI was 28.4. There were no incidences of perforation or failed placements. One catheter was replaced due to outflow failure and one patient discontinued PD due to peri-catheter leak. One year catheter survival was 80%. Our study demonstrates benefits of using ultrasonography and fluoroscopy during percutaneous PD catheter placement by the Seldinger technique in patients with complex abdomen.