Predicting Positive Radial Margin on Restaging MRI of Patients with Low Rectal Cancer: Can We Do Better?

Objective The aim of this study was to characterize the tissue involving the margin and study if this information will affect margin prediction on restaging magnetic resonance imaging (MRI) in low rectal adenocarcinoma (LRC) patients treated with neoadjuvant long-course chemoradiotherapy (LCCRT). Methods In this retrospective study of nonmetastatic LRC (distal margin <5 cm from the anal verge) treated with LCCRT followed by surgery, a radiologist blinded to outcome reread the restaging MRI and documented if the radial margin was involved by tumor, fibrosis, or mucin reaction using T2 high-resolution (HR) and diffusion-weighted imaging (DWI). The diagnostic performance of tumor-involving margin on restaging MRI was assessed using surgical histopathology as a reference. Interobserver agreement between three independent radiologists was assessed in a subset. Results We included 133 patients (80 males and 53 females) with a mean (range) age of 44.7 (21-86) years and 82% of them had well or moderately differentiated adenocarcinoma. Baseline MRI showed T3 ( n = 58) or T4 ( n = 60) disease in 89% of the patients. The pathological margin was positive in 21% ( n = 28) cases. In restaging MRI, the circumferential resection margin (CRM) ≤1 mm in 75.1% ( n = 100) cases and MRI predicted tumor, fibrosis, and mucin reaction at the margin in 60, 34, and 6%, respectively, and histopathology showed tumor cells in 33, 14.7, and 16.6% of them, respectively. LRC with tumor-involving margin and bad response (MR tumor regression grade [mr-TRG] 3-5) on restaging MRI had fourfold increased risk of positive pathological circumferential resection margin (pCRM). There was moderate and fair inter-reader agreement for the tissue type involving the CRM ( κ = 0.471) and mr-TRG ( κ = 0.266), p < 0.05. The use of both distance criteria and tumor-involving margins improved the diagnostic accuracy for margin prediction from 39 to 66% on restaging MRI. Conclusions Margin prediction on restaging MRI can be improved by characterizing the tissue type involving the margin in low rectal cancer patients. The inter-reader agreement was moderate for determining the tissue type.

The Effect of Sepsis and Septic Shock on the Viscoelastic Properties of Clot Quality and Mass Using Thromboelastometry: A Prospective Observational Study.

Background: Sepsis is associated with wide variable coagulation abnormalities. Thromboelastography (TEG) effectively measures the viscoelastic properties of the clots. This study aims to illustrate the viscoelastic properties of clot quality and mass in sepsis and septic shock patients using TEG, as an effective tool over standard coagulation tests. Materials and methods: A single-center, prospective observational study was conducted. 50 patients each meeting the criteria for sepsis and septic shock, and a healthy group of 30 patients was included in the study. Blood samples were obtained and analyzed for standard coagulation tests, platelet count, fibrinogen, and TEG study. Results: A total of 130 patients were included. Septic shock patients had a higher sequential (sepsis-related) organ failure score. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) were increased significantly as compared to the sepsis and control groups. TEG markers such as alpha angle, and maximum amplitude (MA) were significantly prolonged while reaction time (R time), was significantly shortened in the sepsis group as compared to the healthy group, suggestive of a hypercoagulable state in sepsis patients. While in septic shock patients, MA and Lysis Index 30 (LY 30) were significantly prolonged and, R time was significantly shortened compared to all other groups. Even though LY30 in sepsis patients was found to be within the normal range (p < 0.001), 18% of patients had prolonged LY30 indicating a hypercoagulable state with impaired fibrinolysis. Conclusion: Thromboelastography, as a point-of-care test combined with conventional coagulation tests can provide additional, clinically relevant information on coagulopathy, and outcome, and thus help guide treatment modality in sepsis and septic shock-induced coagulopathy. How to cite this article: Mohapatra P, Kumar A, Singh RK, Gupta R, Hussain M, Singh S, et al. The Effect of Sepsis and Septic Shock on the Viscoelastic Properties of Clot Quality and Mass Using Thromboelastometry: A Prospective Observational Study. Indian J Crit Care Med 2023;27(9):625-634.

Nimbolide-based nanomedicine inhibits breast cancer stem-like cells by epigenetic reprogramming of DNMTs-SFRP1-Wnt/ß-catenin signaling axis.

Triple-negative breast cancer (TNBC) harbors a high percentage of breast cancer stem-like cells (BCSCs) that significantly contribute to poor prognosis, metastasis, and relapse of the disease. Thus, targeting BCSCs could be a promising approach to combat TNBC. In this context, we investigated nimbolide (Nim), a limonoid triterpenoid that has potent anticancer properties, but poor pharmacokinetics and low bioavailability limit its therapeutic application. So, to enhance the therapeutic potential of Nim, Nim-encapsulated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (Nim NPs) were formulated and the anticancer stem cell (CSC) effects evaluated in vitro and in vivo. In vitro studies suggested that Nim NPs significantly inhibited several inherent characteristics of BCSCs, such as stemness, self-renewability, chemoresistance, epithelial-to-mesenchymal transition (EMT), and migration in comparison to native Nim. Next, the mechanism behind the anti-CSC effect of Nim was explored. Mechanistically, we found that Nim epigenetically restores tumor suppressor gene secreted frizzled-related protein 1 (SFRP1) expression by downregulating DNA methyltransferases (DNMTs), leading to Wnt/ß-catenin signaling inhibition. Further, in vivo results demonstrated that Nim NPs showed enhanced anti-tumor and anti-metastatic effects compared to native Nim in two preclinical models without any systemic toxicity. Overall, these findings provide proof of concept that Nim-based phytonanomedicine can inhibit BCSCs by epigenetic reprogramming of the DNMTs-SFRP1-Wnt/ß-catenin signaling axis.

In-vitro anticancer evaluation of newly designed and characterized tri/tetra-substituted imidazole congeners- maternal embryonic leucine zipper kinase inhibitors: Molecular docking and MD simulation approaches.

Our cascading attempt to develop new potent molecules now involves designing a series of imidazole derivatives and synthesizing two sets of 2,4,5- tri-substituted (4a-4d) and 1,2,4,5-tetra-substituted (6a-6d) imidazole by the principle of Debus-Radziszewski multicomponent synthesis reaction. The structures of the obtained compounds were confirmed by 1H/13C NMR, FT-IR, elemental analysis, purity and the retention time was analyzed by HPLC. Based upon the binding affinity in the molecular docking studies, we have synthesized different imidazole derivatives from which compound 6c have been found to show more anti-proliferative activity by inducing apoptosis at a higher rate than the other compounds corroborating the in-silico prediction. The structure and crystallinity of compound 4d have been confirmed by single XRD analysis. The synthesized molecules were screened for their in vitro anti-cancer properties in triple negative breast cancer cell line (MDA-MB-231), pancreatic cancer cell lines (MIA PaCa-2) and oral squamous cell carcinoma cell line (H357) and results indicated that all the compounds inhibited the cell proliferation in a concentration-dependent manner at different time points. The compounds 4b and 6d were found to be effective against the S. aureus bacterial strain whereas only compound 4d fairly inhibited the fungal strain of T. rubrum with a MIC 12.5 µg/mL. Molecular docking study reveals good interaction of the synthesized compounds with known target MELK involved in oncogenesis having high binding profiles. The lead compound 6c was further analyzed by the detailed molecular dynamics study to establish the stability of the ligand-enzyme complex.

Phytochemical-Based Nanomedicine for Targeting Tumor Microenvironment and Inhibiting Cancer Chemoresistance: Recent Advances and Pharmacological Insights.

Cancer remains the leading cause of death and rapidly evolving disease worldwide. The understanding of disease pathophysiology has improved through advanced research investigation, and several therapeutic strategies are being used for better cancer treatment. However, the increase in cancer relapse and metastatic-related deaths indicate that available therapies and clinically approved chemotherapy drugs are not sufficient to combat cancer. Further, the constant crosstalk between tumor cells and the tumor microenvironment (TME) is crucial for the development, progression, metastasis, and therapeutic response to tumors. In this regard, phytochemicals with multimodal targeting abilities can be used as an alternative to current cancer therapy by inhibiting cancer survival pathways or modulating TME. However, due to their poor pharmacokinetics and low bioavailability, the success of phytochemicals in clinical trials is limited. Therefore, developing phytochemical-based nanomedicine or phytonanomedicine can improve the pharmacokinetic profile of these phytochemicals. Herein, the molecular characteristics and pharmacological insights of the proposed phytonanomedicine in cancer therapy targeting tumor tissue and altering the characteristics of cancer stem cells, chemoresistance, TME, and cancer immunity are well discussed. Further, we have highlighted the clinical perspective and challenges of phytonanomedicine in filling the gap in potential cancer therapeutics using various nanoplatforms. Overall, we have discussed how clinical success and pharmacological insights could make it more beneficial to boost the concept of nanomedicine in the academic and pharmaceutical fields to counter cancer metastases and drug resistance.

Flavonoids for the Treatment of Breast Cancer, Present Status and Future Prospective.

Breast Cancer is one of the most notorious cancer affecting women globally. Current therapies available for breast cancer treatment have certain limited efficacy; develop drug resistance and severe adverse effects. Thus, identifying novel therapies for treatment will reduce the devastating effect on cancer survivors. The exhilarating and fastgrowing studies on flavonoids have evidenced that it has the potential to inflect various antitumor activity and modulate various signal transduction pathways in carcinogenesis. Flavonoids also have been found to regulate cellular metabolism and oxidative stress, cell cycle progression, angiogenesis and metastasis, ultimately preventing the progression of the diseases. As per the reports, a flavonoid-rich diet appears to be the most potent and promising approach to abate the risk of cancer. Thus, now a day, these are the prime target for drug discovery research. Based on existing findings, it can be concluded that beyond the currently employed chemotherapeutics, natural products (like flavonoids) exhibit pleiotropic, multi-target activities and are budding as possible complementary chemopreventive molecules against breast cancer with fewer side effects than conventional therapy. In this review, we comprehensively highlight an outline of the multiple pleiotropic pharmacological effects of various major classes of flavonoids on breast cancer with their specific mechanisms underlying its anticancer effect.

Long-read 16S-seq reveals nasopharynx microbial dysbiosis and enrichment of Mycobacterium and Mycoplasma in COVID-19 patients: a potential source of co-infection.

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a major global health concern. This virus infects the upper respiratory tract and causes pneumonia-like symptoms. So far, few studies have shown alterations in nasopharyngeal (NP) microbial diversity, enrichment of opportunistic pathogens and their role in co-infections during respiratory infections. Therefore, we hypothesized that microbial diversity changes, with increase in the population of opportunistic pathogens, during SARS-CoV2 infection in the nasopharynx, which may be involved in co-infection in COVID-19 patients. The 16S rRNA variable regions, V1-V9, of NP samples of control and COVID-19 (symptomatic and asymptomatic) patients were sequenced using the Oxford Nanopore™ technology. Comprehensive bioinformatics analysis for determining alpha/beta diversities, non-metric multidimensional scaling, correlation studies, canonical correspondence analysis, linear discriminate analysis, and dysbiosis index were used to analyze the control and COVID-19-specific NP microbiomes. We observed significant dysbiosis in the COVID-19 NP microbiome with an increase in the abundance of opportunistic pathogens at genus and species levels in asymptomatic/symptomatic patients. The significant abundance of Mycobacteria spp. and Mycoplasma spp. in symptomatic patients suggests their association and role in co-infections in COVID-19 patients. Furthermore, we found strong correlation of enrichment of Mycobacteria and Mycoplasma with the occurrences of chest pain and fever in symptomatic COVID-19 patients. This is the first study from India to show the abundance of Mycobacteria and Mycoplasma opportunistic pathogens in non-hospitalized COVID-19 patients and their relationship with symptoms, indicating the possibility of co-infections.

Influence of various drying methods on physicochemical characteristics, antioxidant activity, and bioactive compounds in Centella asiatica L. leaves: a comparative study.

This comparative study aimed to evaluate the effects of different drying methods such as solar drying, shade drying (SHD), freeze drying (FD), oven drying, and microwave drying on the physicochemical properties, bioactive components, and antioxidant activity of Centella asiatica. The results showed that out of all the treated samples, FD-treated samples showed the lowest moisture content (2.4%), the lowest water activity (0.24%), and the highest rehydration ratio (5.51%). For samples treated using different drying methods, significant differences in Commission on Illumination - LAB (L *, a *, and b *) values and total color difference (E ) were observed. FD-treated samples showed the minimum color change (E ) and highest lightness (L *). Additionally, upon Fourier-transform infrared spectral analysis, no major changes in the functional groups were observed between C. asiatica leaves processed using different drying methods. FD-treated samples showed the highest antioxidant activity followed by SHD-treated samples, as measured by 2,2-diphenyl-1-picrylhydrazyl and 2,2-azino-bis-3-ethylbenzo-thiazoline-6-sulphonic acid radical scavenging assays. The phenolic (chlorogenic acid, rutin, kaempferol, and quercetin) and triterpene saponin (madecassoside, asiaticoside, madecassic acid, and asiatic acid) contents of the dried samples of C. asiatica were measured using high-performance liquid chromatography, which showed that the FD method allowed for the highest retention of phenolic and triterpene saponins among the tested drying techniques. The physicochemical characteristics, antioxidant potential, and bioactive retention of the samples that underwent FD treatment were superior to those of other methods, and therefore, FD can be employed as the first-line drying technique for processing C. asiatica leaves.

Nimbolide-encapsulated PLGA nanoparticles induces Mesenchymal-to-Epithelial Transition by dual inhibition of AKT and mTOR in pancreatic cancer stem cells.

Pancreatic ductal adenocarcinoma (PDAC) is associated with poor prognosis and remains highly aggressive despite current advancements in therapies. Chemoresistance and high metastatic nature of PDAC is attributed to a small subset of stem-like cells within the tumor known as Cancer Stem Cells (CSCs). Here, we developed a strategy for targeting pancreatic CSCs through forceful induction of mesenchymal-to-epithelial transition driven by encapsulating a phytochemical Nimbolide in nanoparticles. Binding of Nimbolide with the key regulator proteins of CSCs were studied through molecular docking and molecular dynamic simulation studies, which revealed that it binds to AKT and mTOR with high affinity. Further, in vitro studies revealed that Nim NPs are capable of inducing forceful mesenchymal-to-epithelial transition of pancreatospheres that leads to loss of multidrug resistance and self-renewal properties of pancreatospheres. Our study gives a proof of concept that encapsulation of Nim in PLGA nanoparticles increases its therapeutic effect on pancreatospheres. Further, binding of Nim to AKT and mTOR negatively regulates their activity that ultimately leads to mesenchymal-to-epithelial transition of pancreatic CSCs.

Insights from nanotechnology in COVID-19: prevention, detection, therapy and immunomodulation.

The outbreak of SARS-CoV-2 infection has presented the world with an urgent demand for advanced diagnostics and therapeutics to prevent, treat and control the spread of infection. Nanotechnology seems to be highly relevant in this emergency due to the unique physicochemical properties of nanomaterials which offer versatile chemical functionalization to create advanced biomedical tools. Here, nano-intervention is discussed for designing effective strategies in developing advanced personal protective equipment kits, disinfectants, rapid and cost-effective diagnostics and therapeutics against the infection. We have also highlighted the nanoparticle-based vaccination approaches and how nanoparticles can regulate the host immune system against infection. Overall, this review discusses various nanoformulations that have shown clinical relevance or can be explored in the fight against COVID-19.

Phytonanomedicine: a novel avenue to treat recurrent cancer by targeting cancer stem cells.

Research suggests that tumor relapse and metastasis is caused by minor population of tumor-initiating cells called cancer stem cells (CSCs), which exhibit self-renewability, quiescence, antiapoptosis, and drug resistance. Conventional chemotherapeutics target rapidly proliferating cells but fail to exert cytotoxic effects on CSCs, thus enriching them and driving metastasis and relapse. Hence, targeting CSCs is essential for developing novel therapies for effective cancer treatment. Pertaining to this, several phytochemicals have been identified that exhibit anti-CSC activity. However, poor pharmacokinetics prevents their clinical translation. Hence, developing phytonanomedicine can help to improve the pharmacokinetic profile of these biologically active molecules. In this review, we summarize the current state of the art of phytonanomedicine in the context of CSCs and their clinical status in cancer treatment.

Cavernous sinus melanoma: A rare tumor.

Primay melanoma of the cavernous sinus is very rare with only few cases reported in the literature. We present the cross-sectional imaging findings of this rare tumor. The differential diagnosis for cavernous sinus mass lesion is wide as it contains vital neurovascular structures that may be affected by vascular, neoplastic, infective, and infiltrative lesions arising in the cavernous sinus proper or via extension from adjacent intra and/or extracranial regions. Radiologic imaging can narrow the differential diagnosis, however, imaging cannot definitely reach single diagnosis if they present in atypical form with hemorrage and cystic degeneration. This case report illustrates that primary cavernous sinus melanoma may present as a atypical tumor with diagnostic dilemma.