Breaking the Cycle: Matrix Metalloproteinase Inhibitors as an Alternative Approach in Managing Tuberculosis Pathogenesis and Progression.

Mycobacterium tuberculosis (Mtb) has long posed a significant challenge to global public health, resulting in approximately 1.6 million deaths annually. Pulmonary tuberculosis (TB) instigated by Mtb is characterized by extensive lung tissue damage, leading to lesions and dissemination within the tissue matrix. Matrix metalloproteinases (MMPs) exhibit endopeptidase activity, contributing to inflammatory tissue damage and, consequently, morbidity and mortality in TB patients. MMP activities in TB are intricately regulated by various components, including cytokines, chemokines, cell receptors, and growth factors, through intracellular signaling pathways. Primarily, Mtb-infected macrophages induce MMP expression, disrupting the balance between MMPs and tissue inhibitors of metalloproteinases (TIMPs), thereby impairing extracellular matrix (ECM) deposition in the lungs. Recent research underscores the significance of immunomodulatory factors in MMP secretion and granuloma formation during Mtb pathogenesis. Several studies have investigated both the activation and inhibition of MMPs using endogenous MMP inhibitors (i.e., TIMPs) and synthetic inhibitors. However, despite their promising pharmacological potential, few MMP inhibitors have been explored for TB treatment as host-directed therapy. Scientists are exploring novel strategies to enhance TB therapeutic regimens by suppressing MMP activity to mitigate Mtb-associated matrix destruction and reduce TB induced lung inflammation. These strategies include the use of MMP inhibitor molecules alone or in combination with anti-TB drugs. Additionally, there is growing interest in developing novel formulations containing MMP inhibitors or MMP-responsive drug delivery systems to suppress MMPs and release drugs at specific target sites. This review summarizes MMPs' expression and regulation in TB, their role in immune response, and the potential of MMP inhibitors as effective therapeutic targets to alleviate TB immunopathology.

Recent Advances in Targeting Transition Metals (Copper, Iron, and Zinc) in Alzheimer's Disease.

Changes in the transition metal homeostasis in the brain are closely linked with Alzheimer's disease (AD), including intraneuronal iron accumulation and extracellular copper and zinc pooling in the amyloid plague. The brain copper, zinc, and iron surplus are commonly acknowledged characteristics of AD, despite disagreements among some. This has led to the theory that oxidative stress resulting from abnormal homeostasis of these transition metals may be a causative explanation behind AD. In the nervous system, the interaction of metals with proteins appears to be an essential variable in the development or suppression of neurodegeneration. Chelation treatment may be an option for treating neurodegeneration induced by transition metal ion dyshomeostasis. Some clinicians even recommend using chelating agents as an adjunct therapy for AD. The current review also looks at the therapeutic strategies that have been attempted, primarily with metal-chelating drugs. Metal buildup in the nervous system, as reported in the AD, could be the result of compensatory mechanisms designed to improve metal availability for physiological functions.

Mitochondrial morphology dynamics and ROS regulate apical polarity and differentiation in Drosophila follicle cells.

Mitochondrial morphology dynamics regulate signaling pathways during epithelial cell formation and differentiation. The mitochondrial fission protein Drp1 affects the appropriate activation of EGFR and Notch signaling-driven differentiation of posterior follicle cells in Drosophila oogenesis. The mechanisms by which Drp1 regulates epithelial polarity during differentiation are not known. In this study, we show that Drp1-depleted follicle cells are constricted in early stages and present in multiple layers at later stages with decreased levels of apical polarity protein aPKC. These defects are suppressed by additional depletion of mitochondrial fusion protein Opa1. Opa1 depletion leads to mitochondrial fragmentation and increased reactive oxygen species (ROS) in follicle cells. We find that increasing ROS by depleting the ROS scavengers, mitochondrial SOD2 and catalase also leads to mitochondrial fragmentation. Further, the loss of Opa1, SOD2 and catalase partially restores the defects in epithelial polarity and aPKC, along with EGFR and Notch signaling in Drp1-depleted follicle cells. Our results show a crucial interaction between mitochondrial morphology, ROS generation and epithelial cell polarity formation during the differentiation of follicle epithelial cells in Drosophila oogenesis.

Recent Developments in Tyrosine Kinase Inhibitor-based Nanotherapeutics for EGFR-resistant Non-small Cell Lung Cancer.

The advent of drug resistance in response to epidermal growth factor receptor (EGFR)- tyrosine kinase inhibitor (TKI) targeted therapy represents a serious challenge in the management of non-small cell lung cancer (NSCLC). These acquired resistance mutations, attributed to several advanced EGFR mutations and, necessitated the development of new-generation TKIs. Nanomedicine approaches provide a plausible way to address these problems by providing targeted delivery and sustained release, which have demonstrated success in preclinical trials. This review article provides a summary of nano-formulations designed for EGFR-TKI-resistant NSCLC, highlighting their efficacy in both in vitro and in vivo models. These findings reveal insights into the design of nanoparticles and multifunctional nanosystems, offering a potential avenue for efficacious treatment of EGFR-TKIresistant NSCLC.

Identification of a 10-mer peptide from the death domain of MyD88 which attenuates inflammation and insulin resistance and improves glucose metabolism.

Insulin resistance (IR) is the key pathophysiological cause of type 2 diabetes, and inflammation has been implicated in it. The death domain (DD) of the adaptor protein, MyD88 plays a crucial role in the transduction of TLR4-associated inflammatory signal. Herein, we have identified a 10-residue peptide (M10), from the DD of MyD88 which seems to be involved in Myddosome formation. We hypothesized that M10 could inhibit MyD88-dependent TLR4-signaling and might have effects on inflammation-associated IR. Intriguingly, 10-mer M10 showed oligomeric nature and reversible self-assembly property indicating the peptide's ability to recognize its own amino acid sequence. M10 inhibited LPS-induced nuclear translocation of NF-κB in L6 myotubes and also reduced LPS-induced IL-6 and TNF-α production in peritoneal macrophages of BALB/c mice. Remarkably, M10 inhibited IL-6 and TNF-α secretion in diabetic, db/db mice. Notably, M10 abrogated IR in insulin-resistant L6 myotubes, which was associated with an increase in glucose uptake and a decrease in Ser307-phosphorylation of IRS1, TNF-α-induced JNK activation and nuclear translocation of NF-κB in these cells. Alternate day dosing with M10 (10 and 20 mg/kg) for 30 days in db/db mice significantly lowered blood glucose and improved glucose intolerance after loading, 3.0 g/kg glucose orally. Furthermore, M10 increased insulin and adiponectin secretion in db/db mice. M10-induced glucose uptake in L6 myotubes involved the activation of PI3K/AKT/GLUT4 pathways. A scrambled M10-analog was mostly inactive. Overall, the results show the identification of a 10-mer peptide from the DD of MyD88 with anti-inflammatory and anti-diabetic properties, suggesting that targeting of TLR4-inflammatory pathway, could lead to the discovery of molecules against IR and diabetes.

A descriptive study of hepatitis C in people who inject drugs.

BACKGROUND OBJECTIVES: The seroprevalence of the hepatitis C virus (HCV) in general population is higher than that of human immunodeficiency virus (HIV) in India. People who inject drugs (PWIDs) constitute a high-risk group for all blood-borne infections. Multiple behavioural surveillance surveys have provided a rich typology of HIV-infected PWIDs, but this information is missing for HCV infection. We describe awareness, transmission risk factors and the treatment continuum for HCV infection among PWID. We also report spatial clustering of HCV infection in PWIDs residing in Bengaluru. METHODS: Information from clinical records was collected and telephonic interviews of retrospectively identified PWIDs who received treatment at a tertiary-level addiction treatment facility between 2016 and 2021 were conducted. RESULTS: We identified 391 PWIDs; 220 (56.26%) received an anti-HCV antibody test (4 th Generation HCV-Tridot). Individuals reporting unsafe injection practices were more often tested than those who did not ( χ2 =44.9, df=1, P <0.01). Almost half of the tested and more than a quarter of the whole sample (109/220, 49.9%; 109/391, 27.9%) were seropositive for HCV infection. The projected seropositivity in this group was between 27.9 per cent (best case scenario, all untested assumed negative) and 71.6 per cent (worst case scenario, all untested assumed positive). Only a minority of participants interviewed were aware of HCV (27/183, 14.7%). HCV infection and its associated risk behaviour (PWID) were clustered in certain localities (Diggle and Chetwynd Test; P =0.001) in Bengaluru in the southern district of Karnataka. INTERPRETATION CONCLUSIONS: Undetected HCV infection is common in PWIDs; awareness and treatment uptake is poor in this group. Spatial clustering of infections in a district shows transmission in close networks and provides opportunities for targeted interventions.

Pain Allaying Epalrestat-Loaded Lipid Nanoformulation for the Diabetic Neuropathic Pain Interventions: Design, Development, and Animal Study.

BACKGROUND: Diabetic peripheral neuropathy is the most common complication of diabetes mellitus. Epalrestat, an aldose reductase inhibitor, has been approved for clinical therapy for diabetic peripheral neuropathic pain. In the present study, solid lipid-based nanoparticles are used for oral administration of epalrestat (E-SLN) and evaluated against diabetic neuropathic pain in a rat model. METHODS: Experimental diabetes in rats was induced by a single dose of streptozotocin (STZ) administration. The therapeutic efficiency of Epalrestat nanoparticles (0.25, 0.50, 1, and 5 mg/kg) in diabetic rats was studied. STZinduced diabetic rats were treated with different doses of E-SLN for 8 weeks. The nanoparticles were orally administered at a single dose in rats, and the various parameters related to peripheral neuropathy were evaluated and compared with the bare drug. The blood glucose level was estimated by standard glucometer, HbA1c, triglycerides, total cholesterol, and liver function test (ALT and AST) were analyzed by blood samples collected from retro-orbital plexus. Oxidative stress markers and Na+K+ATPase, TNF-α, and IL-1ß levels were measured in the homogenate of sciatic nerves. Behavioral tests were also performed by the hot plate method and tail-flick method. RESULTS: E-SLN synthesized by the micro-emulsification method was 281 ± 60 nm in size, and encapsulation efficacy was found to be 88 ± 2%. Optimized E-SLN were characterized and found to be optimum in size, spherical shape, decent encapsulation efficiency, stable at acidic gastric pH, and suitable for oral delivery. E-SLNs did not significantly reverse the STZ-induced elevated blood glucose level (FBS and PPBS), HbA1c, triglycerides, and total cholesterol but significantly improved TNF-α, IL-1ß, and increased Na+K+ATPase levels, oxidative stress marker and ALT, AST in the treated rat group as compared with the diabetic group. Doses of E-SLN, i.e. 0.5, 1.0, 2.5, and 5 mg/kg, significantly increased the tail-flick latency time and hot plate response time in a dose-dependent manner compared with the diabetic group. CONCLUSION: Thus, it is suggested that E-SLN were equally effective and less hepatotoxic compared with the standard treatment of epalrestat. To the best of our knowledge, we, for the first time, propose the orally deliverable E-SLN that ameliorates STZ-induced diabetes neuropathic pain effectively as compared with conventional epalrestat.

Taming the Devil: Antimicrobial Peptides for Safer TB Therapeutics.

Tuberculosis (TB) is a highly contagious infection with extensive mortality and morbidity. The rise of TB-superbugs (drug-resistant strains) with the increase of their resistance to conventional antibiotics has prompted a further search for new anti-mycobacterial agents. It is difficult to breach the barriers around TB bacteria, including mycolic cell wall, granuloma, biofilm and mucus, by conventional antibiotics in a short span of time. Hence, there is an essential need for molecules with an unconventional mode of action and structure that can efficiently break the barriers around mycobacterium. Antimicrobial peptides (AMP) are essential components of innate immunity having cationic and amphipathic characteristics. Lines of evidence show that AMPs have good myco-bactericidal and antibiofilm activity against normal as well as antibiotic-resistant TB bacteria. These peptides have shown direct killing of bacteria by membrane lysis and indirect killing by activation of innate immune response in host cells by interacting with the component of the bacterial membrane and intracellular targets through diverse mechanisms. Despite a good anti-mycobacterial activity, some undesirable characteristics are also associated with AMP, including hemolysis, cytotoxicity, susceptibility to proteolysis and poor pharmacokinetic profile, and hence only a few clinical studies have been conducted with these biomolecules. The design of new combinatorial therapies, including AMPs and particulate drug delivery systems, could be new potential alternatives to conventional antibiotics to fight MDR- and XDRTB. This review outlined the array of AMP roles in TB therapy, possible mechanisms of actions, activities, and current advances in pragmatic strategies to improve challenges accompanying the delivery of AMP for tuberculosis therapeutics.

Late Metastasis of Renal Cell Carcinoma in Distal Femur Treated with Knee Joint Preservation: A Case Report.

Introduction: Late metastasis and recurrences after 10 years of curative treatment is a known biological behavior of renal cell carcinoma (RCC) and a long follow-up is required for the detection of metastasis. Late solitary bony metastasis is very rare. No case of a late solitary metastasis of distal femur, treated with wide local excision and reconstruction, is available in the literature. We present a case of solitary metastatic lesion of distal femur 12 years after radical nephrectomy for renal cell carcinoma in a 64-year-old male. Case Report: The patient presented to us with swelling in the right distal thigh for three years with a history of radical nephrectomy for RCC 12-years back. The lesion was not responding to local radiotherapy, and chemotherapy in the form of oral pazopanib, taken before orthopedic consultation. After core biopsy, the tumor was managed by intercalary wide local excision and reconstruction using a cement block and a lateral locking plate. Post-operatively, the histopathology report confirmed the diagnosis to be a clear cell tumor, consistent with metastatic RCC. The patient is independently mobile and tumor-free 2 years after the surgery. Conclusion: Wide resection and reconstruction of the skeletal defect remains the mainstay of the management of metastatic solitary lesion. We have presented a unique case of distal fem-oral solitary metastatic deposit from a primary RCC 12 years post radical nephrectomy treated by intercalary resection and reconstruction with bone cement-plate hybrid construct.

Evaluation of Histomorphological Parameters to Predict Occult Nodal Metastasis in Early-Stage Oral Squamous Cell Carcinoma.

OBJECTIVE: The oral squamous cell carcinoma (OSCC) treatment protocol depends upon lymph node metastasis. Elective neck dissection for early-stage OSCC (pT1/T2) elective neck dissection reduces the morbidity rate. It also reduces the overall survival and thus it becomes important to detect lymph node metastasis in early-stage OSCC. MATERIAL AND METHOD: Various histomorphological parameters have been studied to predict nodal metastasis in early-stage OSCC. We aim to evaluate these parameters in the context of nodal metastasis. 78 cases of early-stage OSCC were included in the study with histopathologic parameters like tumor size, grade, tumor depth of invasion (DOI), lymphovascular invasion (LVI), perineural invasion (PNI), worst pattern of invasion (WPOI), and lymph node level. RESULTS: Out of the 78 patients, 32 patients had lymph node metastasis. T stage, DOI, LVI, and WPOI showed statistically significant deviance from the null model (P-values of 0.007, 0.01, 0.04 and 0.02 respectively). The Odds Ratio (OR) of T stage, DOI, LVI and WPOI were 4.45 (95% C.I =1.47-14.1), 4.4 (95% C.I =1.32-15.88), 8.12 (95% C.I =1.002-198.20), and 3.39 (95% C.I =1.24-9.74) respectively. On multivariate analysis (Firth logistic regression) using DOI, LVI, and WPOI as independent variables, only T-stage and WPOI retained statistical significance. CONCLUSION: The prognostic information supplied by evaluating DOI, LVI, and WPOI warrants the inclusion of these parameters in the standard reporting format for all cases of OSCC.

Biodegradation of waste cooking oil and simultaneous production of rhamnolipid biosurfactant by Pseudomonas aeruginosa P7815 in batch and fed-batch bioreactor.

Biosurfactants are non-toxic, surface-active biomolecules capable of reducing surface tension (ST) and emulsifying interface at a comparably lower concentration than commercial surfactants. Yet, poor yield, costlier substrates, and complex cultivation processes limit their commercial applications. This study focuses on producing biosurfactants by Pseudomonas aeruginosa P7815 in batch and fed-batch bioreactor systems using waste cooking oil (WCO) as the sole carbon source. The batch study showed a 92% of WCO biodegradation ability of P. aeruginosa producing 11 g L-1 of biosurfactant. To enhance this biosurfactant production, a fed-batch oil feeding strategy was opted to extend the stationary phase of the bacterium and minimize the effects of substrate deprivation. An enhanced biosurfactant production of 16 g L-1 (i.e. 1.5 times of batch study) was achieved at a feed rate of 5.7 g L-1d-1 with almost 94% of WCO biodegradation activity. The biosurfactant was characterized as rhamnolipid using Fourier transform infrared spectroscopy (FTIR), and its interfacial characterization showed ST reduction to 29 ± 1 mN m-1 and effective emulsification stability at pH value of 4, temperature up to 40 °C and salinity up to 40 g L-1. The biosurfactant exhibited antibacterial activity with minimum inhibitory concentration (MIC) values of 100 µg mL-1 and 150 µg mL-1 for pathogenic E. hirae and E. coli, respectively. These findings suggest that biodegradation of WCO by P. aeruginosa in a fed-batch cultivation strategy is a potential alternative for the economical production of biosurfactants, which can be further explored for biomedical, cosmetics, and oil washing/recovery applications.

Epistaxis: the cause found beyond the nose.

Renal cell carcinoma (RCC) is a malignant disease that is often diagnosed at a metastatic stage. The head and neck represent up to 3% of the metastatic RCC, and the paranasal sinus area is one of the least involved sites. Here, we introduce the case of a 74-year-old female patient who presented with a history of traumatic nasal bleed. A cranial computed tomography scan and magnetic resonance imaging showed a fronto-ethmoidal mass with pachymeningeal involvement. A nasal biopsy from the paranasal sinuses was taken. On histopathological examination, metastatic clear cell carcinoma was the main hypothesis, which later was confirmed to be RCC on immunohistochemistry. On further radiological examination, an exophytic mass was depicted in the kidney's upper and middle pole. The patient had no renal complaints and was asymptomatic. Fronto-ethmoidal sinus is a rare site for metastatic RCC, especially in cases where the patient is asymptomatic. Early detection by keeping RCC metastasis as the differential diagnosis in such cases can lead to early treatment and improve the overall survival of the patient.

Decannulation following tracheostomy in children: A systematic review of decannulation protocols.

OBJECTIVE: To provide a systematic review of the existing pediatric decannulation protocols, including the role of polysomnography, and their clinical outcomes. METHODS: Five online databases were searched from database inception to May 29, 2020. Study inclusion was limited to publications that evaluated tracheostomy decannulation in children 18 years of age and younger. Data extracted included patient demographics and primary indication for tracheostomy. Methods used to assess readiness for decannulation were noted including the use of bronchoscopy, tracheostomy tube modifications, and gas exchange measurements. After decannulation, details regarding mode of ventilation, location, and length of observation period, and clinical outcomes were also collected. Descriptive statistical analyses were performed. RESULTS: A total of 24 studies including 1395 children were reviewed. Tracheostomy indications included upper airway obstruction at a well-defined anatomic site (35%), upper airway obstruction not at a well-defined site (12%) and need for long-term ventilation and pulmonary care (53%). Bronchoscopy was routinely used in 23 of 24 (96%) protocols. Tracheostomy tube modifications in the protocols included capping (n = 20, 83%), downsizing (n = 14, 58%), and fenestrations (n = 2, 8%). Measurements of gas exchange included polysomnography (n = 13/18, 72%), oximetry (n = 10/18, 56%), blood gases (n = 3,17%), and capnography (n = 3, 17%). After decannulation, children in 92% of protocols were transitioned to room air. Observation period of 48 h or less was used in 76% of children. CONCLUSIONS: There exists large variability in pediatric decannulation protocols. Polysomnography plays an integral role in assessing most children for tracheostomy removal. Evidence-based guidelines to standardize pediatric tracheostomy care remain an urgent priority.

Efficient, enzyme responsive and tumor receptor targeting gelatin nanoparticles decorated with concanavalin-A for site-specific and controlled drug delivery for cancer therapy.

The tumor targeting and stimuli responsiveness behavior of intelligent drug delivery systems imparts effective therapeutic delivery and decreases the toxicity of conventional chemotherapeutic agents in off-target organs. To achieve the receptor targeting and smart drug release, several strategies have been employed to engineer nano-carrier with stimulus sensitivity. In this work, mannose receptor-targeted and matrix metalloproteinase (MMP) responsive gelatin nanoparticles were developed and assessed for its receptor targeting and "on-demand" controlled drug delivery in lung cancer therapeutics. MMPs are protease enzymes and over-expressed in tumorous tissues in all the stages of cancer. The cancer cells also have over-expressed mannose receptors on the cell surface. The surface decoration of gelatin nanoparticles with concanavalin A (con-A) tends to bind with mannose moiety of cell surface glycoproteins which enhances the cancer cell-specific higher uptake of nanoparticles. Gelatin nanoparticles have attracted significant attraction in recent years as a potential drug carrier because of its good biocompatibility and versatile physicochemical properties desirable to deliver the drug. Cisplatin was complexed with the gelatin matrix (CG-NP) to evaluate stimuli responsiveness with the lung cancer cells and its release pattern. In this smart inhalable delivery system, cisplatin loaded gelatin nanoparticles were surface decorated with con-A (CCG-NP). In tumorous cells, con-A coating is expected to enhance mannose receptor-specific cellular internalization of CCG-NP, and subsequently high level of MMP in tumor tissues would help to release cisplatin in response and ensures controlled drug release. The synthesized CCG-NP has shown enzyme triggered drug release and favorable endocytosis after incubation of 12 h compare to uncoated nanoparticles. The efficacy of CCG-NP significantly increased in presence of MMP-2 enzyme in lung cancer cell line A549 cells. It also significantly enhanced reactive oxygen species generation, cell cycle arrest in S and G2/M phase, and apoptosis in cancer cells. Therefore, inhalable CCG-NP promises a pragmatic approach to construct a receptor targeting and an "on-demand" drug delivery system to efficiently deliver the drug at the tumor site only.

Anterior Bridge Plate Osteosynthesis in Comminuted Fracture Shaft of Humerus in Manual Workers- is it Optimum Choice?

BACKGROUND: Bridge plate osteosynthesis of fractures by minimal invasion and near acceptable reduction is becoming popular and acceptable entity. Management of humeral shaft fracture has evolved a lot with their pros and cons. Anterior bridge plate osteosynthesis (ABPO) for humeral shaft fracture is pertinent to a minimal invasive procedure, and it has evolved as a new entrant in the surgical techniques. This study was designed to carry out the results and efficacy of ABPO in the comminuted fracture shaft of the humerus in the manual workers. METHODS: Study included the closed comminuted fracture of shaft of humerus in skeletally mature patients engaged predominantly in manual works, like overhead sports activity, laborers, and industrial workers. All fractures were managed by either 4.5-mm narrow locking compression plate (LCP) or dynamic compression plate (DCP).The functional outcome for elbow was measured by Mayo's elbow performance score (MEPS) and functional outcome of shoulder was measured by UCLA (University of California at Los Angeles) shoulder score system. RESULTS: In this study 37 patients were enrolled. Mean duration for satisfactory radiographic union was 12.3 weeks. The mean duration of follow-up period was 14.5 months. In respect to elbow function, the average Mayo elbow score was 92.42 ±2.17 and average UCLA score of shoulder function was 34 ±0.34. CONCLUSION: The ABPO is an optimum choice for managing the comminuted fracture shaft of humerus in manual labors. The outcomes are favorable and reproducible with very few risks.

Aminocellulose-Grafted Polymeric Nanoparticles for Selective Targeting of CHEK2-Deficient Colorectal Cancer.

We report the formulation of aminocellulose-grafted polymeric nanoparticles containing LCS-1 for synthetic lethal targeting of checkpoint kinase 2 (CHEK2)-deficient HCT116 colon cancer (CRC) cells to surpass the limitations associated with the solubility of LCS-1 (a superoxide dismutase inhibitor). Aminocellulose (AC), a highly biocompatible and biodegradable hydrophilic polymer, was grafted over polycaprolactone (PCL), and a nanoprecipitation method was employed for formulating nanoparticles containing LCS-1. In this study, we exploited the synthetic lethal interaction between SOD1 and CHEK2 for the specific inhibition of CHEK2-deficient HCT116 CRC cells using LCS-1-loaded PCL-AC NPs. Furthermore, the effects of formation of protein corona on PCL-AC nanoparticles were also assessed in terms of size, cellular uptake, and cell viability. LCS-1-loaded NPs were evaluated for their size, zeta potential, and polydispersity index using a zetasizer, and their morphological characteristics were assessed by transmission electron microscopy, scanning electron microscopy, and atomic force microscopy analyses. Cellular internalization using confocal microscopy exhibited that nanoparticles were uptaken by HCT116 cells. Also, nanoparticles were cytocompatible as they did not induce cytotoxicity in hTERT and HEK-293 cells. The LCS-1-loaded PCL-AC NPs were quite hemocompatible and were 240 times more selective in killing CHEK2-deficient cells as compared to CHEK2-proficient CRC cells. Moreover, PCL-AC NPs exhibited that the protein corona-coated nanoparticles were incubated in the human and fetal bovine sera as visualized by SDS-PAGE. A slight increment in hydrodynamic diameter was observed for corona-coated PCL-AC nanoparticles, and size increment was further confirmed by TEM. Corona-coated PCL-AC NPs also exhibited cellular uptake as demonstrated by flow cytometric analysis and did not cause cytotoxic effects on hTERT cells. The nanoformulation was developed to enhance therapeutic potential of the drug LCS-1 for enhanced lethality of colorectal cancer cells with CHEK2 deficiency.

Formulation and optimization of silymarin-encapsulated binary micelles for enhanced amyloid disaggregation activity.

Silymarin (SLY) is a natural hydrophobic polyphenol that possesses antioxidant and amyloid fibril (Aß1-42) inhibition activity, but its activity is hindered due to low aqueous solubility. In this study, SLY is encapsulated in binary micelle (SLY-BM) that has been utilized to enhance the Aß1-42 fibril disaggregation. To enhance the aqueous solubility, SLY payload in micelles were optimized using Box-Behnken Design (BBD) to increase the efficiency of Aß1-42 fibril disaggregation. BBD was used to investigate the effect of ratio of Solutol HS15:Poloxamer-188, amount of acetone and hydration volume on critical quality attributes, particle size, and entrapment efficiency for SLY-BM. Furthermore, SLY-BM was characterized for its physical and drug release properties. The Aß1-42 fibril disaggregation and antioxidant studies were monitored using spectroscopic and microscopic techniques. BBD optimized the particle size <50 nm with %EE > 80%, and solubility factor of SLY-BM was enhanced to 460 folds than free SLY. Inhibitory concentration 50% (IC50) value of SLY-BM was 19.67 µg/mL compared to free SLY (30.06 µg/mL) in diphenylpicrahydrazyl assay. SLY-BM increased the Aß1-42 disaggregation compared to free SLY observed via thioflavin-T assay, photon correlation spectroscopy, and circular dichorism. Further morphological evaluation of Aß1-42 disaggregation was monitored by microscopy which showed that SLY-BM disaggregated the fibrils in 48 h. According to our findings, we concluded that SLY-BM micelles are potential candidates for delivery of neuroprotective agents.

Preoperative successful thrombectomy and thrombolysis of acute extensive splanchnic venous system and TIPSS thrombosis in a child with Budd-Chiari syndrome-Creating a window to enable living donor liver transplantation.

Preoperative extensive PV thrombosis can pose a technical challenge during liver transplantation surgery. Several strategies adopted to mitigate this problem include creation of a superior mesenteric vein-PV jump graft, use of a polytetrafluoroethylene graft, renoportal anastomosis, or cavoportal hemitransposition. Extensive and diffuse thrombosis of the splanchnic venous system may even necessitate multivisceral transplantation. We describe the case of a pediatric patient with Budd-Chiari syndrome and decompensated cirrhosis, who developed extensive thrombosis of the porto-spleno-mesenteric venous system prior to liver transplantation. We used a combination technique of thrombus aspiration by a novel trans-TIPPS approach followed by thrombolysis. Complete preoperative resolution of the extensive thrombosis was achieved. This allowed the creation of a brief window to enable planned LDLT. In prudently selected patients, performing an early mechanical and chemical thrombolysis of an extensive acute splanchnic venous thrombosis can thus help expedite a planned LDLT.

Epistaxis: the cause found beyond the nose

Renal cell carcinoma (RCC) is a malignant disease that is often diagnosed at a metastatic stage. The head and neck represent up to 3% of the metastatic RCC, and the paranasal sinus area is one of the least involved sites. Here, we introduce the case of a 74-year-old female patient who presented with a history of traumatic nasal bleed. A cranial computed tomography scan and magnetic resonance imaging showed a fronto-ethmoidal mass with pachymeningeal involvement. A nasal biopsy from the paranasal sinuses was taken. On histopathological examination, metastatic clear cell carcinoma was the main hypothesis, which later was confirmed to be RCC on immunohistochemistry. On further radiological examination, an exophytic mass was depicted in the kidney's upper and middle pole. The patient had no renal complaints and was asymptomatic. Fronto-ethmoidal sinus is a rare site for metastatic RCC, especially in cases where the patient is asymptomatic. Early detection by keeping RCC metastasis as the differential diagnosis in such cases can lead to early treatment and improve the overall survival of the patient.

Unusual gastric tumour in an adolescent: primary gastric teratoma.

Gastric teratoma is a rare entity beyond infancy and usually presents as a slow-growing asymptomatic abdominal mass. There are a few published reports of these tumours seen in patients beyond the age of 1 year. In resource-constrained population, these masses are usually neglected because of minimal symptoms associated with these tumours. We report a case of a 14-year-old adolescent who was diagnosed to have a large primary gastric teratoma and underwent en bloc excision with wedge resection of the stomach. A systematic review to identify the previously reported cases of primary gastric teratoma in patients of over the age of 1 year in last 50 years yielded only five articles. A high index of suspicion for primary gastric teratomas in young children and adolescents presenting with asymptomatic large abdominal masses would help treat these patients with a curative intent and excellent treatment outcomes.