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Black cohosh ( Cimicifuga racemosa ) (CR) is a popular herb and is medically lauded for ameliorating myriad symptoms associated with menopause. However, its pharmaceutical limitations and non-availability of a patient-compliant drug delivery approach have precluded its prevalent use. Henceforth, the current research premise is aimed at developing an ethosomal gel incorporating triterpene enriched fraction (TEF) obtained from CR and evaluating its effectiveness through the transdermal application. TEF-loaded ethosomes were formulated using solvent injection, optimized and characterised. The optimized ethosomes were then dispersed into a polymeric gel base to form ethosomal gel which was further compared with the conventional gel by in-vitro and ex-vivo experiments. Here, the quality by design (QbD) approach was exploited for the optimization and development of ethosomal gel. The elements of QbD comprising initial risk assessment, design of experimentation (DoE), and model validation for the development of formulation have all been described in detail. The optimized ethosomes (F03) showed a nanometric size range, negative zeta potential and good entrapment. The in vitro release profile of gel revealed a burst release pattern following the Korsmeyer Peppas model having Fickian diffusion. The transdermal flux of ethosomal gel was observed to be more than that of conventional gel. Texture analysis and rheological characterization of the gel, revealed good strength showing shear thinning and pseudoplastic behaviour. The confocal microscope investigation revealed the deeper skin permeation of ethosomal gel than conventional gel. This result was further strengthened by DSC, IR and histological assessment of the animal skin (Wistar rat), treated with the optimized formulation. Conclusively, the implementation of QbD in the formulation resulted in a better understanding of the process and the product. It aids in the reduction of product variability and defects, hence improving product development efficiencies. Additionally, the ethosomal gel was found to be a more effective and successful carrier for TEF than the conventional gel through the transdermal route. Moreover, this demands an appropriate animal study, which is underway, for a stronger outcome.

The objective of this review is to thoroughly investigate herbal nano gels as a promising drug delivery approach for the management of various chronic and acute disorders. Herbal nano gels are a novel and promising drug delivery technique, offering special benefits for better therapeutic efficacy. This review offers a comprehensive analysis of the herbal nano gels with a particular emphasis on their evaluation concerning conventional dosage forms, polymer selection criteria, drug release mechanisms, and applications. The comparison study demonstrates that herbal nano gels have different benefits over conventional dose forms. In the areas of oral administration for improved bioavailability and targeted delivery to the gastrointestinal tract, topical drug delivery for dermatological conditions, and targeted delivery strategies for the site-specific treatment of cancer, inflammatory diseases, and infections, they demonstrate encouraging results in transdermal drug delivery for systemic absorption. A promising platform for improved medication delivery and therapeutic effectiveness is provided by herbal nanogels. Understanding drug release mechanisms further contributes to the controlled and sustained delivery of herbal therapeutics. Some of the patents are discussed and the comparative analysis showcases their superiority over conventional dosage forms, and the polymer selection criteria ensure the design of efficient and optimized formulations. Herbal-based nano gels have become a potential approach for improving drug administration. They provide several advantages such as better stability, targeted delivery, and controlled release of therapeutic components. Herbal nano gels are a promising therapeutic approach with the ability to combat a wide range of conditions like cancer, wound healing and also improve patient compliance., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Breast cancer is the most commonly diagnosed type of cancer and ranks second among cancer that leads to death. From becoming the foremost reason for global concern, this multifactorial disease is being treated by conventional chemotherapies that are associated with severe side effects, with chemoresistance being the ruling reason. Exemestane, an aromatase inhibitor that has been approved by the US FDA for the treatment of breast cancer in post-menopausal women, acts by inhibiting the aromatase enzyme, in turn, inhibiting the production of estrogen. However, the clinical application of exemestane remains limited due to its poor aqueous solubility and low oral bioavailability. Furthermore, the treatment regimen of exemestane often leads to thinning of bone mineral density. Thymoquinone, a natural compound derived from the oil of the seeds of Nigella sativa Linn, possesses the dual property of being a chemosensitizer and chemotherapeutic agent. In addition, it has been found to exhibit potent bone protection properties, as evidenced by several studies. To mitigate the limitations associated with exemestane and to deliver to the cancerous cells overcoming chemoresistance, the present hypothesis has been put forth, wherein a natural chemosensitizer and chemotherapeutic agent thymoquinone will be incorporated into a lipid nanocarrier along with exemestane for combinatorial delivery to cancer cells. Additionally, thymoquinone being bone protecting will help in ousting the untoward effect of exemestane at the same time delivering it to the required malignant cells, safeguarding the healthy cells, reducing the offsite toxicity, and providing potent synergistic action., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objective . While the accuracy of dose calculations in water with Acuros XB is well established, experimental validation of dose in bone is limited. Acuros XB reports both dose-to-medium and dose-to-water, and these values differ in bone, but there are no reports of measurements of validation in bone. This work compares Acuros XB calculations to measurements of absolute dose in aluminum (medium similar to bone). The validity of using selected relative dosimeters in aluminum is also investigated. Approach . A calorimeter with an aluminum core embedded in an aluminum phantom was selected as bone surrogate for the measurement of absolute dose. Matching the medium of the core to the medium of the phantom allowed eliminating the calculation of the conversion between media. The dose was measured at the fixed depth of 3.3 cm in aluminum (∼9 g·cm -2 ) with 6X, 10X, 6FFF and 10FFF photon beams from a TrueBeam Varian linac. In addition, experimental cross-calibration between water and aluminum was performed for an IBA CC13 ionization chamber, a PTW microDiamond and EBT3 Gafchromic film. Main results . Calculations with Acuros XB dose-to-medium in aluminum differed from the calorimetry data by -2.8% to -3.5%, depending on the beam. Use of dose-to-water would have resulted in about 39% discrepancy. The cross calibration coefficient between water and aluminum yielded values of about 0.87 for the CC13 chamber, 0.91 for the microDiamond, and 0.88 for the film, and independent of the beam within about ±1%. Significance . It was demonstrated the value of the dose-to-medium in aluminum (surrogate of bone) computed with Acuros XB is close to the value of the absolute dose measured with a calorimeter, and there is a significant discrepancy when dose-to-water is used instead. The use of an ionization chamber, a microDiamond and Gafchromic film in aluminum required a considerable correction from calibration in water., (© Canadian 2022 Crown copyright.)

Patients with non-small cell lung cancer (NSCLC) who have distant metastases have a poor prognosis. To determine which genomic factors of the primary tumor are associated with metastasis, we analyzed data from 759 patients originally diagnosed with stage I-III NSCLC as part of the AACR Project GENIE Biopharma Collaborative consortium. We found that TP53 mutations were significantly associated with the development of new distant metastases. TP53 mutations were also more prevalent in patients with a history of smoking, suggesting that these patients may be at increased risk for distant metastasis. Our results suggest that additional investigation of the optimal management of patients with early-stage NSCLC harboring TP53 mutations at diagnosis is warranted in light of their higher likelihood of developing new distant metastases., (© 2022. The Author(s).)

The article has been withdrawn at the request of the editor of the journal Current Pharmaceutical Biotechnology., Bentham Science apologizes to the readers of the journal for any inconvenience this may have caused., The Bentham Editorial Policy on Article Withdrawal can be found at https://benthamscience.com/editorial-policies-main.php., Bentham Science Disclaimer: It is a condition of publication that manuscripts submitted to this journal have not been published and will not be simultaneously submitted or published elsewhere. Furthermore, any data, illustration, structure or table that has been published elsewhere must be reported, and copyright permission for reproduction must be obtained. Plagiarism is strictly forbidden, and by submitting the article for publication the authors agree that the publishers have the legal right to take appropriate action against the authors, if plagiarism or fabricated information is discovered. By submitting a manuscript the authors agree that the copyright of their article is transferred to the publishers if and when the article is accepted for publication., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net)

Low aqueous solubility, adverse effects of Cisplatin includes hepatotoxicity and nephrotoxicity necessitates development of nanoparticulate drug delivery. The study pertains to development of CisNLC (Cisplatin loaded Nanostructured Lipid Carrier) by ultrasonication. Physical characterisation includes particle size, zeta potential, TEM, SEM-EDX, DSC. Its ex vivo biocompatibility, pharmacokinetics and biodistribution along with acute toxicity induced oxidative stress in Balb/c mice were evaluated. The mean particle diameter of CisNLC was observed to be 141.5 ± 3.86 nm with zeta potential of -41.5 ± 1.62 mV. In vitro release studies at pH 7.4 and 5.8 showed burst release following a sustained release pattern post-72 h. CisNLC showed anticancer efficacy against PA-1. Negligible ex vivo haemolysis indicated bio-compatibility. Improved pharmacokinetics of CisNLC was observed. Acute toxicity and oxidative stress evaluation proved negligible toxicity by CisNLC. The formulated CisNLC had a good physical stability, biocompatible, indicated enhanced circulation and caused negligible toxicity on liver and kidney as compared to pure Cis.

This work aimed to develop dual drug-loaded nanostructured lipid carriers of raloxifene and naringin (RLX/NRG NLCs) for breast cancer. RLX/NRG NLCs were prepared using Compritol 888 ATO and oleic acid using a hot homogenization-sonication method and optimized using central composite design (CCD). The optimized RLX/NRG NLCs were characterized and evaluated using multiple technological means. The optimized RLX/NRG NLCs exhibited a particle size of 137.12 nm, polydispersity index (PDI) of 0.266, zeta potential (ZP) of 25.9 mV, and entrapment efficiency (EE) of 91.05% (raloxifene) and 85.07% (naringin), respectively. In vitro release (81 ± 2.2% from RLX/NRG NLCs and 31 ± 1.9% from the RLX/NRG suspension for RLX and 93 ± 1.5% from RLX/NRG NLCs and 38 ± 2.01% from the RLX/NRG suspension for NRG within 24 h). Concurrently, an ex vivo permeation study exhibited nearly 2.3 and 2.1-fold improvement in the permeability profiles of RLX and NRG from RLX/NRG NLCs vis-à-vis the RLX/NRG suspension. The depth of permeation was proved with CLSM images which revealed significant permeation of the drug from the RLX/NRG NLCs formulation, 3.5-fold across the intestine, as compared with the RLX/NRG suspension. An in vitro DPPH antioxidant study displayed a better antioxidant potential of RLX/NRG in comparison to RLX and NRG alone due to the synergistic antioxidant effect of RLX and NRG. An acute toxicity study in Wistar rats showed the safety profile of the prepared nanoformulations and their excipients. Our findings shed new light on how poorly soluble and poorly permeable medicines can be codelivered using NLCs in an oral nanoformulation to improve their medicinal performance.

Background: Diabetes mellitus is a chronic noncommunicable disease, and hypertension (HT) is the most common comorbidity which affects their quality of life (QoL)., Aim: The aim of the study was to assess the effects of antihypertensive agents (viz., amlodipine, ramipril, telmisartan, and ramipril with telmisartan) on the blood pressure (BP) and QoL., Methodology: It was an open-labeled prospective intention-to-treat study done in diabetic hypertensive patients ( CTRI /2016/10 /007340 ). Patients were randomly assigned antihypertensive agents, namely, amlodipine, ramipril, telmisartan, and a combination of ramipril with telmisartan (RT) in four groups. They were evaluated for BP, blood sugar level, and QoL at baseline and 24 th week., Results: After 24 weeks of therapy, systolic BP (SBP) and diastolic BP (DBP) were significantly reduced in all groups. In amlodipine, there was a mean percentage fall of SBP by 15.85% (confidence interval [CI]: 21.38-28.13) and DBP by 11.22% (CI: 8.41-12.70); in ramipril - 14.4% (CI: 18.61-25.15) and 12.4% (CI 8.88-13.99); telmisartan - 18.4% (CI: 24.89-10.79) and 14.6% (CI 10.79-16.24); and in RT group, SBP 17.7% (CI: 23.38-29.18) and DBP 12.4% (CI: 9.05-13.02). QoL score increased by 30.56% (CI: 14.30-10.90), 30.94% (CI: 14.21-10.68), 28.07% (CI: 14.89-11.20), and 28.84% (CI: 15.49-11.77), in respective groups ( P < 0.0001, each). However, they were nonsignificant between the study groups ( P > 0.05)., Conclusion: Amlodipine, ramipril, telmisartan, and a combination of RT are equally effective to improve BP and QoL among diabetic hypertensive patients. However, amlodipine and telmisartan lacked in dry cough and more tolerable than the ramipril and RT therapy. Henceforth, amlodipine and telmisartan are better choice to control HT among DM patients., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Perspectives in Clinical Research.)

Background: A clinical study comparing the hemodynamic outcomes of transcatheter mitral valve replacement (TMVR) with vs. without Laceration of the Anterior Mitral leaflet to Prevent Outflow Obstruction (LAMPOON) has never been designed nor conducted., Aims: To quantify the hemodynamic impact of LAMPOON in TMVR using patient-specific computational ( in silico ) models., Materials: Eight subjects from the LAMPOON investigational device exemption trial were included who had acceptable computed tomography (CT) data for analysis. All subjects were anticipated to be at prohibitive risk of left ventricular outflow tract (LVOT) obstruction from TMVR, and underwent successful LAMPOON immediately followed by TMVR. Using post-procedure CT scans, two 3D anatomical models were created for each subject: (1) TMVR with LAMPOON (performed procedure), and (2) TMVR without LAMPOON (virtual control). A validated computational fluid dynamics (CFD) paradigm was then used to simulate the hemodynamic outcomes for each condition., Results: LAMPOON exposed on average 2 ± 0.6 transcatheter valve cells (70 ± 20 mm 2 total increase in outflow area) which provided an additional pathway for flow into the LVOT. As compared to TMVR without LAMPOON, TMVR with LAMPOON resulted in lower peak LVOT velocity, lower peak LVOT gradient, and higher peak LVOT effective orifice area by 0.4 ± 0.3 m/s (14 ± 7% improvement, p = 0.006), 7.6 ± 10.9 mmHg (31 ± 17% improvement, p = 0.01), and 0.2 ± 0.1 cm 2 (17 ± 9% improvement, p = 0.002), respectively., Conclusion: This was the first study to permit a quantitative, patient-specific comparison of LVOT hemodynamics following TMVR with and without LAMPOON. The LAMPOON procedure achieved a critical increment in outflow area which was effective for improving LVOT hemodynamics, particularly for subjects with a small neo-left ventricular outflow tract (neo-LVOT)., Competing Interests: KK has served as a consultant for Abbott Vascular. PB has served as a consultant for Edwards Lifesciences, Tendyne, Neovasc, and Circle Imaging. AG has served as a proctor for Edwards Lifesciences, Medtronic, and Abbott Vascular; and has served as a consultant for and is an equity holder in Transmural Systems. VB has served as a consultant for Edwards Lifesciences and Abbott Vascular; and has served as a consultant for and is an equity holder in Transmural Systems. JK and RL were co-inventors on patents, assigned to the NIH, on devices for leaflet laceration. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Kohli, Wei, Sadri, Siefert, Blanke, Perdoncin, Greenbaum, Khan, Lederman, Babaliaros, Yoganathan and Oshinski.)

One obstacle for human solid tumor immunotherapy research is the lack of clinically relevant animal models. In this study, we sought to establish a chimeric antigen receptor (CAR) T-cell treatment model for naturally occurring canine sarcomas as a model for human CAR T-cell therapy. Canine CARs specific for B7-H3 were constructed using a single-chain variable fragment derived from the human B7-H3-specific antibody MGA271, which we confirmed to be cross-reactive with canine B7-H3. After refining activation, transduction, and expansion methods, we confirmed target killing in a tumor spheroid three-dimensional assay. We designed a B7-H3 canine CAR T-cell and achieved consistently high levels of transduction efficacy, expansion, and in vitro tumor killing. Safety of the CAR T cells were confirmed in two purposely bred healthy canine subjects following lymphodepletion by cyclophosphamide and fludarabine. Immune response, clinical parameters, and manifestation were closely monitored after treatments and were shown to resemble that of humans. No severe adverse events were observed. In summary, we demonstrated that similar to human cancers, B7-H3 can serve as a target for canine solid tumors. We successfully generated highly functional canine B7-H3-specific CAR T-cell products using a production protocol that closely models human CAR T-cell production procedure. The treatment regimen that we designed was confirmed to be safe in vivo. Our research provides a promising direction to establish in vitro and in vivo models for immunotherapy for canine and human solid tumor treatment., (©2022 The Authors; Published by the American Association for Cancer Research.)

Background and Aims: Airborne Low Intensity Multi frequency Ultrasound (ALIMFUS) uses thermal and non thermal principal of ultrasound to facilitate transportation of drugs into the cells and it's metabolism. This is randomized, multi-center, Double Blind, Interventional, Placebo Controlled Study to evaluate efficacy and safety of ALIMFUS as an Add-on therapy to Oral Hypoglycemic Agent (OHA) in Type 2 DM., Methods: Total 103/186 subjects completed the study and received 10 min either ALIMFUS therapy on alternate day for 90 days or placebo. Baseline and end of the study Lab parameters like HbA1c, blood sugars, Lipid Profile, Serum Hs-CRP, Serum Interleukin-6, Serum TNF-α, Serum homocysteine, Serum Vitamin D, Serum Leptin, Serum Adiponectin and Quality of Life score were assessed., Results: At the end of study ALIMFUS group achieved greater (0.77 ± 1.13 vs 0.48 ± 0.79) but non-significant reduction in HbA1c. More subjects in ALIMFUS group (30.76% vs 27.45%) achieved HbA1c < 7%. Significant reduction in fasting and postprandial glucose noted in both groups whose baseline HbA1c was ≥8%. Significant reduction in lipid profile noted in ALIMFUS group compared to placebo. Insulin, adiponectin, CRP and homocysteine and quality of life were significantly better in ALMFUS group compared to baseline; but non-significant compared to placebo. No adverse events were associated with ALIMFUS., Conclusions: Thus, ALIMFUS could be novel technology in diabetes management for patient unable to achieve glycemic targets on combination therapy. However further exploratory long term studies are required to demonstrate its effective role as add-on therapy in diabetes management., Competing Interests: Declaration of competing of interest None., (Copyright © 2022 Diabetes India. Published by Elsevier Ltd. All rights reserved.)

Aims: To characterize the dynamic nature of the left ventricular outflow tract (LVOT) geometry and flow rate in patients following transcatheter mitral valve replacement (TMVR) with anterior leaflet laceration (LAMPOON) and derive insights to help guide future patient selection., Methods and Results: Time-resolved LVOT geometry and haemodynamics were analysed with post-procedure computed tomography and echocardiography in subjects (N = 19) from the LAMPOON investigational device exemption trial. A novel post hoc definition for LVOT obstruction was employed to account for systolic flow rate and quality of life improvement [obstruction was defined as LVOT gradient >30 mmHg or LVOT effective orifice area (EOA) ≤1.15 cm2]. The neo-LVOT and skirt neo-LVOT were observed to vary substantially in area throughout systole (64 ± 27% and 25 ± 14% change in area, respectively). The peak systolic flow rate occurred most commonly just prior to mid-systole, while minimum neo-LVOT (and skirt neo-LVOT) area occurred most commonly in early-diastole. Subjects with LVOT obstruction (n = 5) had smaller skirt neo-LVOT values across systole. Optimal thresholds for skirt neo-LVOT area were phase-specific (260, 210, 200, and 180 mm2 for early-systole, peak flow, mid-systole, and end-systole, respectively)., Conclusion: The LVOT geometry and flow rate exhibit dynamic characteristics following TMVR with LAMPOON. Subjects with LVOT obstruction had smaller skirt neo-LVOT areas across systole. The authors recommend the use of phase-specific threshold values for skirt neo-LVOT area to guide future patient selection for this procedure. LVOT EOA is a 'flow-independent' metric which has the potential to aid in characterizing LVOT obstruction severity., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2021. For permissions, please email: journals.permissions@oup.com.)

Purpose: This study examined changes in force distribution between the neochordae corresponding to different ventricular anchor locations., Description: Seven porcine mitral valves were mounted in a left heart simulator. Neochordae (expanded polytetrafluoroethylene) originated from either a simulated left ventricular apex, papillary muscle base, or papillary muscle tip location. The neochordae were attached at three sites along the P 2 leaflet segment: P 2Lateral ; P 2Center , and P 2Medial . Mitral regurgitation was induced by cutting posterior leaflet P 2 marginal chordae. The forces on each neochord required to restore normal mitral valve coaptation were quantified for different ventricular anchoring origins and leaflet insertion sites., Evaluation: The results showed that under both normotensive and hypertensive conditions, the force exerted was much higher at P 2Center than either P 2Lateral or P 2Medial , independent of ventricular anchor location. Also, forces on both P 2Lateral and P 2Medial were not statistically different., Conclusions: Artificial neochordae treatment for all anchoring locations was effective in correcting induced mitral regurgitation. The P 2 central neochordae had a significantly higher force than both lateral neochords under all conditions., (Copyright © 2022 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Degradation of the mechanical properties of α-titanium, which is used to manufacture parts of jet engines, due to high-temperature oxidation is detrimental for the engine components. Therefore, to overcome this problem there are ongoing endeavors to develop novel oxidation-resistant titanium alloys and improve the properties of the existing ones. In an effort to understand the effect of alloying on oxidation of the α-Ti(0001) surface and to identify descriptors for rational design of oxidation-resistant alloys, in this work, using density functional theory-based calculations, we studied oxygen sorption and surface to subsurface diffusion on pure and alloyed α-Ti(0001) surfaces. Zr, Hf, Nb, and Mo from the d block and Al, Ga, Si, and Ge from the p block were used as alloying elements. We find that the alloying elements prefer to segregate on the surface compared to the subsurface layers. Our calculations show that the diffusion barrier correlates with the difference in the electronegativity between the alloying element and Ti. Elements which are more electropositive than Ti are found to hinder the oxygen dissolution in Ti and vice versa. We propose that the electronegativity difference can act as a good descriptor for choosing alloying elements. Our results are in reasonably good agreement with experimental reports on the growth of oxide layers on these alloyed Ti surfaces.

Drug delivery using oral route is the most popular, convenient, safest and least expensive approach. It includes oral transmucosal delivery of bioactive compounds as the mucosal cavity offers an intriguing approach for systemic drug distribution. Owing to the dense vascular architecture and high blood flow, oral mucosal layers are easily permeable and can be an ideal site for drug administration. Recently, the transmucosal route is being investigated for other therapeutic candidates such as vaccines for their efficient delivery. Vaccines have the potential to trigger immune reactions and can act as both prophylactic and therapeutic conduit to a variety of diseases. Administration of vaccines using transmucosal route offers multiple advantages, the most important one being the needle-free (non-invasive) delivery. Development of needle-free devices are the most recent and pioneering breakthrough in the delivery of drugs and vaccines, enabling patients to avoid needles, reducing anxiety, pain and fear as well as improving compliance. Oral, nasal and aerosol vaccination is a novel immunization approach that utilizes a nanocarrier to administer the vaccine. Nanocarriers improve the bioavailability and serve as adjuvants to elicit a stronger immune response, resulting in increased effectiveness of vaccination. Drugs and vaccines with lower penetration abilities can also be delivered transmucosally while maintaining their biological function. The development of micro/nanocarriers for transmucosal delivery of macromolecules, vaccines and other substances is currently drawing much attention and a number of studies were performed recently. This comprehensive review is aimed to summarize the most recent investigations on needle-free and non-invasive approaches for the delivery of vaccines using oral transmucosal route, their strengths and associated challenges. The oral transmucosal vaccine delivery by nanocarriers is the most upcoming advancement in efficient vaccine delivery and this review would help further research and trials in this field., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mangla, Javed, Sultan, Ahsan, Aggarwal and Kohli.)

Despite the great efforts that have been achieved in breast cancer treatment, it remains a significant cause of death in women and is a serious health problem. Treatment with chemotherapy drugs faces various challenges, such as toxicity and chemoresistance to chemotherapeutic drugs, which hinder their therapeutic success and clinical experiments. This review focuses on targeting nanocarrier approaches to target chemotherapy drugs to receptor targets that are overexpressed on the surface of breast cancer cells. In particular, the most commonly targeted nanocarriers for the chemotherapeutic agents examined by the different researcher groups, such as liposomes, dendrimers, polymeric micelles, lipid particulates, polymeric nanoparticles, and carbon nanotubes, have been reviewed. Moreover, we summarized the molecular receptors or targets that are the most commonly overexpressed in breast cancer cells and the natural and synthetic ligands studied for use as targeting moieties to functionalize chemotherapeutically loaded nanocarriers for potential specific breast cancer targeting., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Immune cell infiltration into solid tumors, their movement within the tumor microenvironment (TME), and interaction with other immune cells are controlled by their directed migration towards gradients of chemokines. Dysregulated chemokine signaling in TME favors the growth of tumors, exclusion of effector immune cells, and abundance of immunosuppressive cells. Key chemokines directing the migration of immune cells into tumor tissue have been identified. In this review, we discuss well-studied chemokine receptors that regulate migration of effector and immunosuppressive immune cells in the context of cancer immunology. We discuss preclinical models that have described the role of respective chemokine receptors in immune cell migration into TME and review preclinical and clinical studies that target chemokine signaling as standalone or combination therapies., (© 2021. The Author(s).)

Breast cancer is the most commonly occurring tumor disease worldwide. Breast cancer is currently managed by conventional chemotherapy, which is inadequate in curbing this heterogeneous disease and results in off-site toxic effects, suggesting effective treatment approaches with better therapeutic profiles are needed. This review, therefore, focuses on the recent advancements in delivering therapeutics to the target site using passive and/or active targeted nanodrug-delivery systems to ameliorate endolysosomal escape. In addition, recent strategies in targeting breast cancer stem cells are discussed. The role of naturally cell-secreted nanovesicles (exosomes) in the management of triple-negative breast cancer is also discussed.

The usefulness of sirolimus (SIR) in the treatment of diseases that involve retinal degeneration like age-related macular degeneration (AMD) has been well documented. However, the problem still remains probably owing to the peculiar environment of the eye and/or unfavourable physiochemical profile of SIR. In the present work, we aimed to fabricate sirolimus loaded PLGA nanoparticles (SIR-PLGA-NP) and chitosan decorated PLGA nanoparticles (SIR-CH-PLGA-NP) to be administered via non-invasive subconjunctival route. Both the nanoparticles were characterized in terms of size, zeta potential, DSC, FTIR and XRD analysis. Quality by Design (QbD) approach was employed during the preparation of nanoparticles and the presence of chitosan coating was confirmed through thermogravimetric analysis and contact angle studies. Cationic polymer modification showed sustained in-vitro SIR release and enhanced ex-vivo scleral permeation and penetration. Further, SIR-CH-PLGA-NP revealed enhanced cellular uptake and thus, reduced lipopolysaccharide (LPS)-induced free-radicals generation by RAW 264.7 cells. The prepared nanoparticles were devoid of residual solvent and were found to be safe in HET-CAM analysis, RBCs damage analysis and histopathology studies. Moreover, high anti-angiogenic potential was observed in SIR-CH-PLGA-NP compared with SIR-PLGA-NP in chorioallantoic membrane (CAM) test. Overall, the current work opens up an avenue for further investigation of CH-PLGA-NP as SIR nanocarrier in the treatment of AMD., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The phytogenous alkaloid berberine (BBR) has become a potential drug for the treatment of diabetes, hyperlipidemia, and cancer. However, its therapeutic potential is limited because ofpoor intestinal absorption due to its efflux by the P -gp expressed in the intestinal lumen. Therefore, we aimed to design and fabricate a nanoparticulate system for delivery of BBR employing naturally derived biodegradable and biocompatible polymers, mainly chitosan and alginate, to enhance the oral bioavailability of BBR. A chitosan-alginate nanoparticle system loaded with BBR (BNPs) was formulated by ionic gelation method and was optimized by employing a three-factor, three-level Box-Behnken statistical design. BNPs were characterized for various physicochemical properties, ex vivo, and in vivo evaluations. The optimized BNPs were found to be 202.2 ± 4.9 nm in size, with 0.236 ± 0.02 of polydispersity index, zeta potential -14.8 ± 1.1 mV, and entrapment efficiency of 85.69 ± 2.6%. BNPs showed amorphous nature with no prominent peak in differential scanning calorimetry (DSC) investigation. Similarly, fourier-transform infrared spectroscopy (FTIR) studies did not reveal any interaction between BBR and excipients used. The drug release followed Higuchi kinetics, since these plots demonstrated the highest linearity (R 2 = 0.9636), and the mechanism of release was determined to be anomalous or non-Fickian in nature. An ex-vivo gut permeation study showed that BNPs were better internalized into the cells and more highly permeated through the intestine. Furthermore, in vivo pharmacokinetic analysis in female Wistar rats showed a 4.10-fold increase in the oral bioavailability of BBR from BNPs as compared to BBR suspension. With these findings, we have gained new insight into the effective delivery of poorly soluble and permeable drugs via a chitosan-alginate nanoparticle system to improve the therapeutic performance of an oral nanomedicine.

Background: Bioprosthetic or native aortic scallop intentional laceration to prevent iatrogenic coronary artery obstruction (BASILICA) and laceration of the anterior mitral leaflet to prevent outflow obstruction (LAMPOON) reduce the risk of coronary and left ventricular outflow obstruction obstruction during transcatheter aortic valve replacement and transcatheter mitral valve replacement. Despite successful laceration, BASILICA or LAMPOON may fail to prevent obstruction caused by inadequate leaflet splay in patients having challenging anatomy such as very small valve-to-coronary distance, diffusely calcified, rigid leaflets, or undergoing transcatheter aortic valve replacement inside existing transcatheter aortic valve replacement. We describe a novel technique of balloon-augmented (BA) leaflet laceration to enhance leaflet splay., Methods: We measured the incremental leaflet splay from BA-BASILICA in vitro. From November 2019 to March 2021, 16 patients underwent BA-BASILICA and 4 BA-LAMPOON at 3 centers., Results: BA-BASILICA increased benchtop leaflet tip splay 17%, maximum splay angle 30%, and splay area 23%, resulting in a more rounded apex and larger effective area. Sixteen patients at risk for inadequate BASILICA leaflet splay, including 4 transcatheter aortic valve replacement inside existing transcatheter aortic valve replacement, underwent BA-BASILICA. All had successful leaflet laceration. One had coronary obstruction requiring immediate orthotopic stenting. Two underwent elective orthotopic coronary stenting through the transcatheter valve cells for leaflet prolapse without coronary ischemia. There were no deaths during the procedure or at 30 days. Four patients at risk for inadequate anterior mitral leaflet splay underwent BA-LAMPOON. All had successful target leaflet laceration without left ventricular outflow obstruction obstruction or procedural death. One died within 30 days., Conclusions: BA leaflet laceration enhances leaflet splay in vitro and may allow transcatheter aortic valve replacement and transcatheter mitral valve replacement in patients otherwise ineligible for traditional BASILICA or LAMPOON due to challenging anatomy. Graphic Abstract: A graphic abstract is available for this article.

The SAPIEN 3 is the only transcatheter heart valve commercially available for compassionate transcatheter mitral valve replacement in patients with previous mitral surgical rings and mitral annular calcification (valve in ring [VIR] and valve in mitral annular calcification [VIM]). Reported outcomes have been inconsistent or poor. The review provides an overview of the authors' approach to achieve largely consistent results despite the intrinsic limitations of SAPIEN 3 VIM and VIR. The approach includes bedside modifications of the valve implant, the delivery system, and of the cardiac substrate itself. Until purpose-built devices are readily available, VIR and VIM procedures will require aggressive multidisciplinary cooperation, meticulous planning and execution, and postprocedure management by experienced, high-volume operators., Competing Interests: Funding Support and Author Disclosures This work was supported by the Emory Structural Heart and Valve program intramural funds, and by National Institutes of Health Grant No. Z01-HL006040. Dr Babaliaros has served as a consultant for Edwards Lifesciences and Abbott Vascular; has an employer with research contracts for clinical investigation of transcatheter aortic, mitral, and tricuspid devices from Edwards Lifesciences, Abbott Vascular, Medtronic, and Boston Scientific; and owns equity interest in Transmural Systems. Dr Lederman has served as the principal investigator on a cooperative research and development agreement between National Institutes of Health and Edwards Lifesciences for transcatheter modification of the mitral valve. Drs Lederman, Khan, and Rogers are co-inventors on patents, assigned to the National Institutes of Health, on devices for electrosurgical leaflet laceration. Drs Khan and Rogers have served as proctors for Edwards Lifesciences and Medtronic. Mr Kohli has served as a consultant for Abbott Laboratories. Dr Paone has served as a consultant and proctor for Edwards Lifesciences. Dr Lisko’s employer has contracts for BASILICA analysis with Medtronic and Edwards Lifesciences. Dr Greenbaum has served as a proctor for Edwards Lifesciences, Medtronic, and Abbott Vascular; owns an equity interest in Transmural Systems; and has an employer with research contracts for clinical investigation of transcatheter aortic, mitral, and tricuspid devices from Edwards Lifesciences, Abbott Vascular, Medtronic, and Boston Scientific. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2021 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Traditionally, herbal supplements have shown an exceptional potential of desirability for the prevention of diseases and their treatment. Sulforaphane (SFN), an organosulfur compound belongs to the isothiocyanate (ITC) group and is mainly found naturally in cruciferous vegetables. Several studies have now revealed that SFN possesses broad spectrum of activities and has shown extraordinary potential as antioxidant, antitumor, anti-angiogenic, and anti-inflammatory agent. In addition, SFN is proven to be less toxic, non-oxidizable, and its administration to individuals is well tolerated, making it an effective natural dietary supplement for clinical trials. SFN has shown its ability to be a promising future drug molecule for the management of various diseases mainly due to its potent antioxidant properties. In recent times, several newer drug delivery systems were designed and developed for this potential molecule in order to enhance its bioavailability, stability, and to reduce its side effects. This review focuses to cover numerous data supporting the wide range of pharmacological activities of SFN, its drug-related issues, and approaches to improve its physicochemical and biological properties, including solubility, stability, and bioavailability. Recent patents and the ongoing clinical trials on SFN are also summarized., (© 2021 John Wiley & Sons Ltd.)

Hepatocellular carcinoma (HCC) remains an important form of cancer-related morbidity and mortality in the U.S. and worldwide. Previous U.S.-based studies on survival suggest ethnic disparities in HCC patients, but the complex interplay of multiple factors that contribute are still incompletely understood. Here we considered the influences of risk factors contributing towards HCC survival, including ethnic background, over ten years at a premier academic medical center with a majority (57.20%) African American (AA) population. Retrospective HCC data were collected from 2008-2018 at LSUHSC-Shreveport, an urban tertiary medical center. Data included demographics, comorbidities, liver disease characteristics, and tumor parameters. Statistical analysis was performed using Chi Square and one-way ANOVA. Results: 229 HCC patients were identified (male 78.6%). The mean HCC age at diagnosis was 61 years (SD = 7.3). Compared to non-Hispanic Caucasians (42.7%), AA patients (57.2% of total) were older at presentation, had more frequent diabetes/dyslipidemia/NAFLD (45 (34.3%) compared with 19 (19.3%) in non-Hispanic Caucasians, p = 0.02), and had a larger HCC burden at diagnosis. We conclude that compared to white patients, despite having similar BMI and MELD scores and rates of portal vein thrombosis, AA patients with HCC in our cohort were older at presentation, had a significantly increased incidence of modifiable metabolic risk factors including diabetes, higher AFP values, increased incidence of gallstones, and larger sized HCCs, and were more likely to be outside Milan criteria. These findings have important prognostic and diagnostic implications for developing a more targeted HCC surveillance program.

In silico modeling has been proposed as a tool to simulate left ventricular (LV) outflow tract (LVOT) obstruction in patients undergoing transcatheter mitral valve replacement (TMVR). This study validated a simplified approach to simulate LV outflow hemodynamics in the setting of TMVR with anterior leaflet laceration, a clinical technique used to mitigate the risk of LVOT obstruction. Personalized, 3-dimensional computational fluid dynamics models were developed from computed tomography images of six patients who underwent TMVR with anterior leaflet laceration. LV outflow hemodynamics were simulated using the patient-specific anatomy and the peak systolic flow rate as boundary conditions. The peak outflow velocity, a clinically relevant hemodynamic metric, was extracted from each simulation (v sim-peak ) and compared with the clinical measurement from Doppler echocardiography (v clin-peak ) for validation. In silico models were successfully developed and implemented for all patients. The pre-processing time was 2 h per model and the simulation could be completed within 3 h. In three patients, the lacerated anterior leaflet exposed open cells of the transcatheter valve to flow. Good agreement was obtained between v sim-peak and v clin-peak (r = 0.97, p < 0.01) with average discrepancies of 5 ± 2% and 14 ± 1% for patients with exposed and unexposed cells of the transcatheter valve, respectively. The proposed in silico modeling paradigm therefore simulated LV outflow hemodynamics in a time-efficient manner and demonstrated good agreement with clinical measurements. Future studies should investigate the ability of this paradigm to support clinical applications.

Introduction: Bruxism is a multifactorial phenomenon that involves grinding or clenching of teeth. The parafunctional habit includes abnormal tooth wear, tooth fracture, pain, and tooth mobility, along with headaches and facial muscle hypertrophy. It is imperative for students to be conscious of teeth grinding along with its possible causes. The student will be alert to visit the dentist if required and contribute to the recognition of etiological factors, to eliminate them., Objective: This study aims to find the prevalence and understanding of bruxism among Gulf Medical University (GMU) students., Materials and Methods: A cross-sectional, questionnaire-based study was conducted among 451 GMU students. The parameters for data collection were age, gender, prevalence, associated signs and symptoms, causes, genetic predisposition, time of day, and effect on the appearance of teeth., Results: While 35.9% were unaware, 41.7% of our samples reported bruxism. The majority recognized temporomandibular joint and facial pain as causative, and 24.8% reported symptoms. Headache (26.4%) was prime and 7.5% were associated with fracture and abnormal tooth wear to bruxism (38.1%) experienced night bruxism. A significant number of students (32.4%) identified abnormal anterior teeth relationship as the cause and (64.3%) associated bruxism and esthetics., Conclusion: Nearly 41.7% of the students reported bruxism. Around 35.9% of the samples were uninformed. Nearly 20.8% believed that bruxism had genetic relevance. Nearly 51.9% of the participants were asymptomatic. Around 38.1% had night bruxism and 32.4% identified abnormal anterior teeth relationship as the cause. The majority of the sample (64.3%) connected bruxism to negative effects on teeth and esthetics., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Journal of Pharmacy and Bioallied Sciences.)

Purpose: To assess dosimetric properties and identify required updates to commonly used protocols (including use of film and ionization chamber) pertaining to a clinical linac configured into FLASH (ultra-high dose rate) electron mode., Methods: An 18MV photon beam of a Varian iX linac was converted to FLASH electron beam by replacing the target and the flattening filter with an electron scattering foil. The dose was prescribed by entering the MUs through the console. Fundamental beam properties, including energy, dose rate, dose reproducibility, field size, and dose rate dependence on the SAD, were examined in preparation for radiobiological experiments. Gafchromic EBT-XD film was evaluated for usability in measurements at ultra-high dose rates by comparing the measured dose to the inverse square model. Selected previously reported models of chamber efficiencies were fitted to measurements in a broad range of dose rates., Results: The performance of the modified linac was found adequate for FLASH radiobiological experiments. With exception of the increase in the dose per MU on increase in the repetition rate, all fundamental beam properties proved to be in line with expectations developed with conventional linacs. The field size followed the theorem of similar triangles. The highest average dose rate (2 × 10 4  Gy/s) was found next to the internal monitor chamber, with the field size of FWHM = 1.5 cm. Independence of the dose readings on the dose rate (up to 2 × 10 4  Gy/s) was demonstrated for the EBT-XD film. A model of recombination in an ionization chamber was identified that provided good agreement with the measured chamber efficiencies for the average dose rates up to at least 2 × 10 3  Gy/s., Conclusion: Dosimetric measurements were performed to characterize a linac converted to FLASH dose rates. Gafchromic EBT-XD film and dose rate-corrected cc13 ionization chamber were demonstrated usable at FLASH dose rates., (© 2021 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals LLC on behalf of American Association of Physicists in Medicine.)

Plastic is referred to as a "material of every application". From the packaging and automotive industries to the medical apparatus and computer electronics sectors, plastic materials are fulfilling demands efficiently. These plastics usually end up in landfills and incinerators, creating plastic waste pollution. According to the Environmental Protection Agency (EPA), in 2015, 9.1% of the plastic materials generated in the U.S. municipal solid waste stream was recycled, 15.5% was combusted for energy, and 75.4% was sent to landfills. If we can produce high-value chemicals from plastic wastes, a range of various product portfolios can be created. This will help to transform chemical industries, especially the petrochemical and plastic sectors. In turn, we can manage plastic waste pollution, reduce the consumption of virgin petroleum, and protect human health and the environment. This review provides a description of chemicals that can be produced from different plastic wastes and the research challenges involved in plastic waste to chemical production. This review also provides a brief overview of the state-of-the-art processes to help future system designers in the plastic waste to chemicals area.

Background: Synovial sarcoma (SS) and myxoid/round cell liposarcoma (MRCL) are ideal solid tumors for the development of adoptive cellular therapy (ACT) targeting NY-ESO-1, as a high frequency of tumors homogeneously express this cancer-testes antigen. Data from early phase clinical trials have shown antitumor activity after the adoptive transfer of NY-ESO-1-specific T cells. In these studies, persistence of NY-ESO-1 specific T cells is highly correlated with response to ACT, but patients often continue to have detectable transferred cells in their peripheral blood following progression., Method: We performed a phase I clinical trial evaluating the safety of NY-ESO-1-specific endogenous T cells (ETC) following cyclophosphamide conditioning. Peripheral blood mononuclear cells (PBMCs) from treated patients were evaluated by flow cytometry and gene expression analysis as well as through ex vivo culture assays with and without IL-15., Results: Four patients were treated in a cohort using ETC targeting NY-ESO-1 following cyclophosphamide conditioning. Treatment was well tolerated without significant toxicity, but all patients ultimately had disease progression. In two of four patients, we obtained post-treatment tumor tissue and in both, NY-ESO-1 antigen was retained despite clear detectable persisting NY-ESO-1-specific T cells in the peripheral blood. Despite a memory phenotype, these persisting cells lacked markers of proliferation or activation. However, in ex vivo culture assays, they could be induced to proliferate and kill tumor using IL-15. These results were also seen in PBMCs from two patients who received gene-engineered T-cell receptor-based products at other centers., Conclusions: ETC targeting NY-ESO-1 with single-agent cyclophosphamide alone conditioning was well tolerated in patients with SS and those with MRCL. IL-15 can induce proliferation and activity in persisting NY-ESO-1-specific T cells even in patients with disease progression following ACT. These results support future work evaluating whether IL-15 could be incorporated into ACT trials post-infusion or at the time of progression., Competing Interests: Competing interests: SMP receives research funding from Merck, EMD Serono, Incyte, Presage, Janssen, Oncosec and Juno. He has consulting, honoraria and advisory activity with GlaxoSmith Kline, Daiichi Sankyo and Blueprint Medicine. SRR has received equity, consulting fees and research funding from Juno Therapeutics/a BMS company and Lyell Immunopharma. He has received consulting fees and equity from Adaptive Biotechnologies.VGP receives research funding from Merck, AstraZeneca, and Ipsen. He has had consulting, honoraria and advisory activity with Merck, GlaxoSmithKline, Imvax, and Takeda. VGP receives research funding from Merck, AstraZeneca, and Ipsen. He has had consulting, honoraria and advisory activity with Merck, GlaxoSmithKline, Imvax, and Takeda.GlaxoSmithKline, Imvax, and Takeda., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP) remains common, and severe complications are associated with ERCP. There is no previous study detailing the effect of race and gender in a US-based population on risk of PEP., Methods: Data were collected on 269 "first-performed" consecutive ERCPs followed by division by race (White vs. African-American) and sex (Female vs. Male). A total of 53 probable risk factors were evaluated by uni- and multivariate analysis followed by outcomes expressed as an odds ratio (OR) (with a 95% confidence interval, 95% CI). Finally, a principal component analysis was performed to construct a risk prediction model for PEP, which can be used by clinicians at bedside., Results: After analyzing the risk factors based on race and gender-based groups, Caucasian males with PEP are more likely to have prior history of pancreatitis ( p = 0.009), lower hemoglobin ( p = 0.02)/blood urea nitrogen (BUN) ( p = 0.01)/creatinine before ERCP ( p = 0.07) and lower BUN ( p = 0.01)/creatinine after ERCP ( p = 0.07), while Caucasian females with PEP are more likely to have higher white blood cell (WBC) count before ERCP ( p = 0.08) and lower amylase ( p = 0.10)/bilirubin ( p = 0.09)/aspartate aminotransferase (AST) after ERCP ( p = 0.08). African-American males with PEP are more likely to have lower weight ( p = 0.001)/smaller height ( p = 0.0005)/lower alkaline phosphatase ( p = 0.002)/AST ( p = 0.04)/alanine transaminase (ALT) ( p = 0.03) before ERCP and lower alkaline phosphatase ( p = 0.002)/AST ( p = 0.01)/ALT ( p = 0.004) after ERCP, while African-American females with PEP are more likely to have prior history of pancreatitis ( p = 0.004)/higher lipase before ( p = 0.0001) and after ( p = 0.05) ERCP along with increased risk with pancreatic duct cannulation ( p = 0.0001) and injection ( p = 0.0001)/biliary sphincterotomy ( p = 0.0001). Importantly, prior history of ERCP, elevated AST after ERCP, and BUN prior to ERCP were found to be important clinical features predicting post-ERCP pancreatitis. To our knowledge, this is a first known attempt at developing a risk scoring system for PEP in a US population with decision tree learning., Conclusions: It is very evident that both patient and procedure-related risk factors vary by race and gender in the US population, leading to the development of a new risk assessment tool for PEP that can be used in clinical practice. We need to follow up with a larger prospective study to validate this novel race and gender-based risk scoring system for PEP.

Microanatomical organization of innate immune cells within lymph nodes (LNs) is critical for the generation of adaptive responses. In particular, steady-state LN-resident dendritic cells (Res cDCs) are strategically localized to intercept lymph-draining antigens. Whether myeloid cell organization changes during inflammation and how that might affect the generation of immune responses are unknown. Here, we report that during type I, but not type II, inflammation after adjuvant immunization or viral infection, antigen-presenting Res cDCs undergo CCR7-dependent intranodal repositioning from the LN periphery into the T cell zone (TZ) to elicit T cell priming. Concurrently, inflammatory monocytes infiltrate the LNs via local blood vessels, enter the TZ, and cooperate with Res cDCs by providing polarizing cytokines to optimize T cell effector differentiation. Monocyte infiltration is nonuniform across LNs, generating distinct microenvironments with varied local innate cell composition. These spatial microdomains are associated with divergent early T cell effector programming, indicating that innate microenvironments within LNs play a critical role in regulating the quality and heterogeneity of T cell responses. Together, our findings reveal that dynamic modulation of innate cell microenvironments during type I inflammation leads to optimized generation of adaptive immune responses to vaccines and infections., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

This work was aimed to improve the efficacy of tacrolimus in the treatment of endotoxin-induced uveitis (EIU) using propylene glycol modified lipid vesicles termed as proglycosome nano-vesicles (PNVs). PNVs were prepared by modified film hydration method. Experimental uveitis in rabbit eye was induced by an intravitreal injection of 20 μL of the endotoxin solution containing 100 ng of lipopolysaccharide endotoxin. In vivo efficacy of PNVs was determined by studying clinical symptoms of uveitis using slit lamp examination and by quantitatively measuring levels of tumor necrosis factor-alpha, interleukin-6, leukocytes and total proteins in aqueous humor, 24 h after intravitreal injection of endotoxin. Comparison was made with healthy, untreated and tacrolimus solution treated eyes. PNVs developed were nano-sized, deformable and showed sustained release of tacrolimus over period of 12 h. In vivo results indicated statistically significant difference between the effects of PNVs in the treatment of EIU compared to tacrolimus. PNV treatment not only subsides clinical symptoms of uveitis but also prevented breakdown of blood aqueous barrier. Tacrolimus loaded PNVs are potential new topical treatment for uveitis., (Copyright © 2020 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.)

Non-alcoholic fatty liver disease (NAFLD) is one of the leading causes of death related to liver diseases worldwide. Despite this, there is no specific treatment approved for the disease till now, which could be due to the poor understanding of the pathophysiology of this disease. In the past few decades, several scientists have speculated the root cause of NAFLD to be dysbalance in the gut microbiome resulting in a susceptibility to the inflammatory cascade in the liver. Herein, we hypothesize to fabricate a novel formulation containing prebiotic with probiotics which thereby would help in maintaining the gut homeostasis, and be used for the treatment of NAFLD. The proposed novel formulation would contain a Bifidobacterium sp. with Faecalibacterium prausnitzii in the presence of a dietary fibre having hepatoprotective activity. These two strains of probiotics would help in increasing the concentration of butyrate in the gut which in turn would inhibit intestinal inflammation and maintain gut integrity. The dietary fibre would serve a dual mechanism; firstly, it would act as a prebiotic helping in the proliferation of administered probiotics, and secondly, it would protect the liver via its own hepatoprotective action. This combinatorial approach would pave a new therapeutic avenue for the treatment of NAFLD., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Hepatocellular carcinoma (HCC) is the primary liver cancer that has shown a high incidence and mortality rate worldwide among several types of cancers. A large variety of chemotherapeutic agents employed for the treatment have a limited success rate owing to their limited site-specific drug targeting ability. Thus, there is a demand to develop novel approaches for the treatment of HCC. With advancements in nanotechnology-based drug delivery approaches, the challenges of conventional chemotherapy have been continuously decreasing. Nanomedicines constituted of lipidic and polymeric composites provide a better platform for delivering and opening new pathways for HCC treatment. A score of nanocarriers such as surface-engineered liposomes, nanoparticles, nanotubes, micelles, quantum dots, etc., has been investigated in the treatment of HCC. These nanocarriers are considered to be highly effective clinically for delivering chemotherapeutic drugs with high site-specificity ability and therapeutic efficiency. The present review highlights the current focus on the application of nanocarrier systems using various ligand-based receptor-specific targeting strategies for the treatment and management of HCC. Moreover, the article has also included information on the current clinically approved drug therapy for hepatocellular carcinoma treatment and updates of regulatory requirements for approval of such nanomedicines., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Aim: The current study aimed to explore the feasibility of the nanoemulgel for the topical delivery of aceclofenac. Materials & methods: Solubility of drugs in the formulation systems was determined and aceclofenac nanoemulsion (NE) was prepared by high-pressure homogenization technique. Carbopol 940 was added as a gelling agent. Results & conclusion: The composition of optimized NE consist of labrafil along with triacetin as oil, tween 80 and cremophor EL in combination as a surfactant and transcutol HP along with PEG 400 and ethanol as cosurfactant. The droplet size of the NE was 141.1 ± 3.65 nm, with low polydispersity index and negative zeta potential. The aceclofenac-nanoemulgel was developed using carbopol 940 and exhibited excellent permeation in comparison to the marketed sample.

Nanotherapeutics in cancer treatment are dominating global science and research, and have been recognized as the pioneering medical care regimen. Raloxifene (RLN) has been used for its anti-proliferative action on mammary tissue, however, it suffers from poor oral bioavailability. This investigation gives an account of the design and development of RLN-loaded nanostructured lipid carriers (RLN-NLCs) using a simple and scalable ultrasonication method for improved oral efficacy and limited offsite toxicity using Compritol ® 888 ATO as a solid lipid and Transcutol ® HP as a liquid lipid. In addition, the optimized RLN-NLCs were in the nanometric range (121 nm) with high % entrapment efficiency (%EE) (81%) for RLN, and were further freeze-dried in the presence of mannitol to enhance the stability of RLN-NLCs in the dry state for long-term use. Morphological observation under a transmission electron microscope and scanning electron microscope revealed the spherical smooth surface nanometric size of RLN-NLCs. Powder x-ray diffraction confirmed the encapsulation of RLN into the RLN-NLC's matrix with reduced crystallinity of the drug. The in vitro release study showed a burst release for an initial 4 h, and sustained release for up to 24 h. Furthermore, the RLN-NLCs showed higher cytotoxicity towards MCF-7 cells in vitro in comparison to RLN suspension, and an ex vivo intestinal permeation study demonstrated improved intestinal permeability of RLN-NLCs. Moreover, the in vivo pharmacokinetic study in female Wistar rats showed a 4.79-fold increment in oral bioavailability of RLN from RLN-NLCs compared to RLN suspension. Taken together, our results pave the way for a new nanotherapeutic approach towards breast cancer treatment.

Aim: This study aims to load tamoxifen (TAM) and sulforaphane (SFN) into nanostructured lipid carriers (NLCs) to enhance their oral delivery. Materials & methods: TAM-SFN-NLCs were prepared using Precirol ® ATO5 and Transcutol ® HP, characterized and evaluated in vitro and ex vivo to assess the drug release profile and intestinal permeability, respectively. In vivo pharmacokinetic and acute toxicity assessment was performed in Wistar rats. Results: Optimized TAM-SFN-NLCs exhibited a particle size of 121.9 ± 6.42 nm and zeta potential of -21.2 ± 2.91 mV. The NLCs enhanced intestinal permeability of TAM and SFN and augmented oral bioavailability of TAM and SFN 5.2-fold and 4.8-fold, respectively. SFN significantly reduced TAM-associated toxicity in vivo . Conclusion: This coencapsulation of a chemotherapeutic agent with a herbal bioactive in NLCs could pave a novel treatment approach against cancer.

Degenerative diseases of eye like Age-related macular degeneration (AMD), that affects the central portion of the retina (macula), is one of the leading causes of blindness worldwide especially in the elderly population. It is classified mainly as wet and dry form. With expanding knowledge about the underlying pathophysiology of the disease, various treatment strategies are being employed to halt the course of the disease progression. Hitherto, there is no ideal therapy which can cure the disease completely, and targeting the posterior segment of the eye is yet another challenge. The purpose of this review is to summarize the recent advances in the management and treatment stratagems (therapies, delivery systems and diagnostic tools) pertaining to AMD viz. molecular targeting, stem cell therapy, nanotechnology and exosomes with special reference to newer technologies like artificial intelligence and 3D printing. Furthermore, the role of diet and nutritional supplements in the prevention and treatment of the disease has also been highlighted. The alarming increase in the said disorder around the globe demands exhaustive research and investigations in the treatment zone. This review thus additionally directs the attention towards the challenges and future perspectives of different treatment approaches for AMD., Competing Interests: Declaration of Competing Interest None., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Tamoxifen (TAM) is the choice of a drug approved by the Food and Drug Administration (FDA) for the treatment of estrogen-positive receptor (ER+) breast cancer. Sulphoraphane (SFN), a natural plant antioxidant compound, also acts on estrogen-positive breast cancer receptor. Thus, a combination of TAM with SFN is preferred as it helps to minimize the drug-related toxicity and increases the therapeutic efficacy by providing synergistic anticancer effects of both drugs. In the present study, a new simple, sensitive, precise, and selective UPLC-MS/MS method was developed for the simultaneous quantification of tamoxifen and sulphoraphane using propranolol as an internal standard (IS) in rat plasma. Chromatographic separation was achieved on reverse phase Acquity UPLC BEH C 18 column (50 mm × 2.1 mm, i.d., 1.7 μm) with an isocratic mobile phase composed of solvent A (0.1% formic acid in acetonitrile) and B (0.1% formic acid in water) (80:20, v/v) at a flow-rate of 0.4 mL/min. The detection and quantification of analytes was performed on Waters Zspray TM Xevo TQD using selected-ion monitoring operated under a positive electrospray ionization mode. The transitions were m/z = 372.0 [M+H] + → 71.92 for tamoxifen, m/z = 177.9 [M+H] + → 113.9 for sulphoraphane and m/z = 260.3 [M+H] + → 116.1 for propranolol. The method was linear over the concentration range of 8-500 ng/mL (r 2  = 0.9996) for tamoxifen, 30-2000 ng/mL (r 2  = 0.9998) for sulphoraphane with insignificant matrix effect and high extraction recovery on spiked quality control (QC) samples. The intra- and inter-batch precisions and accuracy were within the acceptable limits, and both the analytes were found to be stable throughout the short term, long term and freeze thaw stability studies. The validated method was successfully applied for the simultaneous estimation of TAM and SFN in an oral pharmacokinetic study in female Wistar rats. This developed UPLC-MS/MS method could be a valuable tool for future pharmacokinetic interaction, therapeutic drug monitoring and pharmacokinetic characterization of novel formulations., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Various lipid nanovesicular systems have been developed with the aim to enhance the delivery of drugs via transdermal route. However, their clinical applications are often limited due to the barrier nature of skin and lack of flexibility. Herein, we have modified the conventional nanoliposomes (CLs) prepared by a thin-film hydration method by the addition of a polyol (glycerol) to form novel lipid nanovesicular structures termed 'POLYOLIPOSOMES' (PLs). They were further named as PL-B (before film formation) and PL-A (after film formation), depending on the stage of glycerol addition during production. Optimized CLs, PL-B and PL-A showed spherical nanovesicles and hydrodynamic diameter of 181.3 ± 4.11 nm, 114.2 ± 7.21 nm and 170.2 ± 6.51 nm, respectively. PLs showed significantly higher % entrapment efficiency and deformability index in comparison to CLs, indicating their higher flexibility. Furthermore, DSC and attenuated total relection (ATR)-Fourier transform infrared (FTIR) studies revealed the intercalation of glycerol into the lipid bilayer of PLs and interaction between nanovesicles and skin. Moreover, ex vivo and in vivo skin permeation studies confirmed the enhanced drug delivery of PLs via the transdermal route. Taken together, these results illustrate the potential of PLs as a novel lipid nanovesicular system for drug delivery via the transdermal route for both systematic (PL-B) as well as cutaneous diseases (PL-A).

Purpose: Ventricular tachycardia (VT) is a rapid, abnormal heart rhythm that can lead to sudden cardiac death. Current treatment options include antiarrhythmic drug therapy and catheter ablation, both of which have only modest efficacy and have potential complications. Cardiac radiosurgery has the potential to be a noninvasive and efficient treatment option for VT. Cardiac motion, however, must be accounted for to ensure accurate dose delivery to the target region. Cardiac synchronized volumetric modulated arc therapy (CSVMAT) aims to minimize the dose delivered to normal tissues by synchronizing beam delivery with a cardiac signal, irradiating only during the quiescent intervals of the cardiac cycle (when heart motion is minimal) and adjusting the beam delivery speed in response to heart rate changes., Methods: A CSVMAT plan was adapted from a conventional VMAT plan and delivered on a Varian TrueBeam linear accelerator. The original VMAT plan was divided into three interleaved CSVMAT phases, each consisting of alternating beam-on and beam-off segments synchronized to a sample heart rate. Trajectory log files were collected for the original VMAT and CSVMAT deliveries and the dose distributions were measured with Gafchromic EBT-XD film., Results: Analysis of the trajectory log files showed successful synchronization with the sample cardiac signal. Film analysis comparing the original VMAT and CSVMAT dose distributions returned a gamma passing rate of 99.14% (2%/2 mm tolerance)., Conclusions: The film results indicated excellent agreement between the dose distributions of the original and cardiac synchronized beam deliveries. This study demonstrates a proof of principle cardiac synchronization strategy for precise radiation treatment plan delivery and adjustment to a variable heart rate. The cardiac synchronized technique may be advantageous in radioablation for VT., (© 2020 American Association of Physicists in Medicine.)

Edge-to-edge repair for mitral valve regurgitation is being increasingly performed in high-surgical risk patients using minimally invasive mitral clipping devices. Known procedural complications include chordal rupture and mitral leaflet perforation. Hence, it is important to quantitatively evaluate the effect of edge-to-edge repair on chordal integrity. in this study, we employ a computational mitral valve model to simulate functional mitral regurgitation (FMR) by creating papillary muscle displacement. Edge-to-edge repair is then modeled by simulated coaptation of the mid portion of the mitral leaflets. in the setting of simulated FMR, edge-to-edge repair was shown to sustain low regurgitant orifice area, until a two fold increase in the inter-papillary muscle distance as compared to the normal mitral valve. Strain in the chordae was evaluated near the papillary muscles and the leaflets. Following edge-to-edge repair, strain near the papillary muscles did not significantly change relative to the unrepaired valve, while strain near the leaflets increased significantly relative to the unrepaired valve. These data demonstrate the potential for computational simulations to aid in the pre-procedural evaluation of possible complications such as chordal rupture and leaflet perforation following percutaneous edge-to-edge repair.

Background: A pandemic poses a significant challenge to the healthcare staff and infrastructure. We studied the prevalence of anxiety and depressive symptoms among armed forces doctors in India during the COVID-19 pandemic and the factors that contribute to these symptoms., Methods: The study was conducted from March 30, 2020, to April 2, 2020, using a self-administered questionnaire questionnaire using the hospital anxiety and depression scale (HADS), which was sent through Google Forms. Responses were received from 769 respondents. Data were analyzed for demographic details and HADS scores using the chi-square test and backward logistic regression., Results: Anxiety and depressive symptoms were seen in 35.2% and 28.2% of the doctors, respectively. In doctors with anxiety symptoms, significant associations were observed with age (20-35 years, 39.4%, P = 0.01), gender (females, 44.6%, P < 0.001), duration of service (0-10 years, 38%, P = 0.03), and clinical versus non-clinical specialties (non-clinical, 41.3%, P < 0.001) as opposed to marital status, education level, and current department of work.In doctors with depressive symptoms, significant associations were observed with age (P = 0.04), clinical versus non-clinical specialties (P < 0.001), duration of service (0-10 years, 30.1%, P = 0.03), and doctoral degree (P = 0.04) as opposed to gender, marital status, education level, and current working department., Conclusion: The study revealed a high prevalence of anxiety and depressive symptoms among armed forces doctors. The main contributing factors are female gender, young age group, non-clinical specialties, and having a doctoral degree., (© 2020 Indian Psychiatric Society - South Zonal Branch.)

To establish an environmentally friendly and cheaper method to delignify lignocellulosic biomass feedstocks, deep eutectic solvents (DESs) were investigated as a green alternatives to conventional solvents. Six different DESs were facilely prepared and used to delignify miscanthus and birchwood feedstocks, including monocarboxylic acid/choline chloride (ChCl), dicarboxylic acid/ChCl and polyalcohol/ChCl. The enhanced delignification efficiency was evaluated in relation to the nature of the hydrogen bond donors and acid strength of DES. The largest extraction of lignin from the miscanthus and birchwood was achieved using ChCl.formic acid and ChCl.oxalic acid DES, respectively. The TGA and 13 C NMR characterization results of the extracted lignin samples indicated that the different types of lignin were produced using different DESs. The reaction optimization results showed an increase in lignin extraction with increasing temperature from 60 to 130 °C. However, the optimal reaction time was different, 30 min for miscanthus and 60 min for birchwood. A convenient and reliable method for the quantification of lignin was developed using UV-Vis spectrophotometry., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)