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Glioblastoma multiforme (GBM) is a highly aggressive form of primary brain tumor in adults, which unfortunately has an abysmal prognosis and poor survival rates. The reason behind the poor success rate of several FDA-approved drug is mainly attributed to insufficient drug distribution to the tumor site across the blood-brain barrier (BBB) and induction of resistance. In this study, we have developed a novel nanotherapeutic approach to achieve our goal. PLGA-based nanoencapsulation of both Temozolomide (TMZ) and EGFR inhibitor 3,3'-diindoyl methane (DIM) in a combinatorial approach enhances the delivery of them together. Their synergistic mode of actions, significantly enhances the cytotoxic effect of TMZ in vitro and in vivo. Moreover, the dual-loaded nanoformulation works more efficiently on DNA damage and apoptosis, resulting in a several-fold reduction in tumor burden in vivo, systemic drug toxicity, and increased survival. These findings suggest the preclinical potential of this new treatment strategy., 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 © 2024 Elsevier B.V. All rights reserved.)

The use of submucosal injection is crucial for satisfactory submucosal elevation in the early resection of flat polyps originating from the gastrointestinal tract (GIT). Injectable hydrogels derived from natural polypeptides are attractive candidates due to their excellent biocompatibility and easy gelation properties. However, most of the reported hydrogels are not the class of catheter delivery materials due to quick gelation, high inherent viscosity, and injection clogging. This study presents a novel injectable shear-thinning hydrogel platform of small molecules (nonanal) modified gelatin polymer, which offers a promising submucosal injection for effective removal of polyps from GIT. Physicochemical characterizations of hydrogel demonstrate the suitable features as an effective submucosal injection, including shear thinning property, self-assembly, methylene blue dye encapsulation, flow behavior, stability, syringeability (18 G, 21 G, and 24 G needles) and fibrous morphology. Ex vivo investigations of developed submucosal formulation on goat intestines demonstrate the enhanced visibility of cushions and the ability to produce stable, long-lasting cushions of about 8.07 mm up to ∼60 min of submucosal injection. The rapid blood clotting behavior of hydrogel was observed in about 120 s without compromising hemocompatibility with the hemolysis of about 3.77 % only. In vitro biocompatibility of the hydrogel was also verified using the HepG2 and nHDF cells. In vivo study depicts desirable biocompatibility, a non-toxic organ profile, and optimal cushion height in mice models. Studies established the foundation of novel submucosal fluid to improve the therapeutic outcomes of early resection for gastrointestinal polyps., 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 © 2024 Elsevier B.V. All rights reserved.)

GBM is the most common, aggressive, and intracranial primary brain tumor; it originates from the glial progenitor cells, has poor overall survival (OS), and has limited treatment options. In this decade, GBM immunotherapy is in trend and preferred over several conventional therapies, due to their better patient survival outcome. This review explores the clinical trials of several immunotherapeutic approaches (immune checkpoint blockers (ICBs), CAR T-cell therapy, cancer vaccines, and adoptive cell therapy) with their efficacy and safety. Despite significant progress, several challenges (viz., immunosuppressive microenvironment, heterogeneity, and blood-brain barrier (BBB)) were experienced that hamper their immunotherapeutic potential. Furthermore, these challenges were clinically studied to be resolved by multiple combinatorial approaches, discussed in the later part of the review. Thus, this review suggests the clinical use and potential of immunotherapy in GBM and provides the holistic recent knowledge and future perspectives., Competing Interests: Declaration of competing interest All authors declare that there is no competing and conflict of interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Colorectal cancer (CRC) presents ongoing challenges due to limited treatment effectiveness and a discouraging prognosis, underscoring the need for ground-breaking therapeutic approaches. This review delves into the pivotal role of E3 ubiquitin ligases and deubiquitinases (DUBs), underscoring their role as crucial regulators for tumor suppression and oncogenesis in CRC. We spotlight the diverse impact of E3 ligases and DUBs on CRC's biological processes and their remarkable versatility. We closely examine their specific influence on vital signaling pathways, particularly Wnt/β-catenin and NF-κB. Understanding these regulatory mechanisms is crucial for unravelling the complexities of CRC progression. Importantly, we explore the untapped potential of E3 ligases and DUBs as novel CRC treatment targets, discussing aspects that may guide more effective therapeutic strategies. In conclusion, our concise review illuminates the E3 ubiquitin ligases and deubiquitinases pivotal role in CRC, offering insights to inspire innovative approaches for transforming the treatment landscape in CRC., Competing Interests: Declaration of competing interest There is no competing and conflict of interests., (Copyright © 2024. Published by Elsevier B.V.)

Atrial fibrillation (AF) is a prevalent cardiac arrhythmia marked by irregular and frequent tachycardic rhythms in the atria, affecting 1%-2% of the general population. The WATCHMAN™ device from Boston Scientific (Marlborough, MA, USA) and the Amplatzer™ Amulet™ device from Abbott (Chicago, IL, USA) are two devices used globally for left atrial appendage closure (LAAC) in non-valvular AF. A systematic search was conducted in PubMed, the Cochrane Library, and Elsevier's ScienceDirect literature databases to identify studies comparing the WATCHMAN™ procedure with Amulet™ device implantation for LAAC in patients with AF. The analyses were conducted using the random-effects model. A total of 20 studies were identified, with 18 falling into the category of observational studies and 2 being randomized controlled trials. A total of 6310 participants were included in this meta-analysis, with 3198 individuals (50.68%) assigned to the WATCHMAN™ procedure group and 3112 individuals (49.32%) allocated to the Amplatzer™ Cardiac Plug (ACP) group. The analysis revealed a higher risk of stroke associated with the WATCHMAN™ technique (relative risk [RR], 1.14), albeit without statistical significance. Conversely, the WATCHMAN™ approach led to a significantly lower risk of cardiac death (RR, 0.44; P = .04). Notably, the risks of all-cause mortality (RR, 0.89; 95% confidence interval [CI], 0.73-1.08; I 2 = 0%; P = .25) and major bleeding (RR, 0.93; 95% CI, 0.65-1.33; I 2 = 31%; P = .70) were clinically reduced with the WATCHMAN™ procedure, although statistical significance was not achieved. Compared to Amulet™ device implantation, WATCHMAN™ device implantation decreased the risk of cardiac mortality, while the risks of stroke, systemic embolism, all-cause mortality, and major bleeding were not statistically significant., Competing Interests: The authors report no conflicts of interest for the published content. No funding information was provided., (Copyright: © 2024 Innovations in Cardiac Rhythm Management.)

Entomopathogenic nematodes (EPNs) exhibit a bending-elastic instability, or kink, before becoming airborne, a feature hypothesized but not proven to enhance jumping performance. Here, we provide the evidence that this kink is crucial for improving launch performance. We demonstrate that EPNs actively modulate their aspect ratio, forming a liquid-latched closed loop over a slow timescale O (1 s), then rapidly open it O (10 µs), achieving heights of 20 body lengths (BL) and generating ∼ 10 4 W/Kg of power. Using jumping nematodes, a bio-inspired Soft Jumping Model (SoftJM), and computational simulations, we explore the mechanisms and implications of this kink. EPNs control their takeoff direction by adjusting their head position and center of mass, a mechanism verified through phase maps of jump directions in simulations and SoftJM experiments. Our findings reveal that the reversible kink instability at the point of highest curvature on the ventral side enhances energy storage using the nematode's limited muscular force. We investigated the impact of aspect ratio on kink instability and jumping performance using SoftJM, and quantified EPN cuticle stiffness with AFM, comparing it with C. elegans . This led to a stiffness-modified SoftJM design with a carbon fiber backbone, achieving jumps of ∼25 BL. Our study reveals how harnessing kink instabilities, a typical failure mode, enables bidirectional jumps in soft robots on complex substrates like sand, offering a novel approach for designing limbless robots for controlled jumping, locomotion, and even planetary exploration.

We present a colorimetric probe based on polyvinylpyrrolidone-capped gold nanoparticles (PVP-AuNPs) that is sensitive and selective for cysteine (Cys). A microfluidic paper-based analytical device (μ-PAD) with embedded dried PVP-AuNPs at the polyethersulfone (PES) paper surface is used for Cys detection. When thiol molecules attach to PVP-AuNPs in the presence of Cys, they clump together, and this causes the solution's color to shift from red to blue within 5 minutes. The device is capable of detecting Cys levels between 1.0 μM and 50.0 μM with a limit of detection (LOD) of 0.2 μM under optimized conditions. The stability of the μ-PAD was tested for 100 days, demonstrating re-dispersibility to detect Cys levels in blood. Dried PVP-AuNP-μPADs were integrated with blood plasma separation modules for point-of-care (POC) Cys detection. Consequently, the device shows potential as a self-sustaining, quantification platform with a recovery percentage ranging from 98.44 to 111.9 in clinical samples.

The connection between maternal microbiota and infant health has been greatly garnered interest for therapeutic purposes. The early resident microbiota perpetually exhibits much more flexibility as compared to that of the adults, and therefore, constant need of understanding the infant as well as maternal microbiota and their implications however has increased. In this review, we focus mainly on the diversity of overall maternal microbiota including the gut, vaginal, colostrum microbiota and how inflammatory markers fluctuate throughout the normal pregnancy as well in pregnancy with complications. The maternal body undergoes a cascade of physiological changes including hormonal, immunological and metabolic events to support the fetal development. These changes at the time of pregnancy have been correlated with alteration in the composition and diversity of maternal microbiota. Along with alteration in microbiome, the levels of circulatory cytokines fluctuate by complex network of inflammation, in order to prevent the fetal allograft throughout the pregnancy. The dynamic relationship of gut microbiota with the host and its immune system allows one to have greater insights of their role in pregnancy and newborn's health. Emerging evidence suggests that the vertical transmission of bacterial community from mother to newborn may begin in-utero which contributes in developing the immune system and infant gut microbiota., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Elsevier Inc. All rights reserved.)

We and others have shown that [ 18 F]-Flortaucipir, the most validated tau PET tracer thus far, binds with strong affinity to tau aggregates in Alzheimer's (AD) but has relatively low affinity for tau aggregates in non-AD tauopathies and exhibits off-target binding to neuromelanin- and melanin-containing cells, and to hemorrhages. Several second-generation tau tracers have been subsequently developed. [ 18 F]-MK-6240 and [ 18 F]-PI-2620 are the two that have garnered most attention. Our recent data indicated that the binding pattern of [ 18 F]-MK-6240 closely parallels that of [ 18 F]-Flortaucipir. The present study aimed at the direct comparison of the autoradiographic binding properties and off-target profile of [ 18 F]-Flortaucipir, [ 18 F]-MK-6240 and [ 18 F]-PI-2620 in human tissue specimens, and their potential binding to monoamine oxidases (MAO). Phosphor-screen and high resolution autoradiographic patterns of the three tracers were studied in the same postmortem tissue material from AD and non-AD tauopathies, cerebral amyloid angiopathy, synucleopathies, transactive response DNA-binding protein 43 (TDP-43)-frontotemporal lobe degeneration and controls. Our results show that the three tracers show nearly identical autoradiographic binding profiles. They all strongly bind to neurofibrillary tangles in AD but do not seem to bind to a significant extent to tau aggregates in non-AD tauopathies pointing to their limited utility for the in vivo detection of non-AD tau lesions. None of them binds to lesions containing β-amyloid, α-synuclein or TDP-43 but they all show strong off-target binding to neuromelanin and melanin-containing cells, as well as weaker binding to areas of hemorrhage. The autoradiographic binding signals of the three tracers are only weakly displaced by competing concentrations of selective MAO-B inhibitor deprenyl but not by MAO-A inhibitor clorgyline suggesting that MAO enzymes do not appear to be a significant binding target of any of them. These findings provide relevant insights for the correct interpretation of the in vivo behavior of these three tau PET tracers., (© 2024. The Author(s).)

The relationship between insulin resistance and coronary artery disease (CAD) is a crucial study area in understanding the complex connection between metabolic dysregulation and cardiovascular morbidity. This scholarly investigation examines the intricate relationship between insulin resistance, a key characteristic of metabolic syndrome, and CAD development. The goal is to understand the detailed molecular and physiological connections that underlie the dangerous connection between the endocrine and cardiac systems. The recognition of insulin resistance as a key player in cardiovascular disease highlights the need to study the complex relationships between insulin signaling pathways and the development of atherosclerosis. This research analyzes the molecular processes by which insulin resistance leads to disruptions in lipid metabolism, inflammatory reactions, and malfunction of the blood vessel's inner lining. These processes create an environment that promotes the development and advancement of CAD. As we begin this scientific exploration, it becomes clear that insulin resistance acts as a metabolic indicator and a potent mediator of endothelial dysfunction, oxidative stress, and systemic inflammation. The complex interaction between insulin-sensitive tissues and the vascular endothelium plays a crucial role in defining the pathophysiological landscape of CAD. Furthermore, this discussion highlights the mutual interaction between the endocrine and cardiac systems, where CAD produced by myocardial ischemia worsens insulin resistance through complex molecular pathways. Discovering new therapeutic targets that disrupt the harmful cycle between insulin resistance and the development of CAD shows potential for creating specific therapies to reduce cardiovascular risk in people with insulin resistance. This study aims to clarify the complexities of the connection between the endocrine system and the heart, establishing the basis for a thorough comprehension of how insulin resistance contributes to the development and advancement of CAD., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Ashraf et al.)

Recent observations of wingless animals, including jumping nematodes, springtails, insects, and wingless vertebrates like geckos, snakes, and salamanders, have shown that their adaptations and body morphing are essential for rapid self-righting and controlled landing. These skills can reduce the risk of physical damage during collision, minimize recoil during landing, and allow for a quick escape response to minimize predation risk. The size, mass distribution, and speed of an animal determine its self-righting method, with larger animals depending on the conservation of angular momentum and smaller animals primarily using aerodynamic forces. Many animals falling through the air, from nematodes to salamanders, adopt a skydiving posture while descending. Similarly, plant seeds such as dandelions and samaras are able to turn upright in mid-air using aerodynamic forces and produce high decelerations. These aerial capabilities allow for a wide dispersal range, low-impact collisions, and effective landing and settling. Recently, small robots that can right themselves for controlled landings have been designed based on principles of aerial maneuvering in animals. Further research into the effects of unsteady flows on self-righting and landing in small arthropods, particularly those exhibiting explosive catapulting, could reveal how morphological features, flow dynamics, and physical mechanisms contribute to effective mid-air control. More broadly, studying apterygote (wingless insects) landing could also provide insight into the origin of insect flight. These research efforts have the potential to lead to the bio-inspired design of aerial micro-vehicles, sports projectiles, parachutes, and impulsive robots that can land upright in unsteady flow conditions., (© 2023 IOP Publishing Ltd.)

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) causes the complicated disease COVID-19. Clinicians are continuously facing huge problems in the treatment of patients, as COVID-19-specific drugs are not available, hence the principle of drug repurposing serves as a one-and-only hope. Globally, the repurposing of many drugs is underway; few of them are already approved by the regulatory bodies for their clinical use and most of them are in different phases of clinical trials. Here in this review, our main aim is to discuss in detail the up-to-date information on the target-based pharmacological classification of repurposed drugs, the potential mechanism of actions, and the current clinical trial status of various drugs which are under repurposing since early 2020. At last, we briefly proposed the probable pharmacological and therapeutic drug targets that may be preferred as a futuristic drug discovery approach in the development of effective medicines., (© 2023 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd.)

Helicobacter pylori infection is seropositive in ~50% of people globally. Therefore, this study was conducted to evaluate its prevalence in dyspepsia patients., Methods: A cross-sectional study was conducted at Jinnah Postgraduate Medical Centre (JPMC) from January to June 2022 to find out the prevalence and risk factors of H. pylori in dyspepsia patients. A prevalidated questionnaire was used to collect the data from 180 patients. This study adheres to the principles outlined in the Helsinki Declaration. The χ 2 -test was applied, and the odds ratio and 95% CI were calculated to find the association of H. pylori with the risk factors., Results: A total of 180 patients were enrolled in this study, of whom, 73 (40.6%) patients were male and 107 (59.4%) were female. In seropositive H. pylori patients, 80 (60.6%) patients had nausea or vomiting, 110 (83.3%) patients were found to have flatulence, 128 (97.7%) patients were experiencing frequent burping, and 114 (86.4%) patients were having epigastric pain. The household member greater than 4, smoking, rural area residence, NSAIDs consumption, BMI greater than 25, O+ blood group, and Rhesus positive status were significantly associated with H. pylori with a P value of less than 0.05., Conclusion: This study concludes that the prevalence of H. pylori in our population is high, and the risk factors identified are lower class, BMI greater than 25, smoking, O+ blood group, NSAID consumption, rural area residence, household member greater than 4, Rhesus positive status, and the symptoms of nausea or vomiting, frequent burping, epigastric pain, and flatulence. Patients with an increased number of risk factors should be taken into consideration for an appropriate checkup., Competing Interests: No conflicts of interest declared.Sponsorships or competing interests that may be relevant to content are disclosed at the end of this article., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2)-induced COVID-19 is a complicated disease. Clinicians are continuously facing difficulties to treat infected patients using the principle of repurposing of drugs as no specific drugs are available to treat COVID-19. To minimize the severity and mortality, global vaccination is the only hope as a potential preventive measure. After a year-long global research and clinical struggle, 165 vaccine candidates have been developed and some are currently still in the pipeline. A total of 28 candidate vaccines have been approved for use and the remainder are in different phases of clinical trials. In this comprehensive report, the authors aim to demonstrate, classify and provide up-to-date clinical trial status of all the vaccines discovered to date and specifically focus on the approved candidates. Finally, the authors specifically focused on the vaccination of different types of medically distinct populations., (© 2022 British Pharmacological Society.)

Climate change and its impact on agriculture productivity vary among crops and regions. The southeastern United States (SE-US) is agro-ecologically diversified, economically dependent on agriculture, and mostly overlooked by agroclimatic researchers. The objective of this study was to compute the effect of climatic variables; daily maximum temperature (T max ), daily minimum temperature (T min ), and rainfall on the yield of major cereal crops i.e., corn (Zea mays L.), rice (Oryza sativa L.), and wheat (Triticum aestivum L.) in SE-US. A fixed-effect model (panel data approach) was used by applying the production function on panel data from 1980 to 2020 from 11 SE-US states. An asymmetrical warming pattern was observed, where nocturnal warming was 105.90%, 106.30%, and 32.14%, higher than the diurnal warming during corn, rice, and wheat growing seasons, respectively. Additionally, a shift in rainfall was noticed ranging from 19.2 to 37.2 mm over different growing seasons. Rainfall significantly reduced wheat yield, while, it had no effect on corn and rice yields. The T max and T min had no significant effect on wheat yield. A 1 °C rise in T max significantly decreased corn (- 34%) and rice (- 8.30%) yield which was offset by a 1 °C increase in T min increasing corn (47%) and rice (22.40%) yield. Conclusively, overall temperature change of 1 °C in the SE-US significantly improved corn yield by 13%, rice yield by 14.10%, and had no effect on wheat yield., (© 2022. The Author(s).)

Maintaining the balance between eliciting immune responses against foreign proteins and tolerating self-proteins is crucial for maintenance of homeostasis. The functions of programmed death protein 1 (PD-1) and its ligand programmed death ligand 1 (PD-L1) are to inhibit immune responses so that over-reacting immune cells does not cause any damage to its own body cells. However, cancer cells hijack this mechanism to attenuate immune cells functions and create an immunosuppressive environment that fuel their continuous growth and proliferation. Over the past few years' rapid development in cancer immunotherapy has opened a new avenue in cancer treatment. Blockade of PD-1 and PD-L1 has become a potential strategy that rescue the functions of immune cells to fight against cancer with high efficacy. Initially, immune checkpoint monotherapies were not very successful, making breast cancer less immunogenic. Although, recent reports support the presence of tumor infiltrating lymphocytes (TILs) in breast cancer that make it favorable for PD-1/PD-L1 mediated immunotherapy, which is effective in PD-L1 positive patients. Recently, anti-PD-1 (pembrolizumab) and anti-PD-L1 (atezolizumab) gets FDA approval for breast cancer treatment and make PD-1/PD-L1 immunotherapy is meaningful for further research. Likewise, this article gathered understanding of PD-1 and PD-L1 in recent years, their signaling networks, interaction with other molecules, regulations of their expressions and functions in both normal and tumor tissue microenvironments are crucial to find and design therapeutic agents that block this pathway and improve the treatment efficacy. Additionally, authors collected and highlighted most of the important clinical trial reports on monotherapy and combination therapy., (© 2022 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co., Ltd.)

Introduction:  Persistent and prolonged symptoms, termed as long COVID (coronavirus disease), have been reported in several patients who recovered from the acute phase at different intervals. However, there has been largely unclear data regarding the full range of long-term sequelae of coronavirus disease 2019 (COVID-19) patients. This study aims to evaluate the prevalence of long COVID syndrome., Methods: A long-term research was conducted in the COVID-19 unit of a tertiary care hospital in Pakistan from July 2020 to December 2021 in which 2,000 patients who had recovered from COVID-19 and had been discharged were included in the study. Symptoms were noted at the time of discharge and at follow-up after 12 months. Data were analyzed using Statistical Package for the Social Sciences (SPSS) v. 22.0 (IBM Corporation, Armonk, New York, United States)., Results: The mean age of the participants was 43 ± 10 years, 801 (53.8%) males and 688 (46.2%) females. At the time of discharge, the most common symptom was fatigue (26.93%), followed by dyspnea (20.34%) and muscle pain (8.86%). The most common symptom on follow-up was fatigue (6.78%)., Conclusion: We strongly emphasize discussing and exploring further knowledge on the post-infection syndrome, with an aim to bring healthcare professionals' attention to the importance of handling COVID patients, their counseling, warning for alarming signs, and a long-term follow-up with necessary investigations and treatment., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2022, Shivani et al.)

In acute respiratory failure due to severe coronavirus disease 2019 (COVID-19) pneumonia, mechanical ventilation remains challenging and may result in high mortality. The use of noninvasive ventilation (NIV) may delay required invasive ventilation, increase adverse outcomes, and have a potential aerosol risk to caregivers. Data of 30 patients were collected from patient files and analyzed. Twenty-one (70%) patients were weaned successfully after helmet-NIV support (NIV success group), and invasive mechanical ventilation was required in 9 (30%) patients (NIV failure group) of which 8 (26.7%) patients died. In NIV success vs failure patients, the mean baseline PaO 2 /FiO 2 ratio (PFR) (147.2 ± 57.9 vs 156.8 ± 59.0 mm Hg; p = 0.683) and PFR before initiation of helmet (132.3 ± 46.9 vs 121.6 ± 32.7 mm Hg; p = 0.541) were comparable. The NIV success group demonstrated a progressive improvement in PFR in comparison with the failure group at 2 hours (158.8 ± 56.1 vs 118.7 ± 40.7 mm Hg; p = 0.063) and 24 hours (PFR-24) (204.4 ± 94.3 vs 121.3 ± 32.6; p = 0.016). As predictor variables, PFR-24 and change (delta) in PFR at 24 hours from baseline or helmet initiation (dPFR-24) were significantly associated with NIV success in univariate analysis but similar significance could not be reflected in multivariate analysis perhaps due to a small sample size of the study. The PFR-24 cutoff of 161 mm Hg and dPFR-24 cutoff of -1.44 mm Hg discriminate NIV success and failure groups with the area under curve (confidence interval) of 0.78 (0.62-0.95); p = 0.015 and 0.74 (0.55-0.93); p = 0.039, respectively. Helmet interface NIV may be a safe and effective tool for the management of patients with severe COVID-19 pneumonia with acute respiratory failure. More studies are needed to further evaluate the role of helmet NIV especially in patients with initial PFR <150 mm Hg to define PFR/dPFR cutoff at the earliest time point for prediction of helmet-NIV success. How to cite this article Jha OK, Kumar S, Mehra S, Sircar M, Gupta R . Helmet NIV in Acute Hypoxemic Respiratory Failure due to COVID-19: Change in PaO 2 /FiO 2 Ratio a Predictor of Success. Indian J Crit Care Med 2021;25(10):1137-1146., Competing Interests: Source of support: Nil Conflict of interest: None, (Copyright © 2021; Jaypee Brothers Medical Publishers (P) Ltd.)

The carboxy-terminus of Hsp70-interacting protein (CHIP) is a ubiquitin ligase and co-chaperone belonging to Ubox family that plays a crucial role in the maintenance of cellular homeostasis by switching the equilibrium of the folding-refolding mechanism towards the proteasomal or lysosomal degradation pathway. It links molecular chaperones viz . HSC70, HSP70 and HSP90 with ubiquitin proteasome system (UPS), acting as a quality control system. CHIP contains charged domain in between N-terminal tetratricopeptide repeat (TPR) and C-terminal Ubox domain. TPR domain interacts with the aberrant client proteins via chaperones while Ubox domain facilitates the ubiquitin transfer to the client proteins for ubiquitination. Thus, CHIP is a classic molecule that executes ubiquitination for degradation of client proteins. Further, CHIP has been found to be indulged in cellular differentiation, proliferation, metastasis and tumorigenesis. Additionally, CHIP can play its dual role as a tumor suppressor as well as an oncogene in numerous malignancies, thus acting as a double agent. Here, in this review, we have reported almost all substrates of CHIP established till date and classified them according to the hallmarks of cancer. In addition, we discussed about its architectural alignment, tissue specific expression, sub-cellular localization, folding-refolding mechanisms of client proteins, E4 ligase activity, normal physiological roles, as well as involvement in various diseases and tumor biology. Further, we aim to discuss its importance in HSP90 inhibitors mediated cancer therapy. Thus, this report concludes that CHIP may be a promising and worthy drug target towards pharmaceutical industry for drug development., (© 2021 Chongqing Medical University. Production and hosting by Elsevier B.V.)

Background: TDP-43 proteinopathy is a pathological hallmark of many neurodegenerative diseases including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). So far, there is no therapy available for these neurodegenerative diseases. In addition, the impact of TDP-43 proteinopathy on neuronal translational profile also remains unknown., Methods: Biochemical, immunohistology and assay-based studies were done with cell cultures and transgenic mice models. We also used Ribotag with microarray and proteomic analysis to determine the neuronal translational profile in the mice model of ALS/FTD., Results: Here, we report that oral administration of a novel analog (IMS-088) of withaferin-A, an antagonist of nuclear factor kappa-B (NF-ĸB) essential modulator (NEMO), induced autophagy and reduced TDP-43 proteinopathy in the brain and spinal cord of transgenic mice expressing human TDP-43 mutants, models of ALS/FTD. Treatment with IMS-088 ameliorated cognitive impairment, reduced gliosis in the brain of ALS/FTD mouse models. With the Ribotrap method, we investigated the impact of TDP-43 proteinopathy and IMS-088 treatment on the translation profile of neurons of one-year old hTDP-43 A315T mice. TDP-43 proteinopathy caused translational dysregulation of specific mRNAs including translational suppression of neurofilament mRNAs resulting in 3 to 4-fold decrease in levels type IV neurofilament proteins. Oral administration of IMS-088 rescued the translational defects associated with TDP-43 proteinopathy and restored the synthesis of neurofilament proteins, which are essential for axon integrity and synaptic function., Conclusions: Our study revealed that induction of autophagy reduces TDP-43 pathology and ameliorates the translational defect seen in mice models of ALS/FTD. Based on these results, we suggest IMS-088 and perhaps other inducers of autophagy should be considered as potential therapeutics for neurodegenerative disorders with TDP-43 proteinopathies.

Withaferin-A, an active withanolide derived from the medicinal herbal plant Withania somnifera induces autophagy, reduces TDP-43 proteinopathy, and improves cognitive function in transgenic mice expressing mutant TDP-43 modelling FTLD. TDP-43 is a nuclear DNA/RNA-binding protein with cellular functions in RNA transcription and splicing. Abnormal cytoplasmic aggregates of TDP-43 occur in several neurodegenerative diseases including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration (FTLD), and limbic-predominant age-related TDP-43 encephalopathy (LATE). To date, no effective treatment is available for TDP-43 proteinopathies. Here, we tested the effects of withaferin-A (WFA), an active withanolide extracted from the medicinal herbal plant Withania somnifera, in a transgenic mouse model of FTLD expressing a genomic fragment encoding mutant TDP-43 G348C . WFA treatment ameliorated the cognitive performance of the TDP-43 G348C mice, and it reduced NF-κB activity and neuroinflammation in the brain. WFA alleviated TDP-43 pathology while it boosted the levels of the autophagic marker LC3BII in the brain. These data suggest that WFA and perhaps other autophagy inducers should be considered as potential therapy for neurodegenerative diseases with TDP-43 pathology.

Kithul starch was treated by EN (energetic neutral nitrogen) atoms at 6 W,12 W and 18 W for 15 min and incorporated lauric acid for the development of starch-lauric acid inclusion complexes. EN atoms treatment significantly (p ≤ 0.05) increased the complex index (CI). Severe morphological alterations on the kithul starch granules by EN atoms treatment enhanced starch-lauric acid complex formation. Relative crystallinity of EN atoms treated lauric acid incorporated kithul starch samples increased with plasma power. Moreover, lower pasting property, storage modulus (G'), loss modulus (G''), hardness and higher Tanδ indicated decrease in gelation and retrogradation property. ENL-18 W showed the lowest complex viscosity (Ƞ*). Lauric acid incorporation in EN atoms treated kithul starch reduced in vitro digestibility and significantly (p ≤ 0.05) increased RS (resistant starch). Hence, EN atoms treatment on the kithul starch granules prior to fatty acid incorporation is an effective technique for the development of starch-fatty acid complexes., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Hypothesis: Mixing of a chemical trigger of lower surface tension into a microdroplet with relatively higher surface tension can cause a rapid spreading of the droplet on a liquid-sublayer to form a host of metastable liquid morphologies such as sheets, toroids, threads, or droplets. Subsequently, such metastable fluidic objects break into a collection of droplets to form microemulsions., Experiments: Introduction of surfactant loaded water or long-chain alcohols into an oleic acid microdroplet stimulate a rapid spreading of the same on a water sublayer, which helps in the formation of a metastable liquid sheet connected to a liquid toroid. Much like slipping films, the liquid sheet dewets the water underlayer through the formation of holes before they grow and coalesce to form liquid ribbons. While such liquid structures eventually break into an array of microdroplets, the liquid toroid expands before undergoing a Plateau-Rayleigh instability to form microdroplets., Findings: A single step self-organization process in which a chemical trigger can convert a microdroplet into a liquid-toroid on a water surface, in absence of any rotational influence. A symmetric to asymmetric transition in toroid morphology is observed due to the changeover of laminar to turbulent flow regimes with the reduction in viscosity of fluid-sublayer or variation in chemical triggers. The toroid cross-section and droplet spacing after the toroid breakup follow a length scale evaluated from a linear stability analysis., 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 Inc. All rights reserved.)

Native buckwheat starch was extracted and modified by heat-moisture treatment (HMT) with different treatment time (15, 30 and 45 min) to investigate its effect on physicochemical, morphological, functional properties, starch profile (rapidly digestible starch, RDS; slowly digestible starch, SDS and resistant starch, RS fractions) and expected glycemic index (eGI). Results revealed that with increasing time duration of HMT from 15 to 45 min, amylose content, pasting temperature and thermostability increased substantially whereas swelling power, solubility and viscosity parameters decreased. The SEM micrographs showed that HMT caused fissures in the granule and surface indentation. HMT-45 (starch treated for 45 min) had the lowest RDS content (29.33%) and the highest SDS (51.30%) and RS (8.21%) levels. The decreased hydrolysis rate, high amylose and RS content of HMT-45 resulted in a significant decrease in estimated glycemic index (eGI) values from 51.49% (Native) to 44.16% (HMT-45) thus indicating its role in prevention of non-insulin- dependent diabetes., (© Association of Food Scientists & Technologists (India) 2020.)

One of the characteristic features of obesity is increased body weight and accumulation of adipose tissue. It is associated with low grade inflammation and gut dysbiosis. Probiotics and its products could be an ideal strategy to prevent or treat diabetes. In the present study, animals were induced obesity by providing them with high fat diet. Three purified bacteriocins i.e., DT24, PJ4 and TSU4, previously isolated and purified from various probiotic strains, were given as treatment strategies, following the induction of obesity. Upon the completion of the study, animals were sacrificed and were checked for their tissue expression of inflammatory mediators and adipokines. Serum hormone and cytokines analysis were performed to check their inflammatory state. Treatment with purified bacteriocin DT24 did not show any therapeutic effect in any of the parameter studied. Bacteriocin TSU4 on the other hand showed better reversal compared to DT24. Bacteriocin PJ4 showed the most promising results by reversing all the altered parameters significantly. It significantly reversed all the biochemical, immunological in terms of serum cytokines as well as altered morphological characteristics. PJ4 can be further explored to determine its mode of action. The anti-microbial proteins or to be more specific, bacteriocins, which shows broad spectrum efficacy, could be a better alternative in modulating gut microflora for the treatment of obesity and diabetes characteristics. The efficacy of bacteriocin PJ4 may also be due to the source of the host of Lactobacillus., Competing Interests: Conflict of interestThere is no conflicts of interests to disclose., (© King Abdulaziz City for Science and Technology 2020.)

Effect of hydrothermal modifications (autoclaving, annealing and heat moisture treatment) on physico-chemical, rheological properties and in vitro digestibility of kithul starch was studied. Annealing and heat moisture treatment decreased swelling index, solubility and increased crystalline properties as compared with autoclaving. Autoclaving, annealing and heat moisture treatment caused significant morphological damages such as large holes and fissures on the kithul starch, in addition, granules changed from oval to donut shape. Heat moisture treatment formed higher number of agglomerated starch granules. Light transmittance decreased after hydrothermal modifications. Autoclaving and annealing increased the pasting viscosities (except break down viscosity) of kithul starch. A significant increase ( p  ≤ 0.05) in peak temperature, conclusion temperature and enthalpy was found in annealed and heat moisture treated kithul starches. The digestibility of kithul starch decreased with increasing resistant starch after annealing and heat moisture treatment. Autoclaved, annealed and heat moisture treated kithul starches exhibited higher value of storage modulus (G') and loss modulus (G″) than native kithul starch. It entail to higher firmness of modified starch gel. The current study showed that the remarkable changes formed by hydrothermal modifications increased the industrial acceptance of kithul starch., Competing Interests: Conflict of interestThere is no conflict of interest., (© Association of Food Scientists & Technologists (India) 2020.)

The study reveals effect of pre-treatments, i.e., partial drying (PD), partial drying + freezing (PDF) and freezing (F) on physico-chemical, structural and sensory quality of vacuum fried papaya chips (100 °C for 28 min at 13.33 kPa). Pre-treatments significantly ( p  < 0.05) influenced the quality parameters of vacuum fried papaya chips. Partial drying pre-treated sample showed significantly ( p  < 0.05) higher reduction in oil uptake, i.e., 19.61% ( d.b. ) besides retaining significantly ( p  < 0.05) higher total phenolics content (394.07 mg/100 g gallic acid equivalent) as compared to other samples. Ascorbic acid content was retained significantly ( p  < 0.05) high in untreated control samples (209.81 mg/100 g). Freezing pre-treatment was found better in retaining total flavonoids, total carotenoids and antioxidant activity. The SEM micrographs of papaya chips showed dense and shriveled structure due to partial drying pre-treatment, however, more porous structure was observed in freezing pre-treated sample as compared to control. Freezing pre-treated samples were also rated high on hedonic scale for their sensory parameters, i.e., colour, crispness, taste, mouth feel, appearance and overall acceptability, which were in agreement with instrumental CIE colour values, firmness and microstructural characteristics of samples. The percent moisture, fat, protein, total carbohydrate, and ash content of freezing pre-treated vacuum fried papaya chips was found to be 1.51 ± 0.13%, 23.68 ± 0.12%, 3.42 ± 0.14%, 67.64 ± 1.78% and 3.75 ± 0.08%, respectively., (© Association of Food Scientists & Technologists (India) 2020.)

To test the hypothesis that the cerebrospinal fluid (CSF) could provide a spreading route for pathogenesis of amyotrophic lateral sclerosis (ALS), we have examined the effects of intraventricular infusion during 2 weeks of pooled CSF samples from sporadic ALS patients or control CSF samples into transgenic mice expressing human TDP43 WT which do not develop pathological phenotypes. Infusion of ALS-CSF, but not of control CSF, triggered motor and cognitive dysfunction, as well as ALS-like pathological changes including TDP43 proteinopathy, neurofilament disorganization and neuroinflammation. In addition, the neuron-specific translational profiles from peptide analyses of immunoprecipitated ribosomes revealed dysregulation of multiple protein networks in response to ALS-CSF altering cytoskeletal organization, vesicle trafficking, mitochondrial function, and cell metabolism. With normal mice, similar ALS-CSF infusion induced mild motor dysfunction but without significant TDP43 pathology in spinal neurons. We conclude that the CSF from sporadic ALS contains factors that can transmit and disseminate disease including TDP43 proteinopathy into appropriate recipient animal model expressing human TDP43. These findings open new research avenues for the discovery of etiogenic factors for sporadic ALS and for the testing of drugs aiming to neutralize the ALS-CSF toxicity.

In this study, a membraneless photofuel cell, namely, μ-DropFC, was designed and developed to harvest chemical and solar energies simultaneously. The prototypes can also perform environmental remediation to demonstrate their multitasking potential as a sustainable hybrid device in a single embodiment. A hydrogen peroxide (H 2 O 2 ) microdroplet at optimal pH and salt loading was utilized as a fuel integrated with Al as an anode and zinc phthalocyanine (ZnPC)-coated Cu as a cathode. The presence of n-type semiconductor ZnPC in between the electrolyte and metal enabled the formation of a photo-active Schottky junction suitable for power generation under light. Concurrently, the oxidation and reduction of H 2 O 2 on the electrodes helped in the conversion of chemical energy into the electrical one in the same membraneless setup. The suspension of Au nanoparticles (Au NPs) in the droplet helped in enhancing the overall power density under photonic illumination through the effects of localized surface plasmon resonance (LSPR). Furthermore, the presence of photo-active n-type CdS NPs enabled the catalytic photo-degradation of dyes under light in the same embodiment. A 40 μL μ-DropFC could show a significantly high open circuit potential of ∼0.58 V along with a power density of 0.72 mW cm -2 . Under the same condition, the integration of ten such μ-DropFCs could produce a power density of ∼7 mW cm -2 at an efficiency of 3.4%, showing the potential of the prototype for a very large scale integration (VLSI). The μ-DropFC could also degrade ∼85% of an industrial pollutant, rhodamine 6G, in 1 h while generating a power density of ∼0.6 mW cm -2 . The performance parameters of μ-DropFCs were found to be either comparable or superior to the existing prototypes. In a way, the affordable, portable, membraneless, and high-performance μ-DropFC could harvest energy from multiple resources while engaging in environmental remediation., Competing Interests: There are no conflicts to declare., (This journal is © The Royal Society of Chemistry.)

The changes in physico-chemical and rheological properties of kithul starch by the impact of energetic neutral nitrogen atoms produced by the glow discharge air plasma with novel technique were analysed. Here, treatment was carried out at different power levels (5 W & 15 W) and treatment time (30 min & 60 min). Decrease in amylose and moisture content and increase in swelling index and solubility of plasma treated kithul starch were observed. Fourier transform infrared spectra of plasma treated starch showed variation in the peaks corresponding to CH 2 and OH groups. Relative crystallinity significantly (p ≤ 0.05) decreased after plasma treatment. Scanning electron microscopy showed severe damages on the starch granular surface by the effect of energetic neutral nitrogen atoms. Pasting properties increased and thermal properties showed significant (p ≤ 0.05) changes after plasma treatment. Storage modulus (G') and loss modulus (G″) reduced at higher levels of plasma power and it indicated to its weak gel formation., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objective: Gut microbiota is currently targeted for various diseases especially metabolic disorders such as diabetes. Our strategy is to alter gut microflora via specific antibiotic to reduce load of inflammation in the liver that increases as a result of high carbohydrate diet. Th1, Th17 and Treg are important immune cell types which decide the type of inflammatory response. Liver is tolerogenic in nature with low Th17/Treg ratio. In diabetics, this ratio decreases even more, and can cause liver trauma., Method: The present study tries to find relationship between gut flora and immune cells such as Th1/Th17/Treg and their role in liver metabolism using diet induced diabetic mice model., Result: Upon alteration of flora using Cefdinir in different forms, one could help lower the level of Treg cells thus increasing the ratio. Gut flora is strongly associated with the immunity in the liver. Targeted alteration of gut flora helps us to restore insulin sensitivity., Conclusion: Colon targeted Cefdinir gives more promising results, opens colonic bacteria as target for improving gut, liver inflammation and insulin sensitivity., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The region of head and neck is critical for respiration, nutrition, and speech. The management of laryngeal tumours can stimulate mutilations and cosmetic deformities and worsen the life. A “non-operative approach” is preferred for patients to whom radiation following surgery, possibly, will direct severe functional destruction predominantly in advanced stage patients having a bulk of carcinoma larynx. The case material for the study was selected from the cross-section of patients registered at the J. K. Cancer Institute, Kanpur. Histologically squamous cell carcinoma 64 patients were registered and equally and randomly placed into Arm I and Arm II. “Arm I” patients and “Arm II” was comprised of randomly selected 64 patients, having histopathologically proven squamous cell carcinoma of the larynx. All patients (32 patients) belonging to “Arm I” received concurrent chemoradiotherapy of Inj. Cisplatin 100 mg/m2 for three-weekly underwent EBRT with 60 Co/LINAC and photon radiation of 70 Gy in 35 fractions for 7 weeks (2 parallel opposed fields). All the patients (32 patients) belongs to “Arm II” received chemo boost as Inj. Cisplatin 6 mg/m2 on last 15 fractions of treatment underwent EBRT with 60 Co/ LINAC photon radiation of 70 Gy in 35 fractions for 7 weeks. Radiotherapy was delivered in supine position by parallel opposing fields including the primary tumour, disease extension, and neck nodes. The study concluded that the loco-regional responses are analogous in Arm I and Arm 2, however Arm II had additional treatment allied toxicities and resulting from numerous of treatment breaks., (Creative Commons Attribution License)

Targeting dendritic cells (DCs), either ex vivo (Ex. Sipuleucel-T) or in vivo, for stimulating cellular immunity has been a leading approach for cancer vaccines. We have rationally engineered a nanoparticle (NP)-based delivery system for vaccines (InAc-NPs) using inulin acetate (InAc) as the polymer to target DCs. The material and the antigen-encapsulated InAc-NPs (∼190 nm in diameter) were characterized for their physicochemical properties. As a potent vaccine adjuvant, InAc-NPs activated TLR4 on multiple immune cells, including DCs and primary swine and human cells, to secrete various cytokines as detected by enzyme-linked immunosorbent assay and quantitative polymerase chain reaction. In addition, InAc-NPs promoted the maturation of DCs as observed by a decreased phagocytic ability and enhanced capability to activate various maturation markers (MHC-I, MHC-II, CD40, and CD80) quantified using flow cytometry. In mice, the InAc-NPs produced strong serum antibody titers (total IgG, IgG1, and IgG2a) against the encapsulated antigen (ovalbumin) similar to complete Freund's adjuvant. Additionally, as a dose-sparing delivery system, antigen delivered through InAc-NPs generated higher antibody titers (IgG1, 1.57 times; IgG-total, 1.66 times; and IgG2a, 29.8 times) even at 100 times less antigen dose. High amounts of cytokines representing both humoral (IL4 and IL10) and cell-mediated (IL2 and IFN-γ) immunities were secreted from splenocytes of mice immunized with InAc-NPs. Importantly, InAc-NPs provided complete protection in 100% of the vaccinated mice from metastasis of intravenously injected melanoma cells (B 16 -F 10 ) to lungs. In addition, the InAc-NPs were cleared from the injection site within 30 h of injection (in vivo imaging) and displayed no toxicity at the injection site (histology). The current study demonstrates that the multifunctional InAc-based nanovaccine delivery system has potential applications in cancer immunotherapy and delivering vaccines against various infectious diseases.

The concurrence of atrial fibrillation and acute coronary syndrome poses a conundrum in the antithrombotic management as intensification of anticoagulation or antiplatelet therapy inevitably comes at the price of an increased bleeding risk. Various antithrombotic combinations have been attempted to prevent the recurrent cardiovascular events, however, there has been limited success in effective risk reduction for this high risk population. Given the overarching effect of interleukin 1β-driven inflammation on the arrhythmogenesis, thrombogenesis, and hypercoagulability, we hypothesize that the triple-pathway strategy (i.e., incorporating antiinflammatory therapy into anticoagulant and antiplatelet therapy) would grant incremental cardiovascular benefits for atrial fibrillation patients with coexisting acute coronary syndrome and stent placement., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

New and improved vaccines are needed against challenging diseases such as malaria, tuberculosis, Ebola, influenza, AIDS, and cancer. The majority of existing vaccine adjuvants lack the ability to significantly stimulate the cellular immune response, which is required to prevent the aforementioned diseases. This study designed a novel particulate based pathogen-mimicking vaccine delivery system (PMVDS) to target antigen-presenting-cells (APCs) such as dendritic cells. The uniqueness of PMVDS is that the polymer used to prepare the delivery system, Inulin Acetate (InAc), activates the innate immune system. InAc was synthesized from the plant polysaccharide, inulin. PMVDS provided improved and persistent antigen delivery to APCs as an efficient vaccine delivery system, and simultaneously, activated Toll-Like Receptor-4 (TLR-4) on APCs to release chemokine's/cytokines as an immune-adjuvant. Through this dual mechanism, PMVDS robustly stimulated both the humoral (>32 times of IgG1 levels vs alum) and the cell-mediated immune responses against the encapsulated antigen (ovalbumin) in mice. More importantly, PMVDS stimulated both cytotoxic T cells and natural killer cells of cell-mediated immunity to provide tumor (B16-ova-Melanoma) protection in around 40% of vaccinated mice and significantly delayed tumor progression in rest of the mice. PMVDS is a unique bio-active vaccine delivery technology with broader applications for vaccines against cancer and several intracellular pathogens, where both humoral and cellular immune responses are desired., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Application of an electric field on an oil droplet floating on the surface of a deionized water bath showed interesting motions such as spreading, oscillation, and ejection. The electric field was generated by connecting a pointed platinum cathode at the top of the oil droplet and a copper anode coated with polymer at the bottom of the water layer. The experimental setup mimicked a conventional electrowetting setup with the exception that the oil was spread on a soft and deformable water isolator. While at relatively lower field intensities we observed spreading of the droplet, at intermediate field intensities the droplet oscillated around the platinum cathode, before ejecting out at a speed as high as ∼5 body lengths per second at even stronger field intensities. The experiments suggested that when the electric field was ramped up abruptly to a particular voltage, any of the spreading, oscillation, or ejection motions of the droplet could be engendered at lower, intermediate and higher field intensities, respectively. However, when the field was ramped up progressively by increasing by a definite amount of voltage per unit time, all three aforementioned motions could be generated simultaneously with the increase in the field intensity. Interestingly, when the aforementioned setup was placed on a magnet, the droplet showed a rotational motion under the influence of the Lorentz force, which was generated because of the coupling of the weak leakage current with the externally applied magnetic field. The spreading, oscillation, ejection, and rotation of the droplet were found to be functions of the oil-water interfacial tension, viscosity, and size of the oil droplet. We developed simple theoretical models to explain the experimental results obtained. Importantly, rotating at a higher speed broke the droplet into a number of smaller ones, owing to the combined influence of the spreading due to the centripetal force and the shear at the oil-water interface. While the oscillatory and rotational motions of the incompressible droplet could be employed as stirrers or impellers inside microfluidic devices for mixing applications, the droplet ejection could be employed for futuristic applications such as payload transport or drug delivery.

Mass drug administration (MDA) targeting school-age children is recommended by the World Health Organization for the global control of soil-transmitted helminth (STH) infections. Although considered safe and cost-effective to deliver, benzimidazole anthelminthics are variably effective against the three most common STHs, and widespread use has raised concern about the potential for emerging resistance. To identify factors mediating response to albendazole, we conducted a cross-sectional study of hookworm infection in the Kintampo North Municipality of Ghana in 2011. Among 140 school-age children residing in five contiguous communities, the hookworm prevalence was 59% (82/140). The overall cure rate following administration of single-dose albendazole (400 mg) was 35% (27/76), with a community-wide fecal egg reduction rate (ERR) of 61% (95% confidence interval: 51.8-71.1). Significant disparities were observed in albendazole effectiveness by community, with a cure rate as low as 0% ( N = 24) in Jato Akuraa and ERRs ranging from 53% to 95% across the five study sites. Individual host factors associated with response to deworming treatment included time since last meal, pretreatment blood hemoglobin level, and mid-upper arm circumference. These data demonstrate significant community-level variation in the effectiveness of albendazole, even among populations living in close proximity. Identification of host factors that influence response to albendazole, most notably the timing of drug administration and nutritional factors, creates an opportunity to enhance the effectiveness of deworming through targeted interventions. These findings also demonstrate the importance of measuring anthelminthic response as part of the monitoring and evaluation of community-based deworming programs., (© The American Society of Tropical Medicine and Hygiene.)

Vaccine adjuvants are an essential part of modern vaccine design, especially against intracellular pathogens such as M. tuberculosis, malarial parasite, HIV, influenza virus and Ebola. The present work offers a unique approach to designing novel vaccine adjuvants by identifying polymers that mimic "pathogen associated molecular patterns" (PAMPS) and engineering an immune-active particulate vaccine delivery system that uses the polymer. By using this strategy, we report the discovery of the first plant polymer based toll-like receptor-4 (TLR-4) agonist, inulin acetate (InAc). InAc was synthesised from the plant polysaccharide inulin. Inulin acetate as a polymer and particles prepared using InAc were characterised using various physicochemical techniques. The TLR-4 agonistic activity of InAc was established in multiple immune, microglial, dendritic, peripheral blood mononuclear (human and swine) and genetically modified epithelial cells (HEK293) that exclusively express TLR-4 on their surface. InAc activated all the above-mentioned cells to release proliferative cytokines; however, InAc failed to activate when the were cells either pre-incubated with a TLR-4 specific antagonist or isolated from mice deficient in adapter proteins involved in TLR signalling (Mal/MyD88). Antigen encapsulated microparticles prepared with TLR-4 agonist InAc mimicked pathogens to offer improved antigen delivery to dendritic cells compared to soluble antigen (47 times) or antigen encapsulated poly(lactic-co-glycolic acid) (PLGA) particles (1.57 times). In conclusion, InAc represents a novel polymer-based modern vaccine adjuvant targeting specific signalling pathways of the innate immune system, which could be formulated into a platform vaccine delivery system against cancer and viral diseases.

Micellization offers several advantages for the delivery of water insoluble drugs including a nanoparticulate 'core-shell' delivery system for drug targeting. Recently, hydrophobically modified polysaccharides (HMPs) are gaining recognition as micelle forming polymers to encapsulate hydrophobic drugs. In this manuscript, for the first time, we have evaluated the self-assembling properties of a lauryl carbamate derivative of the poly-fructose natural polymer inulin (Inutec SP1(®) (INT)) to form paclitaxel (PTX) loaded micelles. INT self-assembled into well-defined micellar structures in aqueous environment with a low critical micellar concentration of 27.8 μg/ml. INT micelles exhibited excellent hemocompatibility and low toxicity to cultured cells. PTX loaded INT micelles exhibited a mean size of 256.37 ± 10.45 nm with excellent drug encapsulation efficiency (95.66 ± 2.25%) and loading (8.69 ± 0.22%). PTX loaded micelles also displayed sustained release of PTX and enhanced anti-cancer efficacy in-vitro in mouse melanoma cells (B16F10) compared to Taxol formulation with Cremophor EL as solvent. In addition, PTX loaded INT micelles exhibited comparable in-vivo antitumor activity in B16F10 allograft mouse model at half the dose of Taxol. In conclusion, INT offers safe, inexpensive and natural alternative to widely used PEG-modified polymers for the formulation of micellar delivery systems for paclitaxel., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Skin-penetrating peptides (SPPs) are attracting increasing attention as a non-invasive strategy for transdermal delivery of therapeutics. The identification of SPP sequences, however, currently performed by experimental screening of peptide libraries, is very laborious. Recent studies have shown that, to be effective enhancers, SPPs must possess affinity for both skin keratin and the drug of interest. We therefore developed a computational process for generating and screening virtual libraries of disulfide-cyclic peptides against keratin and cyclosporine A (CsA) to identify SPPs capable of enhancing transdermal CsA delivery. The selected sequences were experimentally tested and found to bind both CsA and keratin, as determined by mass spectrometry and affinity chromatography, and enhance transdermal permeation of CsA. Four heptameric sequences that emerged as leading candidates (ACSATLQHSCG, ACSLTVNWNCG, ACTSTGRNACG, and ACSASTNHNCG) were tested and yielded CsA permeation on par with previously identified SPP SPACE (TM) . An octameric peptide (ACNAHQARSTCG) yielded significantly higher delivery of CsA compared to heptameric SPPs. The safety profile of the selected sequences was also validated by incubation with skin keratinocytes. This method thus represents an effective procedure for the de novo design of skin-penetrating peptides for the delivery of desired therapeutic or cosmetic agents., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Curcumin is a natural dietary compound with demonstrated potential in preventing/treating several chronic diseases in animal models. However, this success is yet to be translated to humans mainly because of its poor oral bioavailability caused by extremely low water solubility. This manuscript demonstrates that water insoluble curcumin (~1μg/ml) forms highly aqueous soluble complexes (>2mg/ml) with a safe pH sensitive polymer, poly(butyl-methacrylate-co-(2-dimethylaminoethyl) methacrylate-co-methyl-methacrylate) when precipitated together in water. The complexation process was optimized to enhance curcumin loading by varying several formulation factors. Acetone as a solvent and polyvinyl alcohol as a stabilizer with 1:2 ratio of drug to polymer yielded complexes with relatively high loading (~280μg/ml) and enhanced solubility (>2mg/ml). The complexes were amorphous in solid and were soluble only in buffers with pHs less than 5.0. Hydrogen bond formation and hydrophobic interactions between curcumin and the polymer were recorded by infrared spectroscopy and nuclear magnetic resonance spectroscopy, respectively. Molecular complexes of curcumin were more stable at various pHs compared to unformulated curcumin. In mice, these complexes increased peak plasma concentration of curcumin by 6 times and oral bioavailability by ~20 times. This is a simple, economic and safer strategy of enhancing the oral bioavailability of curcumin., (Copyright © 2015 Elsevier B.V. All rights reserved.)

The immune system has evolved to recognize and respond to a wide variety of pathogens and produce distinct immune responses against diverse pathogenic structures. Despite remarkable advances, the general mechanisms by which the immune system differentiates the structure of antigen presenting particulates have yet to be elucidated. Using particles of various sizes and shapes, we assessed the role of morphological features of particles in antigen presentation and subsequent processing by the immune cells. Ovalbumin was used as a model antigen. Spherical polystyrene particles of 193 nm and 521 nm diameters were successfully stretched to form rod-shaped particles of 376 nm and 1530 nm in length, respectively. Ovalbumin conjugation to these different particle types was optimized to achieve ~50 μg of ovalbumin conjugation per mg of particle. In vivo immunization study results revealed that small spherical particles (193 nm in diameter) produced a Th1-biased response whereas rod-shaped particles (1530 nm in length) produced a Th2-biased response against ovalbumin. Among different particle types, smaller spherical (193 nm) particles generated stronger Th1 and Th2 immune responses compared to the other particle types. In vitro studies with dendritic cells indicated that spherical (193 nm) and rod (1530 nm) shaped particles were internalized by dendritic cells and delivered ovalbumin. These results provide evidence for size- and shape-dependent modulation of immune responses and this knowledge can be leveraged to rationally design and develop next generation vaccines against a wide range of pathogens., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Nucleic acids (NAs) hold significant potential for the treatment of several diseases. Topical delivery of NAs for the treatment of skin diseases is especially advantageous since it bypasses the challenges associated with systemic administration which suffers from enzymatic degradation, systemic toxicity and lack of targeting to skin. However, the skin's protective barrier function limits the delivery of NAs into skin after topical application. Here, we highlight strategies for enhancing delivery of NAs into skin, and provide evidence that translation of topical NA therapies could have a transformative impact on the treatment of skin diseases., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Delivery of nanoparticles to target specific tissues remains a challenge due to their rapid removal from circulation by the reticuloendothelial (RES) system. The majority of past research has addressed this issue via chemical modification of nanoparticles in the form of hydrophilic coatings which reduces adsorption of opsonins that trigger RES clearance. Recently, additional approaches have been developed which leverage the natural mechanisms our own circulatory cells use to avoid immune system clearance. One such method, called 'cellular-hitchhiking', accomplishes this by non-covalent attachment of nanoparticles to the surface of red blood cells. Concomitantly, approaches that make use of modified nanoparticle geometry, that is rod-shaped nanoparticles, have also been used to avoid immune system clearance and improve tissue targeting. Here, we systematically investigate three approaches and their combinations to improve lung targeting while avoiding RES clearance. Our results show that an approach that combines targeting antibodies (anti-ICAM-1), rod-shaped particles and cellular hitchhiking into one delivery system effectively lowered the accumulated concentration of nanoparticles in RES organs by over two-fold as compared to any other combination or single method, while simultaneously increasing the concentration of accumulated nanoparticles in the lungs from 1.2 to 8.9 fold. The strategy described here offers a novel means that combine chemical, physical and biological approaches to maximize tissue targeting., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Combinations of polymer conjugates affording in situ gelation hold promise for treatment of pathological cavities (e.g., arthritis) and sustained drug release. In particular, hyaluronic acid (HA) functionalized with reactive groups is regarded as an excellent biomaterial due to its tunable cross-linking kinetics and mechanical properties. HA-based reagents, however, can be irritating to surrounding tissues due to the reactivity of pendant groups, and their fast gelation kinetics can result in poor cavity filling. In this study, a biocompatible "click" reaction between cyanobenzothiazole (CBT) and d-cysteine (d-Cys) is employed to produce HA-based conjugates for in situ gelation. Rheological studies conducted on a gel obtained from the combination of HA-CBT and HA-d-Cys indicate optimal gelation time and mechanical properties. Further, in vitro studies on porcine skin demonstrate the ability of the gel to form in situ upon subcutaneous injection or topical application, and to act as a reservoir for sustained release of protein therapeutics. Finally, the safety of the HA-based conjugates is demonstrated on human keratinocytes. The presented results demonstrate the applicability of the binary mixture for in situ gelation and the potential of the proposed system for a variety of biomedical applications., (© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

The balance of efficacy and safety of topical corticosteroids (TCs) depends on their ability to penetrate into and be retained within the skin. Here, we evaluated the ability of SPACE™ peptide to enhance epidermal delivery and localization of three model TCs. In vitro and in vivo skin penetration studies were performed to evaluate penetration of TCs into and across the skin in the presence of various formulations of SPACE™ peptide. Topical formulations of corticosterone containing free SPACE™ peptide produced significantly enhanced epidermal penetration and localization. Ratio of drug deposition in the skin and receiver (efficacy/safety, indicative of ratio of local to systemic uptake) exhibited higher values for SPACE™ peptide-based formulation as compared to aqueous and hydroethanolic solutions and Cortizone™ cream. Mass spectrometry analysis showed that SPACE™ peptide associates with corticosterone, which may explain its enhanced retention effect. SPACE™ peptide also enhanced dermal retention of two more TCs (hydrocortisone and triamcinolone acetonide) compared to the vehicle control. An in vivo study in mice further established the ability of SPACE™ peptide to enhance skin retention of hydrocortisone without producing elevated blood concentrations. These results show that SPACE™ peptide is an effective additive to the formulation for enhanced skin localization of topical steroids.

Combinations of topoisomerase inhibitors I and II have been found to synergistically inhibit cancer cell growth in vitro, yet clinical studies of these types of combinations have not progressed beyond phase II trials. The results of clinical combinations of topoisomerase (top) I and II inhibitors typically fall within one of two categories: little to no improvement in therapeutic efficacy, or augmented toxicity compared to the single drug counterparts. Hence, despite the promising activity of top I and II inhibitor combinations in vitro, their clinical applicability has not been realized. Here, we report the use of polymer-drug conjugates as a means to co-deliver synergistic doses of top I and II inhibitors camptothecin (CPT) and doxorubicin (DOX) to tumors in vivo in a 4T1 breast cancer model. At specific molar ratios, DOX and CPT were found to be among the most synergistic combinations reported to date, with combination indices between 0.01 and 0.1. The identified optimal ratios were controllably conjugated to hyaluronic acid, and elicited significant tumor reduction of murine 4T1 breast cancer model when administered intravenously. This study elucidates a method to identify synergistic drug combinations and translate them to in vivo by preserving the synergistic ratio via conjugation to a carrier polymer, thus opening a promising approach to translate drug combinations to clinically viable treatment regimens., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Objective: To review the pathophysiology and therapeutic modalities availble for Nelson syndrome., Methods: We reviewed the current literature including managment for Nelson syndrome., Results: For patients with NS, surgical intervention is often the first-line therapy. With refractory NS or tumors with extrasellar involvement, radiosurgery offers an important alternative or adjuvant option. Pharmacologic interventions have demonstrated limited usefulness, although recent evidence supports the feasibility of a novel somatostatin analog for patients with NS. Modern neuroimaging, improved surgical techniques, and the advent of stereotactic radiotherapy have transformed the management of NS., Conclusions: An up-to-date understanding of the pathophysiology underlying Nelson Syndrome and evidence-based management is imperative. Early detection may allow for more successful therapy in patients with Nelson Syndrome. Improved radiotherapeutic interventions and rapidly evolving pharmacologic therapies offer an opportunity to create targeted, multifocal treatment regiments for patients with Nelson Syndrome., (Copyright © 2015 Elsevier Inc. All rights reserved.)