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We report a novel cancer-targeted nanomedicine platform for imaging and prospect for future treatment of unresected ovarian cancer tumors by intraoperative multimodal phototherapy. To develop the required theranostic system, novel low-oxygen graphene nanosheets were chemically modified with polypropylenimine dendrimers loaded with phthalocyanine (Pc) as a photosensitizer. Such a molecular design prevents fluorescence quenching of the Pc by graphene nanosheets, providing the possibility of fluorescence imaging. Furthermore, the developed nanoplatform was conjugated with poly(ethylene glycol), to improve biocompatibility, and with luteinizing hormone-releasing hormone (LHRH) peptide, for tumor-targeted delivery. Notably, a low-power near-infrared (NIR) irradiation of single wavelength was used for both heat generation by the graphene nanosheets (photothermal therapy [PTT]) and for reactive oxygen species (ROS)-production by Pc (photodynamic therapy [PDT]). The combinatorial phototherapy resulted in an enhanced destruction of ovarian cancer cells, with a killing efficacy of 90%-95% at low Pc and low-oxygen graphene dosages, presumably conferring cytotoxicity to the synergistic effects of generated ROS and mild hyperthermia. An animal study confirmed that Pc loaded into the nanoplatform can be employed as a NIR fluorescence agent for imaging-guided drug delivery. Hence, the newly developed Pc-graphene nanoplatform has the significant potential as an effective NIR theranostic probe for imaging and combinatorial phototherapy.

Sir, Antibodies reactive with neuronal voltage-gated potassium channel (VGKC-Abs) have emerged as a serologic marker of potentially reversible autoimmune encephalopathies. Autoimmune synaptic encephalopathy should be considered as a differential diagnosis in all cases of rapidly progressive cognitive impairment and seizures.

In intravenous immunoglobulins (IVIG), and some other immunoglobulin products, protein particles have been implicated in adverse events. Role and mechanisms of immunoglobulin particles in vascular adverse effects of blood components and manufactured biologics have not been elucidated. We have developed a model of spherical silica microparticles (SiMPs) of distinct sizes 200–2000 nm coated with different IVIG- or albumin (HSA)-coronas and investigated their effects on cultured human umbilical vein endothelial cells (HUVEC). IVIG products (1–20 mg/mL), bare SiMPs or SiMPs with IVIG-corona, did not display significant toxicity to unstimulated HUVEC. In contrast, in TNFα-stimulated HUVEC, IVIG-SiMPs induced decrease of HUVEC viability compared to HSA-SiMPs, while no toxicity of soluble IVIG was observed. 200 nm IVIG-SiMPs after 24 h treatment further increased ICAM1 (intercellular adhesion molecule 1) and tissue factor surface expression, apoptosis, mammalian target of rapamacin (mTOR)-dependent activation of autophagy, and release of extracellular vesicles, positive for mitophagy markers. Toxic effects of IVIG-SiMPs were most prominent for 200 nm SiMPs and decreased with larger SiMP size. Using blocking antibodies, toxicity of IVIG-SiMPs was found dependent on FcγRII receptor expression on HUVEC, which increased after TNFα-stimulation. Similar results were observed with different IVIG products and research grade IgG preparations. In conclusion, submicron particles with immunoglobulin corona induced size-dependent toxicity in TNFα-stimulated HUVEC via FcγRII receptors, associated with apoptosis and mTOR-dependent activation of autophagy. Testing of IVIG toxicity in endothelial cells prestimulated with proinflammatory cytokines is relevant to clinical conditions. Our results warrant further studies on endothelial toxicity of sub-visible immunoglobulin particles.

Platelet extracellular vesicles (PEVs) have emerged as potential mediators in intercellular communication. PEVs exhibit several activities with pathophysiological importance and may serve as diagnostic biomarkers. Here, imaging and analytical techniques were employed to unveil morphological pathways of the release, structure, composition, and surface properties of PEVs derived from human platelets (PLTs) activated with the thrombin receptor activating peptide (TRAP). Based on extensive electron microscopy analysis, we propose four morphological pathways for PEVs release from TRAP-activated PLTs: (1) plasma membrane budding, (2) extrusion of multivesicular α-granules and cytoplasmic vacuoles, (3) plasma membrane blistering and (4) “pearling” of PLT pseudopodia. The PLT extracellular vesiculome encompasses ectosomes, exosomes, free mitochondria, mitochondria-containing vesicles, “podiasomes” and PLT “ghosts”. Interestingly, a flow cytometry showed a population of TOM20 + LC3 + PEVs, likely products of platelet mitophagy. We found that lipidomic and proteomic profiles were different between the small PEV (S-PEVs; mean diameter 103 nm) and the large vesicle (L-PEVs; mean diameter 350 nm) fractions separated by differential centrifugation. In addition, the majority of PEVs released by activated PLTs was composed of S-PEVs which have markedly higher thrombin generation activity per unit of PEV surface area compared to L-PEVs, and contribute approximately 60% of the PLT vesiculome procoagulant potency.

Background Chronic obstructive pulmonary disease (COPD) includes chronic bronchitis and emphysema and is characterized by persistent airflow limitation. It is caused by long-term exposure to harmful particles or gases, leading to significant breathing difficulties and substantially impacting quality of life. Understanding the complexity and socioeconomic burden of COPD is vital for improving patient outcomes and addressing broader implications. This study assesses the self-reported physical activity levels of COPD patients in the United States using the 2021 Behavioral Risk Factor Surveillance System (BRFSS) data, exploring the impact of demographic, socioeconomic, and healthcare access variables. Methodology The 2021 BRFSS data were analysed, focusing on 34,061 individuals diagnosed with COPD, emphysema, or chronic bronchitis. Fisher's exact test and the chi-square test were used to examine associations between self-reported physical activity levels and demographic (age, gender, race), socioeconomic (education, employment, income), and healthcare access (last routine check-up) variables, with 95% confidence intervals. Results Of the 435,780 BRFSS participants, 7.8% reported having COPD. Among these, 55% engaged in physical activity compared to 77.4% of non-COPD individuals. Physical activity levels were significantly lower among COPD patients (p < 0.001), with notable variations across age groups, genders, races, education levels, employment statuses, income categories, and time since the last routine check-up. Conclusions The findings reveal a significant disparity in physical activity between COPD patients and non-COPD individuals. These findings highlight the need for targeted interventions to improve physical activity among COPD patients to enhance their health outcomes and quality of life.

The Indian manufacturing sector satisfies most of the societal product demands by a linear production-consumption model. It dominates in global and national economy, utilizes major proportion of virgin material and energy and generates significant waste and environmental contamination, raising sustainability concerns. To address these issues, radical systemic solutions are needed, such as the adoption of a circular economy model. A circular economy (CE) is a production-consumption system that closes material resource loops, promotes higher value of material cycles, and addresses issues such as energy, waste, environment, social equity, and long-term economic growth. In today’s era, competitive business and variable consumer demand need a transformation from a linear economic business model to a circular business model. Hence, Indian manufacturing organizations (IMOs) need a structured approach with radical and innovative solutions to develop and implement CE enabled business models and related circular supply chains to meet everchanging consumer and market demands, ensuring the sustainability of the business.The research investigates the awareness and level of adoption of CE strategies and practices in Indian manufacturing organizations and assesses their inadequacy to get insight in to the major objectives, enablers and issues to CE implementation and perceive CE performance measurement. Four sectors are selected: electronics and material, engineering, manufacturing and production, and process. The sample organizations are diversified, providing a fair assessment of CE enablement in Indian manufacturing organizations. The implementation of CE in the case organization and obtained results represent the conformity to the same. This work began with a literature review; examining status of adoption of CE that includes the major databases available until October 2023, and involving academic and industrial experts in the implementation process.A tactical plan and methodological framework for CE enabled business model (BM) and circular supply chain (CSC) was developed in the second stage of the work. The framework outlines three categories of CE enablers: tactical, technological, and humanoid. It establishes inter-relationships between circular strategies, practices, adoption of R's, cooperation, and coordination in and of the organization through the involvement of stakeholders and circular consumers for the achievement of circular production. The designed material and information flow channels establish the attachment of each and every stage and ensure the recirculation of material to close loops. The development explicates how CE enablement can yield differential advantages to the organization, SC, and business as a whole.In the third stage, a structured questionnaire was developed to gauge the status and readiness of Indian manufacturing organizations to embrace and espouse CE objectives, strategies, and practices. The survey aspects, involving experts, covered two categories: the role of CE enablement and implementation, and CE performance measurement for effective CE enablement in organizations and SC. A pilot study was conducted. A five-point Likert scale was used to design the questionnaire and the final survey had an effective response rate of 21.62 percent. Further, the sectorial analysis examines the variation in the perception of Indian manufacturing organizations across four identified industrial clusters regarding CE enablement issues, using quantitative tools like descriptive statistics, reliability analysis, and ANOVA to test propositions, developed based on literature. The objective of the sectorial analysis is to study the similarities and dissimilarities among different sectors within the manufacturing organizational cluster.The fourth stage of successful CE implementation in organizations and SC involves understanding the dynamics between CE enablers (CEEs), which drive the process. A hybrid methodology using Interpretive Structural Modelling (ISM) for hierarchical model development and fuzzy MICMAC analysis was used to categorize CEEs into driver and dependent categories through the development of contextual relationships among these variables. The investigation demonstrates that CEEs that have a high driving power require maximum attention and carry the most strategic importance while CEEs having high dependence power need the resultant actions. A fuzzy MICMAC analysis provides a useful tool for top management to differentiate between independent and dependent CEEs, focusing on key CEEs for effective CE implementation. This helps the organization in achieving strategic goals. The hierarchical model of CEEs and their categorization endeavor in the area of CE implementation.Further, a case organization was identified to implement CE enabled business model and CSC framework through CEEs to gain a competitive advantage. The top eleven CEEs identified from LR, survey, and sectorial analysis, modeled by ISM and developed contextual relationship through fuzzy MICMAC were compared and found to be of equal priority. CE enabled business model and CSC framework was adopted through the high driving power CEEs which were adopted and implemented in the case organization and dependence CEEs in the form of performance output was achieved. Proper control of these CEEs during CE adoption made implementation more effective. The issues were identified, and suggestions related to CE were imparted and implemented in consultation with top management and stakeholders. The case organization achieved performance output and a competitive advantage in terms of economic, financial, environmental, and social improvements, including improvements in the health of shop floor workers. The results validate the drafted propositions.The scope of the present research is generally not beyond these Indian Manufacturing organizations though the research implications may also have some bearing on other sectors. Some unexplored sectors are important from CE standpoint but are beyond the scope of the present study. This is mainly due to time constraints to undertake the whole set of sectors operating in India.

The purpose of this study was to develop and evaluate a sublingual tablet of lercanidipine hydrochloride for the direct compression method of treating hypertension by using a solid dispersion technique. The dihydropyridine calcium-channel blocker lercanidipine Hydrochloride is used to treat hypertension, Prinz metal’s variant angina, and chronic stable angina pectoris. It can be administered alone or in combination with an angiotensin-converting enzyme inhibitor. The biological half-life of lercanidipine hydrochloride is 8–10hours, and its duration of action is up to 24hours. Because of its first pass metabolism, lercanidipine hydrochloride has a less than 10% oral bioavailability. BCS class II was applied to lercanidipine hydrochloride due to its high permeability and poor solubility. The aforementioned features and attributes render Lercanidipine Hydrochloride a fitting contender for a sublingual tablet created by robust dispersion and integrating Gelucire 50/13. When compared to pure lercanidipine Hydrochloride, the solubility is high when Gelucire 50/13 was used at the highest concentration. This is the first attempt to improve the solubility of pure lercanidipine HCl free base by the use of various solid dispersion methods, including solvent evaporation, fusion, and physical mixing. Lercanidipine HCl kneading solid dispersion, made with Gelucire 50/13 (1:1)., The prepared lercanidipine HCl sublingual tablets prevent first pass metabolism, avoid swallowing-related issues, particularly in elderly patients, and enhance solubility. The tablet disintegrated in 50 seconds, according to the results. Similarly, a dissolution study conducted in vitro revealed 96.68% drug release in 10 minutes. The prepared lercanidipine HCl sublingual tablets containing a complex with Gelucire 50/13 solid dispersion were found to significantly improve patient compliance and bioavailability.

Drugs with poor aqueous solubility and slow dissolution present a big hurdle for formulation scientists. Numerous techniques are available to overcome this challenge, and supersaturation drug delivery system through particle size reduction and solubilization of drug in oil are particularly promising approaches. Reduction in drug particle size to the nanometer scale can increase the total surface area of the dissolving drug, which can improve dissolution and bioavailability. Also, the solubilized drug in oil plus the large surface area of nanoscale oil globules enhances dissolution and bioavailability. In this project, the two approaches are proposed to produce nanoformulations. The first approach is to produce drug particles in the pores of excipients such as Syloid® 244FP (a porous insoluble excipient). This was done for the model drug ibuprofen (IBU) by imbibing concentrated solutions of IBU in organic solvents (ethanol and acetone) into the Syloid 244FP pores, then removing the solvent by evaporation. This technique is unique because it loads the drug into the pores rather than the outer surface of the carrier particle. It produces the size reduction of drug particles without applying any force or mechanical pressure and heat, which makes it a suitable technique for thermolabile materials. Importantly, it maintains the stability of supersaturated dosage forms by inhibiting confined drug particles motion in tiny pores. In addition, high surface area and surface energy of pore walls inhibit or delay the nucleation and growth. To develop a successful supersaturated formulation, investigation of physicochemical factors and process parameters are unavoidable. Drug concentration, solvents, carrier, soaking time, drug loading mechanisms, wash solvent, etc. were optimized as they are very crucial to control drug release rate from the pores. The supersaturated drug release patterns were also analyzed to understand the formulation process better. The second unique approach includes the development of IBU microemulsion (selfmicroemulsifying drug delivery system, SMEDDS), which are then loaded onto SuperTab® 30GR (a water-soluble excipient) by mixing the microemulsion and SuperTab 30GR, then removing the water by evaporating at 40 °C. This nanoformulation has combined advantages of SMEDDS and solid dosage form. When introduced into a dissolution medium, the water mixes with the formulation to re-produce the microemulsion with very small (nanometer-scale) globules, and the drug is subsequently released. The very small globule size results in a very large surface area, which imparts higher release rates for the drug into the dissolution medium. However, there are numerous problems associated with SMEDDS formulations that can be solved by transforming lipid form into solid form using this technique. The preconcentrate:SuperTab 30GR and oil:surfactant ratios were optimized as they are significant parameters for this type of formulation development. Also, drug release patterns were analyzed to understand drug release mechanisms. Experimental results with IBU demonstrated that both nanoformulation methods significantly enhanced IBU solubility and dissolution rate. It was found that the drug could be loaded into the Syloid pores by two mechanisms, one based on solution imbibing and another based on drug diffusion into the pores from a bulk solution, thus providing options in producing the formulations. The drug melting point depression in thermal analysis confirmed successful deposition of the drug into the pores and size reduction of deposited drugs into the pores. The IBU-Syloid 244FP nanoformulations showed 2.5 times higher drug release compared to pure IBU solubility in PBS pH 2, and some formulations produced \"spring and parachute\" release patterns. Surprisingly, in some cases, the drug loading on Syloid did not correlate well with drug release rates, which suggested only drug loading study is not sufficient to measure to develop nanoformulations, but the drug release study is also a good navigator for nanoformulation development. The percentage drug loss from the samples subjected to aging was minor, indicating the systems were stable. The thermal analysis of IBU-SuperTab® 30GR nanoformulations displayed an absence of drug melting peak in DSC thermograms, which confirmed drug dissolved in lipidic globules in nanoformulations. The changes in globule size were minor before loading drug microemulsions on SuperTab 30GR and after dissolving final formulations into dissolution media. That confirmed that the microemulsions reformed with a very small globule size, when formulations come in contact with dissolution media. The small globule size of re-formed microemulsions results in a huge surface area associated with this type of system. The combined effect of drug solubilized in oil globules plus the huge surface area of oil globules resulted around 27-fold increase in drug solubility and dissolution rate from IBU-SuperTab 30GR nanoformulations compared to pure IBU solubility in PBS pH 2. In microemulsion, the drug is already dissolved in the globule phase during the formulation process, thus avoiding the need for the dissolution step in drug release. This may be the primary reason for higher drug release achieved from the SuperTab formulations compare to Syloid formulations. The percentage drug loads and in-vitro release profiles of stored samples remained the same compared with initial samples, indicating the drug in nanoformulations was stable. To prove these novel nanoformulation methods, analogous formulation work was done using another model drug, griseofulvin (GRIS) with another insoluble porous carrier, Neusilin® US2 and with a soluble carrier, SuperTab 30GR. The GRIS nanoformulations displayed similar characteristics to those seen with IBU nanoformulations. This indicated that the nanoformulation methods developed in this research are not specific to one drug or carrier but are also applicable to many poorly soluble drugs and pharmaceutical carriers. Also, the effects of different particle size of porous carriers, Syloid ® 244FP (particle size 3.5 µm) and Syloid® XDP 3150 (particle size 150 µm) on nanoformulations performance were investigated by formulating IBU-Syloid 244FP and IBU-Syloid XDP 3150 nanoformulations, and comparing drug loading, in-vitro drug release, and thermal analysis. The drug load achieved on Syloid 244FP was more than double than Syloid XDP 3150. The in-vitro drug release was higher from Syloid 244FP than Syloid XDP 3150 due to the higher surface area offered by the small particle size of Syloid 244FP than Syloid XDP 3150. However, both Syloid formulations demonstrated around twofold higher drug release than crystalline IBU solubility in PBS pH 2. The drug melting peak was depressed in both Syloid nanoformulations compared to pure drug. Also, the drug melting peak was more depressed in Syloid 244FP than Syloid XDP 3150 formulations, which indicated drug particle size in Syloid 244FP was smaller than in Syloid XDP 3150 that might be the reason for the better performance of Syloid 244FP than Syloid XDP 3150. In essence, the nanoformulations produced by these two methods are capable enough to produce and maintain supersaturation for enough time frame in dissolution media, which can enhance solubility and dissolution rates of poorly soluble drugs and can enhance bioavailability.