A comparative study to evaluate the cervical spine movements during laryngoscopy using Macintosh and Airtraq laryngoscopes.

Background and Aim: Intubation with Macintosh requires flexing the lower cervical spine and extending the atlanto-occipital joint to create a "line of sight." Primary aim of study was to compare the extent of cervical spine movement during laryngoscopy using conventional Macintosh laryngoscope and Airtraq. Material and Methods: A total of 25 patients of either sex between the age group of 18 and 60 years, having American Society of Anesthesiologists (ASA) physical status of Grade-I and Grade-II, scheduled for elective surgery under image control requiring general anesthesia and intubation were enrolled. A baseline image of the lateral cervical spine including the first four cervical vertebrae was taken by an image intensifier. After administration of general anesthesia, laryngoscopy was first performed using a Macintosh laryngoscope and a second X-ray image of the lateral cervical spine was taken. The second laryngoscopy using a Airtraq laryngoscope was done and the third image of the lateral cervical spine was taken. Angles between occiput and C1; C1 and C2; C2 and C3; C3 and C4; and occiput and C4 were calculated. Atlanto-occipital distance (AOD) was calculated as the distance between occiput and C1. Results: Macintosh showed greater cervical movement as compared with Airtraq but a significant difference in the movement was observed at C2-C3 and C0-C4. Baseline mean AOD was 2.21 ± 1.25 mm, after Macintosh and Airtraq laryngoscopy was found to be 1.13 ± 0.60 and 1.6 ± 0.78 mm, respectively, and was found to be significant (P < 0.05). Conclusion: We conclude that Airtraq allows intubation with less movement of the upper cervical spine makes Airtraq preferred equipment for intubation in patients with a potential cervical spine injury.

Evaluation of the three different doses of cisatracurium during general anaesthesia: A prospective randomized study.

Background and Aims: The present study was conducted to determine the optimal dose of cisatracurium for intubating conditions and onset and offset of neuromuscular blockade. Data in Indian population are scarce, and hence, the present study was planned to evaluate different doses of cisatracurium. Material and Methods: The prospective randomized double-blind study was conducted on 180 patients of either sex in the age group of 20-60 yrs., having physical status class I to III, scheduled for surgery under general anesthesia. After exclusion 154 patients were randomly divided into three groups comprising 52, 51, and 51, respectively, in Group A, Group B, and group C. They received 0.1 mgkg-1, 0.2 mgkg-1, and 0.3 mgkg-1 of cisatracurium, respectively, to facilitate endotracheal intubation. Time of onset, intubating conditions, hemodynamic parameters, signs of histamine release, and recovery time were noted. Results: Mean time to onset was maximum in group A (4.37 ± 0.48 minutes) and minimum in group C (2.33 ± 0.43 minutes). Intubating conditions were found excellent in 88% patients in group. Change in HR was found to be non-significant at all time periods, but decrease in MAP was found between 2 and 10 minutes in group C. Duration of action was longest in group C. Conclusion: We conclude that cisatracurium in dose of 0.2 mgkg-1 and 0.3 mgkg-1 provides good-to-excellent intubating conditions within less than 3 minutes.

A sucrose non-fermenting-1-related protein kinase 1 gene from wheat, TaSnRK1α regulates starch biosynthesis by modulating AGPase activity.

Major portion of wheat grain consist of carbohydrate, mainly starch. The proportion of amylose and amylopectin in starch greatly influence the end product quality. Advancement in understanding starch biosynthesis pathway and modulating key genes has enabled the genetic modification of crops resulting in enhanced starch quality. However, the regulation of starch biosynthesis genes still remains unexplored. So, to expand the limited knowledge, here, we characterized a Ser/Thr kinase, SnRK1α in wheat and determined its role in regulating starch biosynthesis. SnRK1 is an evolutionary conserved protein kinase and share homology to yeast SNF1. Yeast complementation assay suggests TaSnRK1α restores growth defect and promotes glycogen accumulation. Domain analysis and complementation assay with truncated domain proteins suggest the importance of ATP-binding and UBA domain in TaSnRK1α activity. Sub-cellular localization identified nuclear and cytoplasmic localization of TaSnRK1α in tobacco leaves. Further, heterologous over-expression (O/E) of TaSnRK1α in Arabidopsis not only led to increase in starch content but also enlarges the starch granules. TaSnRK1α was found to restore starch accumulation in Arabidopsis kin10. Remarkably, TaSnRK1α O/E increases the AGPase activity suggesting the direct regulation of rate limiting enzyme AGPase involved in starch biosynthesis. Furthermore, in vitro and in vivo interaction assay reveal that TaSnRK1α interacts with AGPase large sub-unit. Overall, our findings indicate that TaSnRK1α plays a role in starch biosynthesis by regulating AGPase activity.

Microwave Doping of Sulfur and Iron in ß12 Borophene.

Borophene, a 2D material exhibiting unique crystallographic phases like the anisotropic atomic lattices of ß12 and X3 phases, has attracted considerable attention due to its intriguing Dirac nature and metallic attributes. Despite surpassing graphene in electronic mobility, borophene's potential in energy storage and catalysis remains untapped due to its inherent electrochemical and catalytic limitations. Elemental doping emerges as a promising strategy to introduce charge carriers, enabling localized electrochemical and catalytic functionalities. However, effective doping of borophene has been a complex and underexplored challenge. Here, an innovative, one-pot microwave-assisted doping method, tailored for the ß12 phase of borophene is introduced. By subjecting dispersed ß12 borophene in dimethylformamide to controlled microwave exposure with sulfur powder and FeCl3 as doping precursors, S- and Fe doping in borophene can be controlled. Employing advanced techniques including high-resolution transmission electron microscopy, Raman spectroscopy, and X-ray photoelectron spectroscopy, confirm successful sulfur and iron dopant incorporation onto ß12 borophene is confirmed, achieving doping levels of up to 11 % and 13 %, respectively. Remarkably, S- and Fe-doped borophene exhibit exceptional supercapacitive behavior, with specific capacitances of 202 and 120 F g-1 , respectively, at a moderate current density of 0.25 A g-1 .

A Comparative Study Evaluating the Quality of Life and Survival Outcomes in Patients Receiving Chemotherapy Versus Oral Tyrosine Kinase Inhibitor in the Third Line and Beyond Setting for Advanced NSCLC.

Introduction: The outcomes in advanced NSCLC have improved owing to the availability of more effective systemic and improved supportive care. This has increased the number of patients who seek treatment in the third line and beyond setting. We conducted this study to compare the quality of life (QoL), toxicity, and outcomes in patients receiving chemotherapy and EGFR tyrosine kinase inhibitors (TKIs) in this setting. Methods: In this phase 3, randomized, open-label study, patients with stage III or IV NSCLC with disease progression on at least two prior lines of chemotherapy, with a life expectancy of at least 3 months, without prior EGFR TKI exposure, and stable brain metastases (if any) were included. Patients were randomized to receive chemotherapy (gemcitabine or docetaxel or paclitaxel or vinorelbine) or an EGFR TKI (erlotinib or gefitinib). The primary end point was the change in QoL at 8 to 10 weeks; the secondary outcomes were safety and overall survival (OS). Patients underwent clinical evaluation at every visit, and toxicity was assessed as per Common Terminology Criteria for Adverse Events version 4.03. A radiological tumor response assessment was done every 8 to 12 weeks from the start of therapy. The QoL was assessed using the EORTC QLQ C30 and LC13 questionnaires. The change in QoL scores was calculated as the difference between scores at baseline and scores at 8 to 10 weeks (Δ) for each QoL domain. The Mann-Whitney U test was used to compare the mean difference (Δ) for each domain. OS and progression-free survival (PFS) were determined using the Kaplan-Meier method and Cox proportional regression analysis. Results: A total of 246 patients were enrolled in the study, with 123 in each arm. There was a male predominance with 69.1% male patients in the chemotherapy arm and 70.7% in the EGFR TKI arm. The median age of patients in the chemotherapy arm was 54 years and 55 years in the chemotherapy and EGFR TKI arms, respectively. There was no significant difference in the change in QoL at baseline and the second visit (Δ) in both arms in all domains of EORTC QLQ C30 except cognitive function (p = 0.0045) and LC13 except alopecia (0.01249). The mean Δ Global Health Status was -28 in the chemotherapy arm and -26.8 in the EGFR TKI arm; this was not statistically significant (p = 0.973). The median follow-up was 88.1 months (95% confidence interval [CI]: 39.04-137.15). On the intention-to-treat analysis, the median PFS was 3.13 months (95% CI: 2.15-4.11) in the chemotherapy arm and 2.26 months (95% CI: 2.1-2.43) in the EGFR TKI arm, with hazard ratio at 1.074 (95% CI: 0.83-1.38) (p = 0.58). There were 120 deaths in each arm. The median OS was 7.63 months (95% CI: 5.96-9.30) in the chemotherapy arm and 7.5 months in the EGFR TKI arm (95% CI: 5.85-9.14); hazard ratio at 1.033 (95% CI: 0.80-1.33) (p = 0.805). The toxicity profile was similar in both arms except for a significantly higher incidence of fatigue (p = 0.043), peripheral neuropathy (0.000), alopecia, hypokalemia (0.037), and pedal edema (0.007) in the chemotherapy arm and dry skin (p = 0.000) and skin rash (p = 0.019) in the EGFR TKI arm. Conclusions: There was no significant difference in most QoL scales (except cognitive function and alopecia), OS, and PFS of patients with advanced NSCLC receiving an EGFR TKI as compared with chemotherapy TKI in the third-line setting. The toxicity profile is consistent with the known toxicities of the agents.

Current Landscape of Therapeutics for the Management of Hypertension - A Review.

Hypertension is a critical health problem. It is also the primary reason for coronary heart disease, stroke, and renal vascular disease. The use of herbal drugs in the management of any disease is increasing. They are considered the best immune booster to fight against several types of diseases. To date, the demand for herbal drugs has been increasing because of their excellent properties. This review highlights antihypertensive drugs, polyphenols, and synbiotics for managing hypertension. Evidence is mounting in favour of more aggressive blood pressure control with reduced adverse effects, especially for specific patient populations. This review aimed to present contemporary viewpoints and novel treatment options, including cutting-edge technological applications and emerging interventional and pharmaceutical therapies, as well as key concerns arising from several years of research and epidemiological observations related to the management of hypertension.

Whole exome sequencing uncovers HRAS mutations as potential mediators of resistance to metronomic chemotherapy.

OBJECTIVES: The aim of this pilot study is to identify the genetic factors that contribute to the response of metronomic chemotherapy in head and neck squamous cell carcinoma (HNSCC) patients using whole-exome sequencing (WES). This study would facilitate the identification of predictive biomarkers, which would enable personalized treatment strategies and improve treatment outcomes for patients with HNSCC. MATERIALS AND METHODS: We have selected patients with recurrent head and neck cancer who underwent metronomic chemotherapy. Sequential tumor biopsies were collected from the patients at different stages of treatment to capture the genomic alterations and tumor evolution during metronomic chemotherapy and sequenced using WES. RESULTS: We identified several known HNSCC hallmark genes reported in COSMIC, including KMT2B, NOTCH1, FAT1, TP53, HRAS, CASP8, and CDKN2A. Copy number alteration analysis revealed amplifications and deletions in several oncogenic and tumor suppressor genes. COSMIC Mutational Signature 15 associated with defective DNA mismatch repair was enriched in 73% of HNSCC samples. Further, the comparison of genomic alterations between responders and non-responders identified HRAS gene uniquely mutated in non-responders that could potentially contribute to resistance against metronomic chemotherapy. DISCUSSION: Our findings corroborate the molecular heterogeneity of recurrent HNSCC tumors and establish an association between HRAS mutations and resistance to metronomic chemotherapy, suggesting HRAS as a potential therapeutic target. Combining HRAS inhibitors with metronomic regimens could improve treatment sensitivity in HRAS-mutated HNSCC patients. Further studies are needed to fully elucidate the genomic mechanisms underlying the response to metronomic chemotherapy.

Development of Automated Risk Stratification for Sporadic Odontogenic Keratocyst Whole Slide Images with an Attention-Based Image Sequence Analyzer.

(1) Background: The categorization of recurrent and non-recurrent odontogenic keratocyst is complex and challenging for both clinicians and pathologists. What sets this cyst apart is its aggressive nature and high likelihood of recurrence. Despite identifying various predictive clinical/radiological/histopathological parameters, clinicians still face difficulties in therapeutic management due to its inherent aggressive nature. This research aims to build a pipeline system that accurately detects recurring and non-recurring OKC. (2) Objective: To automate the risk stratification of OKCs as recurring or non-recurring based on whole slide images (WSIs) using an attention-based image sequence analyzer (ABISA). (3) Materials and methods: The presented architecture combines transformer-based self-attention mechanisms with sequential modeling using LSTM (long short-term memory) to predict the class label. This architecture leverages self-attention to capture spatial dependencies in image patches and LSTM to capture sequential dependencies across patches or frames, making it suitable for this image analysis. These two powerful combinations were integrated and applied on a custom dataset of 48 labeled WSIs (508 tiled images) generated from the highest zoom level WSI. (4) Results: The proposed ABISA algorithm attained 0.98, 1.0, and 0.98 testing accuracy, recall, and area under the curve, respectively, whereas VGG16, VGG19, and Inception V3, standard vision transformer attained testing accuracies of 0.80, 0.73, 0.82, 0.91, respectively. ABISA used 58% fewer trainable parameters than the standard vision transformer. (5) Conclusions: The proposed novel ABISA algorithm was integrated into a risk stratification pipeline to automate the detection of recurring OKC significantly faster, thus allowing the pathologist to define risk stratification faster.

Efficacy of jackfruit components in prevention and control of human disease: A scoping review.

The jackfruit (Artocarpus heterophyllus) is one of the natural remedies significantly used in folk medicine. The ethnopharmacological applications of jackfruit are mainly concerned with the management of inflammation, diarrhea, and diabetes mellitus. Flavonoids, stilbenoids, aryl benzofurans, and lectin jacalin are abundant in jackfruit species. Jacalin is a good indicator for evaluating the immunological state of HIV-1 patients. The extracts and metabolites of jackfruit, particularly those from the leaves, bark, stem, and fruit, contain several beneficial bioactive mixtures. New studies are focused on exploring these bioactive compounds used in various biological activities such as antiviral, antiplatelet, anticancer, antiatherosclerotic, immunomodulatory effects, inhibitors of 5-alpha reductase activity, and the formulation of fast-dissolving tablets (orodispersible, rapid melts porous). Multidisciplinary programs that integrate traditional and modern technology play a crucial role in the lies ahead expansion of jackfruit as the prospective inception of therapeutic compounds. This review aims to highlight significant results on the identification, production, and bioactivity of metabolites found in jackfruit, with current developments in jackfruit research in the control and prevention of human diseases.

Building Automation Pipeline for Diagnostic Classification of Sporadic Odontogenic Keratocysts and Non-Keratocysts Using Whole-Slide Images.

The microscopic diagnostic differentiation of odontogenic cysts from other cysts is intricate and may cause perplexity for both clinicians and pathologists. Of particular interest is the odontogenic keratocyst (OKC), a developmental cyst with unique histopathological and clinical characteristics. Nevertheless, what distinguishes this cyst is its aggressive nature and high tendency for recurrence. Clinicians encounter challenges in dealing with this frequently encountered jaw lesion, as there is no consensus on surgical treatment. Therefore, the accurate and early diagnosis of such cysts will benefit clinicians in terms of treatment management and spare subjects from the mental agony of suffering from aggressive OKCs, which impact their quality of life. The objective of this research is to develop an automated OKC diagnostic system that can function as a decision support tool for pathologists, whether they are working locally or remotely. This system will provide them with additional data and insights to enhance their decision-making abilities. This research aims to provide an automation pipeline to classify whole-slide images of OKCs and non-keratocysts (non-KCs: dentigerous and radicular cysts). OKC diagnosis and prognosis using the histopathological analysis of tissues using whole-slide images (WSIs) with a deep-learning approach is an emerging research area. WSIs have the unique advantage of magnifying tissues with high resolution without losing information. The contribution of this research is a novel, deep-learning-based, and efficient algorithm that reduces the trainable parameters and, in turn, the memory footprint. This is achieved using principal component analysis (PCA) and the ReliefF feature selection algorithm (ReliefF) in a convolutional neural network (CNN) named P-C-ReliefF. The proposed model reduces the trainable parameters compared to standard CNN, achieving 97% classification accuracy.

Echocardiographic and Angiographic Assessment of Right Ventricular Function and Right Coronary Artery Stenosis in Acute Inferior Wall Myocardial Infarction.

BACKGROUND: Cardiovascular diseases (CVDs) are a global concern. CVD remains a primary cause of death despite reduced coronary heart disease death rates. Acute coronary syndrome (ACS) involves myocardial infarction (MI) and unstable angina, sharing mechanisms such as plaque instability. Our study assesses the right ventricular (RV) function's predictive value in acute inferior wall MI (IWMI) to identify high-risk patients with an elevated likelihood of experiencing severe cardiac complications, hemodynamic instability, or a higher mortality risk following an acute IWMI. METHODOLOGY: The research was conducted in the Department of Cardiology at the Rajendra Institute of Medical Sciences (RIMS), Ranchi, from July 2021 to June 2022, following the necessary ethical approval. A cohort of 140 patients with IWMI, carefully chosen according to rigorous criteria, clearly understood the study's objectives before providing informed consent. The evaluations were conducted in the following order: clinical assessments, followed by blood testing, then echocardiography, and finally, coronary angiography. Furthermore, the study examined risk factors and utilized statistical methods to elucidate the associations between qualities and results. RESULTS: The study included 140 participants, with 61% being male and 39% female. Among the participants, 14% were aged 30-45, 50% were aged 46-60, and 30% were over 60. Age shows significant proportions in different categories. Diabetes, dyslipidemia, hypertension, and smoking/tobacco addiction did not differ among stenosis groups. Proximal right coronary artery (RCA) stenosis patients had elevated jugular venous pressure (JVP). The echocardiograms were performed within 48 hours of post-percutaneous coronary intervention, and significant differences between groups were observed. Participants with proximal stenosis had lower tricuspid annular plane systolic excursion (TAPSE) and right ventricular fractional area change (RVFAC), which showed compromised RV systolic function. Proximal stenosis patients had reduced systolic motion velocity (Sm), indicating impaired myocardial contraction. Echocardiographic parameters such as early diastolic velocity (Em), atrial contraction velocity (Am), Em/Am ratio (a marker of diastolic function), isovolumic relaxation time (IVRT), isovolumic contraction time (IVCT), and ejection time (ET) between groups were different, indicating distinct cardiac functions. Proximal stenosis increased the myocardial performance index (MPI), indicating cardiac impairment. The left ventricular ejection fraction (LVEF) was comparable in the two stenosis groups, indicating similar left ventricular performance. CONCLUSION:  Echocardiography showed significant RV function differences in acute inferior wall ST-segment elevation myocardial infarction (STEMI) patients with proximal and distal RCA lesions. RV dysfunction is linked to right ventricle myocardial infarction (RVMI), and echocardiographic markers can provide valuable insights. Results emphasize that acute inferior wall STEMI is diagnosed by electrocardiogram (ECG) criteria, particularly ST-segment elevation. However, these markers emphasize the importance of RV assessment in RCA involvement assessment. These findings suggest that RV function can help diagnose acute inferior wall STEMI RCA involvement. In acute inferior STEMIs, RV function echocardiography is essential for RCA lesion location.

Physiologically Based Pharmacokinetic Modeling of Extracellular Vesicles.

Extracellular vesicles (EVs) are lipid membrane bound-cell-derived structures that are a key player in intercellular communication and facilitate numerous cellular functions such as tumor growth, metastasis, immunosuppression, and angiogenesis. They can be used as a drug delivery platform because they can protect drugs from degradation and target specific cells or tissues. With the advancement in the technologies and methods in EV research, EV-therapeutics are one of the fast-growing domains in the human health sector. Therapeutic translation of EVs in clinics requires assessing the quality, safety, and efficacy of the EVs, in which pharmacokinetics is very crucial. We report here the application of physiologically based pharmacokinetic (PBPK) modeling as a principal tool for the prediction of absorption, distribution, metabolism, and excretion of EVs. To create a PBPK model of EVs, researchers would need to gather data on the size, shape, and composition of the EVs, as well as the physiological processes that affect their behavior in the body. The PBPK model would then be used to predict the pharmacokinetics of drugs delivered via EVs, such as the rate at which the drug is absorbed and distributed throughout the body, the rate at which it is metabolized and eliminated, and the maximum concentration of the drug in the body. This information can be used to optimize the design of EV-based drug delivery systems, including the size and composition of the EVs, the route of administration, and the dose of the drug. There has not been any dedicated review article that describes the PBPK modeling of EV. This review provides an overview of the absorption, distribution, metabolism, and excretion (ADME) phenomena of EVs. In addition, we will briefly describe the different computer-based modeling approaches that may help in the future of EV-based therapeutic research.

Correlating physicochemical and biological properties to define critical quality attributes of a rAAV vaccine candidate.

Recombinant adeno-associated viruses (rAAVs) are a preferred vector system in clinical gene transfer. A fundamental challenge to formulate and deliver rAAVs as stable and efficacious vaccines is to elucidate interrelationships between the vector's physicochemical properties and biological potency. To this end, we evaluated an rAAV-based coronavirus disease 2019 (COVID-19) vaccine candidate that encodes the Spike antigen (AC3) and is produced by a commercially viable process. First, state-of-the-art analytical techniques were employed to determine key structural attributes of AC3, including primary and higher-order structures, particle size, empty/full capsid ratios, aggregates, and multi-step thermal degradation pathway analysis. Next, several quantitative potency measures for AC3 were implemented, and data were correlated with the physicochemical analyses on thermally stressed and control samples. Results demonstrate links between decreasing AC3 physical stability profiles, in vitro transduction efficiency in a cell-based assay, and, importantly, in vivo immunogenicity in a mouse model. These findings are discussed in the general context of future development of rAAV-based vaccine candidates as well as specifically for the rAAV vaccine application under study.

Interaction between long noncoding RNA (lnc663) and microRNA (miR1128) regulates PDAT-like gene activity in bread wheat (Triticum aestivum L.).

Amylose, a starch subcomponent, can bind lipids within its helical groove and form an amylose-lipid complex, known as resistant starch type 5 (RS-5). RS contributes to lower glycaemic index of grain with health benefits. Unfortunately, genes involved in lipid biosynthesis in wheat grain remain elusive. Our study aims to characterize the lipid biosynthesis gene and its post-transcriptional regulation using the parent bread wheat variety 'C 306' and its EMS-induced mutant line 'TAC 75' varying in amylose content. Quantitative analyses of starch-bound lipids showed that 'TAC 75' has significantly higher lipid content in grains than 'C 306' variety. Furthermore, expression analyses revealed the higher expression of wheat phospholipid: diacylglycerol acyltransferase-like (PDAT-like) in the 'TAC 75' compared to the 'C 306'. Overexpression and ectopic expression of TaPDAT in yeast and tobacco leaf confirmed its ability to accumulate lipids in vivo. Enzyme activity assay showed that TaPDAT catalyzes the triacylglycerol synthesis by acylating 1,2-diacylglycerol. Interestingly, the long non-coding RNA, lnc663, was upregulated with the TaPDAT gene, while the miRNA, miR1128, downregulated in the 'TAC 75', indicating a regulatory relationship. The GFP reporter assay confirmed that the lnc663 acts as a positive regulator, and the miR1128 as a negative regulator of the TaPDAT gene, which controls lipid accumulation in wheat grain. Our findings outline TaPDAT-mediated biosynthesis of lipid accumulation and reveal the molecular mechanism of the lnc663 and miR1128 mediated regulation of the TaPDAT gene in wheat grain.

Nanodelivery systems: An efficient and target-specific approach for drug-resistant cancers.

BACKGROUND: Cancer treatment is still a global health challenge. Nowadays, chemotherapy is widely applied for treating cancer and reducing its burden. However, its application might be in accordance with various adverse effects by exposing the healthy tissues and multidrug resistance (MDR), leading to disease relapse or metastasis. In addition, due to tumor heterogeneity and the varied pharmacokinetic features of prescribed drugs, combination therapy has only shown modestly improved results in MDR malignancies. Nanotechnology has been explored as a potential tool for cancer treatment, due to the efficiency of nanoparticles to function as a vehicle for drug delivery. METHODS: With this viewpoint, functionalized nanosystems have been investigated as a potential strategy to overcome drug resistance. RESULTS: This approach aims to improve the efficacy of anticancer medicines while decreasing their associated side effects through a range of mechanisms, such as bypassing drug efflux, controlling drug release, and disrupting metabolism. This review discusses the MDR mechanisms contributing to therapeutic failure, the most cutting-edge approaches used in nanomedicine to create and assess nanocarriers, and designed nanomedicine to counteract MDR with emphasis on recent developments, their potential, and limitations. CONCLUSIONS: Studies have shown that nanoparticle-mediated drug delivery confers distinct benefits over traditional pharmaceuticals, including improved biocompatibility, stability, permeability, retention effect, and targeting capabilities.

Molecular Chaperones' Potential against Defective Proteostasis of Amyotrophic Lateral Sclerosis.

Amyotrophic lateral sclerosis (ALS) is a neuronal degenerative condition identified via a build-up of mutant aberrantly folded proteins. The native folding of polypeptides is mediated by molecular chaperones, preventing their pathogenic aggregation. The mutant protein expression in ALS is linked with the entrapment and depletion of chaperone capacity. The lack of a thorough understanding of chaperones' involvement in ALS pathogenesis presents a significant challenge in its treatment. Here, we review how the accumulation of the ALS-linked mutant FUS, TDP-43, SOD1, and C9orf72 proteins damage cellular homeostasis mechanisms leading to neuronal loss. Further, we discuss how the HSP70 and DNAJ family co-chaperones can act as potential targets for reducing misfolded protein accumulation in ALS. Moreover, small HSPB1 and HSPB8 chaperones can facilitate neuroprotection and prevent stress-associated misfolded protein apoptosis. Designing therapeutic strategies by pharmacologically enhancing cellular chaperone capacity to reduce mutant protein proteotoxic effects on ALS pathomechanisms can be a considerable advancement. Chaperones, apart from directly interacting with misfolded proteins for protein quality control, can also filter their toxicity by initiating strong stress-response pathways, modulating transcriptional expression profiles, and promoting anti-apoptotic functions. Overall, these properties of chaperones make them an attractive target for gaining fundamental insights into misfolded protein disorders and designing more effective therapies against ALS.

Chitosan-collagen-fibrinogen uncrosslinked scaffolds possessing skin regeneration and vascularization potential.

Clinical success of regenerative medicine for treating deep-tissue skin injuries depends on the availability of skin grafts. Though bioengineered constructs are tested clinically, lack of neovascularization provide only superficial healing. Thus constructs, which promotes wound healing and supports vascularization has gained priority in tissue engineering. In this study, chitosan-collagen-fibrinogen (CCF) scaffold was fabricated using freeze-drying method without using any chemical crosslinkers. CCF scaffolds proved cytocompatibility and faster healing in in vitro scratch assay of primary human adult dermal fibroblasts cells with progressively increasing vascular endothelial growth factor-A and reducing vascular endothelial growth factor receptor 1 expressions. Skin regeneration evaluated on in vivo full thickness wound model confirmed faster remodeling with angiogenic signatures in CCF scaffold-implanted mice. Histopathological observations corroborated with stereo-zoom and SS-optical coherence tomography images of wound sites to prove the maturation of healing-bed, after 12 days of CCF implantation. Therefore, it is concluded that CCF scaffolds are promising for skin tissue regeneration and demonstrates pro-angiogenic potential.

Sustained response on sequential anti-FGFR therapy in metastatic gall bladder cancer: a case report and literature review.

PURPOSE: Advanced gall bladder cancer (GBC) is an aggressive disease, and there is no consensus on treatment options beyond first-line chemotherapy. We report a case of an elderly male with FGFR2-altered advanced adenocarcinoma of the gallbladder who failed two prior lines of chemotherapy but had sustained response and stable disease on sequential FGFR-directed targeted therapy. DESIGN: We describe a case of FGFR2-altered metastatic adenocarcinoma of the gallbladder who failed two prior lines of chemotherapy. The treatment was based on comprehensive genomic profiling when the patient was found to have FGFR2 single amino acid mutation (S252W) in one of his tissue samples. A novel therapeutic regimen with sequential anti-FGFR tyrosine kinase inhibitors was later initiated. RESULT: The patient tolerated the sequential targeted therapy very well and had a sustained response and stable disease. He had an overall survival of nearly five years. Unfortunately, GBC is an aggressive disease, and there is no consensus on treatment options beyond first-line chemotherapy. CONCLUSION: Through this patient, we demonstrate that advanced-metastatic GBC with FGFR alterations can be maintained on anti-FGFR therapy for prolonged periods of time, with improved survival. Therefore, we endorse the need for comprehensive genomic profiling in advanced-metastatic GBC and the need to study the role of FGFR inhibitors as a viable treatment option in these patients.

Spirulina- An Edible Cyanobacterium with Potential Therapeutic Health Benefits and Toxicological Consequences.

Spirulina is a blue-green algae which is cultivated not only for its maximum protein content but also due to the presence of other essential nutrients such as carbohydrates and vitamins (A, C and E). It is also a storehouse of minerals including iron, calcium, chromium, copper, magnesium, manganese, phosphorus, potassium, sodium and zinc. Simultaneously, γ- linolenic acid (an essential fatty acid), as well as pigments such as chlorophyll A and phycobiliproteins (C-phycocyanin, allophycocyanin and ß-carotene), is also a major component of its rich nutritional profile. Spirulina is known to have various promising effects on the prevention of cancer, oxidative stress, obesity, diabetes, cardiovascular diseases and anemia. Moreover, it also plays a positive role in treating muscular cramps. The safety recommended dosage of Spirulina is approximately 3-10 g/d for adults and it's biological value (BV) is 75 with a net protein utilization (NPU) of 62. Spirulina does not have pericardium due to which it does not hinder the absorption of iron by chelation with phytates or oxalates. On the contrasting note, it may have some adverse effects due to the toxins (microcystins, ß-methylamino-L-alanine (BMAA)) produced by Spirulina which might contribute to acute poisoning, cancer, liver damage as well as gastrointestinal disturbances. Its long-term consumption may also lead to the pathogenesis of Alzheimer's disease and Parkinson's disease. The current review focuses on the various aspects of spirulina including its cultivation, nutritional composition, extraction techniques, health benefits, adverse effects, industrial scope and market value which could be beneficial for its utilization in the development of value-added products and supplementary foods due to its high content of protein and bioavailability of nutrients.

• Spirulina is a nutrient-dense cyanobacterium which is composed of protein, carbohydrates, vitamins, minerals, essential fatty acids, antioxidants and pigments including chlorophyll A and Phycocyanin.• To avoid the contamination of Spirulina species by other algae, the specific pH maintenance of the media around 9-11 (alkaline) is mandatory.• Positive effects were noticed on the yield and productivity of Spirulina after its biomass was grown in polybags and greenhouse.• Its beneficial effects have been identified in particular reference to obesity, diabetes, hypertension, cardiovascular diseases, anemia, cancer, oxidative stress, arthritis, immunity as well as muscular cramps.• The toxins such as microcystins and hepatotoxins, produced by Spirulina, are accountable to cause acute poisoning, liver damage, gastrointestinal disturbances and cancer.• The safe recommended dosage of Spirulina for adults accounts to approximately 3-10 g/d, with 30 g/d being the maximum limit for consumption.

Multi-Dose Formulation Development for a Quadrivalent Human Papillomavirus Virus-Like Particle-Based Vaccine: Part I - Screening of Preservative Combinations.

The development of multi-dose, subunit vaccine formulations can be challenging since antimicrobial preservatives (APs) often destabilize protein antigens. In this work, we evaluated Human Papillomavirus (HPV) Virus-Like Particles (VLPs) to determine if combining different APs used in approved parenteral products, each at lower concentrations than used alone, would maintain both antimicrobial effectiveness and antigen stability. To identify promising AP combinations, two different screening strategies were utilized: (1) empirical one-factor-at-a-time (OFAT) and (2) statistical design-of-experiments (DOE). Seven different APs were employed to screen for two- and three-AP combinations using high-throughput methods for antimicrobial effectiveness (i.e., microbial growth inhibition assay and a modified European Pharmacopeia method) and antigen stability (i.e., serotype-specific mAb binding to conformational epitopes of HPV6, 11, 16 VLPs by ELISA). The OFAT and DOE approaches were complementary, such that initial OFAT results (and associated lessons learned) were subsequently employed to optimize the combinations using DOE. Additional validation experiments confirmed the final selection of top AP-combinations predicted by DOE modeling. Overall, 20 candidate multi-dose formulations containing two- or three-AP combinations were down-selected. As described in Part 2 (companion paper), long-term storage stability profiles of aluminum-adjuvanted, quadrivalent HPV VLP formulations containing these lead candidate AP combinations are compared to single APs.