Efficacy and Safety of RET-Specific Kinase Inhibitors in RET-Altered Cancers: A Systematic Review.

RET proto-oncogene encodes receptor tyrosine kinase. Selpercatinib and pralsetinib are the only RET-specific tyrosine kinase inhibitors approved by FDA in RET-altered tumors. We searched PubMed, Embase, Cochrane, WOS, and Clinicaltrials.gov. Objective-response, complete-response, and partial-response were 60-89%, 0-11%, and 55-89%, respectively, with the use of RET-specific drugs. ≥Grade 3 adverse events were seen in 28-53% of the patients, with hypertension, change in ALT, QT prolongation, neutropenia, and pneumonitis among the common side effects. Hence, selpercatinib and pralsetinib were effective and well tolerated by most of the patients with RET-altered tumors.

Unrevealing the potential of microbes in decomposition of organic matter and release of carbon in the ecosystem.

Organic matter decomposition is a biochemical process with consequences affecting climate change and ecosystem productivity. Once decomposition begins, C is lost as CO2 or sequestered into more recalcitrant carbon difficult to further degradation. As microbial respiration releases carbon dioxide into the atmosphere, microbes act as gatekeepers in the whole process. Microbial activities were found to be the second largest CO2 emission source in the environment after human activities (industrialization), and research investigations suggest that this may have affected climate change over the past few decades. It is crucial to note that microbes are major contributors in the whole C cycle (decomposition, transformation, and stabilization). Therefore, imbalances in the C cycle might be causing changes in the entire carbon content of the ecosystem. The significance of microbes, especially soil bacteria in the terrestrial carbon cycle requires more attention. This review focuses on the factors that affect microorganism behavior during the breakdown of organic materials. The key factors affecting the microbial degradation processes are the quality of the input material, nitrogen, temperature, and moisture content. In this review, we suggest that to address global climate change and its effects on agricultural systems and vice versa, there is a need to double-up on efforts and conduct new research studies to further evaluate the potential of microbial communities to reduce their contribution to terrestrial carbon emission.

Struvite separation from wastewater and its use with sulfur-oxidizing bacteria improves phosphorus utilization in alkaline soil.

A major portion of phosphatic fertilizer comes from the limiting natural resource, rock phosphate, which demands a timely alternative. Struvite, a crystalline mineral of low solubility, is a worthwhile alternative. Evaluation of the local wastewater streams for their ability to precipitate struvite and its capability as phosphatic fertilizer under an alkaline soil environment was studied. Two stirring speeds, a pH range of 8.0-11.0, and a constant molar ratio were used to optimize local wastewater streams for struvite precipitation. Struvite was used in five different combinations to assess the release of phosphorus (P), including control (no P source), single superphosphate, struvite, struvite + sulfur, and rock phosphate with or without inoculation of sulfur-oxidizing bacteria (SOB). For struvite precipitation, low stirring speeds are ideal because the precipitates readily sink to the bottom once they form. Furthermore, the amalgamation of SOB with sulfur significantly improved P use efficiency under alkaline soils through increased phosphorus sources solubility and enabled optimum wheat production due to its low solubility in an alkaline soil condition. Due to its capacity to recycle phosphorus from wastewater, struvite is poised to emerge as a sustainable fertilizer and had an opportunity to capture a share of this expanding market.

Periostin: A Potential Biomarker and Therapeutic Target in Pulmonary Diseases.

Periostin is a matricellular, nonstructural protein belonging to the fasciclin family and is encoded by the POSTN gene in humans. Periostin plays an important role in maintaining a normal tissue matrix in the lungs. Despite the vital role as a structural mediator in tissue growth and repair, periostin is involved in the pathogenic mechanism during tissue remodeling and fibrosis. Periostin is a chemoattractant mediator, promotes eosinophil recruitment and adhesion on the airways sub-epithelial membrane of asthmatic patients. POSTN gene was identified as one of the highly expressed genes induced by interleukins IL-13, IL-5 and IL-4 - the key cytokines of Th2 immune responses in the bronchial tissues of asthmatic patients. This review highlights the potential role of periostin as a validated biomarker in respiratory disease progression and its candidacy to predict the response to treatments targeting Th-2 cytokines in bronchial asthma. In addition, its potential role in COPD, IPF, lung cancer and lung infection, is also speculated.   Keywords Periostin, Asthma, Pneumonia, COPD, Idiopathic pulmonary fibrosis, Biomarker.

Bi-Directional Mutual Energy Trade between Smart Grid and Energy Districts Using Renewable Energy Credits.

A central authority, in a conventional centralized energy trading market, superintends energy and financial transactions. The central authority manages and controls transparent energy trading between producer and consumer, imposes a penalty in case of contract violation, and disburses numerous rewards. However, the management and control through the third party pose a significant threat to the security and privacy of consumers'/producers' (participants) profiles. The energy transactions between participants involving central authority utilize users' time, money, and impose a computational burden over the central controlling authority. The Blockchain-based decentralized energy transaction concept, bypassing the central authority, is proposed in Smart Grid (SG) by researchers. Blockchain technology braces the concept of Peer-to-Peer (P2P) energy transactions. This work encompasses the SolarCoin-based digital currency blockchain model for SG incorporating RE. Energy transactions from Prosumer (P) to Prosumer, Energy District to Energy District, and Energy District to SG are thoroughly investigated and analyzed in this work. A robust demand-side optimized model is proposed using Genetic Algorithm (GA) and Particle Swarm Optimization (PSO) to maximize Prosumer Energy Surplus (PES), Grid revenue (GR), percentage energy transactions accomplished, and decreased Prosumer Energy Cost (PEC). Real-time averaged energy data of Australia are employed, and a piece-wise energy price mechanism is implemented in this work. The graphical analysis and tabular statistics manifest the efficacy of the proposed model.

Dark Tetrad Personality during COVID-19: An Overview of Psycho-somatic Therapies for Managing Mental Health Response.

The recent empirical data represented the unprecedented opportunity to understand how threatful situations affect people adaptive and mal-adaptive behaviour and diverse ways to cope with the situation. In particular, the people with existing mental health issues such as dark tetrad personality found to be higher in forming an unhealthy relationship on cyber as well as real life during COVID-19. The current paper provides an interesting but alarming picture of how people with dark tetrad personality trait formed relationships with others during COVID-19. Also, the current paper highlights the significance of psycho-somatic therapies in managing their mental health response during COVID-19.

SHORT-COMMUNICATION-Lesson learnt during COVID-19 pandemic in Pakistan.

The outbreak of novel coronavirus (COVID-19) is a major health crisis affecting the several nations. In particular, the high ratio of COVID-19 pandemic in Pakistan is significantly deteriorating human mental as well as physical health. The huge mental and physical loss has taught several lessons, which have been retrieved from already existing literature. The latest researches were consulted to identify the challenges and solution to combat COVID-19. First of all, the pharmacy communities in Pakistan are not sufficient to handle the burden of COVID-19 due to economic issues. However, the Government should provide interest-free loans to students and researchers for conducting scholarly work for manufacturing advance medication to combat against COVID-19. Secondly, the drugs that have been used to control the spread of COVID-19, found to be associated with the development of a neuropsychiatric complication. Therefore, there is a dire need to develop more mental health services to control the medication side effects. Thirdly as the traditional mental health services are not sufficient to provide effective and advanced mental health services, therefore, transformative changes through community psychology are mandatory to implement. Lastly, as communicable disease limit the geographical access to avail mental health services. Therefore, the e-CBT approaches must be provided to mitigate the pre and post-pandemic effects. The findings of the study would provide the direction for preparing to combat communicable diseases in the future.

The dawn of phage therapy.

Bacteriophages or phages, being the most abundant entities on earth, represent a potential solution to a diverse range of problems. Phages are successful antibacterial agents whose use in therapeutics was hindered by the discovery of antibiotics. Eventually, because of the development and spread of antibiotic resistance among most bacterial species, interest in phage as therapeutic entities has returned, because their noninfectious nature to humans should make them safe for human nanomedicine. This review highlights the most recent advances and progress in phage therapy and bacterial hosts against which phage research is currently being conducted with respect to food, human, and marine pathogens. Bacterial immunity against phages and tactics of phage revenge to defeat bacterial defense systems are also summarized. We have also discussed approved phage-based products (whole phage-based products and phage proteins) and shed light on their influence on the eukaryotic host with respect to host safety and induction of immune response against phage preparations. Moreover, creation of phages with desirable qualities and their uses in cancer treatment, vaccine production, and other therapies are also reviewed to bring together evidence from the scientific literature about the potentials and possible utility of phage and phage encoded proteins in the field of therapeutics and industrial biotechnology.

Psychological Aid to COVID-19 Pandemic: A Mental Health Response to Crises Management.

Catastrophic Pandemics have been adversely impacted the globe throughout human history. As a consequence psychiatrist, psychologist and mental health practitioners performed their role to mitigate the adverse impacts through its scientific and clinical lenses. It was observed that due to advance nature of COVI-19 pandemic, more advance approach of psychological aid is required. This work gives an overview of the multi-dimensional and trans-disciplinary techniques, which can be helpful to cope up with the crises that emerged from the threat of COVID-19 Outbreak for victims, survivors, health care practitioners and community.

The New World 2020: A Crucial Paradigm for Meeting Fast Changing World Demands in Pakistan after COVID-19 Outbreak.

The waves of COVID-19 has shaken the world and bring about many changes in society. The changed environment or new world 2020 after COVID-19 pandemic demand high quality protection in all arena of life. The most important arena that require significant changes have been divided into four categories. First of all, the high mental health issues and low mental health services in Pakistan are not sufficient to control the mental health problem ratio. There is a need to develop more mental health services with trans-formative changes to mitigate the obnoxious post-pandemic effects. Secondly, the implementation of online therapeutic interventions must be available prior or after pandemic situation. Thirdly, as the pharmacy and mental health services in Pakistan are not capable to meet the international standards to provide patient care. Therefore, the advanced researchers are needed to investigate the fractures and gaps in social, economic and health care systems. Fourthly the provision of mental health support for children is a key area that needs considerable attention after pandemic or crises. The study has contemporary significance as disasters, crises and communicable disease has been prevalent throughout human history and may attack the world at any time in the future.

Chemical analysis of Dalbergia sissoo (Roxb.) pod oil by (GC-MS) / GC-FID and evaluation of antioxidant potential.

Dalbergia sissoo (Roxb.) is one of the important plant species having extensive commercial and medicinal uses. The current study aims to assess the chemical constituents in pod oil of Dalbergia sissoo (Roxb.) by using two spectroscopic techniques i.e. GC-FID (Gas Chromatography Flame Ionization Detection) and GC-MS (Gas Chromatography Mass Spectroscopy). In GC-FID technique, nine fatty acids were identified with their respective composition, capric acid (1) (1.496%) lauric acid (2) (5.695%), myristic acid (3) (4.925%), palmitic acid (4) (10.130%), palmitoleic acid (5) (2.166%), stearic acid (6) (2.862%), oleic acid (7) (10.232%), linoleic acid (8) (22.350%) and behenic acid (9) (9.283%). In second technique, i.e. GC-MS, a series of hydrocarbons (10-37) along with two triterpenoids (38-39) were found in pod oil of the plant used. Important structure indices such as Iodine value and Saponification values were also determined. These findings can be helpful to understand the important medicinal and commercial aspects of seeds oil of the plant, like fuel value, degree of unsaturation and oxidative stability. Antioxidant testing (DPPH-Radical Scavenging Assay) was also performed on pods oil but no any significant activity was found.

Metastatic Lung Cancer: Emerging Therapeutic Strategies.

Advanced stage nonsmall cell lung cancer had been treated mainly with platinum-based doublet chemotherapy, and other cytotoxic agents that offered significant survival advantage over best supportive care, until recently. Modest improvements were achieved with the addition of antibodies targeting the vascular endothelial growth factor, and the introduction of maintenance chemotherapy. Improvements in our knowledge of lung cancer biology have shifted the current treatment paradigm from being based on histology to one based on molecular biomarkers. Identification of potentially targetable driver mutations in a subgroup of these patients, pertaining to genes directing cell signaling pathways involved in proliferation and survival, has been the single most influential development in the treatment of lung cancer in the last two decades. Personalized medicine based on driver mutations offers enhanced efficacy at the expense of relatively minimal toxicity burden. Targeting the epidermal growth factor receptor pathway in patients with an activating mutation results in substantial improvement in patient outcome. Similarly, targeting ALK (anaplastic lymphoma kinase) fusion gene with first- and second-generation inhibitors results in improved efficacy over chemotherapy. For certain other mutations such as MET exon 14 and BRAF, promising inhibitory strategies are being investigated. In addition, the recent emergence of immune checkpoint inhibitors to reverse exhaustion of T cells has been a major breakthrough in rapidly changing the therapeutic landscape for lung cancer. This article reviews the role of systemic therapy in advanced stage lung cancer.

Economic burden of dengue in four major cities of Pakistan during 2011.

OBJECTIVE: To assess the economic burden of dengue infection by calculating cost per patient and disability adjusted life years lost. METHODS: The cross-sectional study was conducted in Islamabad, Lahore, Faisalabad and Karachi from July 2012 to March 2013. Residential addresses and telephonic numbers of dengue patients were taken from the records of Pakistan Institute of Medical Sciences, Islamabad, Mayo and Ganga Ram Hospital, Lahore, Civil Hospital, Karachi, and Allied Hospital, Faisalabad. A total of 250 dengue confirmed cases - 50 from each hospital - were randomly selected. Information regarding duration of illness and out-of-pocket expenses were collected to estimate the direct cost, while indirect cost (number of work days missed by the patient) was calculated from disability adjusted life years using Murray's formula. RESULTS: Overall, there were 162(65%) men and 88(35%) with a mean age of 30.4±13.5years. More than half 138(55%) were below 30 years of age. Socio-economically, 145(58%) belonged to low, 70(28%) middle and 35(14%) to high socioeconomic groups. Of the total, 210(84%) cases had dengue fever followed by 32(12.8%) dengue haemorrhagic fever and 8(3.2%) dengue shock syndrome cases. Average duration of illness was 32±7.1 days. Overall direct cost per patient was Rs.35,823 (US$358) and average pre-hospitalisation, hospitalisation and post-hospitalisation was Rs.6154, Rs.21,242 and Rs.8,427 respectively. The overall disability adjusted life years per million population was 133.76. CONCLUSIONS: Although the government had provided free treatment for dengue in public-sector hospitals, still patients had to pay Rs.21,242 during hospital stay, resulting in substantial burden which needs to be addressed.

Lung Stereotactic Body Radiation Therapy.

Lung stereotactic body radiation therapy (SBRT) is a novel and effective modality for treatment of early stage non-sail cell lung cancer (NSCLC), with expanding indications in locally advanced and metastatic disease. Herein, we will review current treatment recommendations for early stage NSCLC, detail treatment planning of SBRT, and discuss future directions.

Modulation by Withania somnifera of stress-induced anxiogenesis and airway inflammation in rats.

OBJECTIVES: Stress is an aversive stimulus which disrupts the biological milieu of the organism and a variety of emotional and environmental stressors are known to influence allergic and immunological disorders like bronchial asthma but the pharmacological basis of such interactions is not clearly defined. Withania somnifera (ashwagandha) is a potent anti-stress agent used widely in Indian traditional medicine and the present experimental study evaluated the effects of W. somnifera extract (WSE) on chronic stress-induced neurobehavioral and immunological responses in an experimental model of allergic asthma in rats. METHODS: Wistar rats (200-250 g) were immunized and challenged with ovalbumin (OVA) and exposed to restraint stress (RS) and WSE treatments for 15 days. Following this, anxiety behavior was assessed by the elevated plus maze (EPM) test, and blood and BAL fluid samples were collected for measuring of inflammatory/immune markers by ELISA and biochemical assay. The data of the various treatment groups were analyzed by ANOVA and Tukey's test. RESULTS: Restraint stress (RS) induced anxiogenic behavior in the (EPM) test in OVA immunized rats, and this was attenuated by WSE (200 and 400 mg/kg), in a dose related manner. Examination of blood and BAL fluid in these RS exposed rats also resulted in elevations in IgE, TNF-α and IL-4 levels, which were also attenuated by WSE pretreatments. Further, WSE pretreatment neutralized the such RS induced changes in oxidative stress markers viz. elevated MDA and reduced GSH levels. CONCLUSIONS: The data pharmacologically validates role of stress in asthma and suggests that adaptogens like WSE could be a potential complementary agent for reducing anxiety as well as airway inflammation by a multi-targeted and holistic approach. The study also highlights the significance of integration of traditional and modern medical concepts in such chronic disorders.

Amelioration by Withania somnifera of neurobehavioural and immunological markers in time dependent sensitization induced post traumatic stress disorder in rats.

AIMS AND OBJECTIVES: Posttraumatic stress disorder (PTSD) is a complex neuropsychiatric pathophysiology with an unmet need for safe, effective, and sustainable therapeutic modalities. Thus, the present study evaluated the effects of Withaniasomnifera (WS, Ashwagandha) on an experimental model of PTSD in rats. MATERIALS AND METHODS: Wistar rats (200-250 g) were used and time-dependent sensitization (TDS) was used as the experimental model of PTSD. Standardized WS root extract (100 and 300 mg/kg, p.o. for 15 days) was administered with TDS and their effects were observed on neurobehavioral (anxiety) and brain cytokines, corticosterone, and oxidative stress markers. RESULTS: Exposure to TDS resulted in anxiogenic behavior in the elevated plus maze (EPM) test, i.e., reductions in open arm entries and open arm time, as compared to the control group. Pretreatment with WS extract (100 and 300 mg/kg × 14 days) attenuated the TDS-induced anxiogenic activity in a dose-related manner, and these WS effects were comparable to those seen after the comparator drug fluoxetine (10 mg/kg). Assay of brain homogenates showed that TDS also resulted in elevations in brain interleukin-6 and reduction in corticosterone levels in both the hippocampus and prefrontal cortex (PFC), which were reversed after WS pretreatments. Further, WS pretreatment also reversed the TDS-induced changes in brain oxidative stress markers, namely elevated malondialdehyde and reduced glutathione levels in both the hippocampus and PFC. CONCLUSION: These results suggest that WS could have potential as a therapeutic agent for treating PTSD by attenuating anxiogenesis, neuroimmune axis activation, and oxidative stress.

Biopsychosocial Factors Associated With Pain and Pain-Related Outcomes in Adults and Children With Sickle Cell Disease: A Multivariable Analysis of the GRNDaD Multicenter Registry.

Pain is the primary symptomatic manifestation of sickle cell disease (SCD), an inherited hemoglobinopathy. The characteristics that influence pain experiences and outcomes in SCD are not fully understood. The primary objective of this study was to use multivariable modeling to examine associations of biopsychosocial variables with a disease-specific measure of pain interference known as pain impact. We conducted a secondary analysis of data from the Global Research Network for Data and Discovery national SCD registry. A total of 657 children and adults with SCD were included in the analysis. This sample was 60% female with a median age of 34 (interquartile range 26-42 years) and a chronic pain prevalence of 64%. The model accounted for 58% of the variance in pain impact. Low social (P < .001) and emotional (P < .001) functioning, increasing age (P = .004), low income (P < .001), and high acute painful episodes (P = .007) were most strongly associated with high pain impact in our multivariable model. Additionally, multivariable modeling of pain severity and physical function in 2 comparable samples of registry participants revealed that increasing age and low social functioning were also strongly associated with higher pain severity and low physical functioning. Overall, the results suggest that social and emotional functioning are more strongly associated with pain impact in individuals with SCD than previously studied biological modifiers such as SCD genotype, hemoglobin, and percentage fetal hemoglobin. Future research using longitudinally collected data is needed to confirm these findings. PERSPECTIVE: This study reveals that psychosocial (ie, social and emotional functioning) and demographic (ie, age) variables may play an important role in predicting pain and pain-related outcomes in SCD. Our findings can inform future multicenter prospective longitudinal studies aimed at identifying modifiable psychosocial predictors of adverse pain outcomes in SCD.

Molecular Mechanisms of Ischemic Stroke: A Review Integrating Clinical Imaging and Therapeutic Perspectives.

Ischemic stroke poses a significant global health challenge, necessitating ongoing exploration of its pathophysiology and treatment strategies. This comprehensive review integrates various aspects of ischemic stroke research, emphasizing crucial mechanisms, therapeutic approaches, and the role of clinical imaging in disease management. It discusses the multifaceted role of Netrin-1, highlighting its potential in promoting neurovascular repair and mitigating post-stroke neurological decline. It also examines the impact of blood-brain barrier permeability on stroke outcomes and explores alternative therapeutic targets such as statins and sphingosine-1-phosphate signaling. Neurocardiology investigations underscore the contribution of cardiac factors to post-stroke mortality, emphasizing the importance of understanding the brain-heart axis for targeted interventions. Additionally, the review advocates for early reperfusion and neuroprotective agents to counter-time-dependent excitotoxicity and inflammation, aiming to preserve tissue viability. Advanced imaging techniques, including DWI, PI, and MR angiography, are discussed for their role in evaluating ischemic penumbra evolution and guiding therapeutic decisions. By integrating molecular insights with imaging modalities, this interdisciplinary approach enhances our understanding of ischemic stroke and offers promising avenues for future research and clinical interventions to improve patient outcomes.

Modulation of Immunological, Biochemical, and Histopathological Changes of Airway Remodeling by Withania somnifera in an Experimental Model of Allergic Asthma in Rats.

Objectives: Airway remodeling in asthma involves chronic inflammation associated with structural changes, which result in severe airflow limitation and very few therapeutic options. Thus, the present study was designed to experimentally evaluate the ameliorative effects of Withania somnifera (WS) root extract against Ovalbumin (OVA)-induced airway remodeling in a rat model of asthma. Methods: Wistar rats were immunized (i.p) and challenged (aerosol) with ovalbumin (OVA), and the effects of WS extract were investigated on the development and progress of airway remodeling by assessing immunological, biochemical, and histological changes in these rats. Results: OVA-immunization and challenge in rats resulted in significant increases in the levels of IL-13, 8-OhdG, TGF-ß, hydroxyproline, and periostin in bronchoalveolar lavage fluid (BALF) and serum/lung homogenate compared to normal control (saline only) rats, and these changes were attenuated after WS extract (200 and 400 mg/kg), as well as dexamethasone (DEX, 1 mg/kg) pretreatments. Further, WS extract attenuated histopathological changes and maintained lung integrity. In herb-drug interactions, sub-threshold doses of WS extract and DEX showed synergistic effects on all parameters studied as compared to either form of monotherapy. Conclusion: These results indicated that WS exerted significant protective effects against airway remodeling in the experimental model by modulating inflammatory and fibrotic cytokines, and could have the potential for developing a therapeutic alternative/adjunct for the treatment of airway remodeling of bronchial asthma.