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1.
Efficacy of immune checkpoint inhibitors combinations as first-line systemic treatment in patients with advanced urothelial carcinoma: A systematic review and network meta-analysis.
Monteiro, FSM, Soares, A, Mollica, V, Leite, CA, Carneiro, APCD, Rizzo, A, Bourlon, MT, Sasse, AD, Santoni, M, Gupta, S, et al
Critical reviews in oncology/hematology. 2024;:104321
Abstract
BACKGROUND Combinations of immune checkpoint inhibitors (ICI) with platinum-based chemotherapy (PlatinumCT) or with another ICI in the first-line setting for patients with metastatic urothelial carcinoma (mUC) have mixed results. METHODS Records were searched electronically from January 2019 to January 2024. A meta-analysis was performed to evaluate OS, progression-free survival (PFS), and overall response rate (ORR). RESULTS Immune-based combinations were associated with an OS (HR: 0.75; 95% CI: 0.61-0.92; p < 0.001; I2= 84.1%) and PFS benefit in the intention-to-treat population (HR: 0.67; 95%CI: 0.51-0.89; p < 0.001; I2 = 89.7%). There was no ORR improvement with immune-based combinations (HR: 1.36; 95% CI:0.84-2.20; p < 0.001; I2 = 92.6%). CONCLUSION This systematic review and study-level meta-analysis demonstrated that the immune-based combinations in first-line treatment for patients with mUC are associated with survival benefit.
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2.
Unveiling the impact of Aging on BBB and Alzheimer's disease: Factors and Therapeutic implications.
Jha, NK, Kumar Nelson, V, Nuli, MV, Kanna, S, Gahtani, RM, Hani, U, Singh, AK, Gupta, S, Abomughaid, MM, Abomughayedh, AM, et al
Ageing research reviews. 2024;:102224
Abstract
Alzheimer's disease (AD) is a highly prevalent neurodegenerative condition that has devastating effects on individuals, often resulting in dementia. AD is primarily defined by the presence of extracellular plaques containing insoluble β-amyloid peptide (Aβ) and neurofibrillary tangles (NFT) composed of hyperphosphorylated tau protein (P-tau). In addition, individuals afflicted by these age-related illnesses experience a diminished state of health, which places significant financial strain on their loved ones. Several risk factors play a significant role in the development of AD. These factors include genetics, diet, smoking, certain diseases (such as cerebrovascular diseases, obesity, hypertension, and dyslipidemia), age, and alcohol consumption. Age-related factors are key contributors to the development of vascular-based neurodegenerative diseases such as AD. In general, the process of aging can lead to changes in the immune system's responses and can also initiate inflammation in the brain. The chronic inflammation and the inflammatory mediators found in the brain play a crucial role in the dysfunction of the blood-brain barrier (BBB). Furthermore, maintaining BBB integrity is of utmost importance in preventing a wide range of neurological disorders. Therefore, in this review, we discussed the role of age and its related factors in the breakdown of the blood-brain barrier and the development of AD. We also discussed the importance of different compounds, such as those with anti-aging properties, and other compounds that can help maintain the integrity of the blood-brain barrier in the prevention of AD. This review builds a strong correlation between age-related factors, degradation of the BBB, and its impact on AD.
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3.
A comprehensive review of small molecules targeting PI3K pathway: Exploring the structural development for the treatment of breast cancer.
Dubey, R, Sharma, A, Gupta, S, Gupta, GD, Asati, V
Bioorganic chemistry. 2024;:107077
Abstract
Cancer stands as one of the deadliest diseases, ranking second in terms of its global impact. Despite the presence of numerous compelling theories concerning its origins, none have succeeded in fully elucidating the intricate nature of this ailment. Among the prevailing concerns in today's world, breast cancer proliferation remains a significant issue, particularly affecting females. The abnormal proliferation of the PI3K pathway emerges as a prominent driver of breast cancer, underscoring its role in cellular survival and proliferation. Consequently, targeting this pathway has emerged as a leading strategy in breast cancer therapeutics. Within this context, the present article explores the current landscape of anti-tumour drug development, focusing on structural activity relationships (SAR) in PI3K targeting breast cancer treatment. Notably, certain moieties like triazines, pyrimidine, quinazoline, quinoline, and pyridoxine have been explored as potential PI3K inhibitors for combating breast cancer. Various heterocyclic small molecules are undergoing clinical trials, such as Alpelisib, the first orally available FDA-approved drug targeting PI3K; others include buparlisib, pictilisib, and taselisib, which inhibit class I PI3K. These drugs are used for the treatment of breast cancer but still have various side effects with their high cost. Therefore, the primary goal of this review is to include all current advances in the development of anticancer medicines that target PI3K over-activation in the treatment of breast cancer.
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4.
Glycolytic enzymes in non-glycolytic web: functional analysis of the key players.
Malla, A, Gupta, S, Sur, R
Cell biochemistry and biophysics. 2024
Abstract
To survive in the tumour microenvironment, cancer cells undergo rapid metabolic reprograming and adaptability. One of the key characteristics of cancer is increased glycolytic selectivity and decreased oxidative phosphorylation (OXPHOS). Apart from ATP synthesis, glycolysis is also responsible for NADH regeneration and macromolecular biosynthesis, such as amino acid biosynthesis and nucleotide biosynthesis. This allows cancer cells to survive and proliferate even in low-nutrient and oxygen conditions, making glycolytic enzymes a promising target for various anti-cancer agents. Oncogenic activation is also caused by the uncontrolled production and activity of glycolytic enzymes. Nevertheless, in addition to conventional glycolytic processes, some glycolytic enzymes are involved in non-canonical functions such as transcriptional regulation, autophagy, epigenetic changes, inflammation, various signaling cascades, redox regulation, oxidative stress, obesity and fatty acid metabolism, diabetes and neurodegenerative disorders, and hypoxia. The mechanisms underlying the non-canonical glycolytic enzyme activities are still not comprehensive. This review summarizes the current findings on the mechanisms fundamental to the non-glycolytic actions of glycolytic enzymes and their intermediates in maintaining the tumor microenvironment.
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5.
Barriers and facilitators of lifestyle management among adult South Asian migrants living with chronic diseases: A mixed-methods systematic review.
Gulyani, P, Rawat, P, Elmi, Y, Gupta, S, Wan, CS
Diabetes & metabolic syndrome. 2024;(2):102944
Abstract
BACKGROUND AND AIM South Asian migrants have a higher prevalence of chronic diseases than Caucasians. Despite much literature that has explored challenges in chronic disease management amongst the South Asian population in the past decades, their chronic disease management is still suboptimal. Understanding their determinants of disease management behaviour using the Theoretical Domains Framework will inform the development of a culturally sensitive intervention relevant to consumer-end-users. This study aimed to synthesise qualitative and quantitative studies on chronic disease management among adult South Asian immigrants. METHODS A mixed-methods systematic review was conducted using electronic databases. The Mixed Methods Appraisal Tool assessed the quality of the included studies. Quantitative data were transformed into qualitative data and analysed thematically. Subthemes were mapped in the Theoretical Domains Framework presenting barriers and facilitators under each theme. RESULTS 18293 studies were identified, of which 37 studies were included. The barriers and facilitators identified were categorised into four overarching themes: patient-provider interaction and relationship (e.g., complex language use by health professionals), the impact of migration (e.g., weather conditions had an impact on engagement with physical activity), heritage-based practices (e.g., an obligation to consume energy-dense food in social gatherings), and chronic disease management strategies (e.g., lack understanding of appropriate disease management strategies). CONCLUSION This review provides a comprehensive understanding of the complexity of chronic disease management among South Asian migrants and insights into developing multifaceted interventions to address barriers to chronic disease management, guiding the healthcare professionals in helping overcome South Asians perceived barriers to managing chronic disease in the host countries.
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6.
Birth Cohort Colorectal Cancer (CRC): Implications for Research and Practice.
Gupta, S, May, FP, Kupfer, SS, Murphy, CC
Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association. 2024;(3):455-469.e7
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Abstract
Colorectal cancer (CRC) epidemiology is changing due to a birth cohort effect, first recognized by increasing incidence of early onset CRC (EOCRC, age <50 years). In this paper, we define "birth cohort CRC" as the observed phenomenon, among individuals born 1960 and later, of increasing CRC risk across successive birth cohorts, rising EOCRC incidence, increasing incidence among individuals aged 50 to 54 years, and flattening of prior decreasing incidence among individuals aged 55 to 74 years. We demonstrate birth cohort CRC is associated with unique features, including increasing rectal cancer (greater than colon) and distant (greater than local) stage CRC diagnosis, and increasing EOCRC across all racial/ethnic groups. We review potential risk factors, etiologies, and mechanisms for birth cohort CRC, using EOCRC as a starting point and describing importance of viewing these through the lens of birth cohort. We also outline implications of birth cohort CRC for epidemiologic and translational research, as well as current clinical practice. We postulate that recognition of birth cohort CRC as an entity-including and extending beyond rising EOCRC-can advance understanding of risk factors, etiologies, and mechanisms, and address the public health consequences of changing CRC epidemiology.
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Psychedelics for alzheimer's disease-related dementia: Unveiling therapeutic possibilities and pathways.
Sinha, JK, Trisal, A, Ghosh, S, Gupta, S, Singh, KK, Han, SS, Mahapatra, M, Abomughaid, MM, Abomughayedh, AM, Almutary, AG, et al
Ageing research reviews. 2024;:102211
Abstract
Psychedelics have traditionally been used for spiritual and recreational purposes, but recent developments in psychotherapy have highlighted their potential as therapeutic agents. These compounds, which act as potent 5-hydroxytryptamine (5HT) agonists, have been recognized for their ability to enhance neural plasticity through the activation of the serotoninergic and glutamatergic systems. However, the implications of these findings for the treatment of neurodegenerative disorders, particularly dementia, have not been fully explored. In recent years, studies have revealed the modulatory and beneficial effects of psychedelics in the context of dementia, specifically Alzheimer's disease (AD)-related dementia, which lacks a definitive cure. Psychedelics such as N,N-dimethyltryptamine (DMT), lysergic acid diethylamide (LSD), and Psilocybin have shown potential in mitigating the effects of this debilitating disease. These compounds not only target neurotransmitter imbalances but also act at the molecular level to modulate signalling pathways in AD, including the brain-derived neurotrophic factor signalling pathway and the subsequent activation of mammalian target of rapamycin and other autophagy regulators. Therefore, the controlled and dose-dependent administration of psychedelics represents a novel therapeutic intervention worth exploring and considering for the development of drugs for the treatment of AD-related dementia. In this article, we critically examined the literature that sheds light on the therapeutic possibilities and pathways of psychedelics for AD-related dementia. While this emerging field of research holds great promise, further studies are necessary to elucidate the long-term safety, efficacy, and optimal treatment protocols. Ultimately, the integration of psychedelics into the current treatment paradigm may provide a transformative approach for addressing the unmet needs of individuals living with AD-related dementia and their caregivers.
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Artificial Intelligence in Coronary Artery Calcium Scoring Detection and Quantification.
Abdelrahman, K, Shiyovich, A, Huck, DM, Berman, AN, Weber, B, Gupta, S, Cardoso, R, Blankstein, R
Diagnostics (Basel, Switzerland). 2024;(2)
Abstract
Coronary artery calcium (CAC) is a marker of coronary atherosclerosis, and the presence and severity of CAC have been shown to be powerful predictors of future cardiovascular events. Due to its value in risk discrimination and reclassification beyond traditional risk factors, CAC has been supported by recent guidelines, particularly for the purposes of informing shared decision-making regarding the use of preventive therapies. In addition to dedicated ECG-gated CAC scans, the presence and severity of CAC can also be accurately estimated on non-contrast chest computed tomography scans performed for other clinical indications. However, the presence of such "incidental" CAC is rarely reported. Advances in artificial intelligence have now enabled automatic CAC scoring for both cardiac and non-cardiac CT scans. Various AI approaches, from rule-based models to machine learning algorithms and deep learning, have been applied to automate CAC scoring. Convolutional neural networks, a deep learning technique, have had the most successful approach, with high agreement with manual scoring demonstrated in multiple studies. Such automated CAC measurements may enable wider and more accurate detection of CAC from non-gated CT studies, thus improving the efficiency of healthcare systems to identify and treat previously undiagnosed coronary artery disease.
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Review: Nutrient-nutrient interactions governing underground plant adaptation strategies in a heterogeneous environment.
Singh, K, Gupta, S, Singh, AP
Plant science : an international journal of experimental plant biology. 2024;:112024
Abstract
Plant growth relies on the mineral nutrients present in the rhizosphere. The distribution of nutrients in soils varies depending on their mobility and capacity to bind with soil particles. Consequently, plants often encounter either low or high levels of nutrients in the rhizosphere. Plant roots are the essential organs that sense changes in soil mineral content, leading to the activation of signaling pathways associated with the adjustment of plant architecture and metabolic responses. During differential availability of minerals in the rhizosphere, plants trigger adaptation strategies such as cellular remobilization of minerals, secretion of organic molecules, and the attenuation or enhancement of root growth to balance nutrient uptake. The interdependency, availability, and uptake of minerals, such as phosphorus (P), iron (Fe), zinc (Zn), potassium (K), nitrogen (N) forms, nitrate (NO3-), and ammonium (NH4+), modulate the root architecture and metabolic functioning of plants. Here, we summarized the interactions of major nutrients (N, P, K, Fe, Zn) in shaping root architecture, physiological responses, genetic components involved, and address the current challenges associated with nutrient-nutrient interactions. Furthermore, we discuss the major gaps and opportunities in the field for developing plants with improved nutrient uptake and use efficiency for sustainable agriculture.
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Rusfertide, a Hepcidin Mimetic, for Control of Erythrocytosis in Polycythemia Vera.
Kremyanskaya, M, Kuykendall, AT, Pemmaraju, N, Ritchie, EK, Gotlib, J, Gerds, A, Palmer, J, Pettit, K, Nath, UK, Yacoub, A, et al
The New England journal of medicine. 2024;(8):723-735
Abstract
BACKGROUND Polycythemia vera is a chronic myeloproliferative neoplasm characterized by erythrocytosis. Rusfertide, an injectable peptide mimetic of the master iron regulatory hormone hepcidin, restricts the availability of iron for erythropoiesis. The safety and efficacy of rusfertide in patients with phlebotomy-dependent polycythemia vera are unknown. METHODS In part 1 of the international, phase 2 REVIVE trial, we enrolled patients in a 28-week dose-finding assessment of rusfertide. Part 2 was a double-blind, randomized withdrawal period in which we assigned patients, in a 1:1 ratio, to receive rusfertide or placebo for 12 weeks. The primary efficacy end point was a response, defined by hematocrit control, absence of phlebotomy, and completion of the trial regimen during part 2. Patient-reported outcomes were assessed by means of the modified Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF) patient diary (scores range from 0 to 10, with higher scores indicating greater severity of symptoms). RESULTS Seventy patients were enrolled in part 1 of the trial, and 59 were assigned to receive rusfertide (30 patients) or placebo (29 patients) in part 2. The estimated mean (±SD) number of phlebotomies per year was 8.7±2.9 during the 28 weeks before the first dose of rusfertide and 0.6±1.0 during part 1 (estimated difference, 8.1 phlebotomies per year). The mean maximum hematocrit was 44.5±2.2% during part 1 as compared with 50.0±5.8% during the 28 weeks before the first dose of rusfertide. During part 2, a response was observed in 60% of the patients who received rusfertide as compared with 17% of those who received placebo (P = 0.002). Between baseline and the end of part 1, rusfertide treatment was associated with a decrease in individual symptom scores on the MPN-SAF in patients with moderate or severe symptoms at baseline. During parts 1 and 2, grade 3 adverse events occurred in 13% of the patients, and none of the patients had a grade 4 or 5 event. Injection-site reactions of grade 1 or 2 in severity were common. CONCLUSIONS In patients with polycythemia vera, rusfertide treatment was associated with a mean hematocrit of less than 45% during the 28-week dose-finding period, and the percentage of patients with a response during the 12-week randomized withdrawal period was greater with rusfertide than with placebo. (Funded by Protagonist Therapeutics; REVIVE ClinicalTrials.gov number, NCT04057040.).