Unveiling the promise of pyrimidine-modified CDK inhibitors in cancer treatment.

Cyclin-dependent kinases (CDKs) constitute a vital family of protein-serine kinases, pivotal in regulating various cellular processes such as the cell cycle, metabolism, proteolysis, and neural functions. Dysregulation or overexpression of CDK kinases is directly linked to the development of cancer. However, the currently approved CDK inhibitors by the US FDA, such as palbociclib, ribociclib, Trilaciclib, Abemaciclib, etc., although effective, exhibit limited specificity and often lead to undesirable adverse effects. First and second-generation CDK inhibitors have not gained significant clinical interaction due to their high toxicity and lack of specificity. To address these challenges, a combined approach is being employed in the quest for newer CDK inhibitors aimed at mitigating toxicity and side effects associated with CDKIs. The discovery of therapeutic agents selectively targeting tumorous cells, such as CDK inhibitors, has demonstrated promise in treating various cancers, including breast cancer. Extensive literature reviews have facilitated the development of novel CDK inhibitors by combining medicinally preferred pyrimidine derivatives with other heterocyclic rings. Pyrimidine derivatives substituted with pyrazole, imidazole, benzamide, benzene sulfonamide, indole carbohydrazide, and other privileged heterocyclic rings have shown encouraging efficacy in inhibiting cyclin-dependent kinase activity. This review provides comprehensive data, including structure-activity relationship (SAR), anticancer activity, and kinetics studies of potent compounds. Additionally, molecular docking studies with compounds under clinical trial and patents filed on pyrimidine based CDK inhibitors in cancer treatment are included. This review serves as a valuable resource for further development of CDK kinase inhibitors for cancer treatment, offering insights into their efficacy, specificity, and potential clinical applications.

A comprehensive review of small molecules targeting PI3K pathway: Exploring the structural development for the treatment of breast cancer.

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.

Assessment of structural and activity-related contributions of various PIM-1 kinase inhibitors in the treatment of leukemia and prostate cancer.

One of the most perilous illnesses in the world is cancer. The cancer may be associated with the mutation of different genes inside the body. The PIM kinase, also known as the serine/threonine kinase, plays a critical role in the biology of different kinds of cancer. They are widely distributed and associated with several biological processes, including cell division, proliferation, and death. Aberration of PIM-1 kinase is found in varieties of cancer. Prostate cancer and leukemia can both be effectively treated with PIM-1 kinase inhibitors. There are several potent compounds that have been explored in this review based on heterocyclic compounds for the treatment of prostate cancer and leukemia that have strong effects on the suppression of PIM-1 kinase. The present review summarizes the PIM-1 kinase pathway, their inhibitors under clinical trial, related patents, and SAR studies of several monocyclic, bicyclic, and polycyclic compounds. The study related to their molecular interactions with receptors is also included in the present manuscript. The study may be beneficial to scientists for the development of novel compounds as PIM-1 inhibitors in the treatment of prostate cancer and leukemia.

An insight on medicinal attributes of 1,2,3- and 1,2,4-triazole derivatives as alpha-amylase and alpha-glucosidase inhibitors.

Diabetes Mellitus (DM) is the globe's common leading disease which is caused by high consumption of glucose. DM compiles groups of metabolic disorders which are characterized by inadequate secretion of insulin from pancreas, resulting in hyperglycemia condition. Many enzymes play a vital role in the metabolism of carbohydrate known as α-amylase and α-glucosidase which is calcium metalloenzyme that leads to breakdown of complex polysaccharides into glucose. To tackle this problem, search for newer antidiabetic drugs is the utmost need for the treatment and/or management of increasing diabetic burden. The inhibition of α-amylase and α-glucosidase is one of the effective therapeutic approaches for the development of antidiabetic therapeutics. The exhaustive literature survey has shown the importance of medicinally privileged triazole specifically 1,2,3-triazol and 1,2,4-triazoles scaffold tethered, fused and/or clubbed with other heterocyclic rings structures as promising agents for designing and development of novel antidiabetic therapeutics. Molecular hybrids namely pyridazine-triazole, pyrazoline-triazole, benzothiazole-triazole, benzimidazole-triazole, curcumin-triazole, (bis)coumarin-triazole, acridine-9-carboxamide linked triazole, quinazolinone-triazole, xanthone-triazole, thiazolo-triazole, thiosemicarbazide-triazole, and indole clubbed-triazole are few examples which have shown promising antidiabetic activity by inhibiting α-amylase and/or α-glucosidase. The present review summarizes the structure-activity relationship (SAR), enzyme inhibitory activity including IC50 values, percentage inhibition, kinetic studies, molecular docking studies, and patents filed of the both scaffolds as alpha-amylase and alpha-glucosidase inhibitors, which may be used for further development of potent inhibitors against both enzymes.

Structural Perspectives in the Development of Novel EGFR Inhibitors for the Treatment of NSCLC.

Non-small cell Lung cancer (NSCLC) is the most common type of lung cancer, which is caused by high consumption of tobacco and smoking. It is an epithelial lung cancer that affects about 2.2 million people across the globe, according to International Agency for Research on Cancer (IARC). Non-small cell lung cancer is a malignant tumor caused by EGFR mutation that occurs in the in-frame deletion of exon 19 and L858R point mutation in exon 21. Presently, clinically available inhibitors of EGFR (including erlotinib, lapatinib, gefitinib, selumetinib, etc.) are not specific and responsible for undesirable adverse effects. Moreover, to solve this problem search for newer EGFR inhibitors is the utmost need for the treatment and/or management of increasing lung cancer burden. The discovery of therapeutic agents that inhibit the specific target in tumorous cells, such as EGFR, is one of the successful strategies in treating many cancer therapies, including lung cancer. The exhaustive literature survey (2018-2023) has shown the importance of medicinally privileged pyrimidine derivatives together, fused and/or clubbed with other heterocyclic rings to design and develop novel EGFR inhibitors. Pyrimidine derivatives substituted with phenylamine, indole, pyrrole, piperazine, pyrazole, thiophene, pyridine and quinazoline derivatives substituted with phenylamine, pyrimidine, morpholine, pyrrole, dioxane, acrylamide, indole, pyridine, furan, pyrimidine, pyrazole etc. are privileged heterocyclic rings shown promising activity by inhibiting EGFR and TKIs. The present review summarizes the structure-activity relationship (SAR) and enzyme inhibitory activity, including IC50 values, percentage inhibition, and kinetic studies of potential compounds from various literature. The review also includes various aspects of molecular docking studies with compounds under clinical trials and patents filed on pyrimidine-based EGFR inhibitors in treating non-small cell lung cancer. The present review may benefit the medicinal chemist for developing novel compounds such as EGFR inhibitors.

PIM kinase inhibitors: an updated patent review (2016-present).

INTRODUCTION: PIM Kinases (PIM-1, PIM-2, and PIM-3) have been reported to play crucial role in signaling cascades that govern cell survival, proliferation, and differentiation. Over-expression of these kinases leads to hematological malignancies such as diffuse large B cell lymphomas (DLBCL), multiple myeloma, leukemia, lymphoma and prostate cancer etc. PIM kinases as biomarkers and potential therapeutic targets have shown promise toward precision cancer therapy. The selective PIM-1, PIM-2, and/or PIM-3 isoform inhibitors have shown significant results in patients with advanced stages of cancer including relapsed/refractory cancer. AREAS COVERED: A comprehensive literature review of PIM Kinases (PIM-1, PIM-2, and PIM-3) in oncogenesis, the patented PIM kinase inhibitors (2016-Present), and their pharmacological and structural insights have been highlighted. EXPERT OPINION: Recently, PIM kinases viz. PIM-1, PIM-2, and PIM-3 (members of the serine/threonine protein kinase family) as therapeutic targets have attracted considerable interest in oncology especially in hematological malignancies. The patented PIM kinase inhibitors comprised of heterocyclic (fused)ring structure(s) like indole, pyridine, pyrazine, pyrazole, pyridazine, piperazine, thiazole, oxadiazole, quinoline, triazolo-pyridine, pyrazolo-pyridine, imidazo-pyridazine, oxadiazole-thione, pyrazolo-pyrimidine, triazolo-pyridazine, imidazo-pyridazine, pyrazolo-quinazoline and pyrazolo-pyridine etc. showed promising results in cancer chemotherapy.

Ensemble learning-based early detection of influenza disease.

Across the world, the seasonal disease influenza is a respiratory illness that impacts all age groups in many ways. Its symptoms are fever, chills, aches, pains, headaches, fatigue, cough, and weakness. Seasonal influenza can cause mild to severe illness and lead to death at times. The task of early detection of influenza is an important research area these days. Various studies show that machine learning techniques have attracted many researchers' attention to the early detection of influenza disease. In this paper, early detection of Influenza disease among all age groups is done using various machine learning techniques. Influenza Research Database and the Human Surveillance Records data sets are used. Data analysis is undertaken, and ensemble-based stacked algorithms are implemented on the whole data set. The performance of different models has been evaluated using different performance metrics. Overall, the study proposes efficient machine learning models that can be implemented to provide a cheaper and quicker diagnostic tool for detecting influenza.

A systematic review of smartphone applications for cancer survivors.

PURPOSE: Mobile phone applications are positioned to support, educate, and empower cancer survivors during post-treatment care. We undertook a review to assess the utility of such smartphone applications; determine whether their use correlates with improved quality of life and other self-reported outcomes; and understand the feasibility of integrating mobile apps into routine follow-up care. METHODS: MEDLINE, EMBASE, Emcare, and PsycINFO databases were searched for studies evaluating apps that addressed at least one of the five Cancer Survivorship Care Quality Framework (CSCQF) domains published up until December 2021. Studies were narratively synthesized. Implementation barriers and facilitators were mapped against the Technology Acceptance Model. RESULTS: Twenty-three primary studies were included in this review. Only three randomized controlled trials (RCTs) were identified. Studies generally found mobile apps to be feasible, acceptable, and well-placed to support survivorship care. Health promotion was the most predominant CSCQF domain with apps primarily aiming to support exercise and dietary changes. The domains of monitoring for cancer recurrence (n=5) and management of co-morbidities (n=1) were underrepresented. Barriers to app use included greater time since active treatment, lack of familiarity with technology, and content not tailored to the user. CONCLUSIONS: Mobile apps are both feasible and acceptable in supporting the transition between active treatment and follow-up care. However, understanding the utility of such apps is limited by the low number of RCTs. IMPLICATIONS FOR CANCER SURVIVORS: Mobile apps have the potential to be useful support tools for patients post-treatment. However, given the number of apps developed, targeted, and available to cancer survivors, practical guidance to help cancer survivors choose appropriate apps is needed.

Prevalence and diagnostic significance of de-novo 12-lead ECG changes after COVID-19 infection in elite soccer players.

BACKGROUND AND AIM: The efficacy of pre-COVID-19 and post-COVID-19 infection 12-lead ECGs for identifying athletes with myopericarditis has never been reported. We aimed to assess the prevalence and significance of de-novo ECG changes following COVID-19 infection. METHODS: In this multicentre observational study, between March 2020 and May 2022, we evaluated consecutive athletes with COVID-19 infection. Athletes exhibiting de-novo ECG changes underwent cardiovascular magnetic resonance (CMR) scans. One club mandated CMR scans for all players (n=30) following COVID-19 infection, despite the absence of cardiac symptoms or de-novo ECG changes. RESULTS: 511 soccer players (median age 21 years, IQR 18-26 years) were included. 17 (3%) athletes demonstrated de-novo ECG changes, which included reduction in T-wave amplitude in the inferior and lateral leads (n=5), inferior leads (n=4) and lateral leads (n=4); inferior T-wave inversion (n=7); and ST-segment depression (n=2). 15 (88%) athletes with de-novo ECG changes revealed evidence of inflammatory cardiac sequelae. All 30 athletes who underwent a mandatory CMR scan had normal findings. Athletes revealing de-novo ECG changes had a higher prevalence of cardiac symptoms (71% vs 12%, p<0.0001) and longer median symptom duration (5 days, IQR 3-10) compared with athletes without de-novo ECG changes (2 days, IQR 1-3, p<0.001). Among athletes without cardiac symptoms, the additional yield of de-novo ECG changes to detect cardiac inflammation was 20%. CONCLUSIONS: 3% of athletes demonstrated de-novo ECG changes post COVID-19 infection, of which 88% were diagnosed with cardiac inflammation. Most affected athletes exhibited cardiac symptoms; however, de-novo ECG changes contributed to a diagnosis of cardiac inflammation in 20% of athletes without cardiac symptoms.

Hyperventilation in functional seizures: Evidence for subtypes.

PURPOSE: Functional seizures (FS) are heterogenous, with no agreed way to subdivide them. One FS subtype frequently observed during EEG is those whose seizures are provoked by hyperventilation. We wished to see whether this subtype might reflect a different seizure mechanism. METHODS: We analysed the video-EEG/ECGs of all patients with FS from two hospitals in Melbourne from 2010-6. RESULTS: We identified 120 patients during the study period, 107 of whom had usable recordings. Examining those 11 (10%) whose seizures had been induced by hyperventilation, we compared the heart rates of those where the seizure occurred during the hyperventilation, and those where they occurred afterwards. The during-hyperventilation group had a higher baseline heart rate which increased prior to their seizure; the after-hyperventilation group had a lower baseline heart rate and no pre-ictal increase. In those patients whose seizures were not hyperventilation-induced, the same two heart rate patterns could be found: those with a higher baseline heart rate showed increasing heart rate prior to seizure onset, while those with a lower baseline heart rate did not. Cluster analysis showed the sample was optimally divided into these two groups based on their pre-onset heart rate alone. CONCLUSION: Patients with FS show two distinct patterns of pre-ictal heart rate, which may reflect two distinct seizure mechanisms.

Graphite Foreign Body Misdiagnosed as a Blue Naevus-Like Localised Argyria.

Pencil-tip injuries, although usually insignificant, have the potential to provoke granulomatous reactions. Other undesirable consequences of such injuries include pigmentation and abscess formation. Despite the rarity of such outcomes, it is important that clinicians are aware of the varying presentations of pencil-tip injury, as this can cause diagnostic uncertainty. Here, we present a case of graphite foreign body granuloma, originally thought to be a blue naevus-like localised argyria. The diagnostic work-up was complicated by the absence of a history of injury with a pencil-tip.

Evaluating the Usefulness and Acceptability of a Revision-Purposed 'Specialties' Webinar for Educating UK-Based Fifth and Final Year Medical Students During the COVID-19 Pandemic: Is This the Future of Medical Education?

BACKGROUND: To assess whether an online course is a useful method of learning for medical students revising for specialty examinations in the context of social distancing restrictions during the COVID-19 pandemic. METHODS: A free, one-day webinar was offered to fifth and final year medical students with an examination-based approach. Teaching was delivered by trainees in Psychiatry, Obstetrics and Gynaecology and Paediatrics (the 'specialties'). An online, questionnaire-based cross-sectional study was conducted to assess usefulness and acceptability of the webinar by enrolled students, who were invited to complete the research questionnaire. Student responses pertaining to knowledge, confidence and interest, pre- and post-webinar, were collected and analysed. RESULTS: A total of 247 students attended the webinar, with a 98.4% response rate to the questionnaire. Ninety-one percent of students agreed that webinars offer flexibility and convenience. About 55.1% felt that the pandemic had impacted their ability to learn new information. About 92.7% felt that the webinar was useful. Matched data showed an increase in participants' knowledge (p = <0.001) and confidence (p < 0.001). CONCLUSION: Online learning provides a useful, accessible and safe method of providing medical education in the context of the global pandemic. Webinars adopting a lecture-based, examination-style approach improved students' perceived confidence and knowledge.

Antibacterial activity of medicinal plants against ESKAPE: An update.

Antibiotic resistance has emerged as a threat to global health, food security, and development today. Antibiotic resistance can occur naturally but mainly due to misuse or overuse of antibiotics, which results in recalcitrant infections and Antimicrobial Resistance (AMR) among bacterial pathogens. These mainly include the MDR strains (multi-drug resistant) of ESKAPE (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species). These bacterial pathogens have the potential to "escape" antibiotics and other traditional therapies. These bacterial pathogens are responsible for the major cases of Hospital-Acquired Infections (HAI) globally. ESKAPE Pathogens have been placed in the list of 12 bacteria by World Health Organisation (WHO), against which development of new antibiotics is vital. It not only results in prolonged hospital stays but also higher medical costs and higher mortality. Therefore, new antimicrobials need to be developed to battle the rapidly evolving pathogens. Plants are known to synthesize an array of secondary metabolites referred as phytochemicals that have disease prevention properties. Potential efficacy and minimum to no side effects are the key advantages of plant-derived products, making them suitable choices for medical treatments. Hence, this review attempts to highlight and discuss the application of plant-derived compounds and extracts against ESKAPE Pathogens.