Drug Selection Research Articles

Geriatric anaesthesia: Challenges and recent updates – A review

Geriatric anaesthesia is a rapidly growing subspecialty due to the rising number of elderly individuals undergoing surgical procedures. Older adults present a unique set of challenges, including physiological changes, polypharmacy, and comorbidities, all of which can significantly influence anaesthetic management. Age-related alterations in pharmacokinetics and pharmacodynamics make dosing and drug selection more complex. Additionally, the elderly are at a higher risk of perioperative complications such as postoperative cognitive dysfunction (POCD) and delirium. Recent advancements in geriatric anaesthesia have focused on better preoperative assessments, personalized anaesthetic strategies, and enhanced recovery protocols to reduce postoperative morbidity. This review aims to explore the challenges faced in anaesthetizing the elderly and highlights recent updates in the field, including the development of frailty assessment tools, use of regional anaesthesia, and the role of multidisciplinary teams in perioperative care. By optimizing perioperative care, including pain management, anaesthetic depth monitoring, and the prevention of delirium, outcomes for elderly patients can be significantly improved. This article provides a comprehensive review of the current state of geriatric anaesthesia, with a focus on both the challenges faced and innovations that have emerged to improve patient care.

Comparative analysis of regression algorithms for drug response prediction using GDSC dataset

BackgroundDrug response prediction can infer the relationship between an individual’s genetic profile and a drug, which can be used to determine the choice of treatment for an individual patient. Prediction of drug response is recently being performed using machine learning technology. However, high-throughput sequencing data produces thousands of features per patient. In addition, it is difficult for researchers to know which algorithm is appropriate for prediction as various regression and feature selection algorithms exist.MethodsWe compared and evaluated the performance of 13 representative regression algorithms using Genomics of Drug Sensitivity in Cancer (GDSC) dataset. Three analyses was conducted to show the effect of feature selection methods, multiomics information, and drug categories on drug response prediction.ResultsIn the experiments, Support Vector Regression algorithm and gene features selected with LINC L1000 dataset showed the best performance in terms of accuracy and execution time. However, integration of mutation and copy number variation information did not contribute to the prediction. Among the drug groups, responses of drugs related with hormone-related pathway were predicted with relatively high accuracy.ConclusionThis study can help bioinformatics researchers design data processing steps and select algorithms for drug response prediction, and develop a new drug response prediction model based on the GDSC or other high-throughput sequencing datasets.

Risk Factors and the Treatment of Type 2 Diabetes (T2D)

With the change in lifestyles, the incidence of diabetes is on the increase year by year, seriously affecting the quality of peoples lives. Among all the types of diabetes, type 2 diabetes (T2D) is the most common. The risk of T2D increases with age and the proportion of risk trends now towards youthfulness. T2D has a complex mechanism of etiology. It is generally accepted that this is a metabolic disorder mainly due to defective insulin secretion by pancreatic -cells, reduced responsiveness, and sensitivity of insulin-sensitive organs or tissues (liver, skeletal muscle, adipose tissue, etc.) to insulin. This article will summarize the associated risk factors of T2D, inform clinical practice work, and public health policy designation. Additionally, traditional antihyperglycemic drugs may lead to adverse reactions such as hypoglycemia and gastrointestinal reactions. To better control blood sugar, reduce the occurrence of adverse reactions, and delay or mitigate T2D complications, this article also lays out part of the new target drugs with therapeutic potential on the market, producing more drug selection to treat T2D. More studies targeting patients with all types of T2D are needed to better serve patients

DRESSLER SYNDROME IN VIEW OF MODERN IDEAS

HighlightsThe frequency of Dressler syndrome decreased sharply from 20 to less than 5% with the introduction of early reperfusion into clinical practice. Relapses of Dressler’s post-infarction syndrome are quite common. The review presents current literature data on the etiology and pathogenesis, diagnostic methods and various approaches to the treatment of Dressler syndrome, including the effectiveness of colchicine and reports on the use of immunoglobulins. AnnotationThe development of Dressler syndrome relapses within 1 year after the first occurrence of the event, despite the decrease in the frequency of the disease, emphasizes the relevance of the problem under consideration. Dressler syndrome is based on autoimmune genesis. Echocardiography is the “gold standard” of instrumental diagnostics and the most sensitive imaging method for suspected Dressler syndrome, but in some cases magnetic resonance imaging may be effective. There is currently no single treatment regimen for autoimmune pericarditis. Most literature sources indicate the most frequent use of nonsteroidal anti-inflammatory drugs, glucocorticosteroids and colchicine. The article highlights the literature data on etiology, modern views on pathogenesis, current methods of diagnosis of Dressler syndrome and various approaches to treatment tactics and drug selection. The following resources were used: eLIBRARY.ru, PubMed. The keywords were as follows: “Dressler syndrome”, “postinfarction syndrome”, “postpericardiotomy syndrome”, “myocardial infarction”. The articles published primarily in the last 5 years (2017-2022) were preferred.

Impact of vial quality on interactions, particle formation, container closure integrity, and gas permeability for frozen drug product storage.

The frozen storage of biopharmaceuticals brings new challenges to the primary packaging material. Due to an increasing demand and the downsides of standard type I glass vials, such as vial breakage, novel vial types for special applications of parenteral drug products have been introduced to the market in the past years. Mechanical stresses due to dimensional changes experienced during freezing and thawing could change the material properties, hence affecting the interaction with the drug product stored in the vial or functionality such as overall integrity. Therefore, we studied the suitability of different vial qualities related to the thermally induced mechanical stresses experienced during frozen drug product preparation and storage. First, the possible failure modes for each vial type were identified. The interaction between vial surface and drug product were investigated considering surface hydrophobicity, surface free energy and surface roughness as well as microscopically visible changes analyzed by confocal laser scanning microscopy. Differences in surface hydrophobicity, roughness and surface free energy between the vial types did not impact the performance upon freeze-thaw stress and did not change with the stress. Screening the vial content for particles originating from the container using light and electron scanning microscopy combined with energy-dispersive X-ray spectroscopy showed only rare cases of particles in coated glass vials. Under extreme stress conditions, including a drop-test in the frozen state, a low number of particles was also detected in coated polymer vials. No quality issues regarding the functionality were observed upon container closure integrity testing, while the oxygen permeability was slightly increased for uncoated and especially coated polymer vials. Overall, the results show that several vial types are appropriate for the frozen storage of drug products and selection should be based on the formulation and other product requirements.

Applications of innovative synthetic strategies in anticancer drug Discovery: The Driving Force of new chemical reactions.

The discovery of novel anticancer agents remains a critical goal in medicinal chemistry, with innovative synthetic methodologies playing a pivotal role in advancing this field. Recent breakthroughs in CH activation reactions, cyclization reactions, multicomponent reactions, cross-coupling reactions, and photo- and electro-catalytic reactions have enabled the efficient synthesis of new molecular scaffolds exhibiting potent biological activities, including anticancer properties. These methodologies have facilitated the functionalization of natural products, the modification of bioactive molecules, and the generation of entirely new compounds, many of which demonstrate strong antitumor activity. This review summarizes the latest synthetic strategies employed over the past five years for discovering anticancer agents, focusing on their influence on drug design. Additionally, the role of new chemical reactions in expanding chemical space and overcoming challenges, such as drug resistance and selectivity, is highlighted, further emphasizing the importance of discovering novel reactions as a key trend in future drug development.

Scalable control of stem cell fate by riboswitch-regulated RNA viral vector without genomic integration.

Transgene expression in stem cells is a powerful means of regulating cellular properties and differentiation into various cell types. However, existing vectors for transgene expression in stem cells suffer from limitations such as the need for genomic integration, the transient nature of gene expression, and the inability to temporally regulate transgene expression, which hinder biomedical and clinical applications. Here we report a new class of RNA virus-based vectors for scalable and integration-free transgene expression in mouse embryonic stem cells (mESCs). The vector is equipped with a small molecule-regulated riboswitch and a drug selection marker that allow temporal regulation of transgene expression and stable maintenance of the vector in proliferating stem cells. We demonstrated the utility of the vector by maintaining the pluripotency of mESCs in a differentiation induction medium by expressing Nanog and inducing myogenic differentiation by triggering Myod1 expression, without altering the mESC genome.

Cardiovascular Therapy Benefits of Novel Antidiabetic Drugs in Patients With Type 2 Diabetes Mellitus Complicated With Cardiovascular Disease: A Network Meta-Analysis.

Provide an evidence-based basis for the selection of cardiovascular benefit drugs in Type 2 diabetes mellitus (T2DM) patients with cardiovascular disease (CVD). Conduct a comprehensive search of all relevant literature from PubMed, Embase, Web of Science, Cochrane Library, and Clinical Trials.gov from their establishment until December 13, 2023, and select randomized controlled trials (RCTs) that meet the pre-established inclusion and exclusion criteria. Use the Cochrane bias risk assessment tool to evaluate the quality of the included literature. Use R 4.3.2 software to conduct network meta-analysis for drug category comparison. A total of 24 large-scale randomized controlled trials (RCTs) were included, including 19 intervention measures, and 172 803 patients participated in the study. The results of the network meta-analysis show that: GLP1RA (OR 0.89, 95% CI 0.81-0.97) and SGLT2i (OR 0.91, 95% CI 0.83-0.99) can reduce the occurrence of major adverse cardiovascular events (MACE), GLP1RA (OR 0.88, 95% CI 0.79-0.97) and SGLT2i (OR 0.89, 95% CI 0.81-0.99) reduced the risk of cardiovascular death. SGLT2i (OR 0.68, 95% CI 0.62-0.75) reduced the occurrence of hospitalization for heart failure, GLP1RA (OR 0.88, 95% CI 0.81-0.97) and SGLT2i (OR 0.89, 95% CI 0.80-0.97) reduced the occurrence of all-cause death. In the comparison of new hypoglycemic drug classes, GLP1RA and SGLT2i reduced MACE, cardiovascular mortality and all-cause mortality in T2DM patients with CVD, with no significant difference in efficacy, and DPP4i was noninferior to placebo. Only GLP1RA reduced the risk of nonfatal stroke, and only SGLT2i reduced the risk of HHF.

Efficacy and safety of SHR8554 on postoperative pain in subjects with moderate to severe acute pain following orthopedic surgery: A multicenter, randomized, double-blind, dose-explored, active-controlled, phase II/III clinical trial.

Biased µ-opioid receptor (MOR) agonists enhance pain relief by selectively activating G protein-coupled receptor signaling and minimizing β-arrestin-2 activation, resulting in fewer side effects. This multicenter Phase II/III trial evaluated the optimal dosage, efficacy, and safety of SHR8554, a biased MOR agonist, for postoperative pain management following orthopedic surgery. In Phase II, 121 patients were divided into four groups to receive varying patient-controlled analgesia (PCA) doses of SHR8554 or morphine. Phase III involved 320 patients with similar groupings, including a placebo group. The primary outcome was the resting summed pain intensity difference over 24 hours (rSPID24). Secondary outcomes included rSPID and active-SPID (aSPID) at other time points, rescue analgesia received, cumulative dose of analgesics, and satisfaction scores. Safety endpoints included treatment-emergent adverse events (TEAEs) and AE of special interest (AESIs). In both phases, SHR8554 demonstrated significant analgesic efficacy. In Phase II, the least squares (LS) mean differences in rSPID24 compared to morphine for the 0.05 mg,0.1 mg, and 0.2 mg SHR8554 groups were 16.8 (p = 0.01), 7.4 (p = 0.27), and 0.2 (p = 0.98), respectively. Phase III confirmed the efficacy of the 0.05 mg and 0.1 mg SHR8554 doses compared to placebo, with LS mean differences of 15.4 (p = 0.0001) and -19.8 (p < 0.0001), respectively. Trends in other secondary outcomes mirrored these findings. Safety analysis revealed that the 0.2 mg SHR8554 group had higher incidences of TEAEs (83.3 %) and AESIs (33.3 %) compared to other groups in Phase II. Similarly, in Phase III, the incidences of TEAEs were 81.0 %, 73.4 %, and 74.1 % in the 0.05 and 0.1 mg SHR8554 and morphine groups, respectively, compared with 61.3 % in the placebo group, while the AESIs were 29.1 %, 20.3 %, and 24.7 % compared with 12.5 % in the placebo group. In conclusion, SHR8554 exhibited efficacy compared to placebo and safety comparable to morphine for patients experiencing moderate-to-severe acute pain following unilateral total knee replacement or knee ligament reconstruction surgery. TRIAL REGISTRATION: Trial Name: Study on the Efficacy and Safety of SHR8554 Injection for Postoperative Analgesia in Orthopedics: Multicenter, Randomized, Double Blind, Dose Exploration, Placebo/Positive Control, Phase II/III Clinical Trial Registered on: chinadrugtrials.org.cn Identifier: CTR20220639.

Pro-resolving lipid mediators and therapeutic innovations in resolution of inflammation.

This review summarizes findings presented at the 19th World Congress of Basic & Clinical Pharmacology 2023 (Glasgow, Scotland, July 3rd to 7th, 2023) from 8 speakers in the field of resolution of inflammation, resolution pharmacology and resolution biology. It is now accepted that the acute inflammatory response is protective to defend the host against infection or tissue injury. Acute inflammation is self-limited and programmed to be limited in space and time: this is achieved through endogenous resolution processes that ensure return to homeostasis. Resolution is brought about by agonist mediators that include specialized pro-resolving lipid mediators (SPMs) and pro-resolving proteins and peptides such as annexin A1 and angiotensin-(1-7), all acting to initiate anti-inflammatory and pro-resolving processes. If the inflammatory reaction remains unchecked through dysfunctional resolution mechanism, it can become chronic and contribute to a plethora of human diseases, including respiratory, cardiovascular, metabolic, allergic diseases, and arthritis. Herein, we discuss how non-resolving inflammation plays a role in the pathogenesis of these diseases. In addition to SPMs, we highlight the discovery, biosynthesis, biofunctions, and latest research updates on innovative therapeutics (including annexin-A1 peptide-mimetic RTP-026, small molecule FPR2 agonist BM-986235/LAR-1219, biased agonist for FPR1/FPR2 Cmpd17b, lipoxin mimetics AT-01-KG and AT-02-CT, melanocortin receptor agonist AP1189, gold nanoparticles, angiotensin-(1-7), and CD300a) that can promote resolution of inflammation directly or through modulation of SPMs production. Drug development strategies based on the biology of the resolution of inflammation can offer novel therapeutic means and/or add-on therapies for the treatment of chronic diseases.

Drug Therapy-related Problems Detected by Clinical Pharmacists in a Closed Loop Medication Management; A Cross-sectional Study in UAE.

Drug therapy-related problems (DTRP) can lead to avoidable negative health consequences, particularly during hospital admissions. This study aimed to assess the frequency, causes, and associated factors of DTRPs, which are detected by clinical pharmacists' interventions. This is a prospective cross-sectional study of patients admitted to the medical wards of Fakeeh University Hospital, UAE, over a three-month period from September 2022 to December 2022. The data of patients who were assessed by clinical pharmacists regarding the pretense and causes of DTRPs were collected and analyzed using SPSS version 27.0. 310 patients with the mean age of 33.43 ± 19.98 years were studied (53.9% male). The highest percentage of patients were Asian (31.0%) and Arabs (30.6%). 79 (25.4%) cases had no DTRPs, while 231 (74.6) had DTRPs. The surgical ward had the highest frequency of DTRPs (41.0%). Improper drug selection with 79 cases, drug use without indication with 73 cases, and sub-therapeutic dosage with 26 cases were among the most common causes of DTRPs. Alcohol intake (p= 0.03), food allergy (p = 0.02), age group 31-40 years (p = 0.04), presence of co-morbidities (p = 0.01), family history of diseases (p = 0.02), and admission to the intensive care unit (ICU) (p = 0.01) were amongst the significantly associated factors of DTRPs. The acceptance status for clinical pharmacists' interventions were complete in 90.0% of cases, partial in 4.1 %, and rejection in 5.9%. The study findings show a high prevalence of DTRPs due to drug/dose selection and drug use without indication. It seems that the participation of clinical pharmacists in multidisciplinary teams together with the presence of closed loop medication management facilitates the detection and correction of DTRPs.

Effectiveness of different traditional Chinese medicine injections in patients with diabetic lower extremity arterial disease: A Bayesian network meta-analysis.

Numerous studies have demonstrated the effectiveness of Chinese medicine injections (CMIs) in treating diabetic lower extremity arterial disease (Dia-LEAD). However, with the variety of CMIs available, it has become challenging to determine the optimal choice for Dia-LEAD patients. This study aims to compare and rank the efficacy of CMIs for Dia-LEAD to provide references and evidence for clinicians in optimising drug selection. We conducted a comprehensive search for randomised controlled trials (RCTs) of CMIs for treating Dia-LEAD, which included the China National Knowledge Infrastructure (CNKI), Wanfang, China Weipu Science and Technology Journal Database (VIP), Chinese Biomedical Literature Database (CBM), PubMed, the Cochrane Library, Embase, and Web of Science, covering inception to 15 October 2023. We used the Cochrane Risk of Bias Tool 2.0 to assess bias risk, and RevMan 5.4.1, GeMTC, STATA 13.0, and R 4.2.1 for statistical analysis and visualization of the network meta-analysis. We analysed 38 studies with 12 CMIs. Compared with other interventions, Shuxuening injection (SXN)+conventional treatment (CT) was superior in terms of the total effective rate (surface under the cumulative ranking (SUCRA) 86.2%). Danshen injection (DS)+CT ranked first in improving the ankle-brachial index (ABI) (SUCRA 95.1%) and dorsalis pedis artery blood flow (DPABF) (SUCRA 88.8%). Danhong injection (DH)+CT showed the highest probability of effectiveness in improving the plasma viscosity (SUCRA 91.6%). Chuanxiongqin injection (CXQ)+CT yielded favourable results in regulating fibrinogen levels (SUCRA 77.1%). Furthermore, no significant differences in adverse reactions were detected between the treatment and control groups. The study demonstrated that CMIs have potential as a complementary therapy for treating Dia-LEAD, and it supports the positive effects of combining CMIs with CT on a number of outcome indicators. Especially when it comes to improving the haemodynamics indices and the haemorheology indices, DS in combination with CT may be a more effective intervention. However, further confirmation in more rigorous, high-quality, and multicentre RCTs is needed to strengthen the validity and generalisability of the results.

Shared decision-making in patients with gynecological cancer and healthcare professionals: a cross-sectional observational study in Japan.

This cross-sectional study aimed to understand the actual situation of shared decision-making (SDM) and identify the challenges of implementing SDM among Japanese gynecologic cancer patients and healthcare professionals (HCPs). Adult Japanese women undergoing chemotherapy for endometrial or ovarian/fallopian tube cancer and HCPs who prescribed/administered treatment were enrolled. Data were collected via a web-based questionnaire. Primary endpoints were the actual and desired status of SDM for patients by preferred role (active, collaborative, passive), and important aspects in drug selection for patients and HCPs. SDM treatment preferences were determined using the Control Preferences Scale. Respondents comprised 154 patients (77 for endometrial and 77 for ovarian/fallopian tube cancer), 153 physicians, 166 nurses, and 154 pharmacists. Among patients, 53.9% desired an active role in decision-making, and 55.8% participated; 25.3% desired a collaborative role, and 14.3% participated; and 20.8% desired a passive role, and 29.9% participated. Most patients with a collaborative role in decision-making (86.4%) were "very satisfied" or "somewhat satisfied" with their communication with physicians, compared with 60.4% and 73.9% of respondents with active and passive roles in decision-making, respectively. In daily practice, 23.5%, 47.6%, and 19.5% of physicians, nurses, and pharmacists, respectively, confirmed "awareness" of SDM. Regarding treatment expectations, patients ranked "complete elimination of cancer," and HCPs ranked "live longer" as the most important. Most patients desire involvement in their treatment decisions. Additionally, treatment expectations differ between patients and HCPs. Increasing SDM awareness, implementing it systematically, and addressing patients' needs for collaborative roles in decision-making is essential.

Miniaturization and Characterization of Patient Derived Hepatocellular Carcinoma Tumor Organoid Cultures for Cancer Drug Discovery Applications.

Patient derived tumor organoid (PDTO) models retain the structural, morphological, genetic, and clonal heterogeneity of the original tumors. The ability to efficiently generate, expand, and biobank PDTOs has the potential to make the clinical diversity of cancer accessible for personalized medicine assay guided therapeutic drug selection and drug discovery. We describe the miniaturization and growth in 96- and 384-well formats of a single non-tumor liver and two Hepatocellular carcinoma (HCC) organoids derived from cryopreserved PDTO cells and the application of high content imaging (HCI) to characterize the models and enhance drug sensitivity testing. Non-invasive sequentially acquired transmitted light images showed that seeding cryopreserved cells from non-tumoral and HCC PDTOs into 96- or 384-well plates in reduced growth factor Matrigel (rgf-MG) that were fed with growth medium every 3 days supported organoid growth up to 15 days. The number and sizes of organoids increased with longer times in culture. HCC PDTO's had more heterogeneous morphologies than non-tumor organoids with respect to size, shape, and optical density. Organoids cultured in rgf-MG could be stained in situ with HCI reagents without mechanical, chemical or enzymatic disruption of the hydrogel matrices and quantitative data extracted by image analysis. Hoechst and live/dead reagents provided organoid numbers and viability comparisons. HCC PDTO's stained with phalloidin or immuno-stained with α-tubulin antibodies revealed F-actin and microtubule cytoskeleton organization. HCC PDTO's stained with antibodies to signaling pathway proteins and their phosphorylation status allowed comparisons of relative expression levels and inference of pathway activation. Images of HCC PDTO's exposed to ellipticine showed that drugs penetrate Matrigel hydrogels and accumulate in organoid cells. 9-day 384-well HCC organoid cultures exhibited robust and reproducible growth signals suitable for cancer drug testing. Complimenting cell viability readouts with multiple HCI parameters including morphological features and dead cell staining improved the analysis of drug impact and enhanced the value that could be extracted from these more physiologically relevant three-dimensional HCC organoid cultures.

The Chinese Society of Clinical Oncology (CSCO): Clinical guidelines for the diagnosis and treatment of colorectal cancer, 2024 update.

The 2024 updates of the Chinese Society of Clinical Oncology (CSCO) Clinical Guidelines for the diagnosis and treatment of colorectal cancer emphasize standardizing cancer treatment in China, highlighting the latest advancements in evidence-based medicine, healthcare resource access, and precision medicine in oncology. These updates address disparities in epidemiological trends, clinicopathological characteristics, tumor biology, treatment approaches, and drug selection for colorectal cancer patients across diverse regions and backgrounds. Key revisions include adjustments to evidence levels for intensive treatment strategies, updates to regimens for deficient mismatch repair (dMMR)/ microsatellite instability-high (MSI-H) patients, proficient mismatch repair (pMMR)/ microsatellite stability (MSS) patients who have failed standard therapies, and rectal cancer patients with low recurrence risk. Additionally, recommendations for digital rectal examination and DNA polymerase epsilon (POLE)/ DNA polymerase delta 1 (POLD1) gene mutation testing have been strengthened. The 2024 CSCO Guidelines are based on both Chinese and international clinical research, as well as expert consensus, ensuring their relevance and applicability in clinical practice, while maintaining a commitment to scientific rigor, impartiality, and timely updates.

Everolimus Through Plasmatic Concentrations in Cancer Patients: Prospective Longitudinal Observational Multicentric Study (DIANA-1 Project).

Background: Everolimus, an oral inhibitor of the mammalian target of rapamycin (mTOR), is actually used to prevent organ transplant rejection and treat metastatic breast, renal, and neuroendocrine cancers. Despite significant pharmacokinetic variability among patients, routine therapeutic drug monitoring (TDM) is not commonly used in oncology. Methods: The aim of this multicenter, prospective observational cohort study is to assess the prevalence of everolimus minimum concentration at a steady state (Cminss) falling outside the therapeutic range (10-26.3 ng/mL) during a routine TDM programme. Sixty patients with metastatic breast, neuroendocrine, or renal cancers, either starting or continuing everolimus treatment according to hospital protocols, are to be included between 1st of January 2024 and 31st of December 2025 (patients undergoing clinical trials are excluded). We hypothesize that 30-50% of our patients and their blood samples will not achieve the target optimal plasma concentrations. Blood samples are collected every 4-6 weeks to monitor drug levels. The secondary goal is to explore correlation between out-of-range everolimus levels and factors such as demographic and anthropometric data, treatment specifics, lab results, genetic polymorphisms, and the presence of toxicity. Conclusions: This study could offer valuable insights into optimizing dosing strategies and may contribute to future research on personalizing everolimus and other anticancer treatments. This personalized approach seeks to tailor therapy not only to the tumour's molecular profile but also to the individual characteristics of each patient, improving both drug selection and dosing precision.

Locked Dimerized CXCL12 Exerts Radiosensitizing Effects in Head and Neck Cancer.

Head and neck squamous cell carcinoma (HNSCC) presents significant treatment challenges, particularly in cases unrelated to human papillomavirus (HPV). The chemokine receptor CXCR4, interacting with its ligand CXCL12, plays a crucial role in tumor proliferation, metastasis, and treatment resistance. This study explores the therapeutic potential of engineered monomeric and dimerized CXCL12 variants (CXCL121 and CXCL122, respectively) in HNSCC and evaluates potential additive effects when combined with radiation therapy. Clinical HNSCC biopsies were evaluated for CXCR4 expression in both previously untreated and radiorecurrent disease. HNSCC cell lines were then treated with combinations of CXCL12 variants and radiotherapy and interrogated for proliferation, gene expression change, and underlying molecular mechanisms. Invivo studies evaluated the biodistribution of engineered CXCL12 and tested these treatments in humanized cell line-derived xenograft (CDX) models. CXCL122 significantly reduced HNSCC cell proliferation and enhanced the effects of radiotherapy, likely through biased agonism at the CXCR4 receptor and upregulation of the KISS1R pathway. Invivo, CXCL122 localized to tumor sites and augmented the effects of radiation to inhibit tumor growth. CXCL122, in combination with radiation, demonstrates potent anti-tumor effects in HNSCC. These findings support further clinical investigation of CXCL122 to enhance the effects of radiotherapy.

Assessing the benefit-risk profile of newer glucose-lowering drugs: A systematic review and network meta-analysis of randomized outcome trials.

To comprehensively evaluate the benefits and risks of glucagon-like peptide-1 receptor agonists (GLP-1RA), dipeptidyl peptidase 4 inhibitors (DPP4i), and sodium-glucose cotransporter 2 inhibitors (SGLT2i). A systematic search of PubMed, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL) from inception to November 2023 to identify randomized cardiovascular and kidney outcome trials that enrolled adults with type 2 diabetes, heart failure, or chronic kidney disease and compared DPP4i, GLP-1RAs, or SGLT2i to placebo. Twenty-one outcomes (e.g., major adverse cardiovascular events [MACE], stroke, and hospitalization for heart failure [HHF]) were assessed. Data were pooled using population-averaged odds ratios (ORs) with 95% CIs. Twenty-six trials enrolling 198 177 participants were included. GLP-1RAs were most effective in lowering the risks of MACE (OR, 0.85, [95% CI, 0.79 to 0.92]) and stroke (0.84 [0.77, 0.91]), but increased the risk of thyroid cancer (1.58 [1.36, 2.50]). SGLT2i showed the greatest benefits in reducing the risk of HHF (0.68 [0.64, 0.73]) and improving composite renal outcomes (0.67 [0.58, 0.77]), but increased the risk of genital infections (3.11 [2.15, 4.50]). DPP4i were associated with a lower risk of certain psychiatric disorders, Parkinson's disease (0.54 [0.32, 0.92]), and amputation (0.70 [0.86, 0.93]), but an increased risk of neuropathy (1.10 [1.02, 1.18]) and pancreatitis (1.63 [1.40, 1.91]). The weighted origami plot suggested that GLP-1RAs were more suitable for reducing macrovascular and microvascular outcomes, while DPP4i might be better for neurodegenerative diseases and cancer concerns. Given the distinct benefit-risk profiles, the selection of glucose-lowering drugs should be individualized based on patient characteristics and risk factors.

Exploring Drug Repurposing for Interstitial Cystitis/Bladder Pain Syndrome: Defining Novel Therapeutic Targets.

Interstitial cystitis/bladder pain syndrome (IC/BPS) is a debilitating pain condition of unknown etiology. Effective therapies for this condition could not have been developed in the last century. Drug repurposing is a practical strategy for enhancing patient access to successful therapies. It is an approach for discovering novel applications for licensed or investigational pharmaceuticals that extend beyond the initial medical indication. This work aims to identify repurposable medications through bioinformatics to discover potential drugs or compounds that can reverse the IC/BPS disease signature. The analysis involved examining the differentially expressed genes in IC/BPS patients with two distinct disease phenotypes (Hunner's lesion disease, non-Hunner's lesion disease) and controls using the datasets GSE11783, GSE28242, and GSE57560. The goal was to assess the reversal of the disease signature on the L1000CDS2 and cMAP platforms. Twenty-one compounds were repurposed, consisting of 11 small molecules, 10 chemical compounds, 3 natural products, and 6 FDA-approved drugs, currently used for clinical indications such as cancer, myelofibrosis, and diabetes. Bioinformatics can be useful for identifying therapeutic agents for IC/BPS by accessing and processing big data on molecular and cellular levels. Prospective in vivo experiments must validate repurposed drugs. The expansion of large-scale genome sequencing, gene expression studies, and clinical data for IC/BPS will improve successful drug selection.

Optimizing Drug Selection in Children with Multiple Sclerosis: What Do We Know and What Remains Unanswered?

Pediatric-onset multiple sclerosis (POMS) refers to multiple sclerosis with onset before 18 years of age. It is characterized by a more inflammatory course, more frequent clinical relapses, and a greater number of magnetic resonance imaging (MRI) lesions compared with adult-onset MS (AOMS), leading to significant impacts on both disability progression and cognitive outcomes in affected individuals. Managing POMS presents distinct challenges due to the unique needs of pediatric patients and the limited number of disease-modifying therapies (DMTs) approved for pediatric use. Notably, only one therapy (fingolimod) is approved by the United States (US) Food and Drug Administration (FDA) and three (fingolimod, teriflunomide, and dimethyl fumarate) by the European Medicines Agency (EMA) for use in youth with MS. However, observational evidence identifies use of almost all agents off-label in this population. This review provides a comprehensive overview of literature supporting the use of DMTs for POMS, including evidence from observational studies. In this paper, we highlight the shift in clinical practice, which has led to increased use of high-efficacy therapies (HETs) at or near disease onset. We review emerging evidence indicating better cognitive and motor outcomes in this population with early initiation of therapy. Finally, in this paper, we provide a suggested treatment algorithm for managing POMS. We underscore the need for personalized approaches in POMS management. We identify special considerations unique to pediatric care, including attention to family dynamics, and strategies to improve medication adherence and a smooth transition to adult care. Further research on DMTs in POMS is essential to optimize outcomes and improve long-term prognosis.