Pharmacological Treatment Strategies Research Articles

Targeting the microenvironment in the treatment of arteriovenous malformations

Extracranial arteriovenous malformations (AVMs) are regarded as rare diseases and are prone to complications such as pain, bleeding, relentless growth, and high volume of shunted blood. Due to the high vascular pressure endothelial cells of AVMs are exposed to mechanical stress. To control symptoms and lesion growth pharmacological treatment strategies are urgently needed in addition to surgery and interventional radiology. AVM cells were isolated from three patients and exposed to cyclic mechanical stretching for 24 h. Thalidomide and bevacizumab, both VEGF inhibitors, were tested for their ability to prevent the formation of circular networks and proliferation of CD31+ endothelial AVM cells. Furthermore, the effect of thalidomide and bevacizumab on stretched endothelial AVM cells was evaluated. In response to mechanical stress, VEGF gene and protein expression increased in patient AVM endothelial cells. Thalidomide and bevacizumab reduced endothelial AVM cell proliferation. Bevacizumab inhibited circular network formation of endothelial AVM cells and lowered VEGF gene and protein expression, even though the cells were exposed to mechanical stress. With promising in vitro results, bevacizumab was used to treat three patients with unresectable AVMs or to prevent regrowth after incomplete resection. Bevacizumab controlled bleeding, pulsation, and pain over the follow up of eight months with no patient-reported side effects. Overall, mechanical stress increases VEGF expression in the microenvironment of AVM cells. The monoclonal VEGF antibody bevacizumab alleviates this effect, prevents circular network formation and proliferation of AVM endothelial cells in vitro. The clinical application of bevacizumab in AVM treatment demonstrates effective symptom control with no side effects.Graphical abstractMechanical stress increases VEGF expression in endothelial AVM cells, possibly causing the VEGF upregulation in the microenvironment of AVM cells. The resulting RAS/RAF/MEK/ERK signaling in leads to progression of fast-flow malformations. The monoclonal VEGF-A antibody bevacizumab alleviates this effect, prevents circular network formation and proliferation of AVM endothelial cells in vitro. Sporadically occurring slow-flow malformations (LMs, VMs) have mutations in TEK or PIK3CA. TEK encodes the endothelial receptor tyrosine kinase TIE2. Sporadic extracranial fast-flow malformations (AVMs) show mutations in KRAS, BRAF and MAP2K1, which encodes the dual specificity mitogen-activated protein kinase MEK1. Combined targeting of the molecular causes of the disease could be key to achieve symptom control and reduce lesion growth. Orange: gain-of-function; Blue, circled with orange: enhanced signaling.

Etiologies, Mechanisms, Management, and Outcomes of Electrical Storm.

Electrical storm (ES) is characterized by three or more discrete sustained ventricular tachyarrhythmia episodes occurring within a limited time frame (generally ≤ 24 h) or an incessant ventricular tachyarrhythmia lasting > 12 h. In patients with an implantable cardioverterdefibrillator (ICD), ES is defined as three or more appropriate device therapies, separated from each other by at least 5 min, which occur within a 24-h period. ES may constitute a medical emergency, depending on the number arrhythmic episodes, their duration, the type, and the cycle length of the ventricular arrhythmias, as well as the underlying ventricular function. This narrative review was facilitated by a search of MEDLINE to identify peer-reviewed clinical trials, randomized controlled trials, meta-analyses, and other clinically relevant studies. The search was limited to English-language reports published between 1999 and 2023. ES was searched using the terms mechanisms, genetics, channelopathies, management, pharmacological therapy, sedation, neuraxial modulation, cardiac sympathetic denervation, ICDs, and structural heart disease. Google and Google scholar as well as bibliographies of identified articles were reviewed for additional references. This manuscript examines the current strategies available to treat ES and compares pharmacological and invasive treatment strategies to diminish ES recurrence, morbidity, and mortality.

Fractional Flow Reserve–Negative High-Risk Plaques and Clinical Outcomes After Myocardial Infarction

Even after fractional flow reserve (FFR)-guided complete revascularization, patients with myocardial infarction (MI) have high rates of recurrent major adverse cardiovascular events (MACE). These recurrences may be caused by FFR-negative high-risk nonculprit lesions. To assess the association between optical coherence tomography (OCT)-identified high-risk plaques of FFR-negative nonculprit lesions and occurrence of MACE in patients with MI. PECTUS-obs (Identification of Risk Factors for Acute Coronary Events by OCT After STEMI [ST-segment elevation MI] and NSTEMI [non-STEMI] in Patients With Residual Non-flow Limiting Lesions) is an international, multicenter, prospective, observational cohort study. In patients presenting with MI, OCT was performed on all FFR-negative (FFR > 0.80) nonculprit lesions. A high-risk plaque was defined containing at least 2 of the following prespecified criteria: (1) a lipid arc at least 90°, (2) a fibrous cap thickness less than 65 μm, and (3) either plaque rupture or thrombus presence. Patients were enrolled from December 14, 2018, to September 15, 2020. Data were analyzed from December 2, 2022, to June 28, 2023. The primary end point of MACE, a composite of all-cause mortality, nonfatal MI, or unplanned revascularization, at 2-year follow-up was compared in patients with and without a high-risk plaque. A total of 438 patients were enrolled, and OCT findings were analyzable in 420. Among included patients, mean (SD) age was 63 (10) years, 340 (81.0) were men, and STEMI and non-STEMI were equally represented (217 [51.7%] and 203 [48.3%]). A mean (SD) of 1.17 (0.42) nonculprit lesions per patient was imaged. Analysis of OCT images revealed at least 1 high-risk plaque in 143 patients (34.0%). The primary end point occurred in 22 patients (15.4%) with a high-risk plaque and 23 of 277 patients (8.3%) without a high-risk plaque (hazard ratio, 1.93 [95% CI, 1.08-3.47]; P = .02), primarily driven by more unplanned revascularizations in patients with a high-risk plaque (14 of 143 [9.8%] vs 12 of 277 [4.3%]; P = .02). Among patients with MI and FFR-negative nonculprit lesions, the presence of a high-risk plaque is associated with a worse clinical outcome, which is mainly driven by a higher number of unplanned revascularizations. In a population with a high recurrent event rate despite physiology-guided complete revascularization, these results call for research on additional pharmacological or focal treatment strategies in patients harboring high-risk plaques.

Principles of pharmacological therapy of comorbid diseases in patients with orthopedic pathology

Comorbidity is one of the leading problems in clinical practice. Interaction of diseases, involutive processes of natural aging and pathomorphosis of drugs significantly change clinical picture and course of the disease, the nature and severity of complications, limit or complicate the treatment and diagnostic process. Objective. To analyze current information on available recommendations for the treatment of comorbid diseases in patients with orthopedic pathology. Materials. An overview of the recommendations of the European Society of Cardiology, European Society of Hypertension, European Society for Vascular Surgery, Ukrainian Gastroenterological Association and American Diabetes Association for the period 2017–2019 is presented. Results. The first stage in the treatment of arterial hypertension is the lifestyle optimization, and the initial therapy of most patients with hypertension should be a combination of two drugs. Management of patients with lower extremity artery disease is associated with an increased risk of any cardiovascular events. Therefore, preventive measures are of particular importance. Gastropathies induced by non-steroidal anti-inflammatory drugs are widespread in orthopedic practice. In the prevention of their occurrence, a well-chosen gastroprotective therapy is important. Once the diagnosis of diabetes is made, lifestyle modification should be started immediately along with the start of pharmacotherapy. Metformin remains the first-line drug for treatment, drugs of other groups can be prescribed when there are contraindications to metformin. In the treatment of neuropathic pain in diabetes or pre-diabetes, only pharmacological treatment strategies are effective. Conclusions. In most cases, a number of comorbidities with timely diagnosis and compliance with the algorithms of medical care can be corrected and treated. Properly selected conservative therapy can reduce the risk of peri- and postoperative complications.

Lessons from a multicenter, international, large sample size analysis of patients with obsessive-compulsive disorders: an overview of the ICOCS Snapshot studies.

Obsessive-compulsive disorder (OCD) is a prevalent and highly disabling condition, characterized by a range of phenotypic expressions, potentially associated with geo-cultural differences. This article aims to provide an overview of the published studies by the International College of Obsessive-Compulsive Spectrum Disorders, in relation to the Snapshot database which has, over the past 10years, gathered clinical naturalistic data from over 500 patients with OCD attending various research centers/clinics worldwide. This collaborative effort has provided a multi-cultural worldwide perspective of different socio-demographic and clinical features of patients with OCD. Data on age, gender, smoking habits, age at onset, duration of illness, comorbidity, suicidal behaviors, and pharmacological treatment strategies are presented here, showing peculiar differences across countries.

A Standard Practice Protocol for Addressing Depression in a Hospice Setting.

Depression can worsen physical suffering and psychiatric distresses in individuals with life-limiting illnesses and is associated with increased rates of pain, fatigue, dyspnea, and worse survival outcomes. Evidence supports protocol development to address depression in the hospice setting using validated screening tools and a process for referral and treatment. After protocol development and integration of validated screening tools into the electronic medical record, newly admitted patients meeting inclusion criteria were screened during the social workers' initial psychosocial assessment. Patients were referred for pharmacological and nonpharmacological treatment strategies based on the severity of depression detailed in the protocol. Of all patients who met inclusion criteria, 100% were screened using the Patient Health Questionnaire-2 with 52% being identified as having some severity of depression, 26% being appropriately referred for treatment, and 50% receiving a pharmacological strategy, whereas 26% received nonpharmacological strategies. There was a statistically significant difference in severity of depression found between those identified as having a depressed mood preintervention and those with some severity of depression using a validated screening tool postintervention. Implementing a standardized practice protocol to address depression in a hospice setting allowed for consistent evaluation through the use of validated screening tool(s) and increased recognition of those with symptoms of depression.

A Pilot Study for Effectiveness of Non-Pharmacological versus Pharmacological Treatment Strategies for Lumbar Disc Herniation: A Pragmatic Randomized Controlled Trial.

We aimed to compare the efficacy, safety, and cost-effectiveness of non-pharmacological- and pharmacological treatment strategies for Lumbar disc herniation (LDH) in pragmatic clinical settings. This study was a pilot, two-armed, parallel pragmatic randomized controlled trial. Thirty patients aged 19-70 years with a numeric rating scale (NRS) score ≥5 for sciatica and confirmed LDH on magnetic resonance imaging (MRI) were included. Participants were assigned in a 1:1 ratio to non-pharmacological (non-Phm) or pharmacological (Phm) treatment group. They were treated for 8 weeks and a total follow-up period was 26 weeks after randomization. Non-Phm treatment included acupuncture, spinal manual therapy, etc., Phm included medication, injection, nerve block, etc., The primary outcome was a numeric rating scale (NRS) of radiating leg pain. NRS for low back pain, Oswestry disability index, visual analog scale, Fear-Avoidance Beliefs Questionnaire, patient global impression of change, Short Form-12 Health Survey, version 2, 5-level European Quality of Life-5 dimensions (EQ-5D) were also measured. Linear mixed model was used to evaluated the difference in change of outcomes from baseline between two groups. An economic evaluation was conducted using incremental cost-effectiveness ratios. There was no significant difference between the two groups in the intervention period, but non-Phm group showed significantly greater degree of improvement in follow-up of Week 14. Difference in the NRS for sciatica and ODI were 1.65 (95% CI 0.59 to 2.71, p=0.003) and 8.67 (95% CI 1.37 to 15.98, p=0.21), respectively in Week 14. The quality-adjusted life year (QALY) value calculated by EQ-5D and Short Form-6 Dimension were 0.006 (95% CI -0.012 to 0.024, p=0.472) and 0.015 (95% CI -0.008 to 0.038, p=0.195) higher in non-Phm group than in Phm group. The cost was lower in non-Phm group than in Phm group (Difference: -682, 95% CI -3349 to 1699, p=0.563). We confirmed that the non-Phm treatment could be more cost-effective treatments than Phm treatments and feasibility of a large-scale of main study in future.

In vitro and in vivo Efficacies of Novel Harmine Derivatives in the Treatment of Cystic Echinococcosis.

Cystic echinococcosis (CE) is a chronic zoonotic parasitic disease caused by the larvae of the Echinococcus granulosus sensu lato (s.l.) cluster. The current existing drugs have limited therapeutic efficacy against cystic echinococcosis, and thus, there is an urgent need to develop new drugs. In this study, 7 harmine (HM) derivatives were screened and the effects of HM derivatives on E. granulosus sensu stricto (s.s.) were evaluated by in vitro and mouse experiments. The safety of the HM derivatives was assessed by cytotoxicity assays, acute toxicity study in animals and subacute toxicity study. These results show that the HM derivatives H-2-168 and DH-004 exhibited more significant antiparasitic effects at an initial concentration of 40 μM. The results of further studies showed that H-2-168 and DH-004 had dose-dependent effects against protoscoleces and had satisfactory therapeutic outcomes in vivo. Electron microscopy observations demonstrated that H-2-168 and DH-004 caused severe disruption of the parasite ultrastructure. Notably, the results of the acute toxicity and subchronic toxicity studies showed that H-2-168 and DH-004 had significantly improved safety. In addition, we found that H-2-168 and DH-004 induced DNA damage in E. granulosus s.s., which may be the mechanism by which these drugs produce their therapeutic effects. Overall, the data from this work demonstrate that H-2-168 and DH-004 are highly effective candidate compounds with low toxicity for the treatment of CE and will provide a new therapeutic strategy for CE pharmacological treatment.

Dose imbalance of DYRK1A kinase causes systemic progeroid status in Down syndrome by increasing the un-repaired DNA damage and reducing LaminB1 levels.

People with Down syndrome (DS) show clinical signs of accelerated ageing. Causative mechanisms remain unknown and hypotheses range from the (essentially untreatable) amplified-chromosomal-instability explanation, to potential actions of individual supernumerary chromosome-21 genes. The latter explanation could open a route to therapeutic amelioration if the specific over-acting genes could be identified and their action toned-down. Biological age was estimated through patterns of sugar molecules attached to plasma immunoglobulin-G (IgG-glycans, an established "biological-ageing-clock") in n=246 individuals with DS from three European populations, clinically characterised for the presence of co-morbidities, and compared to n=256 age-, sex- and demography-matched healthy controls. Isogenic human induced pluripotent stem cell (hiPSCs) models of full and partial trisomy-21 with CRISPR-Cas9 gene editing and two kinase inhibitors were studied prior and after differentiation to cerebral organoids. Biological age in adults with DS is (on average) 18.4-19.1 years older than in chronological-age-matched controls independent of co-morbidities, and this shift remains constant throughout lifespan. Changes are detectable from early childhood, and do not require a supernumerary chromosome, but are seen in segmental duplication of only 31 genes, along with increased DNA damage and decreased levels of LaminB1 in nucleated blood cells. We demonstrate that these cell-autonomous phenotypes can be gene-dose-modelled and pharmacologically corrected in hiPSCs and derived cerebral organoids. Using isogenic hiPSC models we show that chromosome-21 gene DYRK1A overdose is sufficient and necessary to cause excess unrepaired DNA damage. Explanation of hitherto observed accelerated ageing in DS as a developmental progeroid syndrome driven by DYRK1A overdose provides a target for early pharmacological preventative intervention strategies. Main funding came from the "Research Cooperability" Program of the Croatian Science Foundation funded by the European Union from the European Social Fund under the Operational Programme Efficient Human Resources 2014-2020, Project PZS-2019-02-4277, and the Wellcome Trust Grants 098330/Z/12/Z and 217199/Z/19/Z (UK). All other funding is described in details in the "Acknowledgements".

Obesity prevalence factors associated with sympathetic overactivity and hypertension

AbstractBackgroundObesity is the most significant worldwide public health problem and is integrally related to negative cardiovascular disease and hypertension results. The association between obesity and overweight elevated blood pressure is well known, and so it is calculated that 65%–78% of primary hypertension cases are accounted for by obesity.AimThis study aims to focus on whether obesity prevalence factors are associated with sympathetic overactivity and hypertension.MethodsThe pathways by which hypertension is induced by obesity are complicated and involve overactivation of the sympathetic nervous system (SNS), enhancement of the renin‐angiotensin‐aldosterone system (RAAS), modifications in cytokines produced from adipose, tolerance to insulin, and structural and functional renal changes.ResultsObesity induces the activation of mineralocorticoid receptors independently of aldosterone or angiotensin II (ANG II). The SNS activation mechanism in obesity has not been completely elucidated; however, leptin and activation of the melanocortin brain system may be needed. Obesity‐associated hypertension becomes much more challenging to handle with continuous obesity, and the progression of target organ injury, especially renal injury, multiple antihypertensive medications, and other medical conditions, such as dyslipidemia, insulin resistance, diabetes mellitus, and inflammation, are also needed.ConclusionThis review aimed to address the consequences of obesity and SNS function, risk factors, the impact of obesity, pharmacological treatment strategies for managing, and recommended exercise and diet.

Exacerbations of COPD.

COPD exacerbations are associated with significant morbidity, mortality, and increased health care expenditures. The recently published Global Initiative for Chronic Obstructive Lung Disease (GOLD) recommendations have further refined the definition of an exacerbation. A better understanding of the risk factors associated with the development of an exacerbation exists, and improvements are being made in earlier detection approaches. Pharmacologic treatment strategies have been the cornerstone of effective therapy. In addition, both pharmacologic and non-pharmacologic strategies have been proven successful in the prevention of future exacerbations. Newer technologies, including the use of artificial intelligence and wearable monitoring devices, are now being used to help in the earlier detection of exacerbations. Such preventive and earlier detection strategies can help to develop a more personalized care model and improve outcomes for patients with COPD.

Human and porcine aortic valve endothelial and interstitial cell isolation and characterization.

Calcific aortic valve stenosis (AVS) is defined by pathological changes in the aortic valve (AV) and their predominant cell types: valvular interstitial (VICs) and endothelial cells (VECs). Understanding the cellular and molecular mechanisms of this disease is a prerequisite to identify potential pharmacological treatment strategies. In this study, we present a unique aortic valve cell isolation technique to acquire specific human and porcine cell populations and compared VICs and VECs of these species with each other for the first time. AV cells were isolated from tissue obtained from human patients undergoing surgical aortic valve replacement (SAVR) or from porcine hearts. Functional analysis and in vitro experiments revealed that endothelial-to-mesenchymal transition (EndMT) can be induced in hVECs, leading to a significant increase in mesenchymal markers. In vitro calcification experiments of VICs demonstrated pronounced expression of calcification markers and visible calcific deposits in Alizarin Red staining in both species after incubation with pro-calcific media. Cells isolated from patient-derived AVs showed mesenchymal and endothelial-specific gene signatures (VIC and VEC, respectively). For instance, von Willebrand factor (vWF) and platelet endothelial adhesion molecule-1 (PECAM1) were upregulated in VECs, while the myofibroblastic markers alpha-smooth muscle actin (α-SMA) and vimentin (VIM) were downregulated in VECs compared to VICs. Analysis of cell function by migration revealed that VECs are more migratory than VICs. Induction of EndMT in vitro in VECs displayed increased expression of EndMT markers and decreased expression of endothelial markers, confirming their mesenchymal transdifferentiation ability. In vitro calcification of VICs revealed upregulation of alkaline phosphatase (ALPL), a hallmark of calcification. In addition, other calcification-related genes such as osteocalcin (BGLAP) and runt-related factor 2 (RUNX2) were upregulated. Alizarin red staining of calcified cells provided a further layer of confirmation that the isolated cells were VICs with osteoblastic differentiation capacity. This study aims to take a first step towards standardizing a reproducible isolation technique for specific human and porcine VEC and VIC populations. A comparison of human and porcine aortic valve cells demonstrated that porcine cells may serve as an alternative cellular model system in settings where human tissue is difficult to obtain.

Serum Metabolite Biomarkers for Pancreatic Tumors: Neuroendocrine and Pancreatic Ductal Adenocarcinomas-A Preliminary Study.

Pancreatic cancer is the most common pancreatic solid malignancy with an aggressive clinical course and low survival rate. There are a limited number of reliable prognostic biomarkers and a need to understand the pathogenesis of pancreatic tumors; neuroendocrine (PNET) and pancreatic ductal adenocarcinomas (PDAC) encouraged us to analyze the serum metabolome of pancreatic tumors and disturbances in the metabolism of PDAC and PNET. Using the AbsoluteIDQ® p180 kit (Biocrates Life Sciences AG, Innsbruck, Austria) with liquid chromatography-mass spectrometry (LC-MS), we identified changes in metabolite profiles and disrupted metabolic pathways serum of NET and PDAC patients. The concentration of six metabolites showed statistically significant differences between the control group and PDAC patients (p.adj < 0.05). Glutamine (Gln), acetylcarnitine (C2), and citrulline (Cit) presented a lower concentration in the serum of PDAC patients, while phosphatidylcholine aa C32:0 (PC aa C32:0), sphingomyelin C26:1 (SM C26:1), and glutamic acid (Glu) achieved higher concentrations compared to serum samples from healthy individuals. Five of the tested metabolites: C2 (FC = 8.67), and serotonin (FC = 2.68) reached higher concentration values in the PNET serum samples compared to PDAC, while phosphatidylcholine aa C34:1 (PC aa C34:1) (FC = -1.46 (0.68)) had a higher concentration in the PDAC samples. The area under the curves (AUC) of the receiver operating characteristic (ROC) curves presented diagnostic power to discriminate pancreatic tumor patients, which were highest for acylcarnitines: C2 with AUC = 0.93, serotonin with AUC = 0.85, and PC aa C34:1 with AUC = 0.86. The observations presented provide better insight into the metabolism of pancreatic tumors, and improve the diagnosis and classification of tumors. Serum-circulating metabolites can be easily monitored without invasive procedures and show the present clinical patients' condition, helping with pharmacological treatment or dietary strategies.

Hypermobility spectrum disorders and active migraine in Israeli adolescents: A nationwide study.

To assess the association between hypermobility spectrum disorders/hypermobile type Ehlers Danlos Syndrome (HSD/hEDS) and migraine in a national sample of adolescents in Israel. The association between HSD/hEDS and migraine is unclear, even more so in pediatric populations. This population-based, cross-sectional study included 1,627,345 Israeli adolescents (945,519/1,626,407 [58%] males; mean age 17 ± 0.5 years) who were medically assessed before mandatory military service during 1998-2020. Diagnoses of migraine with at least one attack per month (active migraine) and HSD/hEDS were confirmed by certified specialists. The prevalences of active migraine in adolescents with and without HSD/hEDS were computed and the association between HSD/hEDS and active migraine was examined. Active migraine was significantly more prevalent in adolescents with HSD/hEDS (307/4686 [6.5%]) compared to those without HSD/hEDS (51,931/1,621,721 [3.2%]) (OR = 2.16, 95% CI 1.90-2.45). The association between HSD/hEDS and active migraine persisted in a multivariable analysis (OR = 2.08, 95% CI 1.85-2.34) and in several sensitivity analyses. We found a significant association between HSD/hEDS and active migraine in both male and female adolescents. Clinical awareness of the association can promote early diagnosis and treatment of migraine. Further research is required to identify appropriate pharmacologic and nonpharmacologic migraine treatment strategies for individuals with HSD/hEDS.

Extracorporeal membrane oxygenation (ECMO) and beyond in near fatal asthma: A comprehensive review

The treatment of choice in severe asthma exacerbations with respiratory failure includes ventilatory support, both invasive and/or non-invasive, along with different kinds of asthma medication. Of note, the rate of mortality of patients with asthma has decreased substantially in recent years mainly due to significant advances in pharmacological treatment and other management strategies. However, the risk of death in patients with severe asthma who require invasive mechanical ventilation has been estimated between 6.5% and 10.3%. When conventional measures fail, rescue strategies, such as extracorporeal membrane oxygenation (ECMO) or extracorporeal CO2 removal (ECCO2R) may need to be implemented. While ECMO does not constitute a definitive treatment per se, it can minimize further ventilator associated lung injury (VALI) and can enable diagnostic-therapeutic maneuvers that cannot be performed without ECMO such as bronchoscopy and transfer for diagnostic imaging. Asthma is one of the diseases that is associated with excellent outcomes for patients with refractory respiratory failure requiring ECMO support, as shown by the Extracorporeal Life Support Organization (ELSO) registry. Moreover, in such situations, the use of ECCO2R for rescue has been described and utilized in both children and adults and is more widely spread in different hospitals than ECMO. In this article, we aim to review the evidence for the usefulness of extracorporeal respiratory support measures in the management of severe asthma exacerbations that lead to respiratory failure.

Mitigating long-term and delayed adverse events associated with cancer treatment: implications for survivorship.

Despite the importance of chemotherapy-associated adverse events in oncology practice and the broad range of interventions available to mitigate them, limited systematic efforts have been made to identify, critically appraise and summarize the totality of evidence on the effectiveness of these interventions. Herein, we review the most common long-term (continued beyond treatment) and lateor delayed (following treatment) adverse events associated with chemotherapy and other anticancer treatments that pose major threats in terms of survival, quality of life and continuation of optimal therapy. These adverse effects often emerge during and continue beyond the course of therapy or arise among survivors in the months and years following treatment. For each of these adverse effects, we discuss and critically evaluate their underlying biological mechanisms, the most commonly used pharmacological and non-pharmacological treatment strategies, and evidence-based clinical practice guidelines for their appropriate management. Furthermore, we discuss risk factors and validated risk-assessment tools for identifying patients most likely to be harmedby chemotherapy and potentially benefit from effective interventions. Finally, we highlight promising emerging supportive-care opportunities for the ever-increasing number of cancer survivors at continuing risk of adverse treatment effects.

Mangiferin Protects DNase 2 Abundance via Nrf2 Activation to Prevent Cytosolic mtDNA Accumulation during Liver Injury.

Mitochondrial DNA (mtDNA) released into the cytosol serves as a member of damage-associated molecular patterns to initiate inflammatory responses. Mangiferin is a xanthonoid derivative, usually isolated from plants including mangoes and iris unguicularis. This study aims to investigate whether mangiferin prevents mtDNA accumulation in the cytosol with a focus on deoxyribonuclease 2 (DNase 2) protection from oxidative damage. Mangiferin administration effectively protects against hepatotoxicity in mice subjected to CCl4 challenge or bile duct ligation (BDL) surgery. Moreover, mangiferin activates nuclear factor erythroid 2-related factor (Nrf2)-antioxidant signaling, reduces cytosolic mtDNA accumulation, and suppresses Toll-like receptor 9 (TLR-9)/myeloid differentiation factor 88 (MyD88)-dependent inflammation in the liver. The study prepares hepatic mtDNA to stimulate hepatocytes, and finds that mangiferin protects DNase 2 protein abundance. mtDNA induces reactive oxygen species (ROS) production to promote DNase 2 protein degradation through oxidative modification, but mangiferin protects DNase 2 protein stability in a Nrf2-dependent manner. In hepatic Nrf2 deficiency mice, the study further confirms that Nrf2 induction is required for mangiferin to clear cytosolic mtDNA and block mtDNA-mediated TLR9/MyD88/nuclear factor kappa-B (NF-κB) inflammatory signaling cascades. These findings provide new insights into the role of mangiferin as a liver protecting agent, and suggest protection of DNase 2 as a novel therapeutic strategy for pharmacological intervention to prevent liver damage.

Identifying hormones and other perioperative risk factors for postoperative delirium after endoscope-assisted transsphenoidal pituitary adenoma resection: A retrospective, matched cohort study.

As a complex and acute brain dysfunction, if postoperative delirium (POD) occurs in the postoperative period, it will lead to a prolonged length of stay in the critical care unit, with increased hospitalization costs and higher mortality. A few case reports inspired us to pay close attention to pituitary tumor-associated delirium. We hypothesized that the changes in hormone levels after pituitary tumor resection might be associated with POD occurrence. Retrospective analysis was performed on data from a single-center cohort study conducted at Southwest Hospital between January 2018 and May 2022. A total of 360 patients with pituitary tumors who underwent endoscope-assisted transsphenoidal pituitary tumor resection were divided into two groups at a 1:3 ratio, with 36 patients in the POD group and 108 patients in the non-POD group matched by propensity score, age, sex, and tumor size. Basic characteristics, pituitary adenoma features, endocrine levels and other biochemical indicators, and Confusion Assessment Method for the Intensive Care Unit (CAM-ICU) for postoperative delirium were documented for further analysis. Lower insulin-like growth factor-1 (IGF-1, p=.024) and corticotropin-releasing hormone (CRH, p=.005) levels were closely associated with postoperative delirium and with high levels of blood glucose (GLU, p=.023) after surgery. Subsequent analysis indicated that serum potassium (OR: 0.311, 95% CI 0.103-0.935), sodium (OR: 0.991, 95% CI 0.983-1.000), CRH (OR: 0.964, 95% CI 0.936-0.994), and GLU (OR: 1.654, 95% CI 1.137-2.406) levels in the perioperative period were independent risk factors for delirium. Our study indicated that lower serum CRH, potassium, sodium, and GLU levels may be associated with the occurrence of POD after endoscopic-assisted transsphenoidal surgery. These data provide preliminary evidence for the management of POD in pituitary adenoma patients after surgery. Further studies are needed to identify pharmacological and nonpharmacological multicomponent treatment strategies.

TReating Incontinence for Underlying Mental and Physical Health (TRIUMPH): a study protocol for a multicenter, double-blinded, randomized, 3-arm trial to evaluate the multisystem effects of pharmacologic treatment strategies for urgency-predominant urinary incontinence in ambulatory older women

BackgroundUrgency-type urinary incontinence affects one in four older community-dwelling women and overlaps with other common aging-associated health syndromes such as cognitive impairment, physical mobility impairment, and depression. Observational studies have raised concern about potentially higher rates of delirium and dementia in older adults taking anticholinergic bladder medications, but few prospective data are available to evaluate the effects of these and other pharmacologic treatments for urgency incontinence on cognition and other multisystem functional domains important to older women.MethodsThe TRIUMPH study is a randomized, double-blinded, 3-arm, parallel-group trial comparing the multisystem effects of anticholinergic versus beta-3-adrenergic agonist bladder therapy and versus no active bladder anti-spasmodic pharmacotherapy in older women with urgency incontinence. Women aged 60 years and older (target N = 270) who have chronic urgency-predominant urinary incontinence and either normal or mildly impaired cognition at baseline are recruited from the community by investigators based in northern California, USA. Participants are randomized in equal ratios to take identically encapsulated oral anticholinergic bladder therapy (in the form of tolterodine 2 mg extended release [ER]), oral beta-3 adrenergic agonist bladder therapy (mirabegron 25 mg ER), or placebo daily for 24 weeks, with the option of participant-directed dose titration (to tolterodine 4 mg ER, mirabegron 50 mg ER, or matching placebo daily). Participants also receive patient-oriented information and instructions about practicing first-line behavioral management strategies for incontinence. The primary outcome is change in composite cognitive function over 24 weeks assessed by a comprehensive battery of cognitive tests, with a secondary exploration of the persistence of change at 36 weeks. Secondary outcomes include changes over 24 and 36 weeks in domain-specific cognitive function; frequency, severity, and impact of urgency-associated urinary symptoms; physical function and balance; sleep quality and daytime sleepiness; psychological function; and bowel function.DiscussionThe TRIUMPH trial addresses the need for rigorous evidence to guide counseling and decision-making for older women who are weighing the potential multisystem benefits and risks of pharmacologic treatments for urgency incontinence in order to preserve their day-to-day functioning, quality of life, and independence in older age.Trial registrationClinicalTrials.gov NCT05362292. Registered on May 5, 2022.

Kidney stones, hypercalciuria, and recent insights into proximal tubule calcium reabsorption.

Most kidney stones are composed of calcium, and the greatest risk factor for kidney stone formation is hypercalciuria. Patients who form kidney stones often have reduced calcium reabsorption from the proximal tubule, and increasing this reabsorption is a goal of some dietary and pharmacological treatment strategies to prevent kidney stone recurrence. However, until recently, little was known about the molecular mechanism that mediates calcium reabsorption from the proximal tubule. This review summarizes newly uncovered key insights and discusses how they may inform the treatment of kidney stone formers. Studies examining claudin-2 and claudin-12 single and double knockout mice, combined with cell culture models, support complementary independent roles for these tight junction proteins in contributing paracellular calcium permeability to the proximal tubule. Moreover, a family with a coding variation in claudin-2 causing hypercalciuria and kidney stones have been reported, and reanalysis of Genome Wide Association Study (GWAS) data demonstrates an association between noncoding variations in CLDN2 and kidney stone formation. The current work begins to delineate the molecular mechanisms whereby calcium is reabsorbed from the proximal tubule and suggests a role for altered claudin-2 mediated calcium reabsorption in the pathogenesis of hypercalciuria and kidney stone formation.