The effect of genetic polymorphisms in STIM1 and ORAI1 on erythropoietin resistance in Egyptian patients with end-stage renal disease.

Chronic renal failure (CRF) is an incurable disease with unique challenges. Anemia is a frequent complication affecting dialysis patients. Erythropoietin (EPO) is used to treat anemia, but a poor response may result. We investigated genetic polymorphisms of store-operated calcium channel (SOC) signaling, an important erythropoietin-activated pathway that may induce EPO resistance in patients with renal failure. A total of 108 end stage renal disease (ESRD) patients were selected for this study. Patients were divided into two groups according to their erythropoietin resistance index (ERI): 39 patients with an ERI>10 and 69 patients with an ERI<10. We selected four tagging single nucleotide polymorphisms (tSNPs) in STIM1 and five in ORAI1 in our study. A polymerase chain reaction was performed, and genotyping against EPO resistance was correlated. Patients with the AG genotype of rs1561876 in STIM1, the TC genotype of rs6486795 in ORAI1, and the TG or GG genotypes of rs12320939 in ORAI1 were associated with an increased risk of erythropoietin resistance. Overall, we reported a moderately significant relationship between genetic polymorphisms of STIM1 and EPO resistance. We also reported a highly significant relationship between genetic polymorphisms of ORAI1 and EPO resistance. The (A-A-G) haplotype of STIM1 and the (G-T-G-T-A, G-C-G-C-G, or G-T-T-C-G) haplotypes of ORAI1 were significantly associated with EPO resistance.

Clinical and cost-effectiveness of clopidogrel resistance genotype testing after ischaemic stroke or transient ischaemic attack: a systematic review and economic model.

Background: Stroke or transient ischaemic attack patients are at increased risk of secondary vascular events. Antiplatelet medications, most commonly clopidogrel, are prescribed to reduce this risk. Factors including CYP2C19 genetic variants can hinder clopidogrel metabolism. Laboratory-based or point-of-care tests can detect these variants, enabling targeted treatment. Objective: To assess the effectiveness of genetic testing to identify clopidogrel resistance in people with ischaemic stroke or transient ischaemic attack. Specific objectives: Do people tested for clopidogrel resistance, and treated accordingly, have a reduced risk of secondary vascular events? Do people with loss-of-function alleles associated with clopidogrel resistance have a reduced risk of secondary vascular events if treated with alternative interventions compared to clopidogrel? Do people with loss-of-function alleles associated with clopidogrel resistance have an increased risk of secondary vascular events when treated with clopidogrel? What is the accuracy of point-of-care tests for detecting variants associated with clopidogrel resistance? What is the technical performance and cost of CYP2C19 genetic tests? Is genetic testing for clopidogrel resistance cost-effective compared with no testing? Design: Systematic review and economic model. Results: Objective 1: Two studies assessed secondary vascular events in patients tested for loss-of-function alleles and treated accordingly. They found a reduced risk, but confidence intervals were wide (hazard ratio 0.50, 95% confidence interval 0.09 to 2.74 and hazard ratio 0.53, 95% confidence interval 0.24 to 1.18). Objective 2: Seven randomised controlled trials compared clopidogrel with alternative treatment in people with genetic variants. Ticagrelor was associated with a lower risk of secondary vascular events than clopidogrel (summary hazard ratio 0.76, 95% confidence interval 0.65 to 0.90; two studies). Objective 3: Twenty-five studies compared outcomes in people with and without genetic variants treated with clopidogrel. People with genetic variants were at an increased risk of secondary vascular events (hazard ratio 1.72, 95% confidence interval 1.43 to 2.08; 18 studies). There was no difference in bleeding risk (hazard ratio 0.98, 95% confidence interval 0.68 to 1.40; five studies). Objective 4: Eleven studies evaluated Genomadix Cube accuracy; no studies evaluated Genedrive. Summary sensitivity and specificity against laboratory reference standards were both 100% (95% confidence interval 94% to 100% and 99% to 100%). Objective 5: Seventeen studies evaluated technical performance of point-of-care tests. Test failure rate ranged from 0.4% to 19% for Genomadix Cube. A survey of 8/10 genomic laboratory hubs revealed variation in preferred technologies for testing, and cost per test ranging from £15 to £250. Most laboratories expected test failure rate to be < 1%. Additional resources could enhance testing capacity and expedite turnaround times. Objective 6: Laboratory and point-of-care CYP2C19 testing strategies were cost-saving and increase quality-adjusted life-years compared with no testing. Both strategies gave similar costs, quality-adjusted life-years and expected net monetary benefit. Conclusions: Our results suggest that CYP2C19 testing followed by tailored treatment is likely to be effective and cost-effective in both populations. Future work: Accuracy and technical performance of Genedrive. Test failure rate of Genomadix Cube in a National Health Service setting. Value of testing additional loss-of-function alleles. Appropriateness of treatment dichotomy based on loss-of-function alleles. Limitations: Lack of data on Genedrive. No randomised 'test-and-treat' studies of dipyramidole plus aspirin. Study registration: This study is registered as PROSPERO CRD42022357661. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR135620) and is published in full in Health Technology Assessment; Vol. 28, No. 57. See the NIHR Funding and Awards website for further award information.

The most common type of stroke occurs when the supply of blood to the brain is cut off. Symptoms of stroke happen suddenly and vary depending on which part of the brain is affected. They usually include problems with movement, speech, vision and the face drooping on one side. A 'transient ischaemic attack' is a milder related condition. There are around 100,000 strokes and 60,000 transient ischaemic attacks every year in the UK. People who have a stroke or transient ischaemic attack are at greater risk of having another stroke. To reduce the chances of this happening, doctors will often prescribe medication. The most common medication used is called 'clopidogrel'. However, clopidogrel does not work for everyone. One reason for this is having specific variations of a gene called the CYP2C19 gene. Around one in three people in the UK have this variation. We wanted to know whether introducing genetic testing to identify variations in the CYP2C19 gene for people who have had a stroke or transient ischaemic attack can help doctors prescribe a treatment that will work for them, reducing the risk of having another stroke. We also wanted to know if doing this test would be a good use of NHS money. Doing a genetic test to identify variations in the CYP2C19 gene, and prescribing an alternative medication for people with these variations, may reduce the chances of having a new stroke. It is likely that a genetic test for variations of the CYP2C19 gene would represent value for money for the NHS.

Identification and CRISPR-Cas9 validation of a novel ß-adrenergic-like octopamine receptor mutation associated with amitraz resistance in Varroa destructor.

Varroa destructor is widely recognized as a significant contributor to colony collapse disorder. Chemical acaricides, such as amitraz, have been extensively used for Varroa control due to their selectivity within beehives. However, the increasing number of cases of amitraz resistance across global V. destructor populations poses a significant challenge. In this study, we conducted a comprehensive molecular screening of the ß-adrenergic-like octopamine receptor (Octß2R), the target-site of amitraz, across 66 Turkish and 63 Belgian V. destructor populations. Although previously reported amitraz resistance mutations were not detected, the screening revealed a novel Y337F mutation located within transmembrane 7 (TM7) of Octß2R in Turkish Varroa populations. Notably, this mutation was identified in the last residue of the highly conserved NPxxY motif associated with the activation of G-protein coupled receptors (GPCR). Among the 66 Varroa samples from Türkiye, twenty harbored the Y337F mutation, with eight samples exhibiting fixation of the mutation. Subsequent bioassays revealed over 8-fold resistance to amitraz in populations that contain the Y337F mutation. Genotyping of mites after exposure to 10 mg a.i./l amitraz demonstrated that all surviving mites were homozygous for the Y337F mutation, whereas dead mites carried susceptible alleles, providing genetic linkage between mutation and phenotype. Further, we used CRISPR-Cas9 editing to introduce the Y337F mutation in the orthologous Octß2R of the model organism Tetranychus urticae. Crispants exhibited over threefold resistance to amitraz. In conclusion, this study identified and validated a novel amitraz resistance mutation. Additional research is required to further evaluate the phenotypic strength of Y337F in the context of operational resistance with current treatment strategies.

Functional analysis of novel cystatins from Haemaphysalis doenitzi and evaluation of their roles in cypermethrin and λ-cyhalothrin resistance.

Currently, the primary strategy for tick control relies on chemical agents. Pyrethrins, which are botanically derived compounds, have demonstrated efficacy in controlling ticks without posing a risk to human or animal health. However, research into pyrethrins' metabolic mechanisms remains sparse. Cystatin, as a reversible binding inhibitor of cysteine protease, may be involved in the initiation of pyrethrin detoxification of Haemaphysalis doenitzi. In this study, two novel cystatins were cloned, HDcyst-3 and HDcyst-4, the relative expression of which was highest in the Malpighian tubules compared with the tick midguts, salivary glands, and ovaries. Prokaryotic expression and in vitro studies revealed that cystatins effectively inhibit the enzymatic activities of cathepsins B and S. RNAi results showed that the reduction of cystatins significantly decreased the engorgement weight, egg mass weight, and egg hatching rate of adult female ticks, and prolonged feeding time by two days. The control rate of rHDcyst-3 and rHDcyst-4 protein vaccination against female adults were 55.9% and 63.2%, respectively. In addition, the tick immersion test showed that cypermethrin and λ-cyhalothrin had significant acaricidal effects against adult unfed H. doenitzi. The qPCR result indicated that compared with the control group, the expression of HDcyst-3 and HDcyst-4 was markedly decreased in the sublethal cypermethrin and λ-cyhalothrin group at LC50. Enzyme activity showed that cypermethrin and λ-cyhalothrin could significantly induce the activities of glutathione S-transferase (GST), carboxylesterase (CarE), and acetylcholinesterase (AchE). The aforementioned results provided indirect evidence that cystatin plays an important role in pyrethrin detoxification and provides a theoretical basis for future acaricide experiments and pest management.

Genotype-driven therapeutics in DEE and metabolic epilepsy: navigating treatment efficacy and drug resistance.

Neonatal intensive care unit (NICU), particularly in treating developmental and epileptic encephalopathy (DEE) and metabolic epilepsy (ME), requires a deep understanding of their complex etiologies and treatment responses. After excluding treatable cases such as infectious or autoimmune encephalitis, our focus shifted to a more challenging subgroup of 59 patients for in-depth genetic analysis using exome sequencing (ES). The ES analysis identified 40 genetic abnormalities, significantly including de novo variants. Notably, we found structural variation as duplications in regions 2q24.3, including SCN1A and SCN2A were observed in 7 cases. These genetic variants, impacting ion channels, glucose transport, transcription regulation, and kinases, play a crucial role in determining medication efficacy. More than one-third (34.2%) of patients with DEE had an unfavorable response to anti-seizure medications (ASMs) in the chronic phase. However, since the ketogenic supplementary diet showed a positive effect, more than three-quarters (80%) of these drug-resistant patients improved during a 3-month follow-up. In contrast, the ME had a lower adverse reaction rate of 9.1% (2/22) to specialized medications, yet there were 5 fatalities and 10 cases with unidentified genetic etiologies. This study suggests the potential of categorizing drug-resistant variants and that a ketogenic diet could be beneficial in managing DEE and ME. It also opens new perspectives on the mechanisms of the ketogenic diet on the discovered genetic variants.

Visceral leishmaniasis complicated with hemophagocytic lymphohistiocytosis and resistant to amphotericin B: a case report.

INTRODUCTION: Hemophagocytic lymphohistiocytosis characterized by hemophagocytosis leading to uncontrolled inflammation; the most common etiology in secondary cases of hemophagocytic lymphohistiocytosis is viral infections, especially Epstein-Barr virus. Visceral leishmaniasis is a vectorborne protozoal disease caused by Leishmania donovani complex. It is common in tropical and subtropical regions, with 50,000-90,000 new cases annually. CASE PRESENTATION: A 15-month-old Arab female was admitted to our hospital with 15 days of fever and decreased weight. On clinical examination, she had a markedly enlarged liver and spleen that were palpable 4 cm and 6 cm below the costal margin, respectively. The peripheral blood smear showed hypochromic microcytic anemia, poikilocytosis, reactive lymphocytosis, and mild thrombocytopenia. Bone marrow aspiration did not show malignancy or any other pathological findings. The patient was put on antibiotic therapy without improvement. Repeated bone marrow aspiration showed erythrophagocytosis; intracellular small round organisms looked like the amastigote form of Leishmania (Donovan bodies) with no evidence of malignancies. Her lab values showed ferritin greater than 500 ug/L, pancytopenia, and hypertriglyceridemia. The patient was diagnosed with hemophagocytic lymphohistiocytosis secondary to visceral leishmaniasis. CONCLUSION: Hemophagocytic lymphohistiocytosis secondary to visceral leishmaniasis is an extensively rare phenomenon in the medical literature that causes challenges in diagnosis and management. Steroids should be used wisely to not cover the symptoms of infections or malignancy, and amphotericin B resistance should be kept in mind in unresponsive Leishmania cases.

Quality, supply chain, and use of Trypanocidal drugs among camel keepers in north-eastern Kenya: A cross-sectional study.

The non-cyclic trypanosomiasis (surra), caused by Trypanosoma evansi, and mechanically transmitted by biting flies, hinders camel productivity in Kenya. Trypanocides are the most commonly used drugs to control surra. However, emergence of drug resistance by the parasites is a major limitation to control efforts. There is limited information on the quality of trypanocides, the supply chain and drug-use practices among camel keepers potentially contributing to development of drug resistance in Kenya. We sought to fill this gap by conducting a cross-sectional study among camel keepers in Isiolo and Marsabit counties, Kenya. We mapped the trypanocide drugs supply chain through quantitative and qualitative surveys. We administered a semi-structured questionnaire to camel keepers to generate data on trypanocides-use practices, including the types, sources, person who administers treatment, reconstitution, dosage, route and frequency of administration, among others. Additionally, we tested the quality of trypanocidal drugs retailed in the region. We mapped a total of 55 and 49 agro-veterinary outlets and general (ordinary) shops retailing veterinary drugs in the two counties, respectively. These comprised of 29 and 26 agro-veterinary outlets, as well as 24 and 25 general shops in Isiolo and Marsabit counties, respectively. Overall, the respondents experienced 283 surra cases in the three-month recall period, which were treated with trypanocides. The majority of these cases were diagnosed by camel owners (71.7%) and herders (24.1%). A significant proportion of the cases were treated by camel owners (54.8%), herders (35.3%), the owner's son (3.2%) and veterinary personnel (1.1%) (χ2 = 24.99, p = 0.000). Most of the households sourced the drugs from agro-veterinary outlets (59.0%), followed by general shops (19.8%), veterinary personnel (2.1%), and open-air markets (0.4%) (χ2 = 319.24, p = 0.000). Quinapyramine was the most (56.9%) predominantly used trypanocide in treatment of surra, followed by homidium (19.8%), isometamidium (15.9%), diminazene aceturate (6.7%), and ethidium (0.7%) (χ2 = 340.75, p < 0.000). Only a meager proportion of respondents (15.2%) used the drugs correctly as instructed by the manufacturers. We recorded an association between correct drug usage, with the person who administers the treatment (χ2 = 17.7, p = 0.003), and the type of trypanocide used (χ2 = 19.4, p < 0.001). All the drug samples tested had correct concentrations of active ingredient (100.0%), and therefore of good quality. We have demonstrated that whereas the trypanocides retailed in the region by authorized vendors are of good quality, there is widespread incorrect handling and use of the drugs by unqualified individuals, which may contribute to treatment failure and emergence of trypanocide resistance.

Antimalarial drug sulfadoxine induces gametocytogenesis in Plasmodium berghei.

BACKGROUND: The spread of antimalarial drug resistance parasites is a major obstacle in eliminating malaria in endemic areas. This increases the urgency for developing novel antimalarial drugs with improved profiles to eliminate both sensitive and resistant parasites in populations. The invention of the drug candidates needs a model for sensitive and resistant parasites on a laboratory scale. METHODS: Repeated Incomplete Treatment (RIcT) method was followed in raising the rodent malaria parasite, Plasmodium berghei, resistant to sulfadoxine. Plasmodium berghei were exposed to an adequate therapeutic dose of sulfadoxine without finishing the treatment to let the parasite recover. Cycles of drug treatment and parasite recovery were repeated until phenotypic resistance appeared. RESULTS: After undergoing 3-4 cycles, phenotypic resistance was not yet found in mice treated with sulfadoxine. Nevertheless, the molecular biology of dhps gene (the target of sulfadoxine) was analyzed at the end of the RIcT cycle. There was no mutations found in the gene target. Interestingly, the appearance of gametocytes at the end of every cycle of drug treatment and parasite recovery was observed. These gametocytes later on would no longer extend their life in the RBC stage, unless mosquitoes bite the infected host. This phenomenon is similar to the case in human malaria infections treated with sulfadoxine-pyrimethamine (SP). CONCLUSIONS: In this study, the antimalarial drug sulfadoxine induced gametocytogenesis in P. berghei, which could raise the risk factor for malaria transmission.

Leishmania spp. genetic factors associated with cutaneous leishmaniasis antimony pentavalent drug resistance: a systematic review.

BACKGROUND: Leishmaniasis is a neglected zoonosis caused by parasites of Leishmania spp. The main drug used to treat cutaneous leishmaniasis (CL) is the antimoniate of meglumine. This drug, which has strong adverse and toxic effects, is usually administered intravenously, further complicating the difficult treatment. Factors such as Leishmania gene expression and genomic mutations appear to play a role in the development of drug resistance. OBJECTIVES: This systematic review summarises the results of the literature evaluating parasite genetic markers possibly associated with resistance to pentavalent antimony in CL. METHODS: This study followed PRISMA guidelines and included articles from PubMed, SciELO, and LILACS databases. Inclusion criteria were studies that (i) investigated mutations in the genome and/or changes in gene expression of Leishmania associated with treatment resistance; (ii) used antimony drugs in the therapy of CL; (iii) used naturally resistant strains isolated from patients. The Joanna Briggs Institute Critical Appraisal Checklist was used to assess article quality and risk of bias. FINDINGS: A total of 23 articles were selected, of which 18 investigated gene expression and nine genomic mutations. Of these 23 articles, four examined gene expression and genomic mutations in the same samples. Regarding gene expression, genes from the ABC transporter protein family, AQP1, MRPA, TDR1 and TRYR were most frequently associated with drug resistance. In one of the articles in which mutations were investigated, a mutation was found in HSP70 (T579A) and in three articles mutations were found in AQP1 (A516C, G562A and G700A). A limitation of this review is that in most of the included studies, parasites were isolated from cultured lesion samples and drug resistance was assessed using in vitro drug susceptibility testing. These approaches may not be ideal for accurate genetic evaluation and detection of treatment failure. MAIN CONCLUSIONS: The development of further studies to evaluate the genetic resistance factors of Leishmania spp. is necessary to elucidate the mechanisms of the parasite and improve patient treatment and infection control.

Towards clinically relevant dose ratios for Cabamiquine and Pyronaridine combination using P. falciparum field isolate data.

The selection and combination of dose regimens for antimalarials involve complex considerations including pharmacokinetic and pharmacodynamic interactions. In this study, we use immediate ex vivo P. falciparum field isolates to evaluate the effect of cabamiquine and pyronaridine as standalone treatments and in combination therapy. We feed the data into a pharmacometrics model to generate an interaction map and simulate meaningful clinical dose ratios. We demonstrate that the pharmacometrics model of parasite growth and killing provides a detailed description of parasite kinetics against cabamiquine-susceptible and resistant parasites. Pyronaridine monotherapy provides suboptimal killing rates at doses as high as 720 mg. In contrast, the combination of a single dose of 330 mg cabamiquine and 360 mg pyronaridine provides over 90% parasite killing in most of the simulated patients. The described methodology that combines a rapid, 3R-compliant in vitro method and modelling to set meaningful doses for new antimalarials could contribute to clinical drug development.

Plasmodium falciparum population dynamics in East Africa and genomic surveillance along the Kenya-Uganda border.

East African countries accounted for ~ 10% of all malaria prevalence worldwide in 2022, with an estimated 23.8 million cases and > 53,000 deaths. Despite recent increases in malaria incidence, high-resolution genome-wide analyses of Plasmodium parasite populations are sparse in Kenya, Tanzania, and Uganda. The Kenyan-Ugandan border region is a particular concern, with Uganda confirming the emergence and spread of artemisinin resistant P. falciparum parasites. To establish genomic surveillance along the Kenyan-Ugandan border and analyse P. falciparum population dynamics within East Africa, we generated whole-genome sequencing (WGS) data for 38 parasites from Bungoma, Western Kenya. These sequences were integrated into a genomic analysis of available East African isolate data (n = 599) and revealed parasite subpopulations with distinct genetic structure and diverse ancestral origins. Ancestral admixture analysis of these subpopulations alongside isolates from across Africa (n = 365) suggested potential independent ancestral populations from other major African populations. Within isolates from Western Kenya, the prevalence of biomarkers associated with chloroquine resistance (e.g. Pfcrt K76T) were significantly reduced compared to wider East African populations and a single isolate contained the PfK13 V568I variant, potentially linked to reduced susceptibility to artemisinin. Overall, our work provides baseline WGS data and analysis for future malaria genomic surveillance in the region.

Machine learning-based predictive model for the development of thrombolysis resistance in patients with acute ischemic stroke.

BACKGROUND: The objective of this study was to establish a predictive model utilizing machine learning techniques to anticipate the likelihood of thrombolysis resistance (TR) in acute ischaemic stroke (AIS) patients undergoing recombinant tissue plasminogen activator (rt-PA) intravenous thrombolysis, given that nearly half of such patients exhibit poor clinical outcomes. METHODS: Retrospective clinical data were collected from AIS patients who underwent intravenous thrombolysis with rt-PA at the First Affiliated Hospital of Bengbu Medical University. Thrombolysis resistance was defined as ([National Institutes of Health Stroke Scale (NIHSS) at admission - 24-hour NIHSS] × 100％/ NIHSS at admission) ≤ 30%. In this study, we developed five machine learning models: logistic regression (LR), extreme gradient boosting (XGBoost), support vector machine (SVM), the least absolute shrinkage and selection operator (LASSO), and random forest (RF). We assessed the model's performance by using receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA), and presented the results through a nomogram. RESULTS: This study included a total of 218 patients with AIS who were treated with intravenous thrombolysis, 88 patients experienced TR. Among the five machine learning models, the LASSO model performed the best. The area under the curve (AUC) on the testing group was 0.765 (sensitivity: 0.767, specificity: 0.694, accuracy: 0.727). The apparent curve in the calibration curve was similar to the ideal curve, and DCA showed a positive net benefit. Key features associated with TR included NIHSS at admission, blood glucose, white blood cell count, neutrophil count, and blood urea nitrogen. CONCLUSION: Machine learning methods with multiple clinical variables can help in early screening of patients at high risk of thrombolysis resistance, particularly in contexts where healthcare resources are limited.

Elevated serum IGFBP-1 levels correlate with cognitive deficits in treatment-resistant and chronic medicated schizophrenia patients.

BACKGROUND: Schizophrenia is a debilitating psychiatric disorder with diverse cognitive impairments. Insulin-like growth factor binding protein 1 (IGFBP-1), a ubiquitous negative regulator of IGF signaling, crosses the blood-brain barrier after peripheral synthesis. Given the crucial role of IGF signaling in cognitive function, we reasoned that altered serum IGFBP-1 concentrations might be associated with cognitive impairments in schizophrenia. To test this hypothesis, we examined the relationship between serum IGFBP-1 levels and cognitive performance in both medicated and treatment-resistant schizophrenia (TRS) patients. METHODS: Serum IGFBP-1 was measured in 31 TRS patients, 49 chronic medicated schizophrenia (CMS) patients, and 53 healthy controls. Clinical symptom severity was evaluated using the Positive and Negative Syndrome Scale (PANSS) and cognitive functions using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS). RESULTS: Both TRS and CMS patients exhibited cognitive deficits compared to healthy controls (p < 0.05). Serum IGFBP-1 concentration differed significantly among groups (F=36.805, p < 0.001) and post hoc tests demonstrated significantly higher concentrations in both schizophrenia groups compared to controls (p < 0.001). Further, serum IGFBP-1 concentration was higher in the TRS group than the CMS group (p = 0.048). Correlation analysis identified a significant relationship between serum IGFBP-1 and attention in the TRS group (r = 0.411, p = 0.021), immediate memory in the CMS group (r = -0.417, p = 0.003), and RBANS total score in the CMS group (r = -0.368, p = 0.009). Multiple regression analysis adjusting for confounding factors revealed that serum IGFBP-1 was independently associated with attention in TRS patients (p = 0.016, 95 %CI. 0.002-0.015) and immediate memory in CMS patients (p = 0.022, 95 %CI-0.012 to -0.001). CONCLUSIONS: Elevated serum IGFBP-1 concentration may serve as a predictive biomarker for distinct cognitive deficits in TRS and CMS patients. Further investigations are warranted.

Change in prostate tissue gene expression following finasteride or doxazosin administration in the medical therapy for prostatic symptoms (MTOPS) study.

Benign prostatic hyperplasia (BPH) may decrease patient quality of life and often leads to acute urinary retention and surgical intervention. While effective treatments are available, many BPH patients do not respond or develop resistance to treatment. To understand molecular determinants of clinical symptom persistence after initiating BPH treatment, we investigated gene expression profiles before and after treatments in the prostate transitional zone of 108 participants in the Medical Therapy of Prostatic Symptoms (MTOPS) Trial. Unsupervised clustering revealed molecular subgroups characterized by expression changes in a large set of genes associated with resistance to finasteride, a 5α-reductase inhibitor. Pathway analyses within this gene cluster found finasteride administration induced changes in fatty acid metabolism, amino acid metabolism, immune response, steroid hormone metabolism, and kinase activity within the transitional zone. We found that patients without this transcriptional response were highly likely to develop clinical progression, which is expected in 13.2% of finasteride-treated patients. Importantly, a patient's transcriptional response to finasteride was associated with their pre-treatment kinase expression. Further, we identified novel expression signatures of finasteride resistance among the transcriptionally responded patients. These patients showed different gene expression profiles at baseline and increased prostate transitional zone volume compared to the patients who responded to the treatment. Our work suggests molecular mechanisms of clinical resistance to finasteride treatment that could be potentially helpful for personalized BPH treatment as well as new drug development to increase patient drug response.

Urine-derived podocytes from steroid resistant nephrotic syndrome patients as a model for renal-progenitor derived extracellular vesicles effect and drug screening.

BACKGROUND: Personalized disease models are crucial for evaluating how diseased cells respond to treatments, especially in case of innovative biological therapeutics. Extracellular vesicles (EVs), nanosized vesicles released by cells for intercellular communication, have gained therapeutic interest due to their ability to reprogram target cells. We here utilized urinary podocytes obtained from children affected by steroid-resistant nephrotic syndrome with characterized genetic mutations as a model to test the therapeutic potential of EVs derived from kidney progenitor cells (nKPCs). METHODS: EVs were isolated from nKPCs derived from the urine of a preterm neonate. Three lines of urinary podocytes obtained from nephrotic patients' urine and a line of Alport syndrome patient podocytes were characterized and used to assess albumin permeability in response to nKPC-EVs or various drugs. RNA sequencing was conducted to identify commonly modulated pathways after nKPC-EV treatment. siRNA transfection was used to demonstrate the involvement of SUMO1 and SENP2 in the modulation of permeability. RESULTS: Treatment with the nKPC-EVs significantly reduced permeability across all the steroid-resistant patients-derived and Alport syndrome-derived podocytes. At variance, podocytes appeared unresponsive to standard pharmacological treatments, with the exception of one line, in alignment with the patient's clinical response at 48 months. By RNA sequencing, only two genes were commonly upregulated in nKPC-EV-treated genetically altered podocytes: small ubiquitin-related modifier 1 (SUMO1) and Sentrin-specific protease 2 (SENP2). SUMO1 and SENP2 downregulation increased podocyte permeability confirming the role of the SUMOylation pathway. CONCLUSIONS: nKPCs emerge as a promising non-invasive source of EVs with potential therapeutic effects on podocytes with genetic dysfunction, through modulation of SUMOylation, an important pathway for the stability of podocyte slit diaphragm proteins. Our findings also suggest the feasibility of developing a non-invasive in vitro model for screening regenerative compounds on patient-derived podocytes.

Anthelmintic resistance of gastrointestinal nematodes in cattle in Brazil and Argentina - current status and global perspectives.

This review outlines the current state of anthelmintic resistance (AHR) of gastrointestinal nematodes (GINs) among cattle in Argentina and Brazil, emphasizing the economic repercussions, animal health and welfare. The analysis explores factors associated with AHR and proposes a potential solution: the use of drug combinations. Both countries are grappling with a severe AHR scenario in cattle, having progressed through incipient, established, and advanced phases, leading to extreme cases of animal mortality due to ineffective control strategies. Genera such as Cooperia and Haemonchus have the highest reports of resistance, with Oesophagostomum radiatum also posing significant problems. While oral benzimidazoles and levamisole remain effective in most herds, moxidectin is entering an advanced resistance phase, and avermectins are increasingly deemed ineffective. The review explores the impact ofclimate, mixed grazing, animal movement and other husbandry practices, and the relationship between ectoparasite control and the emergence of resistant helminths. Notably, the discussion includes the strategic use of drug combinations as a valuable approach to address resistant GINs control in livestock, highlighting its significant potential to mitigate the challenges posed by AHR in the cattle industry of these countries.