Enhanced control efficacy of Bacillus subtilis NM4 via integration of chlorothalonil on potato early blight caused by Alternaria solani.

Early blight caused by Alternaria solani is a common foliar disease of potato around the world, and serious infections result in reduced yields and marketability due to infected tubers. The major aim of this study is to figure out the synergistic effect between microorganism and fungicides and to evaluate the effectiveness of Bacillus subtilis NM4 in the control of early blight in potato. Based on its colonial morphology and a 16S rRNA analysis, a bacterial antagonist isolated from kimchi was identified as B. subtilis NM4 and it has strong antifungal and anti-oomycete activity against several phytopathogenic fungi and oomycetes. The culture filtrate of strain NM4 with the fungicide effectively suppressed the mycelial growth of A. solani, with the highest growth inhibition rate of 83.48%. Although exposure to culture filtrate prompted hyphal alterations in A. solani, including bulging, combining it with the fungicide caused more severe hyphal damage with continuous bulging. Surfactins and fengycins, two lipopeptide groups, were isolated and identified as the main compounds in two fractions using LC-ESI-MS. Although the surfactin-containing fraction failed to inhibit growth, the fengycin-containing fraction, alone and in combination with chlorothalonil, restricted mycelial development, producing severe hyphal deformations with formation of chlamydospores. A pot experiment combining strain NM4, applied as a broth culture, with fungicide, at half the recommended concentration, resulted in a significant reduction in potato early blight severity. Our results indicate the feasibility of an integrated approach for the management of early blight in potato that can reduce fungicide application rates, promoting a healthy ecosystem in agriculture.

Pt,P-codoped carbon nitride nanoenzymes for fluorescence and colorimetric dual-mode detection of cholesterol.

Cholesterol is an important lipid compound found in a variety of foods, and its level in human blood is closely related to human health. Therefore, development of rapid and accurate POCT (point-of-care testing) methods for cholesterol detection is crucial for assessing food quality and early diagnosis of diseases, in particular, in a resource-limited environment. In this study, a smartphone-assisted colorimetric biosensor is constructed based on platinum,phosphorus-codoped carbon nitride (PtCNP2) for the rapid detection of cholesterol. Phosphorus-doped carbon nitride is prepared by thermal annealing of urea and NH4PF6, into which platinum is atomically dispersed by thermal refluxing. The obtained PtCNP2 exhibits an excellent peroxidase-like activity under physiological pH, whereby colorless o-phenylenediamine (OPD) is oxidized to colored 2,3-diaminophenazine (DAP) in the presence of hydrogen peroxide (H2O2), which can be produced during the oxidation of cholesterol by cholesterol oxidase. A smartphone-assisted visual sensing system is then constructed based on the color recognition software, and rapid on-site detection of cholesterol is achieved by reading the RGB values. Meanwhile, the generated DAP shows an apparent fluorescence signal and can realize highly sensitive detection of cholesterol by the change of the fluorescence signal intensity. Such a cholesterol sensor exhibits a wide linear detection range of 0.5-600 µg mL-1 and a low detection limit of 59 ng mL-1. The practicality of the sensor is successfully demonstrated in the rapid detection of cholesterol in serum and food.

Construction of luciferase-expressing Neospora caninum and drug screening.

BACKGROUND: Neospora caninum is an apicomplexan parasite that is particularly responsible for abortions in cattle and neuromuscular disease in dogs. Due to the limited effectiveness of currently available drugs, there is an urgent need for new therapeutic approaches to control neosporosis. Luciferase-based assays are potentially powerful tools in the search for antiprotozoal compounds, permitting the development of faster and more automated assays. The aim of this study was to construct a luciferase-expressing N. caninum and evaluate anti-N. caninum drugs. METHODS: Luciferase-expressing N. caninum (Nc1-Luc) was constructed using clustered regularly interspaced short palindromic repeats (CRISPR)-associated protein 9 (CRISPR/Cas9). After testing the luciferase expression and phenotype of the Nc1-Luc strains, the drug sensitivity of Nc1-Luc strains was determined by treating them with known positive or negative drugs and calculating the half-maximal inhibitory concentration (IC50). The selective pan-rapidly accelerated fibrosarcoma (pan-RAF) inhibitor TAK-632 was then evaluated for anti-N. caninum effects using Nc1-Luc by luciferase activity reduction assay and other in vitro and in vivo studies. RESULTS: The phenotypes and drug sensitivity of Nc1-Luc strains were consistent with those of the parental strains Nc1, and Nc1-Luc strains can be used to determine the IC50 for anti-N. caninum drugs. Using the Nc1-Luc strains, TAK-632 showed promising activity against N. caninum, with an IC50 of 0.6131 µM and a selectivity index (SI) of 62.53. In vitro studies demonstrated that TAK-632 inhibited the invasion, proliferation, and division of N. caninum tachyzoites. In vivo studies showed that TAK-632 attenuated the virulence of N. caninum in mice and significantly reduced the parasite burden in the brain. CONCLUSIONS: In conclusion, a luciferase-expressing N. caninum strain was successfully constructed, which provides an effective tool for drug screening and related research on N. caninum. In addition, TAK-632 was found to inhibit the growth of N. caninum, which could be considered as a candidate lead compound for new therapeutics for neosporosis.

Genome-wide identification, phylogenetic classification of histone acetyltransferase genes, and their expression analysis in sugar beet (Beta vulgaris L.) under salt stress.

MAIN CONCLUSION: This study identified seven histone acetyltransferase-encoding genes (HATs) from Beta vulgaris L. (sugar beet) genome through bioinformatics tools and analyzed their expression profiles under salt stress. Sugar beet HATs are phylogenetically divided into four families: GNAT, MYST, CBP, and TAFII250. The BvHAT genes were differentially transcribed in leaves, stems, and roots of B. vulgaris salt-resistant (Casino) and -sensitive (Bravo) cultivars under salt stress. Histone acetylation is regulated by histone acetyltransferases (HATs), which catalyze ɛ-amino bond formation between lysine residues and acetyl groups with a cofactor, acetyl-CoA. Even though the HATs are known to participate in stress response and development in model plants, little is known about the functions of HATs in crops. In sugar beet (Beta vulgaris L.), they have not yet been identified and characterized. Here, an in silico analysis of the HAT gene family in sugar beet was performed, and their expression patterns in leaves, stems, and roots of B. vulgaris were analyzed under salt stress. Salt-resistant (Casino) and -sensitive (Bravo) beet cultivars were used for gene expression assays. Seven HATs were identified from sugar beet genome, and named BvHAG1, BvHAG2, BvHAG3, BvHAG4, BvHAC1, BvHAC2, and BvHAF1. The HAT proteins were divided into 4 groups including MYST, GNAT (GCN5, HAT1, ELP3), CBP and TAFII250. Analysis of cis-acting elements indicated that the BvHAT genes might be involved in hormonal regulation, light response, plant development, and abiotic stress response. The BvHAT genes were differentially expressed in leaves, stems, and roots under control and 300 mM NaCl. In roots of B. vulgaris cv. Bravo, the BvHAG1, BvHAG2, BvHAG4, BvHAF1, and BvHAC1 genes were dramatically expressed after 7 and 14 days of salt stress. Interestingly, the BvHAC2 gene was not expressed under both control and stress conditions. However, the expression of BvHAG2, BvHAG3, BvHAG4, BvHAC1, BvHAC2 genes showed a significant increase in response to salt stress in the roots of cv. Casino. This study provides new insights into the potential roles of histone acetyltransferases in sugar beet.

Determination of enzalutamide long-term safety and efficacy for castration-resistant prostate cancer patients after combined anti-androgen blockade followed by alternative anti-androgen therapy: a multicenter prospective DELC study.

BACKGROUND: Alternative anti-androgen therapy has been widely used as a first-line treatment for castration-resistant prostate cancer, and it may affect treatment outcome of subsequent agents targeting the androgen receptor axis. We conducted the prospective observational DELC (Determination of Enzalutamide Long-term safety and efficacy for Castration-resistant prostate cancer patients after combined anti-androgen blockade followed by alternative anti-androgen therapy) study to evaluate the efficacy of enzalutamide in patients with castration-resistant prostate cancer who underwent prior combined androgen blockade with bicalutamide and then alternative anti-androgen therapy with flutamide. METHODS: The DELC study enrolled 163 Japanese patients with castration-resistant prostate cancer who underwent alternative anti-androgen therapy with flutamide following failure of initial combined androgen blockade with bicalutamide in multiple institutions between January 2016 and March 2019. Primary endpoint was overall survival. Administration of enzalutamide was started at 160 mg orally once daily in all patients. RESULTS: The rate of decline of prostate-specific antigen by 50% or more was 72.2%, and median overall survival was 42.05 months. Multivariate analysis revealed that higher pretreatment serum levels of prostate-specific antigen (≥11.3 ng/mL; P = 0.004), neuron-specific enolase (P = 0.014) and interleukin-6 (≥2.15 pg/mL; P = 0.004) were independent risk factors for overall survival. Fatigue (30.0%), constipation (19.6%) and appetite loss (17.8%) were the most common clinically relevant adverse events. The enzalutamide dose was not reduced in any patient under the age of 70, but adherence was decreased in those over 70. CONCLUSIONS: In the DELC study, the safety of enzalutamide was comparable to that in previous reports. Serum levels of neuron-specific enolase and interleukin-6 were suggested as prognostic factors for castration-resistant prostate cancer with potential clinical utility.

Selenomethionine modulates the JAK2 / STAT3 / A20 pathway through oxidative stress to alleviate LPS-induced pyroptosis and inflammation in chicken hearts.

Selenium (Se) is involved in many physiopathologic processes in humans and animals and is strongly associated with the development of heart disease. Lipopolysaccharides (LPS) are cell wall components of gram-negative bacteria that are present in large quantities during environmental pollution. To investigate the mechanism of LPS-induced cardiac injury and the efficacy of the therapeutic effect of SeMet on LPS, a chicken model supplemented with selenomethionine (SeMet) and/or LPS treatment, as well as a primary chicken embryo cardiomyocyte model with the combined effect of SeMet / JAK2 inhibitor (INCB018424) and/or LPS were established in this experiment. CCK8 kit, Trypan blue staining, DCFH-DA staining, oxidative stress kits, immunofluorescence staining, LDH kit, real-time fluorescence quantitative PCR, and western blot were used. The results proved that LPS exposure led to ROS explosion, hindered the antioxidant system, promoted the expression of the JAK2 pathway, and increased the expression of genes involved in the pyroptosis pathway, inflammatory factors, and heat shock proteins (HSPs). Upon co-treatment with SeMet and LPS, SeMet reduced LPS-induced pyroptosis and inflammation and restored the expression of HSPs by inhibiting the ROS burst and modulating the antioxidant capacity. Co-treatment with INCB018424 and LPS resulted in inhibited of the JAK2 pathway, attenuating pyroptosis, inflammation, and high expression of HSPs. Thus, LPS induced pyroptosis, inflammation, and changes in HSPs activity by activating of the JAK2 / STAT3 / A20 signaling axis in chicken hearts. Moreover, SeMet has a positive effect on LPS-induced injury. This work further provides a theoretical basis for treating cardiac injury by SeMet.

Usage of vildagliptin among patients with type 2 diabetes mellitus attending a public primary healthcare clinics in Kuala Selangor District, Selangor.

INTRODUCTION: Studies showed that vildagliptin can lower HbA1c levels by 0.8%-1%. However, there is limited data looking at vildagliptin use among suburban populations. The efficacy of vildagliptin use may differ among different populations, especially those with low socio-economic status. Thus, this study aimed to assess the HbA1c reduction after vildagliptin initiation, treatment patterns and the reason for its initiation among patients with type 2 diabetes mellitus attending outpatient clinics in Kuala Selangor District, Selangor. MATERIALS AND METHODS: This is a cross-sectional, retrospective study design. All patients who received vildagliptin in the Pharmacy Integrated Health System (PHIS) registry database from 2016 to 2021 were included as study samples. The exclusion criteria were being less than 18 years old and having type 1 diabetes mellitus. Patients' medical records were retrieved after sampling, and data were collected. One medical record was missing, thus SPSS analysis were performed on 144 vildagliptin users. RESULTS: In total, 84 females (58.3%) and 60 males (41.7%) with a mean age of 62.1 (±10.1) years were analysed in this study. Mean HbA1c pre-therapy was 8.5 ± 2.1%; while posttherapy 6 months demonstrated a mean HbA1c of 7.9 ± 1.8%. Use of vildagliptin alone or as an adjunct was associated with a mean reduction of 0.6% in HbA1c (p = 0.01). Factors influencing this HbA1c reduction were advancing age, specifically individuals aged 62 years and older (p = 0.02), patients who are already receiving insulin therapy (p=0.00) and those who express a willingness to commence insulin treatment during the counselling session prior to initiating the treatment plan (p = 0.00). Reasons for vildagliptin initiation documented by prescribers were non-insulin acceptance (n = 59, 40.97%), frequent hypoglycaemia (n = 6, 4.1%) and non-compliance with medications (n = 23, 15.9%). There was no association between demographic, medical background and reason for starting vildagliptin variables and HbA1c reduction (p < 0.001). CONCLUSION: This study showed that initiating vildagliptin alone or as an adjunct therapy significantly reduced HbA1c and is beneficial for uncontrolled diabetes patients. While advancing age, concurrent administration of insulin and the patients' willingness to accept insulin treatment prior to the commencement of therapy were the factors that influenced HbA1c reduction among patients receiving vildagliptin therapy, we recommend primary care providers prioritise all of the significant variables discovered before initiating vildagliptin for their patients.

Multi-center retrospective review of vitiligo-like lesions in breast cancer patients treated with cyclin-dependent kinase 4 and 6 inhibitors.

PURPOSE: Cutaneous adverse effects from cyclin-dependent 4 and 6 kinase inhibitors (CDK4/6i) used in metastatic breast cancer are prevalent and well described. Vitiligo-like lesions have been reported and are rare. They can negatively impact patients' quality of life and may be associated with survival benefits. We describe the clinical characteristics of vitiligo-like lesions in an international cohort of patients treated with CDK4/6i to help improve recognition and management. METHODS: Retrospective review of patients diagnosed with vitiligo-like lesions from CDK4/6i from five academic institutions in the USA and Europe was performed. Ten patients were included in the study. RESULTS: Median age of our patients was 55 (range 37-86). Median progression-free survival was 24 months in 5 patients. The median time to rash was 10 months. Sun-exposed areas such as the arms and face were the most affected areas. Multiple skin-directed therapies such as topicals, laser, and phototherapy were trialed with minor success. Mild repigmentation was seen in one patient treated with ruxolitinib cream. CDK4/6 treatment was discontinued due to the vitiligo-like lesions in one patient. CONCLUSION: Clinical characteristics are similar to previously reported findings in case reports and series. We add topical ruxolitinib as a potential treatment option for these patients and include data regarding progression-free survival that should continue to be collected. No definitive conclusions can be made regarding survival benefits from our cohort. Clinicians should refer these patients to dermatologists to aid with management.

Corticosteroid-resistant immune-related adverse events: a systematic review.

Immune checkpoint inhibitor (ICI) treatment has become an important therapeutic option for various cancer types. Although the treatment is effective, ICI can overstimulate the patient's immune system, leading to potentially severe immune-related adverse events (irAEs), including hepatitis, colitis, pneumonitis and myocarditis. The initial mainstay of treatments includes the administration of corticosteroids. There is little evidence how to treat steroid-resistant (sr) irAEs. It is mainly based on small case series or single case reports. This systematic review summarizes available evidence about sr-irAEs. We conducted a systematic literature search in PubMed. Additionally, we included European Society for Medical Oncology, Society for Immunotherapy of Cancer, National Comprehensive Cancer Network and American Society of Clinical Oncology Guidelines for irAEs in our assessment. The study population of all selected publications had to include patients with cancer who developed hepatitis, colitis, pneumonitis or myocarditis during or after an immunotherapy treatment and for whom corticosteroid therapy was not sufficient. Our literature search was not restricted to any specific cancer diagnosis. Case reports were also included. There is limited data regarding life-threatening sr-irAEs of colon/liver/lung/heart and the majority of publications are single case reports. Most publications investigated sr colitis (n=26), followed by hepatitis (n=21), pneumonitis (n=17) and myocarditis (n=15). There is most data for mycophenolate mofetil (MMF) to treat sr hepatitis and for infliximab, followed by vedolizumab, to treat sr colitis. Regarding sr pneumonitis there is most data for MMF and intravenous immunoglobulins (IVIG) while data regarding infliximab are conflicting. In sr myocarditis, most evidence is available for the use of abatacept or anti-thymocyte globulin (ATG) (both with or without MMF) or ruxolitinib with abatacept. This review highlights the need for prompt recognition and treatment of sr hepatitis, colitis, pneumonitis and myocarditis. Guideline recommendations for sr situations are not defined precisely. Based on our search, we recommend-as first line treatment-(1) MMF for sr hepatitis, (2) infliximab for sr colitis, followed by vedolizumab, (3) MMF and IVIG for sr pneumonitis and (4) abatacept or ATG (both with or without MMF) or ruxolitinib with abatacept for sr myocarditis. These additional immunosuppressive agents should be initiated promptly if there is no sufficient response to corticosteroids within 3 days.

Effects of Radix dichroae extract supplementation on growth performance, oocysts output and gut microbiota in growing lambs with coccidiosis.

Coccidiosis is an intestinal protozoan disease of sheep, that causes substantial economic losses in the industry due to its intestinal protozoan origins. Many anti-protozoan drugs including ionophores, triazines, and sulfonamides have been widely used to treat sheep coccidiosis. Still, anticoccidial resistance and drug residues in edible tissues have prompted an urgent search for alternatives. In this study, the anti-coccidial effectiveness of the Radix dichroae extract was compared to that of the conventional anti-coccidial drug diclazuril. Here, eighteen 45-day-old lambs naturally-infected with Eimeria spp. were randomly allocated in three groups: control group, Radix dichroae extract group and diclazuril group. The results showed that the body weight gain (BWG) during the treatment and withdrawal periods was considerably improved in the coccidiosis-infected sheep treated with Radix dichroae extract and diclazuril compared to the control group, respectively. Additionally, the Radix dichroae extract and diclazuril had fewer oocysts per gram (OPG) than the control group, showing similar anti-coccidial effects on days 14, 21, 28, 35 and 78, respectively. Furthermore, Radix dichroae extract and diclazuril treatment altered the structure and composition of gut microbiota, promoting the relative abundance of Actinobacteriota, Firmicutes, Alistipes, and Bifidobacterium, while decreasing the abundance of Bacteroidota, Marinilaceae, Helicobacteraceae, and Prevotella. Moreover, Spearman's correlation analysis further revealed a correlation between the OPG and BWG and gut microorganisms. Collectively, the results indicated that Radix dichroae extract had similar anti-coccidial effects as diclazuril, and could regulate gut microbiota balance in growing lambs.

Introducing a protic ionic liquid from aminoethyl piperazine and triflic acid immobilized on pectin as a reusable nanocatalyst for the selective Schmidt synthesis of nitriles.

Preparation of reusable protic ionic liquid, triflic acid-immobilized aminoethyl piperazine-modified pectin (Pec-AEP-TfOH), with excellent activity and selectivity in modified Schmidt synthesis of nitriles from aldehydes and Si(CH3)3N3 has been described. The structure of the catalyst was characterized using FT-IR, XRD, FE-SEM, EDX-mapping, and TGA-DTA. The reaction demonstrated a broad substrate scope for a variety of benzaldehyde derivatives with electron withdrawing/donating substituents and heterocyclic aldehydes with yields between 85 and 96 % at room temperature. Also, the Pec-AEP-TfOH showed an excellent selectivity for the nitriles in which no formanilide was obtained. Furthermore, the Pec-AEP-TfOH revealed a remarkable chemoselectivity for aldehydes in the presence of acids or ketones. It is worth noting that TfOH as a precious superacid was immobilized for the first time in the selective Schmidt synthesis of nitriles to improve the eco-friendliness and economic efficiency of the process. Furthermore, the catalyst was cost-effective, metal-free, safe, scalable, and reusable (5 times) and its heterogeneity was confirmed by hot-filtration test.

Light induces an increasing release of benzyl nitrile against diurnal herbivore Ectropis grisescens Warren attack in tea (Camellia sinensis) plants.

Herbivore-induced plant volatiles (HIPVs) are critical compounds that directly or indirectly regulate the tritrophic interactions among herbivores, natural enemies and plants. The synthesis and release of HIPVs are regulated by many biotic and abiotic factors. However, the mechanism by which multiple factors synergistically affect HIPVs release remains unclear. Tea plant (Camellia sinensis) is the object of this study because of its rich and varied volatile metabolites. In this study, benzyl nitrile was released from herbivore-attacked tea plants more in the daytime than at night, which was consistent with the feeding behaviour of tea geometrid (Ectropis grisescens Warren) larvae. The Y-tube olfactometer assay and insect resistance analysis revealed that benzyl nitrile can repel tea geometrid larvae and inhibit their growth. On the basis of enzyme activities in transiently transformed Nicotiana benthamiana plants, CsCYP79 was identified as a crucial regulator in the benzyl nitrile biosynthetic pathway. Light signalling-related transcription factor CsPIF1-like and the jasmonic acid (JA) signalling-related transcription factor CsMYC2 serve as the activator of CsCYP79 under light and damage conditions. Our study revealed that light (abiotic factor) and herbivore-induced damage (biotic stress) synergistically regulate the synthesis and release of benzyl nitrile to protect plants from diurnal herbivorous tea geometrid larvae.

Ovulation induction with letrozole and dexamethasone in infertile patients with letrozole-resistant polycystic ovary syndrome.

PURPOSE: To assess efficacy of adjuvant dexamethasone during letrozole cycles for ovulation induction (OI) in women with letrozole-resistant polycystic ovary syndrome (PCOS). METHODS: We retrospectively evaluated 42 cycles of OI from 28 infertile women with letrozole-resistant PCOS between September 2019 and November 2022. Letrozole was initiated on cycle day 3 for 5 days and increased via a stair-step approach to 7.5 mg as indicated. Patients were deemed letrozole-resistant if no dominant follicle was identified on transvaginal ultrasound following this dose. Resistant patients then received 5 additional days of letrozole 7.5 mg with low-dose dexamethasone 0.5 mg for 7 days and had a repeat ultrasound. The primary outcome was ovulation rate determined by the presence of a dominant follicle on ultrasound. Secondary outcomes included endometrial thickness, number of measurable follicles, and pregnancy outcomes among responders. RESULTS: Twenty-two of 28 (79%) letrozole-resistant PCOS patients had evidence of ovulation after the addition of dexamethasone in 35 out of 42 (83%) cycles. Clinical pregnancy occurred in 20% of ovulatory cycles with a cumulative rate of 32%. All clinical pregnancies resulted in a live birth. Patients who responded to adjuvant dexamethasone were more likely to have a shorter duration of infertility; however, there were no differences in other demographics, serum androgens including DHEA-S, or pretreatment glycemic status. CONCLUSION: Adding dexamethasone to letrozole increased ovulation rates in letrozole-resistant PCOS patients undergoing OI with similar pregnancy outcomes to prior studies. The addition of dexamethasone is an effective, inexpensive, and safe option for PCOS patients otherwise at risk for cycle cancelation.

Qingdai Decoction suppresses prostate cancer growth in lethal-stage prostate cancer models.

ETHNOPHARMACOLOGICAL RELEVANCE: Contemporary therapy for advanced castration-resistant prostate cancer (CRPC) employs reagents such as enzalutamide and abiraterone acetate targeting the androgen receptor (AR) transcription axis only provide a temporary response and rapidly develop resistance. Additionally, neuroendocrine prostate cancer (NEPC) is an AR pathway-independent and lethal-stage prostate cancer with no standard therapy. Qingdai Decoction (QDT), a traditional Chinese medicine formula, has various pharmacological activities and was widely used for the treatment of different diseases including prostatitis which may contribute to prostate cancer development. AIM OF THE STUDY: This study aims to explore the anti-tumor role and potential mechanism of QDT on prostate cancer. MATERIAL AND METHODS: CRPC prostate cancer cell models and xenograft mice models were established for research. The effect of TCMs on cancer growth and metastasis were determined by CCK-8, wound-healing assays and the PC3-xenografted mice model. The toxicity of QDT in the major organs was investigated by H&E staining. The compound-target network was analyzed with network pharmacology. The correlation of QDT targets with prostate cancer patient's prognosis was analyzed with multiple prostate cancer patient cohorts. The expression of related proteins and mRNA were detected by western blot and real-time PCR. The gene knockdown was achieved with CRISPR-Cas13 technology. RESULTS: By integrating functional screening, network pharmacology analysis, CRISPR-Cas13 directed RNA targeting, and molecular biology validation in different prostate cancer models and clinical prostate cancer cohorts, we found that Qingdai Decoction (QDT), a Traditional Chinese Medicine, can repress cancer growth in advanced prostate cancer models in vitro and in vivo in an AR independent manner by targeting NOS3, TGFB1, and NCOA2. CONCLUSION: This study not only identified QDT as a novel drug for lethal-stage prostate cancer treatment but also provided an extensive Integrative research paradigm for investigating the roles and mechanisms of TCMs for the treatment of other diseases.

Lambda cyhalothrin and chlorantraniliprole caused biochemical, histological, and immunohistochemical alterations in male rabbit liver: Ameliorative effect of vitamins A, D, E, C mixture.

Pesticides can cause serious environmental and human health consequences such as metabolic disruption and even cancers. Preventive molecules such as vitamins can be an effective solution. The present study aimed to investigate the toxic effect of an insecticide mixture formulation of lambda cyhalothrin and chlorantraniliprole (Ampligo® 150 ZC), on the liver of male rabbits (Oryctolagus cuniculus) and the possible ameliorative effect of vitamins A, D3, E, and C mixture. For that, 18 male rabbits were divided into 3 equal groups: Control (distilled water), AP (20 mg/Kg bw of the insecticide mixture every other day, orally for 28 days), AP+ADEC (20 mg/Kg bw of the insecticide mixture + 0,5 ml of vitamin AD3E+ 200 mg/kg bw of vitamin C every other day). The effects were evaluated on body weight, food intake changes, biochemical parameters, liver histology, and immunohistochemical expression of AFP, Bcl2, E-cadherin, Ki67, and P53. Results indicated that AP reduced weight gain (6.71%) and feed intake, increased ALT, ALP, and TC plasma levels, and caused hepatic tissular damages such as dilatation and congestion of the central vein, sinusoidal dilatation, inflammatory cells infiltration, and collagen deposition. Hepatic immunostaining showed an increase in the tissular expression of AFP, Bcl2, Ki67, and P53 and a significant (p < 0,05) decrease in E-cadherin expression. In contrast, supplementation of vitamins A, D3, E, and C mixture improved the previous observed alterations. Our study revealed that a sub-acute exposure to an insecticide mixture of lambda cyhalothrin and chlorantraniliprole induced numerous functional and structural disorders in the rabbit liver and the addition of vitamins ameliorated these damages.

Health economic analysis of patients treated with isavuconazole in a German comprehensive cancer centre.

BACKGROUND: Invasive fungal diseases (IFD) are life-threatening and demand timely and appropriate treatment. Research showed that isavuconazole treatment positively affects clinical outcome and length of hospital stay (LOS). OBJECTIVES: The aim of this study was to assess the hospital costs of patients diagnosed with IFD and treated with isavuconazole using real-world data from a German cancer centre. PATIENTS/METHODS: Data and LOS collected from Jan-2016 to Jun-2021 at Department I of Internal Medicine, University Hospital Cologne were retrieved. Case-related resources consumed during the hospital stay across isavuconazole routes of administration (oral, parenteral, and mixed administration) were identified, quantified, valued and compared via a cost analysis that adopted the healthcare payer perspective. RESULTS: In total, 101 cases with isavuconazole treatment were identified (oral: n = 22, 21.8%; parenteral: n = 59, 58.4%; mixed: n = 20, 19.8%). Median total LOS was greater in the mixed group (46.5 days; p = .009). Median ICU LOS and ventilation duration were both longest in the parenteral-only group (16 days, p = .008; 224 h, p = .003). Invasive aspergillosis was the most frequent isavuconazole indication (n = 86, 85.2%). Average hospital costs were highest in the mixed group (€ 101,226). The median overall costs of cases treated with isavuconazole was € 52,050. CONCLUSIONS: Treating IFD is resource intensive, often requires intensive care and implies high rates of in-hospital mortality. Our study emphasises the high hospital treatment costs and thus the need for reimbursement systems to enable live-saving costly treatments.

Review of Ruxolitinib for Treatment of Non-Segmental Vitiligo.

OBJECTIVE: To review the pharmacokinetics, efficacy, and safety of topical ruxolitinib for treatment of nonsegmental vitiligo. DATA SOURCES: Literature published between January 1983 and October 2022 was reviewed from MEDLINE and ClinicalTrials.gov. STUDY SELECTION AND DATA EXTRACTION: Relevant articles in English and data from clinical trials were included. DATA SYNTHESIS: In 2 phase II trials, treatment with ruxolitinib cream showed significant improvements in Vitiligo Area Scoring Index (VASI) scores compared with controls. The 1.5% concentration applied twice daily showed the best results after 52 weeks, with 50% VASI improvement in 58% of patients, 75% VASI improvement in 52% of patients, and 90% VASI improvement in 33% of patients. In 2 phase III trials, more patients achieved at least 75% improvement in facial VASI at 24 weeks (primary endpoint; trial 1: 29.9%, trial 2: 29.9%) than controls (trial 1: 7.5% [P < 0.0001], trial 2: 12.9% [P < 0.01]). Common adverse effects were erythema, pruritus, and acne; all events were mild. RELEVANCE TO PATIENT CARE AND CLINICAL PRACTICE IN COMPARISON TO EXISTING DRUGS: This review summarizes the pharmacokinetics, efficacy, and safety data regarding topical ruxolitinib for vitiligo. Ruxolitinib is associated with significant clinical improvements with low bioavailability and minimal adverse effects compared with conventional topical steroids, calcineurin inhibitors, phototherapy, and depigmentation agents. CONCLUSIONS: Ruxolitinib cream is the first therapy approved by the Food and Drug Administration for repigmentation of nonsegmental vitiligo. Clinicians should consider these benefits when recommending treatment as conventional therapies may be time-intensive and carry greater risks of adverse effects.

Anemia control program in india needs to be more comprehensive.

Iron-deficiency anemia has continued to remain high in India. It is possibly due to relying on only iron-folic acid (IFA) supplementation through Anemia Control Program (ACP) that is National Iron Plus Initiative (NIPI). Based on the WHO's recommendations, we studied different interventions that can help to increase the effectiveness of NIPI such as Vitamin C supplementation with IFA, low-dose iron (LDI) with intensified health education (IHE), LDI with Vitamin C, and iron-rich food items to increase hemoglobin (Hb%) among adolescent girls through public-private partnership named Rashtriya Kishor Swasthya Karyakram. Increments in Hb after 12 weeks of interventions were compared with that of control groups one with NIPI and the other without any intervention. Highest increment in Hb% was observed in IFA under NIPI plus Vitamin C group, followed by LDI plus IHE group which was comparable to Hb increment in only the NIPI group. It emphasizes the need of making existing NIPI more stringent and comprehensive by integrating effective measures based on up-to-date scientific knowledge.

Asparagus racemosus improves immune-related parameters in Nile tilapia (Oreochromis niloticus) and mitigates deltamethrin-induced toxicity.

Deltamethrin (DM) is one of the most toxic but widely used pyrethroid insecticides. Even though a non-target animal, fish are at high risk as they are deficient in the enzyme system that hydrolyses pyrethroids. Enhancing the immune system is a potential method in preventing fish diseases. The present investigation aims to study the modulations in the immune response-related parameters in Oreochromis niloticus that were exposed to DM, by dietary supplementation of aqueous root extract of Asparagus racemosus (ARE). The experiment compared fish in control, DM (1 µg/L) exposed (added to water), ARE (10 g, 20 g, and 30 g ARE/kg of feed) supplemented, and DM-ARE cotreated groups. After 21 days of experimental period, serological, histopathological, and immune response related-gene and protein analysis were carried out. The DM-ARE cotreated group showed significant increase in weight gain, specific growth rate, and decreased feed conversion ratio compared to the DM exposed group. The ARE cotreatment could significantly revert the alteration induced by DM in lysozyme, respiratory burst, myeloperoxidase, C-reactive protein, glucose, cortisol, total protein, albumin, and triglyceride levels. The liver histopathology showed membrane breakage, severe necrosis, infiltration of inflammatory cells, melano-macrophages, and nuclear atrophy, and the kidney showed tubular necrosis, hematopoietic necrosis, Bowman's capsule edema, and glomerulus degeneration in DM exposed group. In ARE cotreated group, the liver showed regenerative cellular changes and only mild to moderate cellular damages, and the kidney tubules and glomerulus had intact structure. ARE discernibly regulated the expression of immune-related genes and proteins (IgM, TNFα, IFN-γ, IL-1ß, and IL-8) in fish. The DM-ARE cotreated groups showed reduced cumulative mortality and higher relative percent survival on experimental challenge with Aeromonas hydrophila compared to the DM group. Thus, ARE possess protective potential against DM-induced toxicity, and can be used as a cost-effective technique in aquafarming.

Development of a biomarker to monitor target engagement after treatment with dihydroorotate dehydrogenase inhibitors.

Dihydroorotate dehydrogenase (DHODH) catalyzes a key step in pyrimidine biosynthesis and has recently been validated as a therapeutic target for malaria through clinical studies on the triazolopyrimidine-based Plasmodium DHODH inhibitor DSM265. Selective toxicity towards Plasmodium species could be achieved because malaria parasites lack pyrimidine salvage pathways, and DSM265 selectively inhibits Plasmodium DHODH over the human enzyme. However, while DSM265 does not inhibit human DHODH, it inhibits DHODH from several preclinical species, including mice, suggesting that toxicity could result from on-target DHODH inhibition in those species. We describe here the use of dihydroorotate (DHO) as a biomarker of DHODH inhibition. Treatment of mammalian cells with DSM265 or the mammalian DHODH inhibitor teriflunomide led to increases in DHO where the extent of biomarker buildup correlated with both dose and inhibitor potency on DHODH. Treatment of mice with leflunomide (teriflunomide prodrug) caused a large dose-dependent buildup of DHO in blood (up to 16-fold) and urine (up to 5,400-fold) that was not observed for mice treated with DSM265. Unbound plasma teriflunomide levels reached 20-85-fold above the mouse DHODH IC50, while free DSM265 levels were only 1.6-4.2-fold above, barely achieving âˆ¼ IC90 concentrations, suggesting that unbound DSM265 plasma levels are not sufficient to block the pathway in vivo. Thus, any toxicity associated with DSM265 treatment in mice is likely caused by off-target mechanisms. The identification of a robust biomarker for mammalian DHODH inhibition represents an important advance to generally monitor for on-target effects in preclinical and clinical applications of DHODH inhibitors used to treat human disease.