Longer Treatment Research Articles

Optimizing Heavy Metal Uptake in Carpobrotus aequilaterus Through Electrokinetic Treatment: A Comprehensive Study on Phytoremediation from Mine Tailings

Copper mining drives economic growth, with the global demand expected to reach 120 million metric tons annually by 2050. However, mining produces tailings containing heavy metals (HMs), which poses environmental risks. This study investigated the efficacy of phytoremediation (Phy) combined with electrokinetic treatment (EKT) to increase metal uptake in Carpobrotus aequilaterus grown in tailings from the Metropolitan Region of Chile. The plants were exposed to varying voltages and treatment durations. In the control (no EKT), the root metal contents were Fe (1008.41 mg/kg) > Cu (176.38 mg/kg) > Mn (103.73 mg/kg) > Zn (30.26 mg/kg), whereas in the shoots, the order was Mn (48.69 mg/kg) > Cu (21.14 mg/kg) > Zn (17.67 mg/kg) > Fe (27.32 mg/kg). The optimal EKT (15 V for 8 h) significantly increased metal uptake, with roots accumulating Fe (5997.24 mg kg−1) > Mn (672 mg kg−1) > Cu (547.68 mg kg−1) > Zn (90.99 mg kg−1), whereas shoots contained Fe (1717.95 mg kg−1) > Mn (930 mg kg−1) > Cu (219.47 mg kg−1) > Zn (58.48 mg kg−1). Although EKT enhanced plant growth and biomass, higher voltages stressed the plants. Longer treatments were more effective, suggesting that EK–Phy is a promising method for remediating metal-contaminated tailings.

Influence of the new wavy teat liner “Stimulor StressLess” on milk yield performance and its quality in dairy cows: Results of a field study

The ideal milking system meets the physiological needs of dairy cows to increase milk yield, achieve better milk quality and maintain healthy udders. Therefore, the settings of the milking machine and the properties of the teat cup liners are very important on dairy farms. The aim of the present study was to test a new teat cup liner “Stimulor StressLess” (SSL) in two commercial dairy farms and to investigate its influence on daily milk production and quality having different experimental settings. For this purpose, 40 dairy cows of different breeds in Tirol, Austria (farm 1) were investigated for 6 months, where 3 months represent the control phase (Gr 1) and milked with conventional teat liners, and the second 3 months phase (Gr 2) was the experimental phase and milked with SSL teat cup liners. On the second farm 90 dairy cows of Simmental breed in Baden-Württemberg, Germany (farm 2) were examined for one year equally divided in the first 6 months of control phase and second 6 months of treatment phase. All cows on both farms had the same stage of lactation and lactation number. During the study period, the daily milk production of each cow was recorded and milk samples were collected to determine the ingredients. The results showed that higher daily milk production and better milk quality were observed after using the new SSL teat cup liner in the existing milking machines. However, the use of the new teat cup liner SSL was more efficient in the longer treatment in farm 2 than in farm 1. In addition, after the use of the new SSL teat cup liner, the udders remained healthy throughout the study period, showing lower somatic cell counts (SCC). It can be concluded that high milk yield and better milk quality can be achieved by using SSL teat cup liners, as they are adapted to all teat shapes and dimensions.

Influence of the new wavy teat liner “Stimulor StressLess” on milk yield performance and its quality in dairy cows: Results of a field study

The ideal milking system meets the physiological needs of dairy cows to increase milk yield, achieve better milk quality and maintain healthy udders. Therefore, the settings of the milking machine and the properties of the teat cup liners are very important on dairy farms. The aim of the present study was to test a new teat cup liner “Stimulor StressLess” (SSL) in two commercial dairy farms and to investigate its influence on daily milk production and quality having different experimental settings. For this purpose, 40 dairy cows of different breeds in Tirol, Austria (farm 1) were investigated for 6 months, where 3 months represent the control phase (Gr 1) and milked with conventional teat liners, and the second 3 months phase (Gr 2) was the experimental phase and milked with SSL teat cup liners. On the second farm 90 dairy cows of Simmental breed in Baden-Württemberg, Germany (farm 2) were examined for one year equally divided in the first 6 months of control phase and second 6 months of treatment phase. All cows on both farms had the same stage of lactation and lactation number. During the study period, the daily milk production of each cow was recorded and milk samples were collected to determine the ingredients. The results showed that higher daily milk production and better milk quality were observed after using the new SSL teat cup liner in the existing milking machines. However, the use of the new teat cup liner SSL was more efficient in the longer treatment in farm 2 than in farm 1. In addition, after the use of the new SSL teat cup liner, the udders remained healthy throughout the study period, showing lower somatic cell counts (SCC). It can be concluded that high milk yield and better milk quality can be achieved by using SSL teat cup liners, as they are adapted to all teat shapes and dimensions.

Zn-phosphate conversion coatings developed on high-strength steels at reduced processing temperature

The effect of process time, ultrasonic stirring, and the addition of H2PO4- on the morphology and corrosion resistance of phosphate conversion coatings was investigated by Scanning Electron Microscopy and electrochemical tests. The phosphating treatments were performed at 50 °C, lower than traditional processes, and pH 2.9 and 2.4. An enhanced film of bigger mass and reduced corrosion rate was produced when the processing time was extended from 6 to 30 min. at pH 2.9. No important changes were identified in the appearance other than a slight crystal coarsening and Zn enrichment. Both the ultrasonic stirring and the addition of H2PO4- (pH 2.9, 6 min.) accelerate the coating formation rate and assist in the formation of more uniform layers with a greater Zn concentration. An important crystal refinement was also obtained in the ultrasound-induced treatment, whereas no relevant changes were found for the corrosion behaviour. The addition of H2PO4- in the amount of 10 g/L (pH 2.9, 6 min.) facilitates the formation of a layer with a quality like that found in the longest treatment (30 min.). None of the tested variables provided an effective modification to improve the performance of the conversion layers developed for the baths considered in this study at pH 2.4.

Risk-stratified treatment for drug-susceptible pulmonary tuberculosis

The Phase 3 randomized controlled trial, TBTC Study 31/ACTG A5349 (NCT02410772) demonstrated that a 4-month rifapentine-moxifloxacin regimen for drug-susceptible pulmonary tuberculosis was safe and effective. The primary efficacy outcome was 12-month tuberculosis disease free survival, while the primary safety outcome was the proportion of grade 3 or higher adverse events during the treatment period. We conducted an analysis of demographic, clinical, microbiologic, radiographic, and pharmacokinetic data and identified risk factors for unfavorable outcomes and adverse events. Among participants receiving the rifapentine-moxifloxacin regimen, low rifapentine exposure is the strongest driver of tuberculosis-related unfavorable outcomes (HR 0.65 for every 100 µg∙h/mL increase, 95%CI 0.54–0.77). The only other risk factors identified are markers of higher baseline disease severity, namely Xpert MTB/RIF cycle threshold and extent of disease on baseline chest radiography (Xpert: HR 1.43 for every 3-cycle-threshold decrease, 95%CI 1.07–1.91; extensive disease: HR 2.02, 95%CI 1.07–3.82). From these risk factors, we developed a simple risk stratification to classify disease phenotypes as easier-, moderately-harder, or harder-to-treat TB. Notably, high rifapentine exposures are not associated with any predefined adverse safety outcomes. Our results suggest that the easier-to-treat subgroup may be eligible for further treatment shortening while the harder-to-treat subgroup may need higher doses or longer treatment.

Deep brain stimulation targets in drug-resistant epilepsy: Systematic review and meta-analysis of effectiveness and predictors of response

PurposeAnterior nucleus of the thalamus (ANT) is the only deep brain stimulation (DBS) target that is approved by the FDA for treatment of drug-resistant epilepsy (DRE). Hippocampus (HC) and centromedian nucleus (CMN) have been reported as potential DBS targets for DRE. This study aimed to assess the effectiveness and predictors of response among DRE patients treated with DBS in general and among ANT, HC and CMN DBS-targets. MethodsA systematic search was executed on PubMed, SCOPUS and the Cochrane Central Register of Controlled Trials (CENTRAL) electronic databases between Jan 1, 2000 and June 29, 2020. Patients with DRE who underwent DBS treatment with at least three months of follow-up were included. Individual patient data (IPD) meta-analysis was conducted on DBS studies with available IPD. Response was defined as ≥50 % reduction in seizures frequency. Responders group was compared with non-responders group in terms of demographics, epilepsy/seizure characteristics, MRI findings, and DBS targets and duration of use. Subsequently, predictors of response to different DBS targets were investigated. ResultsThirty-nine studies with a total of 296 patients (ANT: 69 %, HC: 11 %, CMN: 21 %) were included. The responders group constituted of 209 patients (70.6 %). The response was significantly higher in patients with generalized seizures compared to those with focal seizures (93.2% vs 63.9 %; p < 0.001). Response was significantly higher with CMN (83.9 %) and HC (77.4 %) compared with ANT (65.5 %) as DBS targets (p = 0.014). Response was also significantly associated with longer duration of DBS use (p = 0.008). The responder rate was higher among the patients with lesional MRIs (76.7 %) than those with non-lesional MRIs (66.7 %), but with no statistically significant difference (p = 0.134). Age, gender, epilepsy etiology, onset zone of focal seizures, and previous use of VNS had no significant differences between the responders and non-responders. A binary logistic regression including the seizure type, MRI findings, DBS targets, and DBS duration showed, after controlling for confounders, that the duration of DBS use was the only significant predictor of response (adjusted OR 1.061; 95 % CI 1.019–1.106; p = 0.005). Regarding DBS targets, the response rate in patients with symptomatic etiology was significantly higher with HC or CMN targets than the ANT (p = 0.003). In patients with non-lesional MRI, response rate was significantly higher with the CMN target compared to the other two targets (p = 0.008). ConclusionDBS proves to be effective in DRE, with progressive success upon longer treatment and possibility of improving quality of life. In addition to focal seizures, DBS has potential for treating generalized seizures as well. While the ANT stands as the most utilized and only approved DBS target for DRE, CMN and HC are alternative targets with high seizure control potential. Patients with symptomatic etiology showed significant seizure reduction when HC or CMN were targeted. Studies revealed noticeable effectiveness of CMN-DBS in treating patients with non-lesional MRI. Despite ANT prominence in research, our findings suggest promising outcomes with CMN and HC, emphasizing the need for future larger-scale comparative clinical trials to better understand the efficacy of different DBS targets.

Risk of dementia after initiation of sodium-glucose cotransporter-2 inhibitors versus dipeptidyl peptidase-4 inhibitors in adults aged 40-69 years with type 2 diabetes: population based cohort study

ObjectiveTo compare the risk of dementia associated with sodium-glucose cotransporter-2 (SGLT-2) inhibitors versus dipeptidyl peptidase-4 (DPP-4) inhibitors in adults aged 40-69 years with type 2 diabetes.DesignPopulation based cohort study.SettingKorean National...

Systematic review and meta-analyses of cytisine to support tobacco cessation.

Cytisine (also known as cytisinicline) is a low-cost partial agonist of nicotinic acetylcholine receptors used to assist tobacco cessation. We aimed to review the effectiveness of cytisine for tobacco cessation and the effects of dose and co-use of behavioural or other pharmacological interventions on cessation outcomes. We searched seven databases, Google Scholar, and reference lists of included publications for randomised controlled trials investigating use of cytisine as a tobacco cessation aid. Studies were eligible if participants were ≥15 years old and used tobacco upon study enrolment. We conducted four random effects meta-analyses and sensitivity analyses with fixed effects models. We used the Cochrane risk-of-bias tool for randomised trials version 2 to assess risk of bias in included studies, with adjustments recommended by the Cochrane Tobacco Addiction Group. Participants using cytisine were significantly more likely to quit tobacco than participants who received placebo/no intervention/usual care (risk ratio [RR] = 2.65, 95% confidence interval [CI] = 1.50-4.67, 6 trials, 5194 participants) or nicotine replacement therapy (RR = 1.36, 95% CI = 1.06-1.73, p = 0.0152, 2 trials, 1511 participants). The difference in cessation rates among participants receiving cytisine versus varenicline was not statistically significant (RR = 0.96, 95% CI 0.63-1.45, P = 0.8464, 3 trials, 2508 participants). Two trials examined longer versus shorter treatment duration, finding higher abstinence rates with longer treatment (RR = 1.29, 95% CI = 1.02-1.63, 2 trials, 1009 participants). The differences in the number of adverse events reported by participants who received cytisine versus placebo (RR = 1.19, 95% CI = 0.99-1.41, P = 0.0624; 6 trials; 4578 participants) or cytisine versus varenicline (RR = 1.37, 95% CI = 0.57-3.33, P = 0.4835; 2 trials; 1345 participants) were not statistically significant. Most adverse events were mild (e.g. abnormal dreams, nausea, headaches). Cytisine is an effective aid for tobacco cessation and appears to be more effective for tobacco cessation than placebo, no intervention, usual care and nicotine replacement therapy.

HDAC I/IIb selective inhibitor purinostat mesylate in relapsed and refractory diffuse large B-cell lymphoma: A single agent phase IIa trial.

LBA7074 Background: Relapsed/refractory diffuse large B-cell lymphoma (r/r DLBCL) has a poor prognosis. Double-expressor (DEL) or TP53 abnormal r/r DLBCL patients(pts) are associated with even worse outcomes. Class I and IIb histone deacetylases (HDACs) are overexpressed in DLBCL and have been identified as a therapy target. Purinostat Mesylate (PM) is a high selective HDAC I/IIb inhibitor. Phase I dose-escalation trial of PM (1.2, 2.4, 4.0, 6.0, 8.4, 11.2, 15 mg/m2) by i.v was conducted in 29 hematologic malignancies at day 1, 4, 8, 11 of a 21-day cycle. PM was generally well tolerated with no DLTs. 61.1% (11/18) ORR was observed in r/r lymphoma pts. Based on these data, we conducted a phase 2a to further explore efficacy and safety of PM and mechanism of actions. Methods: This randomized, multicenter, open-label, phase 2a study was conducted from Nov.2022 to the present(NCT05563844). Key eligibility include r/r DLBCL pts with prior therapy including anti-CD20 antibody and anthracycline-based chemotherapy; ECOG≤2. Thirty pts were randomized 1:1 received PM at 8.4 and 11.2 mg/m2 on Day 1, 4, 8, 11 of a 21-day cycle. Pts continued to receive PM until disease progression or unacceptable toxicity. Primary outcome was ORR and safety. Multiple cell lines and PDX mouse models were used to evaluate the PM activity and mechanism of action in vitro and in vivo. ATAC-seq, bulk RNA-seq, and scRNA-seq from both PDX models and pts were investigated for the activated immune response of PM. Results: Thirty patients were enrolled and 28 patients were evaluable. The ORR (20/28) was 71.4% (95%CI:51.3-86.8) with 5 CR and 15 PR. Fifteen pts at 8.4 mg/m2 achieved an ORR of 66.7%(95%CI:38.4-88.2) with 1 CR and 9 PR. Thirteen pts at 11.2 mg/m2 achieved ORR of 76.9%(95%CI:46.2-95.0) with 4 CR and 6 PR. As of the data cut off in Feb. 2024, 7 pts remained on treatment and the longest treatment has lasted 17 cycles. Median PFS was 4.3m (95%CI:2.8-8.5), OS were immature. In subgroup analyses, 7 DE DLBCL pts obtained 42.9%(3/7) ORR and 11 pts with TP53 abnormal by FISH or NGS test achieved 45.5%(5/11) ORR. Fifteen pts with non-DE or without TP53 abnormal achieved ORR of 86.7%(13/15). The most frequently reported Grade≥3 TRAE were thrombocytopenia, neutropenia, lymphocytopenia. No PM-related death was reported. PM monotherapy showed stronger and superior antitumor effects in DE DLBCL and TP53 mutations PDX models than selinexor and R-CHOP. PM significantly down-regulates the proteins c-MYC, EZH2, and mutated P53. ATAC-seq, bulk RNA-seq and scRNA-seq revealed that PM can stimulate the proliferation and activation of cytotoxic T cells and NKT cells, up-regulate the expression of B-cell tumor MHC I and II and inhibit tumor cell immune escape. Conclusions: This study further supports the recommended dose 11.2 mg/m2 PM as the phase 2b for r/r DLBCL. Currently, the phase 2b, open-label, multicenter study has enrolled in 37 sites in China. Clinical trial information: NCT05563844 .

Multistrain probiotics fail to modulate the asthmatic phenotype, respiratory microbiota, and immune responses in cats.

To determine if multistrain probiotics administered to asthmatic cats treated with anti-inflammatory glucocorticoids would attenuate the asthmatic phenotype and beneficially alter respiratory, blood, and oropharyngeal (OP) microbial communities and immune parameters versus placebo. 13 client-owned asthmatic cats. A randomized, blinded, placebo-controlled clinical trial of asthmatic cats receiving anti-inflammatory glucocorticoids with oral multistrain probiotics or placebo assessed owner-perceived improvement and airway eosinophilia at baseline and after 2 weeks of treatment. Bronchoalveolar lavage fluid (BALF), blood, OP, and rectal microbial communities were compared using 16S rRNA amplicon sequencing. Real-time PCR for transcription factors, activation markers and cytokines, and IgA ELISAs were evaluated. Statistical analyses used 2-way repeated-measures ANOVA or permutational ANOVA (significance, P < .05). After treatment, there were no significant differences in owner-perceived clinical signs or mean ± SEM BALF eosinophils between groups. There was a significant decrease in rectal α-diversity but not in α- or β-diversity in BALF, blood, or OP between groups or over time. There were no significant differences in CD25, FoxP3, GATA, Helios, IL-4, IL-5, IL-10, IL-13, IL-17, IFN-γ mRNA, or serum or BALF IgA between groups or over time. In asthmatic cats, oral multistrain probiotics failed to improve owner-perceived signs, reduce airway eosinophilia, modify microbial community composition, or alter assessed immune responses versus placebo or over time. Longer treatment, different probiotic composition or delivery (eg, aerosolized), or larger number of cats would represent the next stages of study.

Sputum culture reversion in longer treatments with bedaquiline, delamanid, and repurposed drugs for drug-resistant tuberculosis

Sputum culture reversion after conversion is an indicator of tuberculosis (TB) treatment failure. We analyze data from the endTB multi-country prospective observational cohort (NCT03259269) to estimate the frequency (primary endpoint) among individuals receiving a longer (18-to-20 month) regimen for multidrug- or rifampicin-resistant (MDR/RR) TB who experienced culture conversion. We also conduct Cox proportional hazard regression analyses to identify factors associated with reversion, including comorbidities, previous treatment, cavitary disease at conversion, low body mass index (BMI) at conversion, time to conversion, and number of likely-effective drugs. Of 1,286 patients, 54 (4.2%) experienced reversion, a median of 173 days (97-306) after conversion. Cavitary disease, BMI < 18.5, hepatitis C, prior treatment with second-line drugs, and longer time to initial culture conversion were positively associated with reversion. Reversion was uncommon. Those with cavitary disease, low BMI, hepatitis C, prior treatment with second-line drugs, and in whom culture conversion is delayed may benefit from close monitoring following conversion.

Quantitative and Longitudinal Assessment of Systemic Innate Immunity in Health and Disease Using a 2D Gene Model.

Dysregulation of innate immunity is deeply involved in infectious and autoimmune diseases. For a better understanding of pathogenesis and improved management of these diseases, it is of vital importance to implement convenient monitoring of systemic innate immunity. Built upon our previous works on the host transcriptional response to infection in peripheral blood, we proposed a 2D gene model for the simultaneous assessment of two major components of systemic innate immunity, including VirSig as the signature of the host response to viral infection and BacSig as the signature of the host response to bacterial infection. The revelation of dysregulation in innate immunity by this 2D gene model was demonstrated with a wide variety of transcriptome datasets. In acute infection, distinctive patterns of VirSig and BacSig activation were observed in viral and bacterial infection. In comparison, both signatures were restricted to a defined range in the vast majority of healthy adults, regardless of age. In addition, BacSig showed significant elevation during pregnancy and an upward trend during development. In tuberculosis (TB), elevation of BacSig and VirSig was observed in a significant portion of active TB patients, and abnormal BacSig was also associated with a longer treatment course. In cystic fibrosis (CF), abnormal BacSig was observed in a subset of patients, and no overall change in BacSig abnormality was observed after the drug treatment. In systemic sclerosis-associated interstitial lung disease (SSc-ILD), significant elevation of VirSig and BacSig was observed in some patients, and treatment with a drug led to the further deviation of BacSig from the control level. In systemic lupus erythematosus (SLE), positivity for the anti-Ro autoantibody was associated with significant elevation of VirSig in SLE patients, and the additive effect of VirSig/BacSig activation was also observed in SLE patients during pregnancy. Overall, these data demonstrated that the 2D gene model can be used to assess systemic innate immunity in health and disease, with the potential clinical applications including patient stratification, prescription of antibiotics, understanding of pathogenesis, and longitudinal monitoring of treatment response.

Incidence, Outcomes, and Risk Factors for Isoniazid-Resistant Tuberculosis from 2012 to 2022 in Eastern China.

Isoniazid-resistant, rifampicin-susceptible tuberculosis (Hr-TB) is the most frequent drug-resistant tuberculosis (DR-TB) in the world, and unfavorable outcomes of Hr-TB are more common compared to drug-susceptible TB. Considering there is no optimal regimen accepted worldwide, we undertook a retrospective cohort study in eastern China to estimate incidence trends and risk factors associated with unfavorable outcomes of Hr-TB. Between January 2012 and December 2022, all Hr-TB patients' information was extracted from the Tuberculosis Information Management System (TIMS), which is a national electronic information platform, to record TB patients' clinical information in this study. The incidence of Hr-TB was determined by the mid-year population according to census data published by the government. We categorized treatment regimens depending on fluoroquinolone (FQ) use, and potential risk factors were analyzed using multivariable logistic regression. A total of 3116 Hr-TB patients fulfilled the inclusion criteria and were enrolled in this study. The average annual rate of Hr-TB in the 11 years under investigation was 0.34 per 100,000 and increased to 0.53 per 100,000 until 2019. In total, six different treatment regimens were utilized in the study sites, and less than 1% of regimens adopted FQ. There was no difference in the unfavorable outcomes between the FQ-included and FQ-excluded groups (p = 0.22). The average treatment duration was 7.06 months, and the longest treatment was 26 months. Approximately 20% (637/3116) of Hr-TB patients had unfavorable outcomes, and 60.13% (383/637) of them proceeded to multidrug-resistant tuberculosis (MDR-TB). Treatment duration and a positive smear at the end of the 5th month were significantly associated with unfavorable outcomes (p < 0.001). The unfavorable treatment outcomes of Hr-TB are still high in eastern China, and the efficacy of FQ-containing regimens needs to be validated for Hr-TB treatment.

Clinical Characteristics, Treatment, and Prognosis of Osteoarticular Brucellosis: A Retrospective Real-World Study in Shenyang, China, 2014-2019.

This study aimed to assess the clinical characteristics, treatment, and prognosis of osteoarticular brucellosis. We conducted a retrospective study enrolling brucellosis patients from the Sixth People's Hospital of Shenyang between September 2014 and June 2019. A total of 1917 participants were admitted during this period. After applying propensity score matching, we retrospectively analyzed 429 patients with osteoarthritis and 429 patients without osteoarthritis. The primary outcome was treatment completion. The secondary outcome was symptom disappearance and seroconversion. Brucellosis patients with osteoarthritis had longer treatment course (160 [134.3-185.7] vs. 120 [102.3-137.7] d, p = 0.008) than those without osteoarthritis. The most common involved site was lumbar vertebrae (290 [67.6%]) in brucellosis patients with osteoarthritis. Longer symptom duration (90 [83.0-97.0] vs. 42 [40.2-43.8], p < 0.001) along with no significant difference in seroconversion (180 [178.8-181.2] vs. 180 [135.1-224.9], p = 0.212) was observed in osteoarthritis patients with treatment course >90 d. Peripheral joint involvement (adjusted hazard ratio [95% confidence interval] 1.485 [1.103-1.999]; p = 0.009) had a shorter symptom duration compared with shaft joint involvement. No significant differences were observed in treatment therapy between doxycycline plus rifampin (DR) or plus cephalosporins (DRC) in treatment course (p = 0.190), symptom persistence (p = 0.294), and seroconversion (p = 0.086). Lumbar vertebra was the most commonly involved site. Even if all symptoms disappeared, Serum agglutination test potentially remained positive in some patients. Compared with peripheral arthritis, shaft arthritis was the high-risk factor for longer symptom duration. The therapeutic effects were similar between DR and DRC. In summary, our study provided important insights into the clinical characteristics, treatment, and outcomes of osteoarticular brucellosis. Clinical Trial Registration number: NCT04020536.

Abstract 4295: Apoptotic DNase DFFB-induced DNA damage within cancer persister cells underlies acquired resistance to targeted therapies across multiple tumor types

Abstract Cancer acquired drug resistance contributes to a large proportion of patient deaths. A major obstacle to the development of effective therapies which prevent resistance is our lack of understanding of the relevant fundamental molecular adaptive processes. Here we report the discovery that tumor cells rely upon sublethal engagement of apoptotic death machinery and apoptotic DNase DFFB to acquire resistance to targeted therapies in multiple tumor types in cell culture and in vivo. We found that while DFFB wild type tumor cells readily acquire resistance to targeted therapies by escaping from the quiescent “persister” state into proliferating resistant cells, persister cells lacking functional DFFB remain indefinitely in a quiescent state on treatment. Mechanistically, we found that DFFB, which is activated by apoptotic caspases in surviving cancer persister cells, induces persistent DNA damage which promotes resistance through acquired mutations and nongenetic resistance through suppression of growth-arresting interferon signaling. During drug treatment acute interferon induction arises from sublethal mitochondrial outer membrane permeabilization and cytoplasmic exposure of mitochondrial nucleic acids which activate pattern recognition receptors. However, during longer treatments we found that DFFB knockout persister cells exhibit strikingly elevated levels of STAT1 and STAT2 and interferon stimulated gene sets. This interferon signaling is growth arresting because treatment of DFFB knockout persister cells with a JAK1/2 inhibitor rescues their ability to regrow. Furthermore, in DFFB wild type persister cells we found that DFFB-dependent DNA damage activates stress response transcription factor ATF3 which blocks the transcriptional activation of interferon stimulated genes following initial interferon induction. This is consistent with prior data in other contexts demonstrating that ATF3 is induced by DNA damage and that ATF3 directly binds to promoters of multiple interferon genes repressing their expression. These findings reveal that DFFB activation in persister cells prevents chronic interferon signaling and enables escape into proliferating drug resistant tumor cells. Therefore, DFFB-mediated interferon suppression represents a novel mechanism that is fundamental to acquired drug resistance. In addition, high expression of DFFB and ATF3 correlates with worse overall survival in a pan-cancer analysis and DFFB knockout mice develop normally indicating DFFB is a nonessential gene in normal tissue. Therefore, we propose that DFFB is a promising therapeutic target to prevent acquired resistance to targeted therapy. Citation Format: August Finley Williams, David A. Gervasio, Claire E. Turkal, Anna E. Stuhlfire, Michael X. Wang, Brandon E. Mauch, Ariel H. Nguyen, Michelle H. Paw, Mehrshad Hairani, Cooper P. Lathrop, Sophie H. Harris, Jennifer L. Page, Matthew J. Hangauer. Apoptotic DNase DFFB-induced DNA damage within cancer persister cells underlies acquired resistance to targeted therapies across multiple tumor types [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4295.

Herbal therapy in diabetes mellitus: A review

Insulin therapy is the mainstay of treatment in patients with type 1 diabetes, while diet and lifestyle changes, and if left untreated, insulin therapy are effective in treating type 2 diabetes. Research has shown that the oldest treatment for diabetes was the use of herbs. Thus, various medicinal plants were used to relieve many of the complications of diabetes. This study aimed to assess the effectiveness of various medicinal plants in the treatment of diabetes. The data on medicinal plants and diabetes were collected from related articles published from 2014 to 2021 in reputable databases such as Cochrane, PubMed, Scopus, ScienceDirect, Embase, and SID. Data analysis showed that medicinal plants such as Allium sativum, Cinnamomum verum, Trigonella graecum foenum, Silybum marianus, Citrullus colocynthis, Abelmoschus esculentus, Eryngium, Coriandrum sativum L, and Zingiber officinale were the most frequently used herbs in the treatment of diabetes. Medicinal plants can reduce blood sugar in patients due to having effective medicinal compounds and natural antioxidants and due to the least side effects but longer treatment period.Keywords: Diabetes; Medicinal plants; Remedy; Pharmaceutical Plant

Biomarkers predicting the controller dose of omalizumab in patients with chronic spontaneous urticaria.

Clinical trials showed the efficacy of 300 mg/4 weeks of omalizumab (OMA) during 6 months in patients with severe chronic spontaneous urticaria (CSU). Nevertheless, in real life, many patients require higher doses and/or longer treatment. This study assesses the real-life performance of OMA in severe CSU and identifies factors associated with the response. CSU patients eligible for OMA were recruited prospectively. Clinical data and a blood test were collected before OMA initiation. Urticaria Activity Score 7 (UAS7) was calculated at baseline and every 3 months during OMA treatment. CSU control was defined as UAS7 <7 points. This work was partially sponsored by OMA manufacturer. Eighty-nine adults (19.1% males) with severe CSU were recruited. Median duration of CSU prior to OMA initiation was 2 years, and median severity by UAS7 at baseline was 24 points (range 10-42 points). OMA controlled 94.4% of patients, but 17.9% of responders required doses >300 mg/4 weeks. A blood basophil count >20 cells/μL (OR 13.33; 95% CI 3.32-52.63; p < .001) and the absence of hypothyroidism (OR 3.65; 95% CI 0.78-16.95; p = .099) were identified as predictive factors to achieve control with 300 mg/4 weeks. Twelve patients were able to stop OMA during the study (responders in remission, RR). RR had received OMA for a median of 29 months (12-53 months). Conversely, 32 patients had been on OMA for >29 months at the end of the study (active responders, AR). AR had received OMA for a median of 45 months (30-100 months). There were no significant differences in clinical or analytical factors between RR and AR patients. Low blood basophil count and the presence of hypothyroidism might serve as biomarkers for the controller dose of OMA in severe CSU patients.

E14a2 Transcript Favors Treatment-Free Remission in Chronic Myeloid Leukemia When Associated with Longer Treatment with Tyrosine Kinase Inhibitors and Sustained Deep Molecular Response

e13a2 and e14a2 are the most frequent transcript types of the BCR::ABL1 fusion gene in chronic myeloid leukemia (CML). The current goal with tyrosine kinase inhibitors (TKI) is to achieve sustained deep molecular response (DMR) in order to discontinue TKI treatment and remain in the so-called treatment-free remission (TFR) phase, but biological factors associated with these goals are not well established. This study aimed to determine the effect of transcript type on TFR in patients receiving frontline treatment with imatinib (IM) or second-generation TKI (2G-TKI). Patients treated at least 119 months with IM presented less post-discontinuation relapse than those that discontinued IM before 119 months (p = 0.005). In addition, cases with the e14a2 transcript type treated at least 119 months with IM presented a better TFR (p = 0.024). On the other hand, the type of transcript did not affect the cytogenetic or molecular response in 2G-TKI treated patients; however, the use of 2G-TKI may be associated with higher and earlier DMR in patients with the e14a2 transcript.

The Dual Role of Sulforaphane-Induced Cellular Stress-A Systems Biological Study.

The endoplasmic reticulum (ER) plays a crucial role in cellular homeostasis. When ER stress is generated, an autophagic self-digestive process is activated to promote cell survival; however, cell death is induced in the case of excessive levels of ER stress. The aim of the present study was to investigate the effect of a natural compound called sulforaphane (SFN) upon ER stress. Our goal was to investigate how SFN-dependent autophagy activation affects different stages of ER stress induction. We approached our scientific analysis from a systems biological perspective using both theoretical and molecular biological techniques. We found that SFN induced the various cell-death mechanisms in a concentration- and time-dependent manner. The short SFN treatment at low concentrations promoted autophagy, whereas the longer treatment at higher concentrations activated cell death. We proved that SFN activated autophagy in a mTORC1-dependent manner and that the presence of ULK1 was required for its function. A low concentration of SFN pre- or co-treatment combined with short and long ER stress was able to promote cell survival via autophagy induction in each treatment, suggesting the potential medical importance of SFN in ER stress-related diseases.

Cold atmospheric plasma modified polycaprolactone solution prior to electrospinning: A novel approach for improving quercetin-loaded nanofiber drug delivery systems

In this study, we present a novel approach for enhancing the performance of Quercetin-loaded nanofiber drug delivery systems through the modification of Polycaprolactone (PCL) solution using Cold Atmospheric Plasma (CAP) prior to electrospinning. CAP treatment was applied to PCL solutions for varying durations, namely, 0.5, 1, and 3 min. Scanning electron microscopy (SEM) and atomic force microscopy (AFM) collectively demonstrate that CAP application and QU loading induce morphological changes in nanofibers, facilitating the creation of drug delivery systems with modified fiber diameters, devoid of bead formation. CAP treatment duration correlates with varying fiber diameters, with the longest treatment (3 min) producing the largest fibers (1324 ± 387 nm). Concurrently, the incorporation of quercetin (QU) into the PCL nanofibers resulted in reduced fiber diameter. These observations emphasize the pivotal role of CAP modification in tailoring nanofiber size and morphology. Notably, minimal peak shifts indicate no significant molecular structure changes in PCL nanofibers compared to PCL solutions, assuring the absence of unwanted chemical modifications or degradation during electrospinning. Furthermore, specific QU peaks are undetectable in Fourier-transform infrared (FTIR) spectra, suggesting dispersed or amorphous QU molecules within the nanofibers. Additionally, X-ray diffraction (XRD) results demonstrate that CAP treatment does not alter the crystalline structure of the PCL nanofiber drug delivery system. Crystalline planes of PCL remain unchanged, affirming stability under CAP treatment conditions. Water contact angles indicate that CAP treatment affects nanofiber hydrophobicity, with shorter CAP treatment times rendering more hydrophilic surfaces. Cumulative QU release percentages vary, with PCL/CAP-0.5-QU exhibiting the highest release at 56 ± 2.2 %, surpassing unmodified PCL/QU. Moreover, cell viability remains comparable or slightly increased when QU is incorporated into CAP-treated PCL nanofibers, suggesting potential mitigation of cytotoxic effects induced by CAP treatment. The combination of QU and CAP treatment enhances cancer cell viability reduction, QU release from nanofibers, and drug loading efficiency in a synergistic manner.