Effect Of Combined Treatment Research Articles

Combined effects of gibberellin and vermiwash on the life history and antioxidant system of Phthorimaea absoluta (Meyrick) in tomato plants

Tomato (Lycopersicon esculentum Miller), is a globally important agricultural product, yet it is under significant threat from pests such as the tomato leaf miner, Phthorimaea absoluta (Meyrick) (Lepidoptera: Gelechiidae). This study investigates the combined effects of gibberellin and vermiwash treatment on the life history and antioxidant system of P. absoluta. Given the pest’s resistance to many chemical pesticides, alternative control methods are crucial. Gibberellins are plant growth hormones known for their role in plant development and stress responses, while vermiwash is a bio-fertilizer rich in nutrients and microbial agents. We applied gibberellin and vermiwash (GV treatment) to tomato plants and assessed the impact on P. absoluta developmental stages, reproduction, and enzymatic activities. Our results show significant differences in larval development times (32.06 ± 0.39) and survival rates (0.53 ± 0.09) between treated and control groups (27.38 ± 0.35 and 0.80 ± 0.07, respectively). The GV treatment prolonged the total lifespan of P. absoluta (44.31 ± 0.51) but reduced its intrinsic rate of increase (r) (0.086 ± 0.009) and finite rate of increase (λ) (1.090 ± 0.009). Enzymatic assays revealed altered antioxidant and detoxifying enzyme activities in treated larvae. This study suggests that gibberellin and vermiwash treatments could be incorporated into pest management strategies for sustainable tomato production.

Combining procedural and behavioral treatments for chronic low back pain: A pilot feasibility randomized controlled trial.

Individual treatments for chronic low back pain (CLBP) have small magnitude effects. Combining different types of treatments may produce larger effects. To (1) assess feasibility of conducting a factorial randomized controlled trial of these treatments; and (2) estimate individual and combined treatment effects of (a) lumbar radiofrequency ablation (LRFA) of the dorsal ramus medial branch nerves (vs. a simulated LRFA control procedure) and (b) Activity Tracker-Informed Video-Enabled Cognitive Behavioral Therapy program for CLBP (AcTIVE-CBT) (vs. an educational control treatment) on back-related disability at 3 months post-randomization. Participants (n = 13) were randomized in a 1:1:1:1 ratio in a 2 × 2 factorial randomized controlled trial. Feasibility goals included an enrollment proportion ≥ 30%, a randomization proportion ≥ 80%, and a ≥ 80% proportion of randomized participants completing the 3-month Roland-Morris Disability Questionnaire (RMDQ) primary outcome end point. An intent-to-treat analysis was used. The enrollment proportion was 62%, the randomization proportion was 81%, and all randomized participants completed the primary outcome. Though not statistically significant, there was a beneficial, moderate-magnitude effect of LRFA versus control on 3-month RMDQ (-3.25 RMDQ points [95% confidence interval [CI], -10.18 to 3.67]). There was a significant, beneficial, large-magnitude effect of AcTIVE-CBT versus control (-6.29 [95% CI, -10.97 to -1.60]). Though not statistically significant, there was a beneficial, large effect of LRFA+AcTIVE-CBT versus control (-8.37 [95% CI: -21.47, 4.74]). We conclude that it is feasible to conduct a randomized controlled trial combining procedural and behavioral treatments for CLBP. gov Registration: https://clinicaltrials.gov/ct2/show/NCT03520387.

PAR2 Participates in the Development of Cough Hypersensitivity in Guinea Pigs by Regulating TRPA1 Through PKC

Objective: This study was conducted to validate the involvement of the PAR2-PKC-TRPA1 pathway in cough hypersensitivity (CHS) development. Methods: Guinea pigs were divided into a blank control, a citric acid-induced enhanced cough model, and drug intervention groups. The effects of the drugs on capsaicin-induced cough responsiveness in a cough model were observed. The effects of individual and combined treatments (including PAR2 agonists, TRPA1 agonists, PAR2 antagonists, TRPA1 antagonists, PKC agonists, and PKC antagonists) on PAR2, phospho-PKC (pPKC), and TRPA1 expression in bronchial tissues and the vagus ganglion (jugular and nodose) in the cough model and control groups were assessed. Additionally, whole-cell patch-clamp recordings were conducted to evaluate the effects of the drugs on vagus ganglion neuron electrophysiological activity. Results: ① Both PAR2 antagonists and TRPA1 antagonists significantly reduced cough frequency in guinea pigs with a cough, and the PAR2 antagonist inhibited coughing induced by the TRPA1 agonist. ② Western blotting and multiplex immunohistochemistry (mIHC) indicated that PAR2, pPKCα, PKCα, and TRPA1 expression in bronchial and vagus ganglion tissues was elevated in the cough model compared with the control, with TRPA1 expression being regulated by PAR2 and PKC being involved in this regulatory process. ③ Whole-cell patch-clamp recordings demonstrated that TRPA1 agonists induced an inward current in nodose ganglion neurons, which was further amplified by PAR2 agonists; this amplification effect was blocked by PKC antagonist. Additionally, PAR2 antagonists inhibited the inward current induced by TRPA1 agonists. ④ At various concentrations, including the optimal antitussive concentration, PAR2 antagonists did not significantly affect pulse amplitude, arterial oxygen saturation, heart rate, body temperature, or respiratory rate in guinea pigs. Conclusion: PAR2 regulates TRPA1 through PKC in cough syndrome (CHS) pathogenesis, making targeting PAR2 a safe and effective therapeutic strategy for CHS.

Effects of Fish Oil with Heat Treatment on Obesity, Inflammation, and Gut Microbiota in Ovariectomized Mice

Background/Objectives: Menopause induces substantial metabolic changes, including a reduction in metabolic rate and an elevated risk of developing metabolic diseases. Fish oil (FO) supplementation has been shown to ameliorate menopause-associated metabolic risks. Hyperthermia treatment (HT) has recently gained attention for its potential to improve metabolic and immune health. However, it remains to be determined whether HT can confer metabolic benefits comparable to those of FO supplementation or enhance the metabolic benefits of FO supplementation. This study aims to delineate the distinctive and collaborative effects of HT and FO supplementation in mitigating menopause-associated metabolic dysfunction. Methods: Female C57BL/6 ovariectomized (OVX) mice were randomly assigned to four groups (n = 12/group) to evaluate the individual and combined effects of FO supplementation (5% w/w) and HT treatment. For HT, whole-body heat exposure was conducted at 40–41 °C for 30 min, 5 days per week. After 12 weeks, animals were used to evaluate the changes in glucose and lipid metabolism, obesity outcome, and inflammatory markers. The gut microbiome analysis was conducted from cecal content by 16S rRNA sequencing. Acute inflammation was induced by lipopolysaccharide (LPS) injection to evaluate inflammatory responses. Results: HT alone distinctively reduced weight gain, lowered core body temperature, and attenuated insulin resistance comparable to FO supplement in OVX mice. The collaborative effect of FO and HT was not evident in metabolic parameters but more prominent in attenuating proinflammatory responses and microbiota modulation. Conclusions: Our findings suggest that the combined treatment of FO supplementation and HT may serve as an effective strategy to mitigate menopause-associated immune susceptibility and metabolic dysfunction. These benefits are likely mediated, at least in part, through the reduction in inflammation and modulation of the gut microbiota.

Correlation between interfacial bonding behavior and surface treatments in bonded carbon fiber composite joints

AbstractSurface treatments play a crucial role in enhancing the bonding strength of composites. The effect of surface treatment has received much attention in the literature but reported effect of combined treatments are less prevalent. Therefore, this work explored the correlation between plasma, sanding, porous release film treatments, its combination and bonding behavior in bonded carbon fiber composite joints. The bonding performance of composites was predominantly affected by three mechanisms: chemical cross‐linking, chemical adsorption and mechanical interlocking. The bonding strength was enhanced after plasma treatment through the increased polar functional groups and surface wettability, resulting in a 7% (28.6 MPa) improvement compared to untreated samples. Sanding and porous release film treated surfaces exhibited increased roughness and mechanical interlocking, with strength up to 29.5 and 38.7 MPa enhancement in shear strength. Furthermore, plasma and sanding treatments removed surface contaminants and enhanced the bonding strength. Plasma treatment on surfaces treated with porous release film led to a slight decrease in bonding strength (35.9 MPa), as the deep valleys were changed into shallow ones by plasma. Spearman correlation analysis was used to establish the relationship between characterization parameters and shear strength. The results revealed a robust correlation between surface roughness and strength, highlighting its potential for predicting bonding performance.Highlights Comprehensive investigations on the correlation between surface treating techniques and bonding behaviors. The shear strength increased as the integrity of adhesive film decreased. Roughness has the most robust correlation with shear strength.

On the Synergistic Effects of Cold Atmospheric Pressure Plasma Irradiation and Electroporation on Cytotoxicity of HeLa Cells

Cold atmospheric plasma (CAP) treatment induces cancer cell death through the generation of reactive oxygen and nitrogen species (RONS). However, the efficacy of RONS delivery into cells remains limited by membrane permeability. Here, we investigated whether combining CAP with pulsed electric fields (PEFs) could enhance cancer cell death through increased intracellular RONS uptake. HeLa cells were treated with argon atmospheric pressure plasma jet (Ar-APPJ), PEF, or their combination. The combined treatment showed significantly enhanced cell death compared to single treatments. While PEF treatment alone induced membrane permeabilization, the combination with Ar-APPJ resulted in more pronounced and sustained membrane disruption, as evidenced by increased calcein leakage. This enhanced effect was attributed to Ar-APPJ-induced lipid peroxidation interfering with membrane resealing after PEF-induced electroporation. We also demonstrated that PEF-induced membrane electroporation facilitates the intracellular uptake of CAP-generated RONS. These findings provide mechanistic insights into the synergistic effects of combined CAP and PEF treatments, suggesting enhanced cell death via multiple pathways.

Combined Effect of Conventional Chemotherapy with Epigenetic Modulators on Glioblastoma

Background/Objectives: Glioblastoma is the most common malignant primary brain tumor, characterized by necrosis, uncontrolled proliferation, infiltration, angiogenesis, apoptosis resistance, and genomic instability. Epigenetic modifiers hold promise as adjuvant therapies for gliomas, with synergistic combinations being explored to enhance efficacy and reduce toxicity. This study aimed to evaluate the effects of single or combined treatments with various anticancer drugs (Carboplatin, Paclitaxel, Avastin), natural compounds (Quercetin), and epigenetic modulators (suberoylanilide hydroxamic acid and 5-Azacytidine) on the expression of some long noncoding RNAs and methylation drivers or some functional features in the U87-MG cell line. Methods: Treated and untreated U87-MG cells were used for the evaluation of drug-induced cytotoxicity, apoptotic events, and distribution in cell cycle phases, detection of cytokine release, and assessment of gene expression and global methylation. Results: Cytotoxicity assays led to the selection of drug concentrations to be used in further experiments. Expression analysis revealed distinct downregulation of nearly all investigated genes and long noncoding RNAs following treatments. All treatments resulted in a higher percentage of global methylation compared to untreated controls. All treatments effectively increased levels of apoptosis, while the epigenetic modulators exhibited a lower proliferation profile, with combined treatments showing elevated values of cell lysis. Conclusions: The results indicate a link between Carboplatin and Avastin treatments and DNA methylation mechanisms involving EZH2, DNMT3A, and DNMT3B, with Avastin’s direct impact on these enzymes warranting further study. This research underscores the promise of platinum-based therapies combined with epigenetic drugs to reactivate silenced tumor suppressor genes and optimize methylation profiles.

DTPA and anti-inflammatory drug associations to alleviate Pu-induced response of macrophages in vitro.

Internal contamination by inhalation of plutonium poorly soluble compounds leads to their long time retention in alveolar macrophages inducing delayed pathology development. As previous studies highlighted co-localization of retained Pu and inflammatory lesions, this study was designed to assess the combined effect of the reference treatment (DTPA) and anti-inflammatory drugs on Pu-induced early response of macrophages in vitro. Pu colloids, mimicking poorly soluble Pu, were characterized using filtration and solid-state nuclear track detectors CR39. Their bioavailability was determined using a biphasic acellular model. Treatment effects on Pu dissolution and release as well as on Pu-induced pro-inflammatory response were assessed over 7 days on macrophage-like cells. DTPA treatment, associated or not with anti-inflammatory drug, increased Pu dissolution and release from contaminated THP-1 differentiated cells after 7 days. Significant decreases in Pu-induced IL-8 and MCP-1 secretions were also observed with anti-inflammatory treatment associated or not with DTPA. This study highlighted the ability of DTPA to partially dissolve a poorly soluble form of Pu as well as the ability of anti-inflammatory drugs to modulate Pu-induced pro-inflammatory response in macrophage-like cells. These treatments seem a promising strategy to improve the clinical management of Pu pulmonary contaminations and to limit delayed pulmonary pathology occurrence.

Dynamics of platelet hemostasis indicators in different blood pressure profiles in elderly and middle-aged hypertensive patients under combined antihypertensive treatment

In addition to achieving target blood pressure levels an equally important task is risk stratification of probable thrombotic complications in arterial hypertension in the elderly. This is reflected in the updated recommendations for implementing elderly patients with arterial hypertension. Studies of platelet activation in patients with arterial hypertension provide the implementation basis of new approaches to pharmacological prevention of complications associated with increased thrombus formation. Antihypertensive drugs have different effects on hemostasis parameters, which requires further study. Thus, this article attempts to systematise and analyse some literature data on the standard antihypertensive drugs effect. The purpose was to conduct a comparative assessment of the platelet hemostasis parameters dynamics in elderly and middle-aged hypertensive patients depending on the daily rhythm of blood pressure under combined antihypertensive treatment with enalapril and amlodipine. The work is based on the special examination of 93 elderly and 127 middle-aged hypertensive patients who were on inpatient two-week treatment. The state of spontaneous and induced platelet aggregation was determined. When analysing induced platelet aggregation a significant prolongation of time of maximal aggregation from 3.3 ± 0.9 min to 9.3 ± 0.4 min in elderly hypertensive patients with amlodipine treatment is noteworthy (p<0.05). Analysing the indicators of spontaneous platelet aggregation in elderly and middle-aged patients under combined treatment of the dipper group we established a significant decrease (p <0.05) in the amplitude of spontaneous platelet aggregation by 32% and 28%. The analysis of indicators of spontaneous aggregation of platelets showed that in the group of elderly patients of the non-dipper group, spontaneous aggregation slowed down according to the slope by 66.7% (p<0.05). Analysing the indicators of induced platelet aggregation in the elderly dipper group aggregation slope with ADP-inducer was slowed down by 37.6% (p<0.05). With insufficient nocturnal blood pressure reduction in middle-aged hypertensive patients aggregation amplitude during ADP-initiated platelet aggregation significantly decreased by 29.9% (p <0.05). There was a significant acceleration of the aggregation slope by 63.6% (p <0.05) during adrenaline-stimulated aggregation. It can be concluded that the effect of combined treatment with enalapril and amlodipine on platelet hemostasis in elderly patients depends on the initial blood pressure profile. Thus, all this confirms the reduction of thrombogenic potential in elderly patients in the dipper group under combined antihypertensive treatment with enalapril and amlodipine. Among elderly hypertensive patients according to blood pressure profile, the non-dipper group should be considered due to their involvement in a high-risk group for thrombotic events. Keywords: arterial hypertension; essential hypertension; platelet aggregation; elderly and middle-aged hypertensive patients

Combined treatment of HCC with CTLA-4 inhibitors and PD-1/PD-L1 inhibitors: mechanisms, progress and challenges

HCC seriously threatens human health, and the treatment methods are of crucial importance. The tumor microenvironment is critical to the origin and progression of HCC, and aberrant regulation of the immune checkpoint signaling pathway is a key method by which tumor cells avoid immune surveillance. Conventional single-treatment approaches for HCC have drawbacks. Inhibitors of PD-1/PD-L1 and CTLA-4, together known as the "golden combination," are the primary treatment for primary HCC. Compared with single treatment, it has a synergistic effect and benefits in boosting the immune response against the tumor and growing the number of recipients. However, it also has challenges. This study examines the state of combination treatment in HCC clinical trials as well as the current understanding of immune checkpoint inhibitors. By elaborating the cancer immune mechanism, it examines the mechanisms of action of the CTLA-4 and PD-1/PD-L1 immune checkpoints, and also the theoretical underpinnings and synergistic mechanism of combination treatment in HCC. Together with clinical study data, it assesses the effectiveness and potential of combination treatment for the cure of HCC, thoroughly examines the effects of conjunction treatment of CTLA-4 inhibitors and PD-1/PD-L1 inhibitors in the immunologic therapy of HCC, and anticipates the future of combination treatment, offering useful references for HCC immunotherapy.

Preliminary Effectiveness of a Telehealth-Delivered Exercise Program in Older Adults Living With and Beyond Cancer: Retrospective Study.

Exercise can attenuate the deleterious combined effects of cancer treatment and aging among older adults with cancer, yet exercise participation is low. Telehealth exercise may improve exercise engagement by decreasing time and transportation barriers; however, the utility of telehealth exercise among older adults with cancer is not well established. We aimed to evaluate the preliminary effectiveness of a one-on-one, supervised telehealth exercise program on physical function, muscular endurance, balance, and flexibility among older adults with cancer. In this retrospective study, we analyzed electronic health record data collected from the Personal Optimism With Exercise Recovery clinical exercise program delivered via telehealth among older adults with cancer (≥65 y) who completed a virtual initial program telehealth assessment between March 2020 and December 2021. The virtual initial assessment included the following measures: 30-second chair stand test, 30-second maximum push-up test, 2-minute standing march, single leg stance, plank, chair sit and reach, shoulder range of motion, and the clock test. All baseline measures were repeated after 12-weeks of telehealth exercise. Change scores were calculated for all assessments and compared to minimal clinically important difference (MCID) values for assessments with published MCIDs. Paired samples t tests (2-tailed) were conducted to determine change in assessment outcomes. Older adults with cancer who chose to participate in the telehealth exercise program (N=68) were 71.8 (SD 5.3) years of age on average (range 65-92 y). The 3 most common cancer types in this sample were breast (n=13), prostate (n=13), and multiple myeloma (n=8). All cancer stages were represented in this sample with stage II (n=16, 23.5%) and III (n=18, 26.5%) being the most common. A follow-up telehealth assessment was completed by 29.4% (n=20) of older adults with cancer. Among those who completed a follow-up telehealth assessment, there were significant increases in the 30-second chair stand (n=19; mean change +2.00 repetitions, 95% CI 0.12 to 3.88) and 30-second maximum push-up scores (n=20; mean change +2.85 repetitions, 95% CI 1.60 to 4.11). There were no significant differences for the 2-minute standing march, plank, single leg stance, sit and reach, shoulder mobility, or clock test (P>.05). Nine (47.3%) older adults with cancer had a change in 30-second chair stand scores greater than the MCID of 2 repetitions. Our findings suggest a one-on-one, supervised telehealth exercise program may positively influence measures of physical function, muscular endurance, balance, and flexibility among older adults with cancer, but more adequately powered trials are needed to confirm these findings.

The role of mitochondrial dysfunction in the cytotoxic synergistic effect of gemcitabine and arsenic on breast cancer.

Breast cancer is the most common type of cancer in women worldwide. A common approach to cancer treatment in clinical practice is to use a combination of drugs to enhance the anticancer activity of drugs while reducing their side effects. In this regard, we evaluated the effectiveness of combined treatment with gemcitabine (GCB) and arsenic (ATO) and how they affect the cell death pathway in cancer cells. Cytotoxic activity of drugs individually or combined against MDA-MB-231 and MCF-7 was performed by MTT method and isobolographic analysis was used to determine the interaction between these factors. The combination of ATO and GCB showed synergistic anti-cancer activity (CI < 1) in both cancer cell lines. The combination of ATO and GCB induced sub-G1 phase arrest, apoptosis and death rates in MCF-7 and MDA-MB-231 cells. The apoptotic response induced by the combination of GCB and ATO was dependent on caspase 3/7. Combined treatment with mitochondrial membrane potential (MMP) reduction and increased reactive oxygen species (ROS) production caused mitochondrial dysfunction. Co-treatment significantly reduced catalase (CAT) activity in both cancer cells compared to the control group and cells treated with each monotherapy. A significant decrease in cellular GSH was observed in cancer cells treated with ATO and GCB. In addition, migration and invasion were significantly reduced in breast cancer cells treated with the combination of ATO and GCB compared to cells treated with ATO and GCB. In conclusion, the combined treatment of ATO and GCB synergistically increased the anti-cancer activity, and these findings provide an effective approach for the treatment of breast cancer. To the best of our knowledge, this is the first study showing promising results for combination therapy with ATO and GCB in breast cancer.

Enhancing Antituberculosis Treatment Nanoparticles Encapsulated with Catalase and Levofloxacin Under Ultrasound Stimulation: A 3D Spheroid Study.

Tuberculosis (TB) is a chronic infectious disease caused by Mycobacterium tuberculosis (MTB). Tuberculous granuloma is the central and key pathological structure of tuberculosis and is characterized by tissue hypoxia and ineffective drug delivery. To address these issues, this study fabricated a composite nanoparticle loaded with catalase (CAT) and levofloxacin (LEV) (CAT@LEV-NPs) and then combined it with ultrasound (US) to investigate the bactericidal effect and underlying mechanisms using TB spheroids. The TB spheroids were constructed using attenuated Bacillus Calmette-Guérin (BCG) instead of MTB to facilitate operation under general experimental conditions. This study examined the physical properties and oxygen production efficiency of CAT@LEV-NPs. Subsequently, we treated TB spheroids with nanoparticles alone or in combination with US and found that ultrasound significantly increased drug permeability and activated CAT@LEV-NPs to produce a large number of reactive oxygen species (ROS). The combined treatment showed excellent antibacterial effects, resulting in more severe damage to the bacterial structure than other treatments. Additionally, the combined treatment induced a higher M1 polarization of macrophages, increased the apoptosis rate, and improved the anoxic microenvironment in TB spheroids. These factors may be closely related to the enhanced bactericidal effects of combined treatment. In conclusion, our study suggests that US combined with CAT@LEV-NPs could serve as a novel, noninvasive, safe, and effective treatment modality for intractable MTB infections.

MgSO4 as a novel hypothermia infusion solution promotes ischemic stroke recovery through Ca2+ regulation of neurovascular units.

The neuroprotection of acute ischemic stroke (AIS) patients to alleviate the reperfusion injury is a long-standing problem. Although the intra-arterial selective cooling saline infusion (IA-SCSI) is a promising technique to improve the outcome of AIS, the clinical results are not sufficiently satisfactory. Magnesium-containing solutions such as magnesium sulfate (MgSO4) can protect cells by modulating the intracellular Ca2+ content in damaged cells, suggesting that they could be hypothermia infusion solution. In this study, we hypothesized that MgSO4, as a novel hypothermia infusion solution (IA-SCMI), can promote AIS recovery. Methods: First, IA-SCMI was performed in rats subjected to the middle cerebral artery occlusion. The effect of combined hypothermia and MgSO4 treatment on different neurovascular (NVU) cells after oxygen-glucose deprivation/reoxygenation (OGD/R) injury was examined. Results: Compared with the IA-SCSI or IA-MgSO4 infusion alone, IA-SCMI offered the best protective effect by improving neurological defects, and alleviating brain integrity damage and CBF reduction. Meanwhile, in vitro results revealed that the combination of hypothermia and MgSO4 provided maximum protection to the NVU cells, and this protective effect was mainly achieved through the regulation of Ca2+ homeostasis in different cells. Conclusion: MgSO4 may be a promising hypothermia infusion solution to facilitate the recovery of neurological function in AIS patients.

Effects of serum leptin level and combined pharmacological treatments on obese women having premenstrual tension syndrome: A randomized controlled trial

Effects of serum leptin level and combined pharmacological treatments on obese women having premenstrual tension syndrome: A randomized controlled trial

Protein supplementation delivered alone or in combination with presumptive azithromycin treatment for enteric pathogens did not improve linear growth in Bangladeshi infants: results of a cluster-randomized controlled trial.

Protein requirements established for healthy populations may be insufficient to support healthy growth in infants consuming largely cereal-based complementary foods and frequently exposed to enteric pathogens. To assess independent and combined effects of protein supplementation and antibiotic treatment on linear growth of infants from 6-12 months of age. We conducted a 2 x 4 factorial cluster-randomized trial in northwestern Bangladesh, allocating 566 clusters to masked azithromycin (10 mg·kg-1 * 3 d) or placebo at 6 and 9 months of age, and unmasked delivery of an egg white protein-rich blended food supplement (250 kcal; 10 g added protein), a rice-based isocaloric supplement, egg, or nutrition education from 6-12 months. We measured length at 6 and 12 months. For this cluster-level intention-to-treat analysis of the 2 x 2 antibiotic and protein interventions, we used multiple linear or log-binomial regression with generalized estimating equations to assess changes in length-for-age Z (LAZ) score and stunting (LAZ<-2), respectively. We enrolled 2055 infants (283 clusters) and included 1821 infants (281 clusters) with complete anthropometry data at 6 and 12 months in our analysis. There were no significant interactions between the protein and antibiotic interventions for any outcomes. Independently, protein supplement did not improve LAZ (β = 0.05; 95% CI: 0.00, 0.11; P = 0.07) or reduce stunting (prevalence ratio (PR) = 1.12; 95% CI: 0.85, 1.49; P = 0.41) compared to the isocaloric supplement. The antibiotic intervention had no effect on LAZ (β = -0.05; 95% CI: -0.11, 0.01; P = 0.09) or stunting (PR = 0.99; 95% CI: 0.75, 1.31; P = 0.96), relative to the placebo. Supplementation to increase intakes of high-quality protein, provided with or without presumptive treatment for enteric pathogens, did not improve linear growth from 6 to 12 months of age. This trial was registered at clinicaltrials.gov as NCT03683667. This trial was registered at clinicaltrials.gov as NCT03683667.

Investigation of ITGB3 Heterogeneity to Overcome Trastuzumab Resistance in HER2-Positive Breast Cancer.

HER2-positive breast cancer has an aggressive tumour progression among breast cancers characterized by the overexpression of HER2. Trastuzumab is an FDA-approved drug and has significantly improved outcomes for patients; however, drug resistance remains a major challenge. Tumour heterogeneity, describing genetic, epigenetic, and phenotypic differences within and between tumours, complicates tumour treatment and contributes to drug resistance. Understanding the mechanisms underlying Trastuzumab resistance, such as tumour heterogeneity, is crucial for developing new and effective therapeutic strategies. This study investigates the role of ITGB3 heterogeneity in Trastuzumab resistance, focusing on its impact on TGF-β signalling and migration marker response. It also evaluates the potential of combining Trastuzumab with the integrin β3 inhibitor cilengitide to overcome resistance associated with ITGB3 levels. Trastuzumab-resistant HER2-positive HCC1954 and SKBR3 breast cancer cell lines were generated and analysed for ITGB3 expression heterogeneity. The impact of ITGB3 on TGF-β-responsive genes (WWP1, CARM1, RASGRP1, THBS1, KCTD5, SGCA, EIF3S6, MCAM, FXR2, MTMR3, SOCS3, SLC2A4RG, MMP2, MMP9, and HSP47) and cell migration (Col4a1, fibronectin, ICAM1, Timp2, and vimentin) was analysed using luciferase reporter assays and real-time PCR. The effects of combined treatment with Trastuzumab and cilengitide were also evaluated via wound closure assay. ITGB3 expression varied significantly among resistant clones, correlating with increased expression of TGF-β-responsive genes and enhanced migration markers. Combined treatment with Trastuzumab and cilengitide significantly reduced TGF-β signalling and migration-related gene expression, particularly in high ITGB3-expressing cells. ITGB3 plays a critical role in Trastuzumab resistance through the modulation of TGF-β signalling, migration, and contributing to tumour heterogeneity. Targeting ITGβ3, alone or in combination with cilengitide, offers a promising strategy to resensitize resistant HER2-positive breast cancer cells to Trastuzumab. These findings provide valuable insights into the mechanisms of Trastuzumab resistance and suggest potential therapeutic avenues for improving patient outcomes.

Radiotherapy-resistant prostate cancer cells escape immune checkpoint blockade through the senescence-related ataxia telangiectasia and Rad3-related protein.

The majority of patients with prostate cancer (PCa) exhibit intrinsic resistance to immune checkpoint blockade (ICB) following radiotherapy (RT). This resistance is generally attributed to the limited antigen presentation of heterogeneous cells within tumors. Here, we aimed to isolate and characterize these diverse subgroups of tumor post-RT to understand the molecular mechanisms of their resistance to ICB. Single-cell RNA-sequencing (scRNA-seq) was used to profile senescent cancer cell clusters induced by RT in LNCaP cells. The expression and phosphorylation levels of ataxia telangiectasia and Rad3-related protein (ATR) were assessed by immunohistochemistry in clinical samples from patients with or without RT. Co-immunoprecipitation, mutagenesis, and Western blotting were used to measure the interactions between proteins. Xenograft experiments were performed to assess the tumor immune response in the mice. We identified a subset of PCa cells that exhibited resistance to RT, characterized by a reduced antigen presentation capability, which enhanced their ability to evade immune detection and resist cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) blockade. scRNA-seq revealed that the senescent state was a transient phase of PCa cells post-RT, particularly in CTLA-4 blockade treatment-resistant cells. This state was marked by increased cytosolic ATR level. Cytosolic ATR phosphorylated CD86 in its cytosolic domain and enhanced the interaction between CD86 and its E3 ligase MARCH1 through electrostatic attraction. Depletion or inhibition of Atr increased the sensitivity to immune attack and improved responses to anti-Ctla-4 antibody treatment in a mouse model. Our findings indicate that the activation of cytosolic ATR, which is associated with cellular senescence, impedes the effectiveness of combined RT and ICB treatments. This discovery may provide valuable insights for improving the efficacy of combined RT and ICB therapies in PCa.

Unlocking higher methane yields and digestate nitrogen availability in soil through thermal treatment of feedstocks in a two-step anaerobic digestion

BackgroundThere is an increasing interest in using lignocellulosic feedstocks for biogas production. Treatment of these feedstocks prior to anaerobic digestion (AD) can enhance their accessibility to microorganisms involved in the process. To improve the digestion of recalcitrant feedstocks and boost biogas yields, many biogas plants now employ two-step AD systems, extending substrate residence times. However, the combined effect of feedstock treatment and two-step AD on methane yield and fertiliser value of digestates are underexplored. This study, therefore, evaluated the effectiveness of thermal treatment (TT) of pre-digested agricultural feedstocks before a secondary AD step on the carbon (C) and nitrogen (N) dynamics of digestates following application to soil. It also investigated the effects of TT on methane yields. Pre-digested feedstock (PDF) was treated at three different temperatures (70 °C, 120 °C and 180 °C) for 60 min, followed by parallel secondary AD steps using lab-scale continuous stirred-tank reactors (CSTR) and a batch test. Thermally treated feedstocks with and without a secondary AD step were applied to soil to study C and N dynamics and turnover for 2 months.ResultsTT at 180 °C increased ultimate CH4 yields by 7.2%; however, it decreased the net mineral N release in soil from 42 to 34% (of N input). Adding a secondary AD step increased the net mineral N release in soil from an average of 39% to 47% (of N input), with the effect of TT levelling off. Moreover, the secondary AD step significantly reduced C mineralisation rates from an average of 37% to 26% (of C applied).ConclusionsOverall, TT at 120–180 °C can improve biogas yields of recalcitrant feedstocks, but it may lead to the formation of refractory nitrogen compounds resistant to further degradation during AD, potentially resulting in a lower N fertiliser value of digestates.Graphical

Applying Predictive Safety Analysis to Complete Streets: A Case Study

Complete Streets encompasses policymaking, planning, design, and operations to improve safety, connectivity, and equity for all road users. Existing safety performance analysis and evaluation methods have gaps related to predicting the safety benefits of Complete Streets projects. Specifically, the methods do not fully capture expected multi-modal safety performance effects or address the combined effects of multiple safety treatments implemented in combination. This paper describes a research effort to 1) apply predictive safety analysis methods to quantify the safety performance effects of Complete Streets projects in the project planning stage and 2) compare the predicted safety performance effects with actual effects estimated with a project evaluation after construction. The paper serves as a basis for understanding the current capabilities, challenges, and needs associated with safety performance analysis of Complete Streets projects.