Combined Treatment Research Articles

Anti-PD-L1 antibody ASC22 in combination with a histone deacetylase inhibitor chidamide as a “shock and kill” strategy for ART-free virological control: a phase II single-arm study

The combination of ASC22, an anti-PD-L1 antibody potentially enhancing HIV-specific immunity and chidamide, a HIV latency reversal agent, may serve as a strategy for antiretroviral therapy-free virological control for HIV. People living with HIV, having achieved virological suppression, were enrolled to receive ASC22 and chidamide treatment in addition to their antiretroviral therapy. Participants were monitored over 24 weeks to measure changes in viral dynamics and the function of HIV-specific CD8+ T cells (NCT05129189). 15 participants completed the study. At week 8, CA HIV RNA levels showed a significant increase from baseline, and the values returned to baseline after discontinuing ASC22 and chidamide. The total HIV DNA was only transiently increased at week 4 (P = 0.014). In contrast, integrated HIV DNA did not significantly differ from baseline. Increases in the proportions of effector memory CD4+ and CD8+ T cells (TEM) were observed from baseline to week 24 (P = 0.034 and P = 0.002, respectively). The combination treatment did not succeed in enhancing the function of HIV Gag/Pol- specific CD8+ T cells. Nevertheless, at week 8, a negative correlation was identified between the proportions of HIV Gag-specific TEM cells and alterations in integrated DNA in the T cell function improved group (P = 0.042 and P = 0.034, respectively). Nine adverse events were solicited, all of which were graded 1 and resolved spontaneously. The combined treatment of ASC22 and chidamide was demonstrated to be well-tolerated and effective in activating latent HIV reservoirs. Further investigations are warranted in the context of analytic treatment interruption.

The efficacy and safety of neoadjuvant immunochemotherapy in resectable stage I-III non-small cell lung cancer: a systematic review and network meta-analysis.

Neoadjuvant immunochemotherapy (NICT) is a new treatment method for resectable non-small-cell lung cancer (NSCLC). Network meta-analysis assessed efficacy, safety, and optimal treatment. We searched for randomized controlled trials (RCTs) comparing NICT with neoadjuvant chemotherapy (NCT) in PubMed, Embase, Web of Science, Cochrane Library, and international conferences. Outcomes were surgical resection rate, pathological complete response(pCR),event-free survival (EFS), and Grade 3-5 treatment-related adverse events (TRAEs). RCTs of 3,387 patients, six treatment combinations, and two modalities were included. Meta-analysis showed that NICT yielded higher pCR and EFS rates than NCT. The toripalimab-chemotherapy combination had the highest surgical resection rate (OR = 1.68, 95% CI: 1.05-2.73), pCR (OR = 38.84, 95% CI: 11.05-268.19) and EFS (HR = 0.40, 95% CI: 0.28-0.58).This regimen worked well for patients with low programmed death-ligand 1 (PD-L1) expression or squamous cell pathology. For high PD-L1 expression and patients with NSCLC, neoadjuvant nivolumab with chemotherapy had the most efficacy. The incidence of treatment-related adverse events increased with longer treatment cycles, with perioperative nivolumab combined with chemotherapy showing the worst safety profile (RR = 1.32, 95% CI: 1.00-1.76), while neoadjuvant nivolumab combined with chemotherapy alone had the best safety profile (RR = 0.91, 95% CI: 0.68-1.21). Indirect comparison showed no survival benefit for neoadjuvant-adjuvant immunotherapy (HR = 0.93, 95% CI: 0.65-1.35). In the indirect comparison between the two immune checkpoint inhibitors(ICIs), although there was no significant difference in EFS (HR = 0.81, 95% CI: 0.61-1.08), PD-1 inhibitors may still be the most effective treatment option. NICT effectively and safely treats resectable NSCLC. The optimal treatment combination is typically toripalimab and chemotherapy. Treatment based on PD-L1 expression and pathological type is recommended.

Leaf and soil nutritional composition of purple passion fruit (Passiflora edulis Sims) as influenced by organic nutrients amended with biofertilizer consortium

The use of organic nutrient regimes is regarded as holistic and ecological approach for agricultural sustainability. It offers improved soil health, increased crop growth and enhanced fruit quality, whilst minimizing costs and sustaining the use of natural resources. The present investigation was conducted over two consecutive seasons, viz. 2021–22 and 2022–23 at Mizoram University, Aizawl, India to study the effect of different combinations of organic manures along with consortium of biofertilizers on leaf and soil characteristics of purple passion fruit (Passiflora edulis Sims). The investigation comprises of fourteen treatments of various combinations of organic manures along with consortium of biofertilizers, viz. farmyard Manure (FYM) vermicompost (VC) pig manure (PIM), poultry manure (POM), Azospirillum, phosphate solubilizing bacteria (PSB), potash solubilizing bacteria (KSB), and vesicular arbascular mycorrhiza (VAM). The results demonstrated that the use of organic amendments in combination with biofertilizers enhanced leaf nutrient status as well soil properties in the passion fruit orchard. Among the different treatment combinations used in the investigation, POM + Azospirillum + PSB + KSB + VAM was the most efficient in improving the leaf and soil nutrient status of passion fruit. This consortium may achieve high microbial load, high nutrient availability for soil which results in better growth of the crop. This treatment may therefore be recommended as an alternative option to meet the demand for long term maintenance of soil fertility as well agro-ecosystem conservation and sustainability.

Effect of different sources of organic manures on growth and yield of Broccoli

Indiscriminate use of chemical fertilizers is a common practice that is hazardous both for soil health and the environment. It has been more than three decades that global agriculture has been depicted towards organic agriculture owing to sustainability and reduced environmental effects. An experiment was conducted in Randomized Complete Block Design (RCBD) with three replications to study the effect of different sources of organic nutrients on growth and yield of broccoli. The experiment consisted of five different sources of manures; control (no manure), cowdung (25 t/ha), Trichoderma compost (10 t/ha), vermicompost (12 t/ha) and poultry litter (14 t/ha) along with two cultivars of broccoli; ‘Imperial’ and ‘Premium Crop’. Different sources of manures and cultivars had significant influence on plant height, height up to curd, number of leaves per plant, length of leaf, breadth of leaf, plant canopy, diameter of curd, diameter of stem, weight of primary curd, number of secondary curds, weight of secondary curd, yield per plant, yield per unit plot and yield per hectare. The maximum yield (17.32 t/ha) was obtained from vermicompost, followed by poultry litter in ‘Premium Crop’ (15.68 t/ha) cultivar. The minimum yield (6.62 t/ha) was recorded by no manure in ‘Imperial’. Control treatment showed the lowest values for all the parameters studied. Combination of vermicompost and ‘Premium Crop’ cultivar was found the best among all other treatment combinations, including in respect of net return (Tk. 234099/ha) and BCR (3.08). Res. Agric. Livest. Fish. Vol. 11, No. 2, August 2024: 197-204

Observations on the efficacy of edaravone dexborneol in preventing post-stroke depression and its inflammatory mechanism: a prospective, randomized, control trial

ObjectiveThis study aimed to observe the effect of edaravone dexborneol (EDB) on the incidence of early post-stroke depression (PSD) and explore its inflammatory mechanisms.MethodsA prospective, randomized controlled study was conducted from January 2022 to June 2023, involving patients with acute ischemic stroke (AIS) at the Neurology Department of the Third Affiliated Hospital of Beijing University of Traditional Chinese Medicine. The control group received routine treatment, while the experimental group received routine combined EDB treatment. The main outcome measures included PSD incidence, Patient Health Questionnaire (PHQ-9) and Hamilton Depression Scale (HAMD) scores on days 14 and 30, and inflammatory factor levels on day 14.ResultsA total of 93 patients were included in the study, 51 in the experimental group and 42 in the control group. On day 14, the PSD incidence was 13.7% in the experimental group, lower than 31.0% in the control group (95%CI 0.127–0.996; p = 0.044). Compared to the control group, the experimental group showed significantly lower concentrations of pro-inflammatory cytokines IL-1β (95%CI 3.353–5.184), IL-6 (95%CI 2.694–3.426), TNF-α (95%CI 4.985–12.196), IFN-γ (95%CI 0.163–0.451), MCP-1 (95%CI 0.335–0.787), IL-17A (95%CI 0.543–1.024), and IL-23p19 (95%CI 1.677–1.959) (all p < 0.001), and higher levels of anti-inflammatory cytokines IL-4 (95%CI −1.087 to −0.941), IL-10 (95%CI −6.125 to −1.662), and IL-13 (95%CI −6.078 to −2.953) (all p ≤ 0.001). On day 30, the PSD incidence in the experimental group was 15.7%, lower than 40.5% in the control group (95%CI 0.103–0.725; p = 0.007). Compared with the control group, the experimental group had lower PHQ-9 scores on day 14 (95%CI 0.034–1.577; p = 0.041) and day 30 (95%CI 0.018–1.573; p = 0.045), and also had lower HAMD scores on day 14 (95% CI 0.281–2.856; p = 0.018) and day 30 (95% CI 0.647–3.482; p = 0.005).ConclusionEDB could reduce the incidence of early PSD, reduce pro-inflammatory cytokine levels, and elevate anti-inflammatory cytokine levels, which was possibly related to the anti-inflammatory mechanism of EDB.Clinical trial registrationhttp://www.chictr.org.cn/, identifier [ChiCTR2300067750].

Neurophysiological effects of a combined treatment of lovastatin and minocycline in patients with fragile X syndrome: Ancillary results of the LOVAMIX randomized clinical trial.

Fragile X syndrome (FXS) is the primary hereditary cause of intellectual disability and autism spectrum disorder. It is characterized by exacerbated neuronal excitability, and its correction is considered an objective measure of treatment response in animal models, a marker albeit rarely used in clinical trials. Here, we used an extensive transcranial magnetic stimulation (TMS) battery to assess the neurophysiological effects of a therapy combining two disease-modifying drugs, lovastatin (40 mg) and minocycline (100 mg), administered alone for 8 weeks and in combination for 12 weeks, in 19 patients (mean age of 23.58 ± 1.51) with FXS taking part in the LOVAmix trial. The TMS battery, which included the resting motor threshold, short-interval intracortical inhibition, long-interval intracortical inhibition, corticospinal silent period, and intracortical facilitation, was completed at baseline after 8 weeks of monotherapy (visit 2 of the clinical trial) and after 12 weeks of dual therapy (visit 4 of the clinical trial). Repeated measure ANOVAs were performed between baseline and visit 2 (monotherapy) and visit 3 (dual therapy) with interactions for which monotherapy the participants received when they began the clinical trial. Results showed that dual therapy was associated with reduced cortical excitability after 20 weeks. This was reflected by a significant increase in the resting-motor threshold after dual therapy compared to baseline. There was a tendency for enhanced short-intracortical inhibition, a marker of GABAa-mediated inhibition after 8 weeks of monotherapy compared to baseline. Together, these results suggest that a combined therapy of minocycline and lovastatin might act on the core neurophysiopathology of FXS. This trial was registered at clinicaltrials.gov (NCT02680379).

Efficacy and safety of two fixed doses of ibalizumab plus optimized background regimen in treatment-experienced HIV-positive individuals.

Sustained viral suppression in patients with multidrug-resistant (MDR) human immunodeficiency virus (HIV) infection remains difficult; accordingly, agents targeting different steps in the HIV life cycle are needed. Ibalizumab, a humanized immunoglobulin G4 monoclonal antibody, is a cluster of differentiation (CD4)-directed post-attachment inhibitor. In this Phase IIb study, 113 individuals with MDR HIV-1 and limited treatment options were assigned an optimized background regimen (OBR) and randomized to either 800 mg ibalizumab every two weeks (q2wk; n=59) or 2,000 mg ibalizumab every four weeks (q4wk; n=54) up to Week 24. Viral loads (VL) below the detection limit were achieved in 44% and 28% of patients in the 800 mg q2wk and 2,000 mg q4wk groups, respectively, at Week 24. Mean (standard deviation) VL (log10 copies/mL) decreased from Baseline (4.6(0.8), 800 mg q2wk; 4.7(0.7), 2,000 mg q4wk) to Week 2, with the reduction maintained through Week 24 (2.9(1.5), 800 mg q2wk; 3.2(1.4), 2,000 mg q4wk). Baseline CD4+ counts were 80.5 and 54.0 cells/μL in the 800 mg q2wk and 2,000 mg q4wk groups, respectively. Mean CD4+ T-cell count was increased at Week 24 in both groups. No serious adverse events were related to ibalizumab. In heavily treatment-experienced patients with HIV (PWH) at a more advanced baseline disease severity, clinically significant response rates at Week 24 were achieved with ibalizumab plus OBR. Ibalizumab's unique mechanism of action and lack of cross-resistance to other antiretroviral agents make it an important component of combination treatment regimens for PWH with limited treatment options.

Lynch Syndrome-associated Genomic Variants.

Lynch Syndrome, a hereditary disorder characterized by germline mutations in mismatch repair (MMR) genes, is a major contributor to colorectal cancers. It has also been identified in endometrial cancer. Despite the established role of MMR deficiency in tumorigenesis, the specific genomic alterations driving Lynch syndrome-associated endometrial cancer, and their overlap with colorectal cancer, remain incompletely understood. This study aims to fill this gap by performing a detailed comparative analysis of germline and somatic mutations in endometrial cancer within the context of Lynch syndrome. We conducted whole exome sequencing on matched germline and somatic DNA from 13 patients diagnosed with Lynch syndrome-associated endometrial cancer. High-depth sequencing was performed, followed by rigorous bioinformatics analysis to identify and annotate variants, focusing on their potential pathogenicity and relevance to both endometrial and colorectal cancer. Our analysis revealed 1,118 germline and 14,051 somatic variants, with 493 variants common to both. Recurrent pathogenic mutations in MLH1, MSH2, and MSH6 were confirmed, highlighting their critical role in Lynch syndrome. Notably, frequent somatic mutations in the PIK3CA and PTEN genes were identified, implicating the PI3K/AKT/mTOR pathway as a key oncogenic driver in these cancers. Additionally, novel somatic mutations in genes related to the extracellular matrix such as FBN1 and SPARC were uncovered, suggesting a possible unique role in endometrial tumor progression. This study provides new insights into the molecular basis of Lynch syndrome-associated endometrial cancer, emphasizing the overlap in oncogenic pathways with colorectal cancer. The discovery of shared and unique genetic mutations highlights the importance of developing combined treatment strategies and suggests that targeting these specific mutations could improve therapy for patients with Lynch syndrome-associated cancers.

FACT inhibitor CBL0137, administered in an optimized schedule, potentiates radiation therapy for glioblastoma by suppressing DNA damage repair.

Standard-of-care for glioblastoma remains surgical debulking followed by temozolomide and radiation. However, many tumors become radio-resistant while radiation damages surrounding brain tissue. Novel therapies are needed to increase the effectiveness of radiation and reduce the required radiation dose. Drug candidate CBL0137 is efficacious against glioblastoma by inhibiting histone chaperone FACT, known to be involved in DNA damage repair. We investigated the combination of CBL0137 and radiation on glioblastoma. In vitro, we combined CBL0137 with radiation on U87MG and A1207 glioblastoma cells using the clonogenic assay to evaluate the response to several treatment regimens, and the Fast Halo Assay to examine DNA repair. In vivo, we used the optimum combination treatment regimen to evaluate the response of orthotopic tumors in nude mice. In vitro, the combination of CBL0137 and radiation is superior to either alone and administering CBL0137 two hours prior to radiation, having the drug present during and for a prolonged period post-radiation, is an optimal schedule. CBL0137 inhibits DNA damage repair following radiation and affects the subcellular distribution of histone chaperone ATRX, a molecule involved in DNA repair. In vivo, one dose of CBL0137 is efficacious and the combination of CBL0137 with radiation increases median survival over either monotherapy. CBL0137 is most effective with radiation for glioblastoma when present at the time of radiation, immediately after and for a prolonged period post-radiation, by inhibiting DNA repair caused by radiation. The combination leads to increased survival making it attractive as a dual therapy.

A Photoactivatable Self-Assembled Nanoagonist for Synergistic Therapy against Pancreatic Ductal Adenocarcinoma.

Immunotherapy has revolutionized the cancer treatment paradigm, yet efficient immunotherapeutic responses against immune-cold/desert cancers remain challenging. Herein, we report that photoactivatable nanoagonists yield a potent antitumor synergy of photoimmunotherapy against pancreatic ductal adenocarcinoma (PDAC). The nanoagonist was fabricated by assembling an amphiphilic boron dipyrromethene-derived polymer conjugated with a Toll-like receptor agonist via a photocleavable linker and stimulator of interferon genes agonist. The nanoagonist enables light-induced generation of reactive oxygen species and on-demand release of the agonists to yield synergistic photoimmunotherapy. The produced tumor antigens promote dendritic cell maturation, which is further amplified by these agonists for eliciting adaptive immunity, accompanied by apparently abscopal and long-term memory effects. The nanoagonist further alleviates the fibrosis of tumor stroma and the immunosuppressive microenvironment, leading to the deep infiltrations of clinically used therapeutics and immune cells to yield preferable combinational treatments against PDAC models. These results provide valuable insights into activatable nanoparticles for cancer therapy against immune-desert cancers.

Unlocking Selective Anticancer Mechanisms: Dinuclear Manganese Superoxide Dismutase Mimetics Combined with Pt(II) Complexes.

We exploration the in vitro activities of the dinuclearMn2L2AcandMn2L2complexes (where HL = 2-{[di(2-pyridyl)methylamino]-methyl}phenol), possessing dual superoxide dismutase (SOD) and catalase (CAT) activity, both individually and in conjunction with various Pt(II)-complexes, either as mixtures or astheMn2-Ptadducts. Our findings revealed a notable up to 50% enhancement in the viability of healthy human breast cells, contrasted with a viability decrease as low as 50% in breast cancer cells upon combined treatments withMn2SOD mimics and Pt(II) complexes.Specifically, we synthesized and characterized the self-assembledMn2-Ptadducts(isolatedMn2L2Ptandin situMn2L2Pt'), linkingMn2L2-core with the carboxylate group ofPtDAPCl2(dichloro(2,3-diaminopropionic acid) platinum(II)). The SOD activity of the isolatedMn2L2Ptadduct (kSOD= 1.7 × 107M-1s-1) remained intact. We elucidated key mechanisms underlying the observed biological effects.We demonstrated thatMn2-containing formulations predominantly target mitochondrial processes, differently affecting the proteome of cancerous and healthy cells. They induced downregulation of H2S signaling and expression of mitochondrial complex I and III, as well as increased oxidative phosphorylation pathways and upregulation of EGFR in cancer cells. In contrast, healthy cells showed a decrease in EGFR expression and a moderate enrichment in oxidative phosphorylation pathways.

Evaluation of Five Sesame (Sesamum Indicum L.) Varieties Under Varying Fertilizer Rates and Establishment Methods for Growth and Yield in Anyigba, Kogi State, Nigeria

Global sesame seed market is projected to have USD 7.24 billion in consumption value by 2024. However, its supply has not been able to match the demand due to several constraints to its production. This study was conducted at the Prince Abubakar Audu University Research and Demonstration Farm, during the 2023 cropping season to evaluate five sesame varieties for growth and yield under varying fertilizer rates and establishment methods. Treatment consisted of five sesame varieties, two establishment methods, and three fertilizer levels respectively combined factorially to obtain a total of thirty factorial treatment combinations and laid out in a Randomized Complete Block Design (RCBD) with three replicates. Results showed that varieties differed significantly (P < 0.05) in growth, yield and yield characters. YANDEV55 produced the widest leaf area at 9WAS, NCRIBEN-02M produced the highest number of leaves per plant (36) at 12WAS. The same variety (NCRIBEN-02M) consistently produced the tallest stems (42.48, 56.10, 80.48 & 93.46 cm) at 3, 6, 9 & 12WAS. YANDEV55 produced 73.6 % germination which was highest amongst others. E8 produced the highest number of capsule/plant (23.3) and number of seeds/plant (1428.94). NCRIBEN-05E performed optimally in yield characters such as total plant biomass yield (2908.0g/plot) and final seed yield (887.9kgha-1). NCRIBEN-02M had the highest haulm yield (33.0g/plot) while NCRIBEN-01M had the longest days (54.16) to 50% anthesis. Seed/capsule and Harvest index were not significantly affected by varieties. Broadcast method produced significantly widest leaf areas of 53.9 and 40.5 cm2 at 6 and 12 WAS respectively, higher number of leaves (18.0) at 3WAS. Drilling method of crop establishment produced the highest biomass yield (2894.6g/plot) and final seed yield (879.2 kgha-1). Similarly, fertilizer rates affect growth and yield characters; 100 kg NPKha-1 produced the widest leaf area, tallest plants and highest number of leaves/plant at all stages of sampling. These were at par with values obtained when plots were treated with 150kg NPKha-1. Alternatively, highest number of capsules/plant (22.4), seeds/capsule (62.46), seeds/plant (1502.73), total plant biomass yield (2879.7g/plot), haulm yield (33.0g/plot), final seed yield (870.7kgha-1) and longest number of days to 50% anthesis (53.6) were all obtained when plots were treated with 150 kgha-1 but was at par with 100kg NPKha-1. Fertilizer rates did not affect the establishment count and harvest index. The best variety with respect to yield/ha is NCRIBEN-02M, Application of 100 kg NPK/ha appears maximum for optimum yield of the crop, drilling appears to produce higher yield than broadcast for some varieties with an overall marginal increase of 8.4 % over broadcast and thus recommended for Anyigba environment. An economic study of the cost implication for both operations (drilling and broadcast) could be embarked upon to ascertain the veracity of this assertion, more so that broadcast requires higher seed rate than drilling. Significant interaction of varieties x establishment method was also an indication that very high yielding varieties (NCRIBEN-02M and NCRIBEN-01M) do better when drilled compared to broadcast. Significant positive relationship between some growth, yield and yield characters is an indication that effective crop improvement through selection can be carried out by selecting for those characters that correlated positively with yield.

Aging of microplastics and its photo-catalytic degradation of coexisting tetracycline

Photodegradation processes play a crucial role in the transforming of antibiotics in aqueous environments, while photochemical aging influences the properties of microplastics (MPs). In this study, the efficacy of ultraviolet (UV) irradiation in eliminating tetracycline (TC) was examined. Especially, TC degradation was mediated by polyethylene microplastics (PE-MPs) was subjected to aging through UV exposure and a combination of UV and thermal-activated persulfate treatments. The effects of MPs concentration, salinity, and pH on TC degradation were investigated. The characteristics of aging PE-MPs and the corresponding active free radicals were analyzed to understand the mechanism of TC degradation. The results showed that the existence of PE-MPs significantly influenced TC degradation under photosensitized conditions. However, as the concentration of PE-MPs increased, the degradation rate initially increased and subsequently declined. TC degradation increased from approximately 35 % to 85 % when pH increased from 3 to 11 mediated by aged PE-MPs. Moreover, the TC degradation ability increased with increasing salinity, and a higher aging degree facilitated the photodegradation of TC, achieving a removal rate of 62 %. At the same time, free radical quenching confirmed that the singlet oxygen (1O2), hydroxyl radical (OH), and superoxide radical (O2·−) produced all involved in the photolysis process of TC mediated by PE-MPs, especially 1O2. The analysis of the degradation products of TC and prediction of its toxicity revealed that the ecological risk associated with the degradation solution diminished compared with that of the TC mother solution.

Geotechnical Forensic Investigations of a Gravity Dam: Addressing Seepage and Sliding Problems in the Basalt Foundations of Karjan Dam, Gujarat, India

Geotechnical forensic engineering plays a crucial role in identifying and mitigating potential issues in large gravity dams. The Karjan Dam in Gujarat, India, a 100-meter-high gravity dam built 38 years ago on Deccan basalt, encountered significant geotechnical challenges during construction due to early investigation oversights. These oversights failed to detect sub-horizontal weathered rock seams within the basalt during the pre-construction investigations, which could have posed significant seepage and sliding risks during the dam's operation. Subsequent detailed investigations during the construction phase revealed that these seams extended throughout the foundations of the dam blocks. In-situ shear tests were conducted to determine the shear parameters, namely cohesion (C) and the angle of internal friction (ϕ) of the seams. The test results indicated low shear strength parameters, necessitating a re-evaluation of the dam's safety. Stability analysis revealed that the spillway and certain non-overflow blocks were at risk of sliding and seepage after reservoir filling. To address these geotechnical challenges, a combination of treatments—including concrete shear keys, grouting, and design enhancements—was implemented to prevent sliding and control seepage. The timely forensic investigation and treatment during the construction stage ensured the dam's safety, which has operated without issues since 1986. This study underscores the critical importance of integrating engineering and geological assessments at various stages of dam construction. Re-evaluating and addressing evolving foundation conditions, particularly during construction, is essential for applying effective treatments to prevent dam failure during operation. The findings from this case study provide valuable geotechnical insights required for enhancing the safety and resilience of dam infrastructure globally.

Patient-derived acellular ascites fluid affects drug responses in ovarian cancer cell lines through the activation of key signalling pathways.

Malignant ascites is commonly produced in advanced epithelial ovarian cancer (EOC) and serves as unique microenvironment for tumour cells. Acellular ascites fluid (AAF) is rich in signalling molecules and has been proposed to play a role in the induction of chemoresistance. Through in vitro testing of drug sensitivity and by assessing intracellular phosphorylation status in response to mono- and combination treatment of five EOC cell lines after incubation with AAFs derived from 20 different patients, we investigated the chemoresistance-inducing potential of ascites. We show that the addition of AAFs to the culture media of EOC cell lines has the potential to induce resistance to standard-of-care drugs (SCDs). We also show that AAFs induce time- and concentration-dependent activation of downstream signalling to signal transducer and activator of transcription 3 (STAT3), and concomitantly altered phosphorylation of mitogen-activated protein kinase kinase (MEK), phosphoinositide 3-kinase (PI3K)-protein kinase B (AKT) and nuclear factor NF-kappa-B (NFκB). Antibodies targeting the interleukin-6 receptor (IL6R) effectively blocked phosphorylation of STAT3 and STAT1. Treatments with SCDs were effective in reducing cell viability in only a third of 30 clinically relevant conditions examined, defined as combinations of drugs, different cell lines and AAFs. Combinations of SCDs and novel therapeutics such as trametinib, fludarabine or rapamycin were superior in another third. Notably, we could nominate effective treatment combinations in almost all conditions except in 4 out of 30 conditions, in which trametinib or fludarabine showed higher efficacy alone. Taken together, our study underscores the importance of the molecular characterisation of individual patients' AAFs and the impact on treatment resistance as providing clinically meaningful information for future precision treatment approaches in EOC.

Impact of conservation agriculture and weed management on carbon footprint, energy efficiency, and sustainability in maize-wheat cropping systems

This study assesses the impact of conservation agriculture (CA) and weed management practices on the productivity, profitability, energy use, and carbon sustainability of a maize-wheat cropping system. Fifteen treatment combinations, incorporating five tillage methods (conventional-till maize and wheat [CT-CT], conventional-till maize and zero-till wheat [CT-ZT], zero-till maize and zero-till wheat [ZT-ZT], zero-till maize and zero-till plus residue in wheat [ZT-ZTR], and zero-till plus residue maize and wheat [ZTR-ZTR]) and three weed management practices (recommended herbicide [H-H], integrated weed management [IWM-IWM], and hand weeding [HW-HW]), were tested in a strip plot design. The results showed that ZTR-ZTR significantly increased system productivity (6.90 Mg ha−1), net returns, and benefit-cost ratio (BCR; 2.69), compared to CT. However, CT systems had 173 % higher energy use efficiency (EUE) and 170 % higher energy intensity (EI) than CA systems. CA-based treatments used about 15 % direct renewable energy and 85 % indirect renewable energy, while CT systems used 15–20 % direct non-renewable energy and 85–86 % indirect non-renewable energy. Among weed management practices, recommended herbicides (H-H) led to the highest productivity (6.71 Mg ha−1), EUE (9.80), net returns (3003 US$ ha−1), and BCR (3.08), but also higher carbon footprints. This underscores the balance between productivity, energy efficiency, and carbon in agriculture.

Combined treatment of wounded with traumatic aneurysm of posterior communicating artery complicated by intraventricular hemorrhage

Cerebral blood vessel trauma (CBVT) is a serious condition of craniocerebral injury. According to literature data, different varieties of CBVT in penetrating gunshot craniocerebral injuries are found in 30–45 % of cases. Traumatic pseudoaneurysms are the most common finding in late evaluation and can lead to life-threatening episodes of intracranial hemorrhage.In addition, CBVT includestraumatic occlusion, dissection of vessels, rupture of cerebral arteries, formation of arteriovenous fistulas (carotid-cavernous anastomoses), venous stasis, etc. Injured persons with traumatic dissection and injury of vertebrobasilar pool have the highest risks of lethal outcome. There are no largerandomised trials and national recommendations for the treatment of CBVT, individual observations and small series of clinical cases have been published. In this connection, there is a need for a detailed analysis of all clinical cases, the development of tactics for early diagnosis and an algorithm for the treatment of wounded with CBVT.The article presents a review of the literature data that characterizes the current understanding of CBVT, and a clinical case of traumatic occlusion of the middle cerebral artery and pseudoaneurysm of the posterior communicating artery in a wounded man with a gunshot penetrating cranioorbital wound, who was treated at the neurosurgical center of the N.N. Burdenko Main Military Clinical Hospital.In the early period after the injury, the patient underwent endovasal occlusion of a traumatic aneurysm of the posterior connective artery by microspirals followed by local thrombolysis of intraventricular hematomas through a ventricular catheter. The catamnesis was 150 days, the score on the modified Rankin scale was 3, the Glasgow outcome scale extended was 5.

Evaluation of Tractor Mounted Axial Flow Combine Harvester for Mung Bean (Vigna radiata L.)

A cost-effective, tractor mounted axial flow combine harvester designed to minimize harvesting losses was evaluated. Performance evaluation of the machine was done on summer mung bean (Vigna radiata L. Wilczek) under various operational conditions: three forward speeds (FS): 2.1, 3.0, and 4.8 km h-1, three-cylinder peripheral speeds (PS): 11.08, 13.16, and 14.79 m s-1, and days after irrigation (DAI): 2, 4, and 6 days after last irrigation. Threshing efficiency, cleaning efficiency, broken percentage, shattering losses, and non-collectable losses were estimated. Cost of operation of the combine harvester was compared with manual harvesting and subsequent threshing using a spike tooth type thresher. The results show that the threshing efficiency and grain breakage increased by 1.1% and 1.01%, respectively, with an increase in DAI and PS, however, both these parameters decreased with an increase in FS. The non-collectable loss increased by 0.9% with an increase in FS and DAI; however, PS did not affect the non-collectable losses. The cleaning efficiency increased with an increase in FS, but it decreased with an increase in PS and DAI. The shattering loss increased with an increase in FS and DAI, although PS had no impact. The best combination of operational variables for threshing operation was found for treatment combination of 6 days after last irrigation, with a cylinder peripheral speed of 14.79 m s-1 and a forward speed of 3.0 km h-1. At this combination, threshing efficiency, non-collectable losses, grain breakage, and cleaning efficiency were 99.28%, 4.53%, 2.96%, and 95.89%, respectively. This combine-harvester saved 91.75% in labor costs and 53.71% in harvesting costs compared to the combination of manual harvesting and subsequent threshing using a spike tooth type thresher.

Acyl-coenzyme a binding protein (ACBP) - a risk factor for cancer diagnosis and an inhibitor of immunosurveillance

BackgroundThe plasma concentrations of acyl coenzyme A binding protein (ACBP, also known as diazepam-binding inhibitor, DBI, or ‘endozepine’) increase with age and obesity, two parameters that are also amongst the most important risk factors for cancer.MethodsWe measured ACBP/DBI in the plasma from cancer-free individuals, high-risk patients like the carriers of TP53 or BRCA1/2 mutations, and non-syndromic healthy subjects who later developed cancer. In mice, the neutralization of ACBP/DBI was used in models of non-small cell lung cancer (NSCLC) and breast cancer development and as a combination treatment with chemoimmunotherapy (chemotherapy + PD-1 blockade) in the context of NSCLC and sarcomas. The anticancer T cell response upon ACBP/DBI neutralization was characterized by flow cytometry and single-cell RNA sequencing.ResultsCirculating levels of ACBP/DBI were higher in patients with genetic cancer predisposition (BRCA1/2 or TP53 germline mutations) than in matched controls. In non-syndromic cases, high ACBP/DBI levels were predictive of future cancer development, and especially elevated in patients who later developed lung cancer. In preclinical models, ACBP/DBI neutralization slowed down breast cancer and NSCLC development and enhanced the efficacy of chemoimmunotherapy in NSCLC and sarcoma models. When combined with chemoimmunotherapy, the neutralizing monoclonal antibody against ACBP/DBI reduced the frequency of regulatory T cells in the tumor bed, modulated the immune checkpoint profile, and increased activation markers.ConclusionThese findings suggest that ACBP/DBI acts as an endogenous immune suppressor. We conclude that elevation of ACBP/DBI constitutes a risk factor for the development of cancer and that ACBP/DBI is an actionable target for improving cancer immunosurveillance.

Simultaneous inhibition of FLT3 and HDAC by novel 6-ethylpyrazine-2-Carboxamide derivatives provides therapeutic advantages in acute myelocytic leukemia

Synergetic inhibition of FMS-like tyrosine kinase 3 (FLT3) and histone deacetylase (HDAC) by small molecule chimera presents a promising therapeutic approach for acute myeloid leukemia (AML) with FLT3 mutations. In this study, we first observed that the combined use of FLT3 inhibitor gilteritinib and HDAC inhibitor vorinostat increased the survival rate of leukemia xenograft mouse model. Then, we employed a pharmacophore fusion strategy to develop a novel series of FLT3/HDAC dual inhibitors. Among them, compound 25h demonstrated superior inhibitory activity against both FLT3 and HDAC. In particular, compound 25h exhibited enhanced anti-proliferation activity against MOLM-13 cells in comparison to gilteritinib, vorinostat, and their combination, while maintaining reduced cytotoxicity towards normal cells. Mechanistically, the heightened anti-tumor effect of compound 25h was attributed to its more potent regulation of intracellular pathways, notably phosphorylation of ERK, compared to single drug and combination treatments. Furthermore, compound 25h demonstrated superior anti-tumor efficacy in the MOLM-13 xenograft model compared to combination therapy, along with reduced in vivo toxicity. To conclude, we have identified a novel FLT3/HDAC dual inhibitor that could serve as a potential candidate for the treatment of AML.