Dose Levels Research Articles

Quantitative Label-Free Proteomic Analysis of Mouse Ovarian Antral Follicles Following Oral Exposure to a Human Relevant Mixture of Three Phthalates.

Dibutyl phthalate (DBP), di-2-ethylhexyl phthalate (DEHP), and benzyl butyl phthalate (BBP) are used in personal and medical care products. In the ovary, antral follicles are essential for steroidogenesis and ovulation. DBP, BBP, and DEHP are known to inhibit mouse antral follicle growth and ovulation in vitro, and associate with decreased antral follicle counts in women. Given that the in vivo effects of a three-phthalate mixture on antral follicles are unknown, we evaluated the effects of a human relevant mixture of DBP, BBP, and DEHP on ovarian follicles through proteome profiling analysis. Adult CD-1 female mice were fed corn oil (vehicle), or two dose levels of a phthalate mixture based on estimated exposures in general (32 µg/kg/day; PHT 32) and occupationally exposed (500 µg/kg/day; PHT 500) populations for 10 days. Antral follicles (>250 µm) were isolated and subjected to proteome profiling via label-free tandem mass spectrometry. A total of 5,417 antral follicle proteins were detected, of which 194 were differentially abundant between vehicle and PHT 32, and 136 between vehicle and PHT 500. Bioinformatic analysis revealed significantly different responses between the two phthalate doses. Protein abundance differences in the PHT 32 exposure mapped to cytoplasm, mitochondria, and lipid metabolism; while those in the PHT 500 exposure mapped to cytoplasm, nucleus, and phosphorylation. When both doses altered proteins mapped to common processes, the associated predicted transcription factors were different. These findings provide novel mechanistic insight into phthalate-associated, ovary-driven reproductive outcomes in women.

Application of microalgae in cauliflower fertilisation

In a circular bioeconomy, balancing inorganic fertilisers and microalgae supplementation is important for ensuring sustainable agriculture. This study aimed to evaluate the fertilising effects of live microalgae (mostly Chlorella vulgaris and a mixture of Chlorophyceae and Trebouxiophyceae) on cauliflower (Brassica oleracea L. subsp. botrytis) plant morphology, yield, and quality of cauliflower heads. Microalgae fertilisation effects were analysed by employing an experimental factorial design with two factors: inorganic fertiliser and microalgae, each at high and low dosage levels, and the results revealed higher plant height, wider stem diameter, and lower stem slenderness in high-dose combinations than those in other combinations. In addition, an increase in nitrate, calcium, potassium, and sodium content was observed in the sap of cauliflower leaves in high-dose combinations compared to those in low-dose combinations. The high-dose combination also increased the yield, number of commercial heads, weight of the heads, and number of curds per head of cauliflower. Overall, the study demonstrates that increasing the dose of inorganic fertilisers and microalgae significantly increases nutrient concentration in the sap, which translates into a larger plant, an increase in the number of leaves and yield, and an improvement in the quality of cauliflower heads. These findings underscore the necessity for further research to ascertain the optimal combination of inorganic fertilisers and microalgae to maximise crop yield and cauliflower head quality.

Regorafenib plus FOLFIRINOX as first-line treatment for patients with RAS-mutant metastatic colorectal cancer (FOLFIRINOX-R trial): a dose-escalation study.

The combination of bevacizumab and FOLFIRINOX is used in patients with RAS-mutant metastatic colorectal cancer (RASm-mCRC). Regorafenib, an oral multi-tyrosine kinase inhibitor, has antiangiogenic properties, cytostatic effects and also true cytotoxic effects, unlike bevacizumab. The aim of this study was to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) of the regorafenib-FOLFIRINOX combination in patients with RASm-mCRC. The FOLFIRINOX-R trial was a phase 1/2 study where the dose-escalation part (3 + 3 design with three dose levels, DLs) was completed before its early termination. FOLFIRINOX (14-day cycle) included oxaliplatin (standard dose), folinic acid, fluorouracil and irinotecan (150 or 180mg/m²). Regorafenib (120 or 160mg daily) was given from day 4 to day 10 of each cycle. Dose-limiting toxicity (DLT) was studied in the first three cycles. Eligibility criteria included ECOG performance status ≤ 1 and not previously treated RASm-mCRC. Thirteen patients (median age: 65 years; min-max: 40-76) were enrolled. DLT could not be evaluated in one patient (DL3) due to poor observance. The median treatment duration and median follow-up were 6.2 (min-max: 2.3-10) and 13.4 (min-max: 3.8-18.0) months, respectively. Dose was modified in 12/13 (92%) patients. One grade 3 hypokalemia occurred at DL2. MTD was not reached at DL3. Grade 3 diarrhea was recorded in 7/13 patients (13 events) equally distributed in all DLs. The RP2D for this regorafenib-FFX combination could not be determined due to a high prevalence of grade 3 diarrhea related to treatment as advised by our Independent Data Monitoring Committee. ClinicalTrials.gov : NCT03828799.

Design and synthesis of dexmedetomidine capped silver nanoparticles: Investigation of its catalytic application for reduction of nitrobenzenes and its effects on anesthetic, anti-inflammatory, antioxidant and analgesic applications

In the present work, the mono-dispersed produced dexmedetomidine capped silver nanoparticles were described. Dexmedetomidine-stabilized silver nanoparticles were prepared from the facile reduction of silver nitrate by NaBH4 as a reducing agent and dexmedetomidine as a stabilizing agent. The successful reduction of Ag+ ions into Ag0 NPs was confirmed by a visual formation of a deep brown color solution and the appearance of λmax nearing 450 nm in the UV–Vis study. The desired Ag NPs/Dexmedetomidine nanocomposite were characterized by various techniques such as UV/Vis, SEM-EDX, TEM and XRD. The abundant amino groups of dexmedetomidine provided the uniform dispersion and nano spherical shape of silver with sizes of 30–40 nm. The Ag NPs/Dexmedetomidine nanocomposite was applied in the catalytic reduction of diverse aromatic nitro functions using sodium borohydride as reducing agent. An excellent yield were achieved within very short reaction time. During the in vivo study, it was noted that the combination of Ag NPs/Dexmedetomidine showed local anesthetic properties in frog and guinea pig models. Additionally, oral administration of Ag NPs/Dexmedetomidine led to a notable decrease in paw edema in mice. The convulsive episodes triggered by acetic acid were markedly decreased in a dose-dependent manner in every group that was administered Ag NPs/Dexmedetomidine treatment. Additionally, the pain-relieving and anti-inflammatory properties of Ag NPs/Dexmedetomidine were assessed at different dosage levels. The data of this research provide evidence for the Ag NPs/Dexmedetomidine potential use as a pain-relieving and anesthetic substances in future investigations and medical trials involving human participants. In the antioxidant assessment, Ag NPs/Dexmedetomidine demonstrated IC50 values of 77 µg/mL against DPPH free radicals.

THE COMPARISON OF FERTILIZING CAPACITY OF NATIVE AND NEW HAMPSHIRE MALE CHICKENS

This experiment was conducted to compare and estimate the fertilizing capacity of native with New Hampshire chicken semen. Also to study the effect. Of different levels of semen dosage on fertility percentage, duration’ of fertility and duration of fertilizing ability. In this experiment (12) native and (12) N.H. male chicken with (240) Hisex laying hens have been used. The results of the statistical analysis showed that there were no significant (P>0.05) differences between the native and N.H. male chickens for the fertilizing capacity. fertilizing percentage in duration of fertility and fertility duration. The values were 90.40, 90.73%; 85.77, 85.60%; 12.11, 12.3 days for native and N.H. chickens, respectively. There were no significant (P>0.05) effect of increasing semen concentration (100, 200, 300 million sperm) per single insemenation on the percentage of fertilization and duration of fertility percentage. The values for percentage of fertilization, duration of fertility percentage and fertility duration were 89.76%, 91.79, 90.14; 85.33%, 88.72, 83.01; 12.24, 11.90, 12.50 days, respectively. Using the above mentioned concentration levels, no significant interaction was found between semen concentration and male groups.

Tumor-localized interleukin-2 and interleukin-12 combine with radiation therapy to safely potentiate regression of advanced malignant melanoma in pet dogs.

Interleukin-2 and -12 cytokines have potent anti-cancer activity, but suffer a narrow therapeutic window due to off-tumor immune cell activation. Engineering cytokines with the ability to bind and associate with tumor collagen after intratumoral injection potentiated response without toxicity in mice, and was previously safe in pet dogs with sarcoma. Here we sought to test the efficacy of this approach with in dogs with advanced melanoma. This study examined fifteen client-owned dogs with histologically- or cytologically-confirmed malignant melanoma who received a single 9 Gray fraction of radiation therapy, followed by six cycles of combined collagen-anchored IL-2 and IL-12 therapy Q2W. Cytokine dosing followed a 3+3 dose escalation design, with the initial cytokine dose chosen from prior evaluation in canine sarcomas. No exclusion criteria for tumor stage or metastatic burden, age, weight, or neuter status were applied for this trial. Median survival regardless of tumor stage or dose level was 256 days and 10/13 (76.9%) dogs that completed treatment had CT-measured tumor regression at the treated lesion. In dogs with metastatic disease, 8/13 (61.5%) dogs had partial responses across their combined lesions, evidence of locoregional response. Profiling by Nanostring of treatment-resistant dogs revealed that B2m loss was predictive of poor response to this therapy. Collectively, these results confirm the ability of locally administered tumor-anchored cytokines to potentiate responses at regional disease sites when combined with radiation. This evidence supports the clinical translation of this approach and highlights the utility of comparative investigation in canine cancers.

Effect of Integrated Nutrient Management in China Aster cv. Arka Poornima Under Mid Hills of Himalayas

The present investigation was conducted to investigate the effect of integrated nutrient management on vegetative parameters of China aster cv. Arka Poornima under the mid hills of Himachal Pradesh. The experiment was laid out in simple randomized design (RBD) with eighteen treatments. The experiment was conducted at the Kakhali research farm of Dr. Khem Singh Gill Akal College of Agriculture, Eternal University, Baru Sahib, Himachal Pradesh during kharif season in 2023. For integrated nutrient management eighteen treatments were constituted with three levels of recommend dose of inorganic fertilizers (50, 75 and 100 %) and three biofertilizers viz., Azotobacter, PSB and KSB along with control. The observations for the vegetative parameters plant height (cm) at maturity, numbers of leaves, number of primary branches, number of secondary branches, leaf area per plant, leaf area index and plant spread were recorded and analyzed. The plant height (91.40 cm), No. of leaves (356.13), No. of primary branches (12.40) and secondary branches (33.70) were found maximum in treatment T12 (RDF@75% + Azotobacter + PSB + KSB), while the lowest values were observed in T0 (control). The highest leaf area (27.49 cm2) was found in T8 (RDF@75% + Azotobacter), while the leaf area index (12.02) and plant spread (16.57 cm) were found in treatment T11 (RDF@75% + Azotobacter + PSB). The lowest values for leaf area (17.77 cm2), leaf area index (5.48) and plant spread (11.82 cm) were found in treatments T14 (RDF@100% + Azotobacter), T16 (RDF@100% + KSB) and T10 (RDF@75% + KSB), respectively. Therefore, it can be concluded that, application of T12 (RDF@75% + Azotobacter + PSB + KSB) is best for the getting higher production in China aster followed by T11 (RDF@75% + Azotobacter + PSB). This study will reduce the use of inorganic fertilizer without polluting the soil and environment.

Climate Change Impacts on Future Wheat (Triticum aestivum) Yield, Growth Periods and Irrigation Requirements: A SALTMED Model Simulations Analysis

Climate change poses emerging threats to wheat growth in coming future. These threats need to be explored to ensure sustainable wheat production. To do this, the SALTMED model was calibrated using data from experiments conducted on different levels of irrigation and nitrogen doses. The performance of the SALTMED model was assessed based on values of the root mean square error (RMSE), normalized root mean square error (NRMSE), coefficient of determination (R2) and coefficient of residual mass (CRM) that ranged from 0.23–1.82, 0.09–0.17, 0.91–0.93 and −0.01–0.02, respectively for calibration and 0.31–1.89, 0.11–0.31, 0.87–0.90 and −0.02–0.01, respectively for validation. Projections for future climate scenarios for wheat growth indicated that by the end of the century, sowing dates advanced by nine days under the RCP4.5 scenario and eleven days under the RCP8.5 scenario, while harvesting dates shifted earlier by twenty-four days under RCP4.5 and twenty-eight days under RCP8.5. Consequently, the overall crop duration was shortened by fifteen days under RCP4.5 and eighteen days under RCP8.5. Further simulations revealed that the wheat yield was reduced by 14.2% under RCP4.5 and 21.0% under RCP8.5; the dry matter was reduced by 14.9% under RCP4.5 and 23.3% under RCP8.5; the irrigation amount was expected to increase by 14.9% under RCP4.5 and 18.0% under RCP8.5; and water productivity was expected to be reduced by 25.3% under RCP4.5 and 33.0% under RCP8.5 until the end of century. The hypothetical scenarios showed that adding an extra 20–40% more nitrogen can enhance wheat yield and dry matter by 10.2–23.0% and 11.5–24.6%, respectively, under RCP4.5, and by 12.0–23.4% and 12.9–29.6%, respectively, under RCP8.5. This study offers valuable insights into the effects of climate change on future wheat production so that effective contingency plans could be made by policymakers and adopted by stakeholders for higher wheat productivity.

Identifying SCS Trial Responders Immediately After Postoperative Programming with ECAP Dose-Controlled Closed-Loop Therapy.

Drawbacks of fixed-output spinal cord stimulation (SCS) screening trials may lead to compromised trial outcomes and poor predictability of long-term success. Evoked compound action potential (ECAP) dose-controlled closed-loop (CL) SCS allows objective confirmation of therapeutic neural activation and pulse-to-pulse stimulation adjustment. We report on the immediate patient-reported and neurophysiologic treatment response post-physiologic CL-SCS and feasibility of early SCS trial responder prediction. Patient-reported pain relief, functional improvement, and willingness to proceed to permanent implant were compared between the day of the trial procedure (Day 0) and end of trial (EOT) for 132 participants in the ECAP Study undergoing a trial stimulation period. ECAP-based neurophysiologic measurements from Day 0 and EOT were compared between responder groups. A high positive predictive value (PPV) was achieved with 98.4% (60/61) of patients successful on the Day 0 evaluation also responding at EOT. The false-positive rate (FPR) was 5.6% (1/18). ECAP-based neurophysiologic measures were not different between patients who passed all Day 0 success criteria ("Day 0 successes") and those who did not ("needed longer to evaluate the therapy"). However, at EOT, responders had higher therapeutic usage and dose levels compared to non-responders. The high PPV and low FPR of the Day 0 evaluation provide confidence in predicting trial outcomes as early as the day of the procedure. Day 0 trials may be beneficial for reducing patient burden and complication rates associated with extended trials. ECAP dose-controlled CL-SCS therapy may provide objective data and rapid-onset pain relief to improve prognostic ability of SCS trials in predicting outcomes. The ECAP Study is registered with ClinicalTrials.gov (NCT04319887).

Aggregation behaviour of radiolytically degraded diglycolamide based solvent system

AbstractThe 0.1 M TODGA + 0.2 M DOHyA/n-DD phase was irradiated to various absorbed dose levels and the extraction behaviour of nitric acid and Nd(III) in the irradiated organic phases were studied. The organic phase was then subjected to dynamic light scattering studies to understand the aggregation behaviour in the organic phase. The results showed that the polar degradation products formed in the organic phase decreased the aggregation, while the higher homologue of n-DD enhanced aggregation.

Physiologically based Kinetic Modeling-Facilitated Quantitative In Vitro to In Vivo Extrapolation to Predict the Effects of Aloe-Emodin in Rats and Humans.

Aloe-emodin, a natural hydroxyanthraquinone, exerts both adverse and protective effects. This study aimed at investigating these potential effects of aloe-emodin in humans upon the use of food supplements and herbal medicines using a physiologically based kinetic (PBK) modeling-facilitated quantitative in vitro to in vivo extrapolation (QIVIVE) approach. For this, PBK models in rats and humans were established for aloe-emodin including its active metabolite rhein and used to convert in vitro data on hepatotoxicity, nephrotoxicity, reactive oxidative species (ROS) generation, and Nrf2 induction to corresponding in vivo dose-response curves, from which points of departure (PODs) were derived by BMD analysis. The derived PODs were subsequently compared to the estimated daily intakes (EDIs) resulting from the use of food supplements or herbal medicines. It is concluded that the dose levels of aloe-emodin from food supplements or herbal medicines are unlikely to induce toxicity, ROS generation, or Nrf2 activation in liver and kidney.

Toxicological Assessment of Pesticide Exposure in Wistar Rats: An Acute and Sub-Acute Inhalation Study

Background: Pesticide ubiquity and extensive applications have attendant public health implications. This study examines the immediate and prolonged inhalation toxicity of various commonly used insecticides in male Wistar rats. Methods: 192 male Wistar rats were utilized and kept in regular housing. The study was carried out in three stages: a preliminary test, an acute test, and a sub-acute. Wistar rats, housed in an improvised chamber, were exposed to varying doses of insecticides in each phase to assess their toxicities to insecticides. For comparativeness, we withdrew 57 of the rats from exposure to ascertain possible recovery. The study included monitoring behavioral changes, recording mortality rates, and conducting necropsies to evaluate organ pathology. Dose-response relationships were analyzed to determine lethal doses (LD50) and potential sublethal effects. Results: Overall, we found a dose-related increase in the severity of the response, which potentially indicates an alteration of a specific biochemical process. The range-finding test assessed the effects of DD Force, Sniper, Industrial Camphor, Edible Camphor, Kerosene, and combined pesticides. It revealed significant physiological impacts followed by mortalities at specific dosage levels. Subsequent acute toxicity testing determined LC50 values for each insecticide. Rats showed a dose-dependent health deterioration following sub-acute exposure, particularly in the combined pesticide group, indicating synergistic toxicity. Conclusion: Exposure to the combined pesticide at high doses was associated with severe toxicities in the tested rats. This evidence suggests that commonly used pesticides could potentiate adverse health outcomes when results are extrapolated in humans.

A pharmacokinetic-pharmacodynamic analysis of l-glutamine for the treatment of sickle cell disease: Implications for understanding the mechanism of action and evaluating response to therapy.

The mechanisms of action of l-glutamine for the treatment of sickle cell disease (SCD) are not well understood and there are no validated clinical biomarkers to assess response. We conducted a three-week, dose-ascending trial of glutamine and measured the pharmacokinetic (PK) exposure parameters, peak concentration (Cmax) and area under the curve (AUC). We used a panel of biomarkers to investigate the pharmacodynamics (PD) of glutamine and studied PK-PD relationships. There was no plasma accumulation of glutamine, glutamate, arginine or other amino acids over time, but modestly improved arginine bioavailability was observed. In standard analysis by dose levels over time, there were no measurable effects on blood counts, viscosity, ektacytometry or reactive oxygen species (ROS). In PK-PD analysis, however, higher glutamine exposure (Cmax or AUC) was associated with increased whole blood viscosity and cellular dehydration, yet also with higher haemoglobin concentration, increased haematocrit-to-viscosity ratio, decreased reticulocyte ROS, improved RBC deformability and decreased point of sickling. This novel PK-PD analysis identified biomarkers reflecting the positive and negative effects of glutamine, helping to elucidate its mechanisms of action in SCD. PK-optimized dosing to achieve glutamine exposure (AUC or Cmax) that is associated with salutary biological effects should be studied to support its therapeutic use.

Ophthalmic Nanoemulsion Fingolimod Formulation for Topical Application.

Purpose: Fingolimod (FTY720; FT), a structural analog of sphingosine, has potential ocular applications. The goal of this study was to develop an FT-loaded nanoemulsion (NE; FT-NE) formulation for the efficient and prolonged delivery of FT to the posterior segment of the eye through the topical route. Methods: FT-NE formulations were prepared using homogenization followed by the probe sonication method. The lead FT-NE formulations (0.15% and 0.3% w/v loading), comprising soybean oil as oil and Tween® 80 and Poloxamer 188 as surfactants, were further evaluated for in vitro release, surface morphology, filtration sterilization, and stability at refrigerated temperature. Ocular bioavailability following topical application of FT-NE (0.3%) was examined in Sprague-Dawley rats. Results: The formulation, at both dose levels, showed desirable physicochemical characteristics, a nearly spherical shape with homogenous nanometric size distribution, and was stable for 180 days (last time point checked) at refrigerated temperature postfiltration through a polyethersulfone (0.22 µm) membrane. In vitro release studies showed prolonged release over 24 h, compared with the control FT solution (FT-S). In vivo studies revealed that effective concentrations of FT were achieved in the vitreous humor and retina following topical application of FT-NE. Conclusions: The results from these studies demonstrate that the FT-NE formulation can serve as a viable platform for the ocular delivery of FT through the topical route.

Preclinical evaluation of [18F]SYN1 and [18F]SYN2, novel radiotracers for PET myocardial perfusion imaging

BackgroundPositron emission tomography (PET) is now an established diagnostic method for myocardial perfusion imaging (MPI) in coronary artery disease, which is the main cause of death globally. The available tracers show several limitations, therefore, the 18F-labelled tracer is in high demand nowadays. The preclinical studies on normal Wistar rats aimed to characterise two potential, novel radiotracers, [18F]SYN1 and [18F]SYN2, to evaluate which is a better candidate for PET MPI cardiotracer.ResultsThe dynamic microPET images showed rapid myocardial uptake for both tracers. However, the uptake was higher and also stable for [18F]SYN2, with an average standardized uptake value of 3.8. The biodistribution studies confirmed that [18F]SYN2 uptake in the cardiac muscle was high and stable (3.02%ID/g at 15 min and 2.79%ID/g at 6 h) compared to [18F]SYN1 (1.84%ID/g at 15 min and 0.32%ID/g at 6 h). The critical organs determined in dosimetry studies were the small intestine and the kidneys. The estimated effective dose for humans was 0.00714 mSv/MBq for [18F]SYN1 and 0.0109 mSv/MBq for [18F]SYN2. The tested dose level of 2 mg/kg was considered to be the No Observed Adverse Effect Level (NOAEL) for both candidates. The better results were achieved for [18F]SYN2, therefore, further preclinical studies were conducted only for this tracer. Radioligand binding assays showed significant responses in 3 from 68 assays: muscarinic acetylcholine M1 and M2 receptors and potassium channel hERG. The compound was mostly metabolised via an oxidative N-dealkylation, while the fluor substituent was not separated from the molecule.Conclusion[18F]SYN2 showed a favourable pharmacodynamic and pharmacokinetic profile, which enabled a clear visualization of the heart in microPET. The compound was well-tolerated in studies in normal rats with moderate radiation exposure. The results encourage further exploration of [18F]SYN2 in clinical studies.

FDA approval summary: fam-trastuzumab deruxtecan-nxki for unresectable or metastatic non-small cell lung cancer with activating HER2 mutations.

On August 11, 2022, FDA granted accelerated approval to fam-trastuzumab deruxtecan-nxki (DS-8201a, T-DXd, ENHERTU, Daiichi Sankyo) for adult patients with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have activating human epidermal growth factor receptor 2 (HER2) mutations, as detected by an FDA-approved test, and who have received a prior systemic therapy. The approval was based on a prespecified interim analysis of DESTINY-Lung02 (Study U206), a multi-center, randomized, dose-optimization trial in patients with NSCLC harboring activating HER2-mutations. At the approved dose of 5.4 mg/kg given intravenously every 3 weeks, the overall response rate (ORR) was 58% (95% confidence interval [CI]: 43, 71). The median duration of response was 8.7 months (95% CI: 7.1, not estimable). These results were consistent with response rates observed at the 6.4 mg/kg dose level. The most common (≥ 20%) adverse reactions were nausea, constipation, decreased appetite, vomiting, fatigue, and alopecia. The rate of interstitial lung disease (ILD) or pneumonitis was 6% at the 5.4 mg/kg dose level and 14% at the 6.4 mg/kg dose level. In the setting of similar efficacy and reduced toxicity, approval was granted for the 5.4 mg/kg dose level. The applicant conducted a randomized, dose-optimization study with guidance from the FDA Oncology Center of Excellence's Project Optimus. This is the first approval of a targeted therapy for HER2-mutated NSCLC.

A phase-I study of second-line S-IROX for unresectable pancreatic cancer after gemcitabine plus nab-paclitaxel failure.

Gemcitabine plus nab-paclitaxel (GnP) and FOLFIRINOX are widely used as first-line regimens for unresectable pancreatic cancer (PC). When GnP therapy is selected, considering patient age or condition, second-line FOLFIRINOX is sometimes difficult to administer owing to its toxicity. This study aimed to determine the recommended dose (RD) of S-IROX (S-1, oxaliplatin, and irinotecan combination) regimens in patients with unresectable PC after first-line GnP failure. This phase-I study used the "3 + 3" dose-escalation design with two dose levels. Patients who failed first-line GnP therapy for unresectable PC were enrolled. Oxaliplatin and irinotecan were administered on day 1, and S-1 was administered orally twice daily on days 1-7, followed by 7days of rest. The primary endpoints were dose-limiting toxicities (DLTs) and determination of RD. The secondary endpoint was the evaluation of potential antitumor activity. Nine patients received the second-line S-IROX regimen. In level-0 (S-1, 80mg/m2; oxaliplatin, 85mg/m2; and irinotecan, 120mg/m2), no patient experienced DLT; however, one patient experienced grade 3 neutropenia. At level-1 (irinotecan increased to 150mg/m2), one of six patients experienced DLTs, including G3 diarrhea. The RD was confirmed at the level-1 dose. The response rate, disease control rate, median progression-free survival, and median overall survival were 33.3%, 77.8%, 172 (range:77-422) days, and 414 (101-685) days, respectively. One patient underwent surgery after the second-line S-IROX therapy. Second-line S-IROX treatment was deemed acceptable. The RD was set at level-1 dose (S-1, 80mg/m2; oxaliplatin, 85mg/m2; and irinotecan, 150mg/m2).

Biodistribution of the cationic host defense peptide LL-37 using SPECT/CT

Human cathelicidin LL-37, a cationic host defense peptide (CHDP), has several important physiological roles, including antimicrobial activity, immune modulation, and wound healing, and is a being investigated as a therapeutic candidate for several indications. While the effects of endogenously produced LL-37 are well studied, the biodistribution of exogenously administered LL-37 are less known. Here we assess the biodistribution of a gallium-67 labeled variant of LL-37 using nuclear imaging techniques over a 48 h period in healthy mice. When administered as an intravenous bolus just over 20 µg, the LL-37-based radiotracer was rapidly cleared from the blood, largely by the liver, while an appreciable fraction of the dose temporarily distributed to the lungs. When administered subcutaneously at the same dose level, the radiotracer was absorbed systemically following a two-phase kinetic model and was predominately cleared renally. Uptake into sites rich in immune cells, such as the lymph nodes and the spleen, was observed for both routes of administration. Scans of free gallium-67 were also performed as controls. Important preclinical insights into the biodistribution of exogenously administered LL-37 were gained from this study, which can aid in the understanding of this and related cationic host-defense peptides.

First-in-human clinical trial results with ABBV-184, a first-in-class T-cell receptor/anti-CD3 bispecific protein, in adults with previously treated AML or NSCLC

ABSTRACT Background ABBV-184, a novel survivin peptide-targeting T-cell receptor (TCR)/anti-CD3 bispecific protein, demonstrated preclinical T-cell activation and cytotoxicity toward HLA-A2:01-positive tumor lines. This first-in-human trial evaluated ABBV-184 monotherapy in patients with acute myeloid leukemia (AML) and non-small cell lung cancer (NSCLC). Research design and methods This phase 1 multicenter, open-label, dose escalation trial (NCT04272203) enrolled adult patients with relapsed/refractory AML or NSCLC with an HLA-A2:01 restricted genotype. Patients received ABBV-184 at 0.07 ug/kg initially, with 2- to 3-fold dose increases. The primary objective was determining the ABBV-184 recommended phase 2 dose. Secondary objectives included safety, tolerability, pharmacokinetics, and immunogenicity assessments. Results Fifteen patients enrolled in the dose escalation (8 AML and 7 NSCLC). ABBV-184 doses ranged from 0.07 mg/kg–0.7 µg/kg, with a half-life of approximately 13–29 hours. Transient cytokine increases were observed at all dose levels, and in patients with NSCLC, transient peripheral blood lymphocyte decreases were observed. The most frequently reported treatment-emergent adverse events (TEAEs) were anemia, diarrhea, and headache. Grade 1–2 infusion-related reaction (IRR) and cytokine release syndrome (CRS) TEAEs were reported. Conclusions ABBV-184 was well tolerated and demonstrated preliminary evidence of CD3 engagement with transient cytokine increases and peripheral lymphocyte decreases. Clinical trial Registration NCT04272203

Improving the insecticidal efficacy of Thuja orientalis essential oil by gamma radiation against Trogodermagranarium

The essential oils isolated by hydrodistillation from Thuja orientalis unripe fruits exposed to gamma radiation at dose levels of 0, 1, 3, and 5 kGy were analyzed by GC–mass spectrometry (MS) and assessed for their insecticidal activities on Trogoderma granarium Everts. The results showed slight changes were observed in the chemical composition of essential oil. The results showed that irradiated oil treatments induced higher toxicity to larvae of T. granarium than unirradiated oil with LD50 values (41.5, 54.2, and 87.1 μl/larva), and LD90 values (122.8, 207.5, and 314.7 μl/larva) for irradiated oil with 5.0, 3.0, and 1.0 kGy, respectively compared with unirradiated oil (LD50 = 153.8 μl/larva) and (LD90 = 622.8 μl/larva) by contact method. The same trend was obtained in the fumigant assay, the irradiated oil treatments with 3.0 and 5.0 kGy increased the toxicity to larvae of T. granarium than unirradiated oil with LC50 values were 280.7 and 183.6 μl/L, and LC90 values were 1171.6 and 687.4 μl/L, respectively compared with unirradiated oil (LC50 = 449.4 μl/L) and (LC90 = 1656.1 μl/L). The results showed also, that at 0.063 and 0.126 μl/cm2, the irradiated T. orientalis with 5.0 kGy, showed strong repellent activity against T. granarium larvae with the percentage repellency 100% (Class V) compared with the unirradiated oil (23.3 and 53.3%) after 2 h treatment. While at 0.252 μl/cm2, all three irradiated T. orientalis essential oil doses caused complete repellence for T. granarium larvae compared with the unirradiated oil (90%) after 2 h treatment. The present findings indicated that gamma radiation improves the insecticidal efficacy of T. orientalis essential oil and could be successfully used for the management of this insect pest.