Dose Levels Research Articles

CNSC-02. PEDIATRIC BRAIN TUMOR CONSORTIUM (PBTC)-056: A PHASE 1 STUDY OF THE ADAM-10 INHIBITOR, INCB007839, IN CHILDREN WITH RECURRENT/PROGRESSIVE HIGH-GRADE GLIOMAS TO TARGET MICROENVIRONMENTAL NEUROLOGIN-3

Abstract BACKGROUND Pediatric high-grade gliomas (pHGGs), including diffuse intrinsic pontine glioma (DIPG), are a leading cause of central nervous system tumor-related morbidity and mortality in children. Neuronal activity promotes growth of HGGs; one key mechanism is neuronal activity-regulated shedding of neuroligin-3 into the glioma microenvironment, mediated by the protease (A Disintegrin and Metalloprotease) ADAM10. ADAM10 inhibition slows tumor growth in preclinical pHGG models. Here, we report results of the clinical trial PBTC-056 (NCT04295759) evaluating safety and tolerability of INCB007839, an inhibitor of the ADAM 10 and 17 proteases. METHODS Patients aged 3-21 years old with recurrent/progressive pHGGs, including DIPG, were eligible. Additional eligibility criteria included measurable disease and failure of at least 1 standard treatment. One dose level (120mg/m2/dose twice daily [BID]) was tested, and the trial was subsequently amended to require prophylactic anticoagulation with enoxaparin due to an unanticipated toxicity. The primary objective was to assess the safety and tolerability of INCB007839 for children with pHGGs. RESULTS 12 of 13 eligible subjects were evaluable. Median age was 13.5 years (4.9-20.7 years). Diagnoses included: DIPG (54%), glioblastoma multiforme (31%), anaplastic astrocytoma (8%) and CNS primary tumor NOS (8%). All patients were treated at DL1 and remained on study for 1-4 courses. The most common toxicities were lymphopenia, elevated transaminases, and fatigue. There were 3 dose-limiting toxicities: Grade 5 cerebral venous thrombosis (n=1), Grade 3 alanine aminotransferase increase (n=1) and Grade 2 thrombocytopenia (n=1). Ten patients progressed/relapsed during active treatment, 1 patient died on treatment, and 2 patients withdrew (1 prior to starting therapy). CONCLUSIONS INCB007839 was generally well tolerated with a recommended phase 2 dose of 120mg/m2/dose BID and concurrent prophylactic anti-coagulation. These data, combined with foundational preclinical studies targeting neuron-cancer interactions, open the door to possible cancer neuroscience strategies, including combination therapy, for pediatric high-grade gliomas.

Safety and feasibility of third-party cytotoxic T lymphocytes for high-risk patients with COVID-19

AbstractCytotoxic T lymphocytes (CTLs) destroy virally infected cells and are critical for the elimination of viral infections such as those caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Delayed and dysfunctional adaptive immune responses to SARS-CoV-2 are associated with poor outcomes. Treatment with allogeneic SARS-CoV-2–specific CTLs may enhance cellular immunity in high-risk patients providing a safe, direct mechanism of treatment. Thirty high-risk ambulatory patients with COVID-19 were enrolled in a phase 1 trial assessing the safety of third party, SARS-CoV-2–specific CTLs. Twelve interventional patients, 6 of whom were immunocompromised, matched the HLA-A∗02:01 restriction of the CTLs and received a single infusion of 1 of 4 escalating doses of a product containing 68.5% SARS-CoV-2–specific CD8+ CTLs/total cells. Symptom improvement and resolution in these patients was compared with an observational group of 18 patients lacking HLA-A∗02:01 who could receive standard of care. No dose-limiting toxicities were observed at any dosing level. Nasal swab polymerase chain reaction testing showed ≥88% and >99% viral elimination from baseline in all patients at 4 and 14 days after infusion, respectively. The CTLs did not interfere with the development of endogenous anti–SARS-CoV-2 humoral or cellular responses. T-cell receptor β analysis showed persistence of donor-derived SARS-CoV-2-specific CTLs through the end of the 6-month follow-up period. Interventional patients consistently reported symptomatic improvement 2 to 3 days after infusion, whereas improvement was more variable in observational patients. SARS-CoV-2–specific CTLs are a potentially feasible cellular therapy for COVID-19 illness. This trial was registered at www.clinicaltrials.gov as #NCT04765449.

DIPG-47. SEQUENTIAL INTRAVENOUS AND INTRACEREBROVENTRICULAR GD2-CAR T-CELL THERAPY FOR H3K27M-MUTATED DIFFUSE MIDLINE GLIOMAS

Abstract BACKGROUND H3K27M-mutant diffuse midline gliomas (DMGs) express uniformly high levels of the GD2 disialoganglioside. In preclinical models, chimeric antigen receptor modified T-cells (CAR T-cells) targeting GD2 robustly regressed orthotopically xenografted DMGs. METHODS This Phase I trial (NCT04196413) administered one IV dose of autologous T-cells transduced with a GD2-CAR retroviral vector to patients with H3K27M-mutant pontine (DIPG) or spinal (sDMG) diffuse midline gliomas at two dose levels (DL1=1e6 GD2-CAR T-cells/kg; DL2=3e6 GD2-CAR T-cells/kg) following standard lymphodepleting (LD) chemotherapy. Patients with clinical or imaging benefit following IV infusion were eligible for subsequent intracerebroventricular (ICV) GD2-CAR T-cell infusions (10-30e6 GD2-CAR T-cells). Primary objectives were to determine feasibility of manufacturing, assess tolerability of IV GD2-CAR T-cells in patients with DIPG and sDMG, and identify a maximally tolerated dose of IV GD2-CAR T-cells following lymphodepleting chemotherapy. Secondary objectives included preliminary assessments of benefit. Here we report the final results of Arm A. RESULTS Thirteen patients enrolled and 11 received one IV GD2-CAR T infusion on study [n=3 DL1(3 DIPG); n=8 DL2(6 DIPG/2 sDMG). GD2-CAR T-cells were successfully manufactured for each patient. After IV infusion, no dose-limiting toxicities (DLTs) occurred on DL1, but three patients experienced DLT on DL2 due to grade 4 cytokine release syndrome (CRS). Nine patients received ICV infusions, which were not associated with DLTs. All patients exhibited tumor inflammation-associated neurotoxicity (TIAN). Four patients demonstrated major volumetric reductions of 52%, 54%, 91% and 100%. One patient exhibited a complete response durable for >30 months since therapy began. Eight patients demonstrated neurological benefit based upon a protocol-directed Clinical Improvement Score. CONCLUSIONS Sequential IV followed by ICV GD2-CAR T-cells infusions induced tumor regressions and neurological improvements. DL1 was established as the maximally tolerated IV GD2-CAR T-cell dose. Neurotoxicity was safely managed with intensive monitoring and close adherence to a management algorithm.

TRLS-06. PHASE 1 STUDY OF THE CD40 AGONISTIC MONOCLONAL ANTIBODY APX005M (SOTIGALIMAB) IN PEDIATRIC, ADOLESCENT, AND YOUNG ADULT PATIENTS WITH RECURRENT OR PROGRESSIVE CNS TUMORS AND NEWLY DIAGNOSED BRAIN STEM GLIOMA: A PEDIATRIC BRAIN TUMOR CONSORTIUM STUDY (PBTC-051; NCT03389802)

Abstract BACKGROUND CD40 is a co-stimulatory receptor present on antigen-presenting cells. CD40 agonists are hypothesized to reverse cancer-induced immune suppression and induce tumor cell killing. The PBTC completed a first-in-pediatrics phase 1 study (PBTC-051) of the CD40 agonistic monoclonal antibody APX005M (sotigalimab). METHODS Patients 1-21.99 years old with recurrent/progressive/refractory malignant non-brainstem central nervous system (CNS) tumors were eligible for stratum 1, and those with post-radiation pre-progression diffuse intrinsic pontine glioma (DIPG) for stratum 2. Patients received APX005M (sotigalimab) via IV on day 1 of each 21 day cycle. A 3 + 3 statistical design was used for dose escalation through 3 planned dose levels (DL). Patients could receive APX005M (sotigalimab) for 36 cycles or until disease progression, unacceptable toxicity, or death. RESULTS 31 eligible patients enrolled (20 on stratum 1, 11 on stratum 2) between 2018-2023; 29 were evaluable for dose finding. The most common diagnosis in stratum 1 was ependymoma (35%). DL3 (0.6 mg/kg) was the recommended phase 2 dose (RP2D) for stratum 1 and DL2 (0.3 mg/kg) for stratum 2. Five patients had dose limiting toxicities—two stratum 1 patients at DL3 and three stratum 2 patients at DL3. The most common grade 3+ adverse events at least possibly attributable to APX005M (sotigalimab) were lymphopenia, neutropenia, leukopenia, and increased ALT. Median number of cycles was 2 (1-36) for stratum 1 and 3 (1-19) for stratum 2. No patients had an objective response to APX005M. 6 month progression-free survival (PFS) for stratum 2 patients (calculated from start of treatment) was 30.7±12.8%; median PFS was 3.7 months. CONCLUSIONS APX005M was well-tolerated in pediatric patients with both recurrent/refractory/progressive CNS tumors and post-radiation pre-progression DIPG. A RP2D was established for both populations. Future studies of this agent in pediatric neuro-oncology patients should prioritize combination therapy.

MDB-65. RESULTS FROM THE SJ-ELIOT PHASE 1 CLINICAL TRIAL EVALUATING PREXASERTIB (LY2606368) IN COMBINATION WITH CYCLOPHOSPHAMIDE OR GEMCITABINE FOR CHILDREN AND ADOLESCENTS WITH REFRACTORY OR RECURRENT MEDULLOBLASTOMA

Abstract BACKGROUND SJ-ELIOT (NCT04023669) was a phase 1 trial that explored the combination of the checkpoint kinase inhibitor, prexasertib with the DNA-damaging agents, cyclophosphamide and gemcitabine, in recurrent or refractory medulloblastoma. METHODS Participants ≥ 1 year and < 25 years were stratified to one of two treatment strata: stratum A prexasertib and cyclophosphamide and stratum B prexasertib and gemcitabine. Patients with Group 3/4 medulloblastoma were assigned to either stratum A or B, whereas patients with SHH medulloblastoma were assigned to stratum A. A Rolling-6 design was used. RESULTS Fifteen patients were enrolled on stratum A and six patients on stratum B. The study was closed early due to drug supply issues. In stratum A, three patients were escalated to dose level (DL) 3 and none had dose limiting toxicity (DLT). For stratum B, of the first three patients enrolled on DL1, two had DLTs (grade 3 hypotension) related to drug reactions. Consequently, stratum B was amended to add hydrocortisone prophylaxis. A further three patients were enrolled. One patient had a grade 3 DLT (ALT increase). The remaining two patients electively stopped therapy within the first two courses. One patient on stratum A, with SHH TP53 mutant, MYCN amplified medulloblastoma, achieved a complete sustained response, received 12 cycles, and electively stopped treatment after 408 days. They progressed nine months later. The remaining 14 patients on stratum A progressed. There were no objective responses on stratum B. Median PFS were 1.9 and 2.1 months for stratum A and B respectively. CONCLUSIONS The MTD/RP2D was not established for either arm. In stratum A, DL3 was tolerated, whereas DL1 for Stratum B was not tolerated. Despite robust preclinical data, no efficacy signal was observed. Intriguingly, one patient with a highly aggressive tumor (SHH TP53 mutant, MYCN amplified) appeared to derive a sustained benefit from the combination of prexasertib and cyclophosphamide.

DIPG-84. PHASE 1 DOSE-ESCALATION STUDY OF ACT001 IN PEDIATRIC PATIENTS WITH ADVANCED BRAIN AND SOLID TUMORS SHOWS ACTIVITY IN DIFFUSE MIDLINE GLIOMA (DMG)

Abstract BACKGROUND ACT001, an oral parthenolide derivative targeting STAT3 and NF-κB pathways, has shown activity in preclinical models of DMG. We evaluated safety, toxicity and activity of ACT001 in this recently completed, first-in-child study of DMG and other relapsed/refractory brain and solid tumors. METHODS Eligible patients ≥ 1 and ≤ 21 years old were enrolled with dose escalation following a rolling 6 design and tumor lesions evaluated every 8 weeks per RANO/ RECIST criteria. RESULTS A total of 29 patients were enrolled across 5 cohorts, including 19 with DMG (13 with Diffuse Intrinsic Pontine Glioma (DIPG)). Median age was 11 years for the whole cohort and 7 years (3-17) for DMG patients. Safety was evaluated in escalating doses in 188, 533, 700, 875 and 1100 mg/m2,BID cohorts. No DLT nor grade 3 and above TRAE was identified. One SUSAR was noted for a grade 1 pain in extremity event. Peak ACT001 concentration for each dose cohort were estimated based on limited PK sampling time (cycle 1 day 1 at pre-dose, 2 and 4 hours post dose; cycle 1 day 15 and cycle 2 day 1 both at pre-dose). ACT001 peak concentration plateaued at the highest dose levels, fluctuating in the range of 6360, 5430 and 5980 mg/m2 for 700, 875 and 1100 mg/m2 cohorts respectively. The half-life was approximately 3 hours. 8/14 DMG patients treated at ≥ 700 mg/m2 exhibited objective response or stable disease (SD), including one patient with SD for 14 months, another patient with confirmed Partial Response who remained on study for 11-months before disease progression and five other patients with different degrees of tumor burden reduction. CONCLUSION ACT001 was well tolerated and showed preliminary evidence of anti-tumor activity in DMG/DIPG patients dosed at the highest dose levels. A Phase 2 trial is planned using 875 mg/m2 as the RP2D.

Secondary cancer risk assessment in healthy organs following craniospinal irradiation

Introduction Medulloblastoma is a central nerves tumor that often occurs in pediatrics. The main radiotherapy technique for this tumor type is craniospinal irradiation (CSI), through which the whole brain and spinal cord are exposed to radiation. Due to the immaturity of healthy organs in pediatrics, radiogenic side effects such as second cancer are more severe. Accordingly, the current study aimed to evaluate the risk of secondary cancer development in healthy organs following CSI. Materials and methods Seven organs at risk (OARs) including skin, eye lens, thyroid, lung, liver, stomach, bladder, colon, and gonads were considered and the dose received by each OAR during CSI was measured inside an anthropomorphic RANDO phantom by TLDs. Then, the mean obtained dose for each organ was used to estimate the probability of secondary malignancy development according to the recommended cancer risk coefficients for specific organs. Results The results demonstrated that the stomach and colon are at high risk of secondary malignancy occurrence, while the skin has the lowest probability of secondary cancer development. The total received dose after the treatment course by all considered organs was lower than the corresponding tolerable dose levels. Conclusions From the results, it can be concluded that some OARs during CSI are highly at risk of secondary cancer development. This issue may be of concern due to organ immaturity in pediatrics which can intensify the radiogenic effects of radiation exposure. Accordingly, strict shielding the OARs during craniospinal radiotherapy and/or sparing them from the radiation field through modern techniques such as hadron therapy is highly recommended.

Cannabidiol (CBD) Products: Use Patterns and Perceptions Within a Sample of Anxious Users

Introduction Cannabidiol (CBD) shows promise for a variety of indications, including anxiety. Prior survey work indicates anxiety ranks as a top reason for which people use cannabidiol (CBD), but no work has evaluated individuals using CBD specifically for anxiety. Method The current study evaluated CBD product use patterns and perceptions within a sample of 81 participants (Mage = 32.63, SDage = 12.99) who reported using CBD products for anxiety-related concerns within the past 30 days. Results Family and friends, followed by popular and scientific literature, were the most common sources informing participants’ decision to use CBD products to target anxiety. On average, participants reported using CBD products daily for at least a year and indicated it was very effective in targeting anxiety-related symptoms. The top three ranked symptoms improved by CBD products were subjective anxiety, difficulty falling asleep, and irritability. These findings were despite the fact that the most frequent dosing levels (∼50mg) were well below those empirically observed to yield anxiolytic effects. Most participants denied side effects, adding to the literature supporting CBD products’ safety and tolerability. Finally, participants were generally poorly informed about the nature of CBD products (e.g., distinction from THC), suggesting a need for consumer education. Conclusion Collectively, the current study extends prior survey work suggesting powerful expectancies about CBD products, particularly in terms of anxiety reduction, including among those using it to target anxiety-related symptoms. Findings also highlight the importance of addressing the gap between scientific and consumer knowledge.

TRLS-10. CLINICAL TRIAL IN PROGRESS - CONNECT2007: PHASE I/II STUDY OF LUTATHERA IN PATIENTS WITH RECURRENT AND/OR PROGRESSIVE HIGH-GRADE CENTRAL NERVOUS SYSTEM (CNS) TUMORS AND MENINGIOMAS THAT DEMONSTRATE UPTAKE ON DOTATATE PET

Abstract BACKGROUND Somatostatin type-2A receptors (SST2A) regulate cell growth through complex downstream modulation of proliferation and apoptosis signaling, thereby representing a potential therapeutic target. Lutetium (177Lu-DOTATATE), a radionuclide therapy which binds SST2A and delivers local radiation via beta particle emission, gained FDA approval for gastroenteropancreatic neuroendocrine tumors, a disease characterized by SST2A expression. Potential expansion of Lutathera into pediatric neuro-oncology is supported by evidence that medulloblastoma, other embryonal tumors, and meningiomas consistently express membranous SST2A, exhibit corresponding uptake on SST2A-radiolabeled nuclear imaging (DOTATATE PET), and have demonstrated radiographic response to SST2A-targeted therapy, suggesting sufficient CNS penetration to achieve therapeutic benefit. METHODS CONNECT2007 (NCT05278208) is an international, multicenter phase I/II study investigating safety and efficacy of Lutathera in children and adults with SST2A-expressing CNS tumors. Patients with recurrent/progressive high-grade CNS tumors and meningiomas can undergo screening, consisting of DOTATATE PET imaging for functional confirmation of SST2A expression, requiring adequate uptake (Krenning score ≥2) by central review. The phase I cohort will enroll patients aged 4-<12 years to determine the pediatric recommended phase II dose (RP2D) following a Rolling Six design, with three potential dose levels, starting at the adult RP2D (200mCi), scaled by body surface area. The phase II cohort will enroll patients aged ≥12 years to assess anti-tumor activity through evaluation of 6-month progression-free survival in medulloblastoma/embryonal tumors (descriptive in other histologies). Lutathera is administered intravenously, with concurrent amino acids for nephroprotection, dosed every 8 weeks for up to 4 cycles. Longitudinal correlative studies include 1) evaluating prevalence, heterogeneity, and clinical, histologic molecular, and radiographic predictors of SST2A expression, 2) characterizing radiation dosimetry of Lutathera in organs at risk of toxicity and within CNS to assess tumor penetration, and 3) identifying imaging and molecular biomarkers of response. Enrollment began in January 2023; both cohorts remain open to accrual.

SURG-07. A PHASE I STUDY EXAMINING THE FEASIBILITY OF INTERMITTENT CONVECTION-ENHANCED DELIVERY (CED) OF MTX110 FOR THE TREATMENT OF CHILDREN WITH NEWLY DIAGNOSED DIFFUSE MIDLINE GLIOMAS

Abstract BACKGROUND Histone deacetylase inhibitors have been found preclinically to be among the most active agents against Diffuse Midline Gliomas (DMGs), however, they are clinically ineffective with systemic delivery due to low blood brain barrier penetration and systemic toxicity. Using an implantable subcutaneous pump connected with a catheter directly implanted into the pons we have conducted a phase I, 3 + 3 dose escalation study to investigate the safety and feasibility of repeated infusions of MTX110 (Biodexa Ltd), a water-soluble formulation of panobinostat, via CED. METHODS Eligible patents were between 3 and 18 years of age with newly diagnosed DMG following radiation therapy, without evidence of hemorrhage or cyst in the tumor, and having normal organ function. First, patients underwent tumor biopsy and device implantation, then received two 48-hour-infusion pulses 7 days apart. Three dose levels of MTX110 infusions (30, 60, 90 mcM) were studied. The infusion pump was prefilled with MTX110 (and gadolinium for co-infusion as a contrast agent), which was then administered using the wireless N’Vision clinical programmer at a rate of 0.2 mL/hr. RESULTS Nine patients were treated in the study (30 mcM group, n=3; 60 mcM group, n=4; 90 mcM group, n=2). All patients had an H3K27M mutated tumor. All but one patient had adequate tumor coverage with the infusate. One patient suffered a severe adverse event related to the infusion and tumor anatomy. Four patients had Grade 2 transient neurological deficits related to biopsy (n=1) or infusion (n=3). We observed one objective response. Median PFS was 10 months from diagnosis (range 8 to 20 months) while median OS was 16.5 months (range 12 to 35 months). CONCLUSIONS The study has demonstrated safety and feasibility of repeated infusions of MTX110 via CED in DMG patients with a favorable trend in overall survival warranting further trials with higher number of infusion pulses.

The effects of Artemisia Sieberi, Achillea Fragrantissima, and Olea Europaea leaves on the performance and physiological parameters in heat-stressed broiler chickens.

High temperatures have detrimental effects on the performance and physiology of broiler chickens. Medicinal plants have various biological activities and may enhance the heat resistance of chickens during heat waves. Therefore, this study aimed to explore the potential roles of using specific local medicinal plants to alleviate the negative impacts of heat stress (HS) in broilers. In this study, 180 day-old chicks were used to investigate the effects of HS and dietary indigenous medicinal plants on growth performance, antioxidant biomarkers, and intestinal health. The chicks were assigned to six groups (18 pens with 10 chicks per pen) with three replicates each. In the first group, the chicks were kept under thermoneutral conditions (CON) and fed a basal diet. The other five groups were exposed to recurrent heat stress and fed a basal diet (T1, HS group) or supplemented with Artemisia Sieberi (1.25 g/kg of feed; T2), Achillea Fragrantissima (15 g/kg of feed; T3), Olea europaea (10 g/kg of feed; T4), and all the previous additives (all-in-one) combined at the same dose levels mentioned above (T5). At 21 days of age, the chicks from each group were exposed to two phases of heat stress: phase 1 from days 21 to 34 (34 ± 1°C) followed by phase 2 from days 35 to 39 (37 ± 1°C). The results indicate that HS significantly increased rectal temperature and respiration rate in broiler chickens. Feed intake and body weight gain were improved in all supplemented groups, while the feed conversion ratio was decreased in response to the dietary inclusion of medicinal plants. Additionally, glutathione peroxidase and immunoglobulin G levels were increased in the T3, T4, and T5 groups compared to the other groups. HS induced significant upregulated in the mRNA levels of heat shock protein 70 and interleukin-8, while the mRNA of occludin was decreased. The T3, T4, and T5 showed significantly decreased expression of hepatic HSP70 and ileum IL-8 genes and increased ileum mRNA occludin levels relative to the CON and T1 groups. In conclusion, supplementation with these plants enhances growth performance and maintains intestinal health sustaining the productivity of broiler chickens under HS conditions.

Possible association of dose rate and the development of late visual toxicity for patients with intracranial tumours treated with pencil beam scanned proton therapy

Background and purposeRare but severe toxicities of the optic apparatus have been observed after treatment of intracranial tumours with proton therapy. Some adverse events have occurred at unusually low dose levels and are thus difficult to understand considering dose metrics only. When transitioning from double scattering to pencil beam scanning, little consideration was given to increased dose rates observed with the latter delivery paradigm. We explored if dose rate related metrics could provide additional predicting factors for the development of late visual toxicities.Materials and methodsRadiation-induced intracranial visual pathway lesions were delineated on MRI for all index cases. Voxel-wise maximum dose rate (MDR) was calculated for 2 patients with observed optic nerve toxicities (CTCAE grade 3 and 4), and 6 similar control cases. Additionally, linear energy transfer (LET) related dose enhancing metrics were investigated.ResultsFor the index cases, which developed toxicities at low dose levels (mean, 50 GyRBE), some dose was delivered at higher instantaneous dose rates. While optic structures of non-toxicity cases were exposed to dose rates of up to 1 to 3.2 GyRBE/s, the pre-chiasmatic optic nerves of the 2 toxicity cases were exposed to dose rates above 3.7 GyRBE/s. LET-related metrics were not substantially different between the index and non-toxicity cases.ConclusionsOur observations reveal large variations in instantaneous dose rates experienced by different volumes within our patient cohort, even when considering the same indications and beam arrangement. High dose rate regions are spatially overlapping with the radiation induced toxicity areas in the follow up images. At this point, it is not feasible to establish causality between exposure to high dose rates and the development of late optic apparatus toxicities due to the low incidence of injury.

Investigation on the sustainable use of different sizes of sawdust aggregates in eco-friendly foam concretes: Physico-mechanical, thermal insulation and durability characteristics

The extensive mining of natural resources, such as sand, for the construction industry, poses a hazard to the environment. To preserve the environment, the researcher must thus take into account the use of industrial byproducts rather than natural materials. The use of sawdust (SD) produced by the wood industry in foam concretes (FC) has been investigated in this study. This study examined the physical, mechanical, thermal, microstructural and durability characteristics of FC containing SD as a replacement of silica sand (SS) in the rates of 0, 25, 50 and 100 %. Two different SD sizes of 0–4 mm (SD4) and 0–1 mm (SD1) were used in the fabrication of FC mixtures. Protein-based foam agent was used to create FC mixtures. Fourteen mixtures with a 0.6 water/binder (w/b) ratio were produced at two different cement contents of 400 kg/m3 and 500 kg/m3. The fresh, mechanical, physical, and sorptivity characteristics of the FC mixtures were investigated in relation to the impacts of cement dosage, SD size, and SD replacement levels of SS. Durability of FC against high temperature, sulfate attack and freeze-thaw cycles was assessed. Costs and CO2 emissions from the blends were also assessed. The outcomes revealed that a 25 %SD1 integrated FC mixture with a cement content of 500 kg/m3 generated the highest 28-day compressive strength of 3.56 MPa with a 20 % strength loss as per the Ref.500 mixture. 17 % lower thermal conductivity was gained with the inclusion of 100 %SD4 as per the Ref.400 mixture. The mixture with 50 %SD4 and 400 kg/m3 cement dosage exhibited the best resistance to high temperature. The mixture with 25 %SD1 and 400 kg/m3 cement dosage showed the best frost resistance. SD incorporated mixtures showed better durability performance than the reference mixtures.

Effects of confounding and effect-modifying lifestyle, environmental and medical factors on risk of radiation-associated cardiovascular disease

BackgroundCardiovascular disease (CVD) is the leading cause of death worldwide. It has been known for some considerable time that radiation is associated with excess risk of CVD. A recent systematic review of radiation and CVD highlighted substantial inter-study heterogeneity in effect, possibly a result of confounding or modifications of radiation effect by non-radiation factors, in particular by the major lifestyle/environmental/medical risk factors and latent period.MethodsWe assessed effects of confounding by lifestyle/environmental/medical risk factors on radiation-associated CVD and investigated evidence for modifying effects of these variables on CVD radiation dose–response, using data assembled for a recent systematic review.ResultsThere are 43 epidemiologic studies which are informative on effects of adjustment for confounding or risk modifying factors on radiation-associated CVD. Of these 22 were studies of groups exposed to substantial doses of medical radiation for therapy or diagnosis. The remaining 21 studies were of groups exposed at much lower levels of dose and/or dose rate. Only four studies suggest substantial effects of adjustment for lifestyle/environmental/medical risk factors on radiation risk of CVD; however, there were also substantial uncertainties in the estimates in all of these studies. There are fewer suggestions of effects that modify the radiation dose response; only two studies, both at lower levels of dose, report the most serious level of modifying effect.ConclusionsThere are still large uncertainties about confounding factors or lifestyle/environmental/medical variables that may influence radiation-associated CVD, although indications are that there are not many studies in which there are substantial confounding effects of these risk factors.

Phytochemical Analysis, Antioxidant and Anti Hyperlipidemic Activity of Nyctanthes arbor-tristis in Male Wistar Rats

The current study's objective was to assess the antihyperlipidemic, in vitro antioxidant, and qualitative and quantitative phytochemical analysis of Nyctanthes arbor-tristis flowers hydroalcoholic extract at 200 and 400 mg/kg in rats that were made hyperlipidemic by a high-fat diet. The Folins Ciocalteau reagent and the aluminium chloride method were used for the quantitative measurement of flavonoids and phenolics, respectively. Through phytochemical investigation, alkaloids, carbohydrates, glycosides, tannins, phenolic compounds, triterpenoids, and steroids were found in the hydroalcoholic extracts of N. arbor-tristis flowers. The hydroalcoholic extract flowers had a total phenolic content of 126.000 mg/gm, which was followed by flavonoids at 103.104 mg/gm. Hydroalcoholic extracts of flowers showed concentration-dependent antioxidant activity in vitro against DPPH and superoxide radical scavenging test technique. In this investigation, rats were given a high-fat diet as part of an experimental induction procedure. By lowering LDL and VLDL cholesterol levels and raising HDL levels, the HANAT therapy and the medication atorvastatin dramatically reduce body weight. grew When hydroalcoholic flower extracts were given orally to animals that had been forced to become hyperlipidaemic due to a high cholesterol diet, the levels of HDL cholesterol, triglycerides, low density lipoproteins, and very low-density lipoproteins were all much lower. The p value (p<0.001) indicated that the results were significant. The triton-induced study results indicate that animals treated with HANAT at dose levels of 200 mg/kg and 400 mg/kg had considerably lower blood lipid parameters (p<0.01) than the control group; however, the 400 mg/kg of HANAT group animals showed significantly higher serum lipid parameters (p<0.001) than the control group. Additionally, a higher HDL level was noted at this time. Keywords: Nyctanthes arbor-tristis, Physicochemical analysis, Antioxidant activity, DPPH. Antihyperlipidemic activity

Parametric analysis of SARS-CoV-2 dose-response models in transportation scenarios.

Transportation systems involve high-density crowds of geographically diverse people with variations in susceptibility; therefore, they play a large role in the spread of infectious diseases like SARS-CoV-2. Dose-response models are widely used to model the relationship between the trigger of a disease and the level of exposure in transmission scenarios. In this study, we quantified and bounded viral exposure-related parameters using empirical data from five transportation-related events of SARS-CoV-2 transmission. Dose-response models were then applied to parametrically analyze the infection spread in generic transportation systems, including a single-aisle airplane, bus, and railway coach, and then examined the mitigating efficiency of masks by performing a sensitivity analysis of the related factors. We found that dose level significantly affected the number of secondary infections. In general, we observed that mask usage reduced infection rates at all dose levels and that high-quality masks equivalent to FFP2/N95 masks are effective for all dose levels. In comparison, we found that lower-quality masks exhibit limited mitigation efficiency, especially in the presence of high dosage. The sensitivity analysis indicated that a reduction in the infection distance threshold is a critical factor in mask usage.

Effects of Cadmium and Nickel Mixtures on Multiple Endpoints of the Microalga Raphidocelis subcapitata.

It is crucial to investigate the effects of mixtures of contaminants on aquatic organisms, because they reflect what occurs in the environment. Cadmium (Cd) and nickel (Ni) are metals that co-occur in aquatic ecosystems, and information is scarce on their joint toxicity to Chlorophyceae using multiple endpoints. We evaluated the effects of isolated and combined Cd and Ni metals on multiple endpoints of the chlorophycean Raphidocelis subcapitata. The results showed that Cd inhibited cell density, increased reactive oxygen species (ROS) production (up to 308% at 0.075 mg L-1 of Cd), chlorophyll a (Chl a) fluorescence (0.050-0.100 mg L-1 of Cd), cell size (0.025-0.100 mg L-1 of Cd), and cell complexity in all concentrations evaluated. Nickel exposure decreased ROS production by up to 25% at 0.25 mg L-1 of Ni and Chl a fluorescence in all concentrations assessed. Cell density and oxygen-evolving complex (initial fluorescence/variable fluorescence [F0/Fv]) were only affected at 0.5 mg L-1 of Ni. In terms of algal growth, mixture toxicity showed antagonism at low doses and synergism at high doses, with a dose level change greater than the median inhibitory concentration. The independent action model and dose-level-dependent deviation best fit our data. Cadmium and Ni mixtures resulted in a significant increase in cell size and cell complexity, as well as changes in ROS production and Chl a fluorescence, and they did not affect the photosynthetic parameters. Environ Toxicol Chem 2024;43:1855-1869. © 2024 SETAC.

Oral subchronic toxicity study and genetic toxicity evaluation of mitoquinone mesylate

AbstractMitochondrial dysfunction and excessive reactive oxygen species production contributes to the pathophysiology of aging. Coenzyme Q10 is thought to protect mitochondria from oxidative damage; thus, mitoquinone was developed as mitochondria‐targeted analogue with similar antioxidant activity. Mitoquinone is the oxidized form of mitoquinol. Mitoquinone/mitoquinol mesylate has been proposed as a food ingredient. As part of the safety analysis, we performed genotoxicity assays and a 39‐week toxicity study to determine overall toxicity potential. Mitoquinone mesylate showed no evidence of genotoxic potential in two in vitro assays, bacterial reverse mutation and human lymphocyte chromosome aberration, nor in the in vivo micronucleus test in rats. In the 39‐week study in dogs, there were no findings observed, which were considered to represent adverse systemic toxicity; therefore, the high dose level (40 mg/kg/day) was considered the NOAEL. The principal findings in this study were fecal disturbances and vomiting. These findings were considered to be due to a local, possibly irritant effect of the test substance on the gastrointestinal tract and were not considered adverse as there were no impacts on clinical or histopathology. This highest dose exceeds the expected daily human intake more than 100‐fold. Data from well‐designed clinical trials actively collecting safety endpoints corroborate that 20 mg/day can be safely consumed and is not likely to result in significant gastrointestinal complaints. These results support the conclusion that the use of mitoquinone/mitoquinol mesylate as a food ingredient is safe.

Effect of Genistein and Glycitein on production performance, egg quality, antioxidant function, reproductive hormones and related-genes in pre-peak laying hens

Genistein (GEN) and Glycitein (GLY), are types of isoflavone extracted mainly from soy plants, although GEN is associated with stronger antioxidant and growth-promoting effects. The impact of dietary GEN and GLY on reproductive performance, egg quality, and bone quality were investigated in the study. Additionally, to explore the underlying mechanism of action, the serum hormone levels and reproductive-related genes were investigated. A total of 378 Hy-Line Brown laying hens (120 days old) were randomly allocated to 3 dietary groups (Control), (GLY, and GEN at 50 mg/kg respectively) for a period of 8 wk. Each treatment has 126 birds (7 replicates of 18 birds each). Results were analyzed in 2 phases: wk 1 to 4, and 5 to 8 of feeding trial. The results indicated that supplemental GEN significantly increased egg number, hen-day production (HDP), and egg mass during wk 1 to 4, whereas, both glycitein and genistein increased egg number, egg weight, egg mass, HDP and improved feed-egg-ratio during wk 5 to 8. Egg quality analysis revealed significant improvements in eggshell quality; gloss, thickness, strength, and albumen quality indices (albumen height, Haugh unit, thick albumen fraction) due to dietary treatments. Also, the tibia strength, Ca content in the tibia ash and bone mineral content, were significantly increased by the dietary treatments. Significant increases in the serum levels of E2, LH, FSH, T3, T4, and GH, and the activity of antioxidant enzymes; SOD, CAT, GSH while reducing the level of MDA, was notable with the treatments. Additionally, reproductive-related genes: ESR1, FSHR, PRLR, GNRH1 were significantly upregulated by the supplementation of GEN and GLY. The efficacy of GEN in relation to the evaluated parameters was superior to that of GLY. Conclusively, we speculate that the improvement on laying performance, egg quality and tibia quality may be related to promoting effect of isoflavones on calcium metabolism, antioxidant function, reproductive hormones and related genes. Therefore, supplemental GEN at a dosage level of 50 mg/kg, can be used to promote laying performance, sustain egg production and maintain the physiological function of young laying hens.

PRGN-2012, a novel gorilla adenovirus-based immunotherapy, provides the first treatment that leads to complete and durable responses in recurrent respiratory papillomatosis patients.

LBA6015 Background: Recurrent respiratory papillomatosis (RRP) is a rare, neoplastic disorder caused by chronic infection with human papillomavirus (HPV) type 6 or 11. Significant morbidity can occur due to airway obstruction and, although rare, transformation into malignant cancer. There are no approved therapeutics. RRP is currently managed with frequent ablative procedures that can lead to irreversible laryngotracheal scarring and disability. PRGN-2012 is a gorilla adenovirus-based gene therapy/immunotherapy designed to generate HPV6/11-specific T cell immunity. The FDA has granted PRGN-2012 Breakthrough Therapy Designation for the treatment of RRP recognizing that this single arm study can serve as pivotal to support a licensing application. Methods: This pivotal trial (NCT04724980) evaluates the safety and efficacy of PRGN-2012 in patients with RRP requiring a minimum of 3 surgeries in the 12 months prior to treatment. Eligible patients received 4 subcutaneous (SC) injections of PRGN-2012 at dose level (DL) 1 (1x1011 Particle Units (PU) per injection; n=3) or DL2 (5x1011 PU per injection; n=35) over 12 weeks. The primary endpoint was the rate of complete response (CR), defined as no requirement for surgery in the 12 months following completion of treatment. Other key endpoints include duration of response, change in extent of papilloma growth (anatomic Derkay score) and vocal function. Results: PRGN-2012 was well-tolerated, with no serious adverse events, grade > 2 treatment-related adverse events, or early treatment discontinuations. The most common adverse events were injection-site reaction, fatigue, chills, fever, and myalgia. PRGN-2012 treatment at DL2 significantly (p<0.0001) decreased the requirement for surgery, with a median number of surgeries in the 12 month period decreasing from 4 (3-10) prior to treatment to 0 (0-7) surgeries post-treatment. Approximately 90% of patients experienced a decrease in the number of surgeries in the 12 months post-treatment compared to pre-treatment with PRGN-2012. The primary endpoint evaluation demonstrated a confirmed complete response in 17/31 (55%) of evaluable patients. The median duration of complete response has yet to be reached with a median follow up of 15 months (12 - 30) at the time of data cutoff (March 6, 2024). Additionally, PRGN-2012 treatment resulted in a significant reduction in Derkay score, improvement in vocal function and generation of HPV-specific immune responses. Conclusions: These data demonstrate the overall favorable safety profile and significant clinical benefit of PRGN-2012 in adult RRP patients. These findings support PRGN-2012 as a potential therapeutic option for this patient population where no FDA-approved therapeutics exist. Clinical trial information: NCT04724980 .