Dose Group Research Articles

Phase I clinical study of a multi-kinase inhibitor TG02 capsule for the treatment of recurrent high-grade gliomas with failed temozolomide treatment in Chinese patients

Introduction: Here, we report the safety, tolerability, pharmacokinetic characteristics and preliminary efficacy of a multi-kinase inhibitor (TG02 capsule) as a new therapy for patients with recurrent high-grade gliomas in China. Methods: This is a single-center, dose-escalation, open-label phase I study, which enrolled patients with recurrent high-grade gliomas who failed to temozolomide. Patients were assigned sequentially into different dose groups and received TG02 every 4 weeks. The dose was increased in a traditional 3+3 design. Primary endpoints were the dose-limited toxicity (DLT) and the maximum tolerated dose (MTD). Results: Twelve patients (8 glioblastomas, 4 diffuse astrocytoma) were enrolled between May 2019 and November 2021. Three patients received 100 mg and 9 received 150 mg TG02 twice a week. The plasma concentration of TG02 reached the maximum at 2 hours after administration, and the elimination half-life was about 7 hours. No DLT occurred and MTD was not defined in this study. Eleven patients had one or more investigator-assessed treatment-related adverse events (TRAEs). The most frequent TRAEs were vomiting (91.7%) and diarrhea (75.0%), and 50% of the patients had grade 3 or 4 adverse events. There were no treatment-related deaths. The median progression-free survival and overall survival were 1.77 (95% confidence interval [CI]: 0.82-4.24) and 9.63 (95%CI: 2.66-not estimated) months, respectively. Conclusions: TG02 capsule 150mg twice a week is safe and tolerable in Chinese patients with recurrent high-grade gliomas. Patients who failed to temozolomide showed obvious tumor reduction when switching to TG02 capsule. The efficacy for recurrent gliomas warrant further investigation.

Bimekizumab Safe and Effective Self-administration Using 2 mL Devices by Patients with Moderate to Severe Plaque Psoriasis: Results from Two Multicenter, Randomized, Open-label Studies

Introduction: Safe and effective self-injection of subcutaneous bimekizumab (BKZ) in patients with moderate to severe plaque psoriasis using a 1­ mL safety syringe (sy) or auto-injector (AI) has previously been associated with an overall positive patient experience.1 Here, the ability of patients to safely and effectively self-administer subcutaneous BKZ using a 2 mL sy or AI is reported. Methods: DV0002 (North America) and DV0006 (Germany, Hungary and Poland) were sub-studies of the phase 3 open-label extension (OLE) study, BE BRIGHT.1,2 Included patients received BKZ 320 mg every 4 weeks (Q4W) or Q8W based on treatment regimen and Psoriasis Area Severity Index (PASI) response at BE BRIGHT entry. Patients were randomized 1:1 to BKZ-sy-2 mL or BKZ-AI-2 mL, and performed self-injections (after training in the self-injection technique) at baseline and Wk8. Safe and effective self-injection defined as complete dose delivery of BKZ and absence of adverse events related to the device which led to study withdrawal. Primary and secondary objectives were to assess patients’ ability to safely and effectively self-administer BKZ at Wk8 and baseline, respectively. Other objectives included to evaluate patient experience of self-injection, using the injection site pain visual analog scale (VAS; 0 [no pain]–100 [worst possible pain]) and the Self-Injection Assessment Questionnaire (SIAQ; subscale scores ranged 0-10 [higher scores better]), and the post-use structural and mechanical integrity of each device. Data analyzed using two full analysis sets (BKZ-sy-2 mL and BKZ-AI-2 mL) and reported for the combined BKZ dose groups (BKZ Total) using observed cases. Results: In DV0002, 19 patients each were randomized to use BKZ-sy-2 mL and BKZ-AI-2 mL. All patients using BKZ-sy-2 mL (n=19) self-injected BKZ safely and effectively at baseline and Wk8. All (n=19) and 94.7% (n=18/19) of patients using BKZ-AI-2 mL self-injected BKZ safely and effectively at baseline and Wk8, respectively. In DV0006, 44 and 45 patients were randomized to use BKZ-sy-2 mL and BKZ-AI-2 mL, respectively. All patients using BKZ-sy-2 mL (n=44) and BKZ-AI-2 mL (n=45) safely and effectively self-injected BKZ at baseline and Wk8. In DV0002/6, median pre-injection and post-injection SIAQ scores were ≥7.5 across both devices, and >9.0 for feelings about injections, self-image, and injection-site reactions subscales. In DV0002/6, low median VAS scores across both devices indicate variable but generally low pain. All devices maintained their structural and functional integrity post-use. One device deficiency complaint was received. Conclusions: A positive self-administration experience was associated with the 2 mL devices, as reported with 1 mL devices,1 providing patients with an option to self-administer a single injection of BKZ.

Exposure-Response Analyses of Sacituzumab Govitecan Efficacy and Safety in Patients With Metastatic Triple-Negative Breast Cancer.

Sacituzumab govitecan (SG), a Trop-2-directed antibody-drug conjugate, is approved for patients with metastatic triple-negative breast cancer (mTNBC) who received ≥2 prior systemic therapies (≥1 in metastatic setting). Exposure-response (E-R) relationships between SG exposure and efficacy and safety outcomes were characterized in 277 patients with mTNBC using data from the phase I/II IMMU-132-01 and phase III ASCENT (IMMU-132-05) studies. Evaluated endpoints included complete response (CR), objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety endpoints (individual first worst grade of select adverse events (AEs)). E-R analyses were also conducted for time to first dose reduction or delay. Patients received SG at 8 or 10 mg/kg intravenously on days 1 and 8 of a 21-day cycle. Average SG-related serum exposure over the treatment duration (until the event) was consistently the most significant exposure metric correlated with efficacy and safety endpoints. Higher average concentration over the treatment duration for SG (CAVGSG) was the best predictor of CR and ORR. The model-predicted proportions of patients with CR and ORR at 10 mg/kg were 4.26% and 32.6%, respectively. Higher CAVG for total antibody was the best predictor of OS and PFS. The model-predicted probability of OS at 12 months at median lactate dehydrogenase (227 IU/L) was 53%. The probability of grade ≥1 evaluated AEs and the risk of dose reductions and delays significantly increased with increasing CAVGSG. The model-predicted proportions of patients with any-grade AEs were 35.9%, 67.4%, 64.7%, and 67.1% for vomiting, diarrhea, nausea, and neutropenia, respectively (10 mg/kg dose group). Neutropenia was the only evaluated AE for which CAVGSG was significantly associated with grade ≥3 events. The clinically meaningful efficacy and manageable safety achieved with SG 10 mg/kg on days 1 and 8 of every 21-day cycle dosing regimen supports the appropriateness of this clinical dosage in patients with mTNBC.

Development of a robust SNP marker set for genotyping diverse gene bank collections of polyploid roses.

Due to genetic depletion in nature, gene banks play a critical role in the long-term conservation of plant genetic resources and the provision of a wide range of plant genetic diversity for research and breeding programs. Genetic information on accessions facilitates gene bank management and can help to conserve limited resources and to identify taxonomic misclassifications or mislabelling. Here, we developed SNP markers for genotyping 4,187 mostly polyploid rose accessions from large rose collections, including the German Genebank for Roses. We filtered SNP marker information from the RhWag68k Axiom SNP array using call rates, uniformity of the four allelic dosage groups and chromosomal position to improve genotyping efficiency. After conversion to individual PACE® markers and further filtering, we selected markers with high discriminatory power. These markers were used to analyse 4,187 accessions with a mean call rate of 91.4%. By combining two evaluation methods, the mean call rate was increased to 95.2%. Additionally, the robustness against the genotypic groups used for calling was evaluated, resulting in a final set of 18 markers. Analyses of 94 pairs of assumed duplicate accessions included as controls revealed unexpected differences for eight pairs, which were confirmed using SSR markers. After removing the duplicates and filtering for accessions that were robustly called with all 18 markers, 141 out of the 1,957 accessions showed unexpected identical marker profiles with at least one other accession in our PACE® and SSR analysis. Given the attractiveness of NGS technologies, 13 SNPs from the marker set were also analysed using amplicon sequencing, with 76% agreement observed between PACE® and amplicon markers. Although sampling error cannot be completely excluded, this is an indication that mislabelling occurs in rose collections and that molecular markers may be able to detect these cases. In future applications, our marker set could be used to develop a core reference set of representative accessions, and thus optimise the selection of gene bank accessions.

Favorable inhibitory effect of clodronate on hepatic steatosis in short bowel syndrome model rats.

This study investigated the anti-inflammatory effect of clodronate, a vesicular nucleotide transporter (VNUT) inhibitor, on intestinal-failure-associated liver disease (IFALD) in a rat model of short bowel syndrome (SBS). The rats underwent jugular vein catheterization for continuous total parenteral nutrition (TPN) and 90% small bowel resection. The animals were divided into the following groups: TPN/SBS (Control group), TPN/SBS/intravenous administration of low-dose clodronate (20mg/kg twice per week; Low group), or TPN/SBS/intravenous administration of high-dose clodronate (60mg/kg twice per week; High group). On day 7, the rats were euthanized. Hepatic steatosis and hepatocellular injury were also assessed. Hepatic steatosis and lobular inflammation in the liver were observed in all groups. The High group showed histologically reduced hepatic steatosis compared with the Control group. IL-6 and Nlrp3 expression in the High group was significantly suppressed compared to that in the Control group. The expression of other inflammatory cytokines tended to be lower in the High dose group than in the control group. The lipid metabolism gene expression in the liver specimens showed no significant differences among the groups. The high-dose administration of clodronate may, therefore, inhibit hepatic steatosis and inflammation associated with IFALD in patients with SBS.

Enhanced Prenatal and Postnatal Development Study in Marmoset Monkeys Following Administration of Felzartamab.

Felzartamab is a recombinant fully human immunoglobulin G1 anti-CD38 monoclonal antibody under clinical investigation for immune-mediated diseases. In support of felzartamab clinical development, toxicology studies were conducted in marmoset monkeys, which was the most relevant species based on CD38 binding affinity, pharmacologic activity, and target expression. The felzartamab toxicology program included an enhanced prenatal and postnatal development (ePPND) study to identify potential reproductive and postnatal development risks. In this ePPND study, pregnant marmoset monkeys were randomized to receive vehicle (0mg/kg) or felzartamab at two dose levels (15mg/kg and 75mg/kg) twice per week until parturition, and maternal animals and infants were evaluated for 6 months thereafter. Felzartamab exposure was confirmed in maternal animals and infants in both dosing groups. Overall, felzartamab was well tolerated by pregnant animals at the evaluated doses, with no effect on body weight or body weight gain during pregnancy. No felzartamab-related effects on pregnancy loss or stillbirth rate were observed, and litter counts and numbers of liveborn infants were similar between the vehicle and felzartamab groups. Among infants, there were no felzartamab-related malformations or variations in external anatomy or skeletal morphology and no felzartamab-related observations in histopathology, hematologic and immune cell development, or humoral immune response to vaccination. In conclusion, among pregnant marmoset monkeys dosed with felzartamab, the lack of reproductive toxicity and felzartamab-related effects on offspring supports the clinical evaluation of felzartamab in women of childbearing potential and further demonstrates the suitability of the marmoset monkey for ePPND studies.

A Phase 2 Sensitivity and Selectivity Study of High-Dose 5-Aminolevulinic Acid in Adult Patients Undergoing Resection of a Newly Diagnosed or Recurrent Glioblastoma.

The utility of oral 5-aminolevulinic acid (5-ALA)/protoporphyrin fluorescence for the resection of high-grade gliomas is well documented, but the problem of false-negative observations remains. This study compares high-grade glioma visualization with low/standard dose 5-ALA (<30 mg/kg) to high-dose 5-ALA (>40 mg/kg) to see if by using this higher dose, it is possible to reduce the rate of false-negative observations without increasing the rate of false-positive (FP) observations and therefore increase the sensitivity. This is a prospective study of consecutive patients with radiological evidence of presumed high-grade glioma. We reviewed the data from patients who received preoperative low/standard doses and patients who received a preoperative high dose of 5-ALA. Adverse events, dose to observation time, intensity of tumor fluorescence, and results of biopsies in areas of tumor and tumor bed under deep blue light were recorded. A total of 22 patients with high-grade glioma received a dose >40 mg/kg (high-dose) and 9 patients received <30 mg/kg (low/standard dose). There were no serious adverse events related to 5-ALA in any subject. There was a very high sensitivity and specificity of 5-ALA for the presence of tumor in both groups. There were no FP observations (fluorescence with no tumor) in either group. The specificity and the positive predictive value were 100% in both groups. The sensitivity and the negative predictive value were 53.3% and 30.0% in the low/standard dose group and 59.5% and 31.8% in the high-dose group, respectively. High-dose oral 5-aminolevulinic/protoporphyrin fluorescence is a safe and effective aid to the intraoperative detection of high-grade gliomas with high sensitivity and specificity. False-negative observations with a high dose do not seem to be less than that with a low/standard dose. The rate of FP observations with both groups remains very low.

A Dynamic, D-dimer-based Thromboprophylaxis Strategy in Patients with COVID-19

Background COVID-19 pandemics increases venous thromboembolism (VTE) risk during hospitalization, despite prophylactic anticoagulation. Limited radiological diagnosis in pandemic requires a guided protocol for anticoagulant adjustment. Methods This retrospective cohort study was conducted at a single center as part of a quality improvement program evaluating the efficacy and safety of anticoagulation protocols. The study focused on implementing a guideline for anticoagulant dosing protocol based on dynamic changes in D-dimer levels in COVID-19 hospitalized patients. The dosing guideline allowed for dose escalation from standard prophylactic levels to escalated prophylactic or therapeutic levels, depending on the patient's risk profile for VTE. The primary endpoints included in-hospital survival comparing between fix and dynamic adjustment treatment groups. Secondary endpoints encompassed major and clinically relevant non-major bleeding (CRNMB) events, incidence of breakthrough thrombosis, length of hospitalization and ICU stay, days of mechanical ventilator use, and survival duration. Findings Among the 260 COVID-19-infected patients hospitalized between March 15th and June 15th, 2020. The patients received fixed anticoagulant dosage in 188, 72.3%) patients, while 72 (27.7%) were up-titrated according to the protocol. In-hospital survival at 30 days demonstrated superiority among patients whose anticoagulation was up-titrated to either escalated prophylactic or therapeutic (80.2%) compared to receiving fixed anticoagulant dosage (51.3%) (p=0.01). Bleeding events were significantly higher in up-titrate group (12.5%) compared to fixed anticoagulant dosage group (2.13%). Most of them are CRNMB. Conclusion A dynamic, D-dimer-based dose escalation of anticoagulation for hospitalized patients with COVID-19 holds promise in improving in-hospital mortality rates without a significant increase in fatal bleeding events.

Repeated inhalation of GM-CSF by nonhuman primates induces bronchus-associated lymphoid tissue along the lower respiratory tract

BackgroundRepeated inhalation of granulocyte-macrophage colony-stimulating factor (GM-CSF) was recently approved in Japan as a treatment for autoimmune pulmonary alveolar proteinosis. However, the detailed physiological and pathological effects of repeated inhalation in the long term, especially at increasing doses, remain unclear.MethodsIn this chronic safety study, we administered 24 cynomolgus monkeys (Macaca fascicularis) aged 2–3 years with aerosolized sargramostim (a yeast-derived recombinant human GM-CSF [rhGM-CSF]) biweekly for 26 weeks across four dosing groups (0, 5, 100, and 500 µg/kg/day). We measured the serum GM-CSF antibody (GM-Ab) concentration by an ELISA and assessed the neutralizing capacity of GM-Ab using the GM-CSF-dependent cell line TF-1. We subjected lung tissue samples taken from all monkeys at 27 weeks to histopathological assessment using a sargramostim-specific monoclonal antibody to detect localization of residual sargramostim.ResultsAll the animals maintained good body condition and showed steady weight gain throughout the study. The pathological analyses of the lung revealed the formation of induced bronchus-associated lymphoid tissue (iBALT) in the lower respiratory tract, even at the clinical dose of 5 µg/kg/day. There was a relationship between the number or size of BALT and sargramostim dose or the serum GM-Ab levels. Immunohistochemical analyses revealed GM-Ab–producing cells in the follicular region of iBALT, with residual sargramostim in the follicles. Leucocyte counts were inversely correlated with GM-Ab levels in the high-dose groups. Additionally, serum GM-Ab from the treated animals significantly suppressed the alveolar macrophage proliferation activity of both Cynomolgus recombinant and rhGM-CSF in vitro.ConclusionLong-term repeated inhalation of sargramostim led to iBALT formation in the lower respiratory tract, even at the clinical dose of 5 µg/kg/day, with the extent of iBALT formation increasing in a dose-dependent manner. Inhaled sargramostim was localized to the follicular region of iBALT nodules, which may induce the production of GM-Ab.

Tanshinone IIA inhibits the apoptosis process of nerve cells by upshifting SIRT1 and FOXO3α protein and regulating anti- oxidative stress molecules and inflammatory factors in Cerebral Infarction Model

: Background as a prevalent cerebrovascular disorder, cerebral infarction (CI) has garnered extensive attention globally due to its high incidence and substantial fatality rate. Ischemia-reperfusion injury (IRI) exacerbates not only neuronal demise but also amplifies neural functional impairment. Tanshinone IIA (Tan IIA) has been identified to confer protection against IRI, yet the precise underlying mechanisms remain elusive. This work aimed to delve into the mechanistic role of Tan IIA in CI, with the goal of furnishing more distinct theoretical substantiation for its clinical application. Methods initially, a middle cerebral artery embolization model group (MCAO) model was established, followed by the categorization of rats into distinct groups based on different administration modes. Therapeutic effects were evaluated through indices including mortality rate, cerebral tissue water content, CI proportion, and neural functional scoring. Meanwhile, cellular apoptosis rates in hippocampal and cortical tissues, as well as levels of oxidative stress molecules (OSM), Sirtuin 1 (SIRT1), Forkhead box O3 (FOXO3α), and inflammatory factors, were examined to explore the mechanism of action. Results this work revealed that within varying doses of Tan IIA groups, as dosage escalated, mortality rate, cerebral edema severity, CI proportion, and neural functional scoring gradually diminished. Notably, the 35 mg/kg dose group exhibited the most significant reductions, with decreases of 74.9%, 12.7%, 47.5%, and 54% respectively. Cellular apoptosis rates in hippocampal and cortical tissues displayed a stepwise descending trend, with the 35 mg/kg dose group showcasing the largest reduction. SIRT1 and FOXO3α proteins exhibited a steady increase, with the 35 mg/kg dose group manifesting respective elevations of 87.9% and 65.5%, the highest among all groups. Antioxidant molecules glutathione (GSH) and superoxide dismutase (SOD) contents progressively increased, whereas malondialdehyde (MDA) and nitric oxide (NO) content decreased. The 35 mg/kg dose group recorded the highest increments of 49.1% and 58.1% for GSH and SOD content, while achieving the greatest reductions of 55.6% and 56.2% for MDA and NO content. Expression of inflammatory factors, namely tumor necrosis factor-alpha (TNF-α), C-reactive protein (CRP), and interleukin-6 (IL-6), gradually declined, with reductions of 42.1%, 32.2%, and 29.1% respectively in the 35 mg/kg dose group, exhibiting drastic differences (P < 0.05). Conclusion In conclusion, this research elucidates that Tan IIA improves cerebral edema and neural function by elevating intracellular expression of SIRT1 and FOXO3α proteins, modulating OSM and inflammatory factors. These findings yielded robust experimental support for the potential use of Tan IIA as a therapeutic agent for CI.

Based on Serum Pharmacochemistry and Metabolomics Studied the Pharmacodynamic Material Basis and Mechanism of Rubi Fructus (Fupenzi) in Improving the Symptom of Kidney-Yang Deficiency.

Rubi fructus (Fupenzi) is the immature fruit of East China Rubi fructus, which is widely used in medicine, food, health food and other fields. Since ancient times, Fupenzi has been considered to be an important medicine for tonifying the kidney in terms of nourishing the liver and kidney, fixing essence and reducing urine, but its effective components and mechanism are not clear. In this paper, the effective components of Rubi fructus were analyzed by detecting the components of Fupenzi in vivo and in vitro. Adenine was used to replicate the model of kidney yang deficiency, and organ index, biochemical index and histopathology were used to evaluate the effect of different doses of Fupenzi on tonifying kidney yang. Metabonomics technique was used to analyze the metabolic regulation mechanism of Fupenzi in improving kidney yang deficiency syndrome. The results showed that 61 chemical constituents of Fupenzi were identified in vitro, including 18 flavonoids, 19 organic acids, 5 coumarins, 8 terpenoids, 7 amino acids and 4 other components. A total of 51 chemical components were identified, including 30 prototype components and 21 metabolic components, which may be the effective components of Fupenzi. The results of pharmacodynamics showed that compared with the model group, the renal index, testicular index and epididymal index of rats in each Fupenzi group were significantly improved (p<0.01), cAMP significantly increased (p<0.05), cGMP decreased (p<0.05) and cAMP/cGMP ratio increased significantly (p<0.05). The content of ACTH in low dose group increased significantly (p<0.05), while the content of ACTH in middle and high dose groups increased, but there was no significant difference. The results of HE staining showed that compared with the model group, the kidney, testis and epididymis of rats in each treatment group were significantly improved. In general, these changes may be mainly through primary bile acid biosynthesis, linoleic acid metabolism, steroid hormone biosynthesis, β-alanine metabolism, glutathione metabolism, porphyrin and chlorophyll metabolism, unsaturated fatty acid biosynthesis, arachidonic acid metabolism, arginine and proline metabolism and other metabolic pathways to improve adenine-induced metabolic disorders in rats with kidney-yang deficiency syndrome.

Inetetamab for injection in combination with vinorelbine weekly or every three weeks in HER2-positive metastatic breast cancer: A multicenter, randomized, phase II clinical trial.

We aimed to investigate the pharmacokinetics, safety, efficacy, and immunogenicity of different dosing regimens (weekly and every three weeks) of inetetamab in combination with vinorelbine in human epidermal growth factor receptor 2 (HER2)+ patients with metastatic breast cancer who had received one or more chemotherapy regimens. HER2+ patients with metastatic breast cancer who had received one or more chemotherapy regimens were included. Eligible patients received inetetamab administered weekly or every three weeks in combination with vinorelbine injection chemotherapy. Pharmacokinetics, safety, efficacy, and immunogenicity were compared between the groups. Sixty HER2+ patients were randomized into a single-week administration group ( n = 29) and a three-week administration group ( n = 31). After the final dose in the single-week administration group and the three-week administration group, the mean Cmax values were 79.773 μg/mL and 146.083 μg/mL; the mean Cmin values were 30.227 μg/mL and 11.926 μg/mL; the mean AUCtau values were 7328.443 μg·h/mL and 22647.101 μg·h/mL; and the mean Cav values were 43.622 μg/ mL and 44.935 μg/mL, respectively. The best overall response (BOR) rates at 24 weeks and unconfirmed BOR rates at 24 weeks were both 40.7% in the single-week dosing group and 40.7% in the three-week dosing group, and the 24-week confirmed disease control rates (DCRs) were 88.9% and 81.5%, respectively. The incidence of adverse events (AEs) was generally consistent across all levels. There were slight differences in the mean Cmax, Cmin, AUCtau and Cav between the three-week dosing group and the single-week dosing group, and the mean steady-state concentrations of Cav were comparable; however, there were no differences in efficacy, safety or immunogenicity between the two groups.

Effect of wild-type vaccine doses on BA.5 hybrid immunity, disease severity, and XBB reinfection risk.

Vaccination against the wild-type (WT) severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus did not produce detectable levels of neutralizing antibodies (NAbs) against the BA.5 strain before it emerged. However, coronavirus disease-2019 (COVID-19) severity varied highly between unvaccinated, partially vaccinated, and fully vaccinated individuals, for unknown reasons. We assessed the severity of BA.5 infection and the risk of XBB strain reinfection and measured serum levels of NAbs against WT, BA.5, and XBB.1.9.1 SARS-CoV-2 strains at varying time points in 1,373 individuals who received zero, one, two, or three WT vaccine doses. We found that two to three WT doses significantly increased WT and BA.5 NAb levels and reduced the incidence of COVID-19-associated pneumonia upon BA.5 strain infection compared to zero to one dose. Regarding XBB reinfection, those who received two to three doses and were infected with the BA.5 variant exhibited a significantly lower reinfection risk compared to those who received zero to one dose. RNA analysis revealed that the differentially expressed genes between the two to three dose and unvaccinated groups were enriched in B cell activation, cytokine-cytokine receptor interaction, complement, and monocyte activation functions-indicating that vaccination increased the antibody response and reduced inflammation. Our results suggest that multiple antigen exposures to either matched or unmatched SARS-COV-2 variants, through vaccination or infection, may be necessary to achieve significant immune imprinting.IMPORTANCEThe administration of coronavirus disease-2019 (COVID-19) vaccines that do not perfectly match the viral strains that individuals become infected with has been found to impact the resultant illness severity-although the precise mechanism underlying this phenomenon remains unclear. We assessed viral clearance, as well as serum levels of inflammatory cytokines and neutralizing antibodies (NAbs) against wild-type, BA.5, and XBB.1.9.1 variants of the severe acute respiratory syndrome coronavirus 2 among individuals who received varying doses of such strain-mismatched vaccines. Notably, vaccination with ≥2 doses of strain-mismatched COVID-19 vaccines appeared to stimulate the production of specific NAbs during infection with new variants, as well as attenuate the inflammatory response and enhance viral clearance. Such vaccination regimens can also reduce the risk of reinfection. These findings may be important for guiding the development of future COVID-19 vaccination strategies that target both matched and mismatched viral variants.

Black Garlic Supplementation and Glomerular Protection in Hyperuricemic Rats: A Study on Kidney Health Prevention

Introduction: Hyperuricemia is a significant risk factor for the development of chronic kidney disease. Excessive uric acid can deposit in the kidneys, triggering inflammatory reactions and oxidative stress, leading to structural damage in the glomeruli. Black garlic, with its antioxidant and bioactive compounds, has the potential to protect the kidneys from hyperuricemia-induced damage. Our objective is to evaluate the effect of black garlic supplementation on the histopathological features of glomeruli in a hyperuricemic rat model. Methods: This study was an analytical observational study using Biological Remnant Materials (BRM) from a previous study. The sample consisted of 30 male Sprague-Dawley rats divided into 5 groups: disease control, drug control (allopurinol), and 3 black garlic dose groups (240 mg/day, 480 mg/day, and 960 mg/day). Data were collected through histopathological examination of kidney tissue using the glomerular damage scoring method (0-3). Data analysis was performed using one-way ANOVA and post hoc LSD tests. Results: Black garlic demonstrated protective effects on the histopathological features of glomeruli in hyperuricemic rats. The 240 mg/day dose showed the most significant improvement in kidney health, reducing glomerular damage scores compared to the disease control group (p &lt; 0.05). These findings suggest that black garlic can serve as a preventive agent against kidney complications caused by hyperuricemia. Conclusion: Black garlic provides protective effects on glomerular histopathology in hyperuricemic rats, with the 240 mg/day dose being the most effective. These results suggest potential use for black garlic in preventing kidney complications in hyperuricemia.

Effectiveness of pulse methylprednisolone in patients with non-human immunodeficiency virus pneumocystis pneumonia: a multicentre, retrospective registry-based cohort study

BackgroundA recent database study and meta-analysis reported that adjunctive glucocorticoid therapy reduces mortality in patients with non-human immunodeficiency virus-associated (non-HIV) Pneumocystis jirovecii pneumonia (PCP), having hypoxemia. However, the optimal glucocorticoid dose remains unclear. Our study aimed to evaluate the effectiveness of pulse methylprednisolone compared with mild-to-moderate steroid doses in patients with non-HIV PCP.MethodsThis multicentre retrospective cohort study included adults with non-HIV PCP receiving adjunctive steroids at three Japanese tertiary care hospitals from June 2006 to March 2021. Patients were categorised into pulse methylprednisolone and mild-to-moderate dose groups. Pulse methylprednisolone involved an initial intravenous infusion of 500–1000 mg methylprednisolone daily, while the mild-to-moderate dose was lower. Primary and secondary outcomes were 30-day and 180-day mortality from treatment initiation. Patient characteristics were adjusted using propensity score analysis with overlap weighting. Subgroup analysis focused on patients with respiratory failure.ResultsThe study included 139 patients with non-HIV PCP: 55 in the pulse methylprednisolone group and 84 in the mild-to-moderate dose group. After adjusting for patient background, 30-day mortality (14.2% vs. 15.5%, P = 0.850) and 180-day mortality (33.5% vs. 27.3%, P = 0.516) did not differ significantly between groups. Subgroup analysis revealed no significant associations among patients with respiratory failure.ConclusionsAfter adjusting for patient characteristics, no difference in prognosis was observed between pulse methylprednisolone and mild-to-moderate dose groups in patients with non-HIV PCP. A mild-to-moderate dose of adjunctive corticosteroid may suffice for treating non-HIV PCP.

Bisphenol A-induced polycystic ovary syndrome (PCOS) with hormonal and metabolic implications in rats.

There is a rising incidence of polycystic ovary syndrome (PCOS) cases worldwide in women of reproductive age due to environmental factors. We evaluated the effect of an environmental estrogen, bisphenol A for its reprotoxicity regarding the induction of PCOS in rats and also assessed its hormonal and metabolic implications. There was 66.6% and 50% disorder, in the estrus cycle at low (50µg/kg) and high (500µg/kg) doses of BPA. While animals treated with the positive control (dehydroepiandrosterone, DHEA at 6mg/100g) caused 100% disorder. Cystic and atretic follicles along with two corpus luteum were found in the low dose group. However, no corpus luteum was found in the high dose group. Furthermore, hyperplasia and hypertrophy were found in the myometrium, endometrium, and luminal epithelium of the uterus of the low dose and DHEA groups. Additionally, 17β estradiol, progesterone, DHEA, androstenedione, testosterone, dihydrotestosterone (DHT), dehydroepiandrosterone sulphate (DHEAS), antimullerian hormone (AMH), ratio of LH/FSH and testosterone/DHT were increased significantly (P < 0.01) in BPA groups. A significantly higher TSH (P < 0.01) indicates hypothyroidism. Furthermore, hyperglycemia, hyperinsulinemia, HOMA-IR, and HOMAβ indicate insulin resistance in the low-dose group. Thus, the low dose of BPA was found to be more potent as compared to the higher dose and defining the hyperandrogenic state. Our study revealed that BPA may not only be a causative factor in the induction of PCOS but also has metabolic implications bearing on its estrogenic nature.

Predictive Value of Immune Activity Changes in Breast Cancer Patients Treated With Dose-dense Neoadjuvant Chemotherapy: A Retrospective Study.

Dose-dense chemotherapy is recommended for patients with breast cancer who have a high recurrence risk. However, whether dose-dense neoadjuvant chemotherapy (ddNAC) improves patient prognoses compared to the normal-dose regimen remains controversial. In this study, we evaluated the predictive value of immune activities on short-term outcomes for patients treated with ddNAC. We classified 82 patients with human epidermal growth factor receptor 2-negative breast cancer treated with NAC into a normal dose group (62 patients) and ddNAC group (20 patients) and examined the differences in clinicopathological features. The ddNAC group was further divided according to patient responses to NAC and the predictive factors for pathological complete response (pCR) were evaluated. There were no differences in the clinicopathological features before NAC between the normal dose and ddNAC groups. Although the pCR rates tended to be higher in the ddNAC group compared than those in the normal dose group (35.0% vs. 25.8%), there was not significant difference (p=0.264). Among all patients treated with ddNAC, the absolute lymphocyte count decreased and the neutrophil-to-lymphocyte ratio increased during dose-dense doxorubicin plus cyclophosphamide treatment. There was no significant correlation between the pCR and any of the clinicopathological parameters tested including systemic peripheral markers and tumor-infiltrating lymphocyte levels. ddNAC affected the levels of systemic peripheral immune markers. However, monitoring these markers may not be useful for predicting responses to ddNAC.

The protective effect of rutin on sciatic nerve injury in acrylamide-exposed rats and its mechanisms

Rutin (Rut) is a flavonoid with pharmacological activities such as anti-inflammatory and antioxidant. Acrylamide (ACR) is a toxic substance widely found in human life that can induce neurotoxicity. Some studies have confirmed that neurotoxicity caused by ACR induces myelin damage, which in turn causes neurological dysfunction. Therefore, we established a rutin intervention model to investigate the protective effect of Rut on ACR-induced sciatic nerve injury in rats and its mechanism. The results showed that superoxide dismutase (SOD) activity and glutathione (GSH) content increased and lactate dehydrogenase (LDH) activity decreased in the middle and high dose groups of Rut compared with the ACR group, and the expression of Myelin basic protein (MBP), Extracellular-regulated kinase 1/2(ERK1/2), Phosphorylated extracellular regulated kinase 1/2 (P-ERK1/2), and Nuclear factor E-2-associated factor (Nrf2) was promoted in the Rut-protected group, which suggests that Rutin has a protective effect on ACR-induced sciatic nerve injury and that the mechanism of Rutin's protective effect is related to activation of the ERK1/2 pathway and alleviation of oxidative stress injury.

Optimal infused CD34+ cell dose in multiple myeloma patients undergoing upfront autologous hematopoietic stem cell transplantation

Autologous transplantation remains the standard of care for eligible multiple myeloma (MM) patients, yet optimal CD34+ cell dose remains unclear. We conducted a retrospective study on MM patients undergoing upfront transplant between 2005 and 2021 and divided them into low (≤2.5 × 106 cells/kg) and high (>2.5 × 106 cells/kg) CD34+ dose groups. We included 2479 patients, 95 in the low CD34+ group and 2384 in the high CD34+ group. Patients in the low CD34+ group were older (63.2 vs 61.1 years, p = 0.013), more often had R-ISS III (19% vs 9%, p = 0.014), received plerixafor (60% vs 35%, p < 0.001) and transplanted after 2009 (88% vs 80%, p = 0.047). Time to neutrophil and platelet recovery was longer in the low CD34+ group. Median PFS and OS were lower in the low CD34+ group (31.6 vs. 43.6 months, p = 0.011 and 76.4 vs. 108.2 months, p < 0.001, respectively). Evaluation of incrementally higher CD34+ dose did not show significant improvement in survival at thresholds >2.5 × 106 cells/kg. Multivariable analysis affirmed that CD34+ >2.5 × 106 cells/kg was associated with better PFS (HR 0.71, p = 0.008) and OS (0.59, p < 0.001). After propensity score matching, a CD34+ dose >2.5 × 106 cells/kg remained a predictor of better OS (0.42, p < 0.001). In conclusion, CD34+ dose >2.5 × 106 cells/kg was associated with improved survival, without any additional benefit at incrementally higher doses.

Transgenerational Effects on Lifespan and Pathology of Paternal Pre-conceptional Exposure to Continuous Low-dose-rate Gamma Rays in C57BL/6J Mice

The present work investigates the multigenerational effects of paternal pre-conceptional exposure to continuous low-dose-rate gamma rays in C56BL/6J mice. Male C57BL/6J (F0 sires) mice were exposed to low dose rates of 20, 1, and 0.05 mGy/day for 400 days, to total accumulated doses of 8,000, 400, and 20 mGy, respectively. Upon completion of the radiation exposure, the F0 male mice were immediately bred to non-irradiated 8-week-old C57BL/6J females (F0 dams) to produce the first-generation (F1) mice. Randomly selected F1 males and females were then bred to produce the second-generation (F2) mice. All the mice, except the F0 dams, were subjected to pathological examination upon natural death. Reproductive parameters, lifespan, causes of death, neoplasm incidences and non-neoplastic disease incidences were used as parameters to evaluate the biological effects of continuous pre-conceptional exposure of the sires (F0) to continuous low-dose-rate radiation. There were no significant differences in the pregnancy and weaning rates among the parent (F0) generation. Average litter size and average number of weaned pups (F1) from dams bred to males (F0) exposed to 20 mGy/day were significantly decreased compared to the non-irradiated controls. Significant lifespan shortening in the sires (F0) was observed only in the 20 mGy/day group due to early death from malignant lymphomas. Life shortening was also observed in the F1 progeny of sires (F0) exposed to 20 and 1 mGy/day, but could not be attributed to a specific cause. No significant differences in the causes of death were found between dose groups in any generation. The number of primary tumors per mouse was significantly increased only in the F0 males exposed to 20 mGy/day. Except for the increased incidence rate for Harderian gland neoplasms in sires (F0) exposed to 20 mGy/day, there was no significant difference in neoplasm incidences and tumor spectra in all 3 generations in each sex regardless of radiation exposure. No multi- or transgenerational effects in the parameters examined were observed in the F1 and F2 progeny of sires exposed to 0.05 mGy/day for 400 days.