Application of quantitative pharmacology analysis to support early clinical development of oncology drugs: dose selection.

The selection of appropriate starting dose and suitable method to predict an efficacious dose for novel oncology drug in the early clinical development stage poses significant challenges. The traditional methods of using body surface area transformation from toxicology studies to predict the first-in human (FIH) starting dose, or simply selecting the maximum tolerated dose (MTD) or maximum administered dose (MAD) as efficacious dose or recommended phase 2 dose (RP2D), are usually inadequate and risky for novel oncology drugs.Due to the regulatory efforts aimed at improving dose optimization in oncology drug development, clinical dose selection is now shifting away from these traditional methods towards a comprehensive benefit/risk assessment-based approach. Quantitative pharmacology analysis (QPA) plays a crucial role in this new paradigm. This mini-review summarizes the use of QPA in selecting the starting dose for oncology FIH studies and potential efficacious doses for expansion or phase 2 trials. QPA allows for a more rational and scientifically based approach to dose selection by integrating information across studies and development phases.In conclusion, the application of QPA in oncology drug development has the potential to significantly enhance the success rates of clinical trials and ultimately support clinical decision-making, particularly in dose selection.

Evidence of Spin Density Waves in La_{3}Ni_{2}O_{7-δ}.

The recently discovered superconductivity with critical temperature T_{c} up to 80 K in the double-layer Nickelate La_{3}Ni_{2}O_{7-δ} under pressure has drawn great attention. Here, we report the positive muon spin relaxation (µ^{+}SR) study of polycrystalline La_{3}Ni_{2}O_{6.92} under ambient pressure. Zero-field µ^{+}SR experiments reveal the existence of magnetic order in La_{3}Ni_{2}O_{6.92} with T_{N}=154 K. The weak transverse field µ^{+}SR measurements reveal the bulk nature of magnetism. In addition, a small quantity of oxygen deficiencies can greatly broaden the internal magnetic field distribution sensed by muons.

Effect of anesthesia mode during endovascular treatment on neurological functional outcomes in patients with acute posterior circulation stroke. / éº»é†‰æ–¹å¼å¯¹æ€¥æ€§åŽå¾ªçŽ¯è„‘å’ä¸­è¡€ç®¡å† æ²»ç–—æ‚£è€ ç¥žç»åŠŸèƒ½ç»“å±€çš„å½±å“.

OBJECTIVES: To compare the effect of anesthesia mode on the neurological functional outcomes in patients undergoing endovascular treatment for acute posterior circulation ischemic stroke. METHODS: Clinical data of 656 patients undergoing intravascular therapy for acute posterior circulation ischemic stroke registered in online Acute Stroke Patients for Stroke Management Quality Evaluation Database from January 2017 to December 2022 were retrospectively analyzed. The data included 163 cases with conscious sedation and 493 cases with general anesthesia during the procedure. After propensity score matching, 428 patients were included in the analysis, including 155 cases in the conscious sedation group and 273 cases in the general anesthesia group. The differences of operation mode, etiology type, vascular recanalization, hemorrhagic transformation at 24 h, modified Rankin Scale (mRS) score at 3 months and mortality within 3 months were compared between the two groups. Binary logistic regression was used to explore the effect of different anesthesia mode on neurological functional outcomes. RESULTS: There was a significant difference in operation mode between the two groups (P<0.01), while there were no significant differences in etiology type, vascular recanalization, hemorrhagic transformation at 24 h, mRS score at 3 months or mortality within 3 months (all P>0.05). Binary logistic regression analysis revealed that anesthesia modes were not significantly associated with functional outcomes of patients (OR=1.151, 95%CI: 0.751-1.765, P>0.05). CONCLUSIONS: Anesthesia mode (conscious sedation or general anesthesia) will not affect the neurological functional outcomes in patients with acute posterior circulation ischemic stroke undergoing endovascular treatment.

Dual-Confinement Effect of Nanocages@Nanotubes Suppresses Polysulfide Shuttle Effect for High-Performance Lithium-Sulfur Batteries.

The shuttle effect of lithium polysulfides (LiPSs) severely hinders the development and commercialization of lithium-sulfur batteries, and the design of high-conductive carbon fiber-host material has become a key solution to suppress the shuttle effect. In this work, a unique Co/CoN-carbon nanocages@TiO2-carbon nanotubes structure (NC@TiO2-CNTs) is constructed using an electrospinning and nitriding process. Lithium-sulfur batteries using NC@TiO2-CNTs as cathode host materials exhibit high sulfur utilization (1527 mAh g-1 at 0.2 C) and can still maintain a discharge capacity of 663 mAh g-1 at a high current density of 5 C, and the capacity loss is only 0.056% per cycle during 500 cycles at 1 C. It is worth noting that even under extreme conditions (sulfur-loading = 90%, surface-loading = 5.0 mg cm-2 (S), and E/S = 6.63 µL mg-1), the lithium-sulfur batteries can still provide a reversible capacity of 4 mAh cm-2. Throughdensity functional theory calculations, it has been found that the Co/CoN heterostructures can adsorb and catalyze LiPSs conversion effectively. Simultaneously, the TiO2 can adsorb LiPSs and transfer Li+ selectively, achieving dual confinement for the shuttle effect of LiPSs (nanocages and nanotubes). The new findings provide a new performance enhancement strategy for the commercialization of lithium-sulfur batteries.

MGA-seq: robust identification of extrachromosomal DNA and genetic variants using multiple genetic abnormality sequencing.

Genomic abnormalities are strongly associated with cancer and infertility. In this study, we develop a simple and efficient method - multiple genetic abnormality sequencing (MGA-Seq) - to simultaneously detect structural variation, copy number variation, single-nucleotide polymorphism, homogeneously staining regions, and extrachromosomal DNA (ecDNA) from a single tube. MGA-Seq directly sequences proximity-ligated genomic fragments, yielding a dataset with concurrent genome three-dimensional and whole-genome sequencing information, enabling approximate localization of genomic structural variations and facilitating breakpoint identification. Additionally, by utilizing MGA-Seq, we map focal amplification and oncogene coamplification, thus facilitating the exploration of ecDNA's transcriptional regulatory function.

Influence of titanate photocatalyst in biohydrogen yield via photo fermentation from corn stover.

The effects of three common titanate photocatalysts (TPC) on the photo fermentation biohydrogen production (PFHP) from corn stover were studied in this paper. Compared with CaTiO3 and BaTiO3, the experimental group with the addition of MgTiO3 showed stronger potential for PFHP, the maximum hydrogen yield of 344 mL (68.8 mL/g TS) was obtained at 3 g/L MgTiO3, increased by 48.3%. For CaTiO3, BaTiO3, the optimal amount of addition was 8 and 7 g/L, respectively, in which, the hydrogen yield was 308 and 288 mL (61.6 and 57.6 mL/g TS). TPC addition could shorten the delay period of hydrogen production lower the Oxidation-Reduction Potential (ORP) of fermentation broth, especially MgTiO3 addition, the delayed hydrogen production could be shortened by 33.2% compared with control group, and the ORP could reach the lowest value of -371 mV.

Estimating the potential of biohydrogen production and carbon neutralization contribution from crop straw.

In order to achieve the carbon neutrality goal set by Chinese government, the potential contribution of hydrogen production from crop residues by microbial fermentation technology and Greenhouse gas (GHGs) reduction have been studied. Firstly, the annual yield of crop straw was estimated according to crop yield and grass grain ratio, and then the grey model GM (1, 1) was applied to predict the crop residues resources available for hydrogen production in various provinces in China in 2021. The results showed that the maximum resource of straw being available for hydrogen production is about 4.54 × 108 t, corresponding to 1.31 × 1011 m3 of hydrogen, the energy carried by the obtained hydrogen was 73 % and 1.15 times than the energy of national civil natural gas consumption and energy of transportation gasoline consumption, respectively. The potential reduction of greenhouse gas emission was 2.42 × 108 t/a CO2-eq, representing 2.4 % of GHGs emissions.

The effect of the day 3 embryo cell number on the neonatal outcomes of day 5 single blastocyst transfer in frozen embryo transfer cycles.

OBJECTIVE: To evaluate the influence of the day 3 embryo cell number on the neonatal outcomes of day 5 single blastocyst transfer in frozen embryo transfer (FET) cycles. METHODS: This retrospective study analysed a total of 2315 delivery cycles of day 5 single blastocyst transfer in FET cycles, including 489, 761 and 1103 live-born infants segregated according to a day 3 embryo cell number of <8, 8 and >8 cells, respectively. The neonatal outcomes of the three groups were compared. RESULTS: The day 3 embryo cell number did not significantly affect the incidence of monozygotic twins. The sex ratio increased as the day 3 embryo cell number increased, but the difference was not statistically significant. There were no significant differences in the rates of preterm birth or low birth weight among the three groups. The rates of stillbirths and neonatal deaths were also not significantly different among the three groups. Moreover, the day 3 embryo cell number did not increase the risk of birth defects in newborns. CONCLUSIONS: The day 3 embryo cell number did not significantly affect neonatal outcomes.

Elevated serum progesterone levels on the hCG trigger day have a negative impact on the live birth rate in the first fresh IVF-ET cycle.

To investigate whether there is a relationship between elevated serum progesterone (PROG) on the hCG trigger day and the live birth rate (LBR) in IVF/ICSI cycles, the retrospective analysis was carried out from the patients undergoing the first ART cycles throughout 2016. The PROG levels were measured on the hCG trigger day. The LBR, clinical pregnancy rate (CPR), implantation rate (IR) and other parameter rate values were compared among the three different PROG elevations. A total of 2550 IVF/ICSI cycles fulfilling all the inclusion and exclusion criteria were selected. Finally, three groups [PROG <0.40 ng/mL, 0.40 ≤ PROG < 1.5 ng/mL, PROG ≥ 1.5 ng/mL] were categorised based on the serum PROG levels. LBR, CPR and IR declined as the PROG value increased, while there was no difference in the embryo utilisation rates. Serum PROG levels on the day of hCG administration were negatively associated with the LBR, even in ETs with a good prognosis.Impact StatementWhat is already known on this subject? The clinical effects of PROG are still controversial. Some studies have confirmed that there was not too much association between premature elevation of PROG and live birth, some are still convincing that there is a negative correlation and will result in ART cycles of pregnancy and LBR reduction.What do the results of this study add? Our data substantiated that the high serum PROG level had the lowest LBR, IR and CPR, but the embryo utilisation rate may not have too much to do with the elevated PROG.What are the implications of these findings for clinical practice and/or further research? This study further strengthens the negative impact of elevated PROG levels on pregnancy outcomes, and suggests that frozen thawed embryo transfer appears to be a reasonable and advantageous approach for this subset of patients.

The influence of day 3 embryo cell number on the clinical pregnancy and live birth rates of day 5 single blastocyst transfer from frozen embryo transfer cycles.

BACKGROUND: To evaluate the influence of day 3 embryo cell number on the clinical pregnancy and live birth rates of day 5 single blastocyst transfer in frozen embryo transfer (FET) cycles. METHODS: Our retrospective study included 3761 day 5 single blastocyst FET cycles between January 2015 and December 2019. These FET cycles were divided into three groups according to the day 3 embryo cell number: 939 cycles in the < 8-cell group, 1224 cycles in the 8-cell group and 1598 cycles in the > 8-cell group. The clinical pregnancy and live birth rates were compared among the three groups. RESULTS: The clinical pregnancy rate of day 5 single blastocyst transfer in FET cycles increased significantly as the day 3 embryo cell number increased (52.2%, 61.4% and 66.8%, P < 0.001). Similarly, the live birth rate increased significantly as the day 3 embryo cell number increased (42.7%, 49.8% and 54.9%, P < 0.001). The results of the subgroup analysis showed that the clinical pregnancy and live birth rates were not significantly different among the three groups when good-quality blastocysts were transferred. The clinical pregnancy and live birth rates increased significantly as the day 3 embryo cell number increased when fair- and poor-quality blastocysts were transferred. CONCLUSION: The day 3 embryo cell number needs to be considered when day 5 single blastocyst transfer is performed in FET cycles, especially when fair- and poor-quality blastocysts are used for transfer. The transfer of a day 5 single blastocyst derived from an embryo with faster development on day 3 may shorten the time to achieving a live birth.

Circular RNA circFoxo3 Promotes Granulosa Cell Apoptosis Under Oxidative Stress Through Regulation of FOXO3 Protein.

Oxidative stress leads to ovarian functional decline by inducing granulosa cell (GC) apoptosis. Circular RNA circFoxo3 acts as a critical factor in regulating cell cycle and apoptosis, and cellular senescence in tumor cells. However, function of circFoxo3 is little understood in oxidative stress-induced injury of follicular GCs. In this study, we aimed to illustrate the regulation pattern of circFoxo3 in GCs under oxidative stress. CircFoxo3 was confirmed to be expressed in both human and mouse GCs by amplification with divergent primers and sequencing. In vitro and in vivo ovarian oxidative stress model, the expression of circFoxo3, FOXO3 protein, and its downstream targets were examined by quantitative real-time PCR and Western blotting, respectively. Knockdown of circFoxo3 was performed to evaluate the effects of circFoxo3-mediated GC apoptosis in vitro. RNA pull-down was used to discover the protein that interacted with circFoxo3 so as to illustrate the mechanism of circFoxo3 in GCs. Our results demonstrated that circFoxo3 was significantly upregulated in hydrogen peroxide (H2O2)-treated GCs and a 3-nitropropionic acid (3-NP)-induced mouse model of ovarian oxidative stress. Protein level of transcriptional factor FOXO3 was also remarkably increased in both in vitro and in vivo oxidative stress model, but FOXO3 mRNA expression revealed no significant difference. Knockdown of endogenous circFoxo3 downregulated FOXO3 protein level and blocked H2O2-induced cell apoptosis. CircFoxo3 could pull down high levels of MDM2 protein that induced FOXO3 ubiquitination and degradation. Furthermore, knockdown of MDM2 and circFoxo3 showed remarkably higher level of apoptosis when compared with the knockdown of circFoxo3 alone. Our study suggested that circFoxo3 regulated FOXO3 protein level in GCs by reducing interactions between FOXO3 and MDM2. In conclusion, circFoxo3 was positively associated with FOXO3 protein and jointly played crucial roles in mediating GC apoptosis induced by oxidative stress.

Primary stent implantation for bilateral spontaneous cervical ICA dissections with hypoperfusion after 72 h from onset: a case report.

BACKGROUND: Spontaneous cervical internal carotid artery dissection (cICAD) is a common cause of stroke in young adults. Endovascular therapy is an indispensable treatment for cICAD in some cases, but it faces great challenges. CASE PRESENTATION: A bilateral spontaneous cICADs with hypoperfusion-related AIS after 72 h from the onset was presented herein. The patient responded well to primary Solitaire stent detachment at the critical flow-limiting site. CONCLUSIONS: Primary stent implantation at the critical flow-limiting site rather than covering the entire dissection may be a therapeutic option in spontaneous cICAD complicated with cerebral hypoperfusion. The Solitaire stent may be a good choice at the acute and subacute stages of cICAD.

Influence Factors and Predictive Models for the Outcome of Patients with Ischemic Stroke after Intravenous Thrombolysis: A Multicenter Retrospective Cohort Study.

Objective: Intravenous thrombolysis (IVT) is currently the main effective treatment for patients with ischemic stroke. This study aimed to analyze the factors affecting the early neurological recovery and prognosis of thrombolytic therapy after surgery and to construct predictive models. Materials and Methods: A total of 849 patients with ischemic stroke who received IVT treatment at six centers from June 2017 to March 2021 were included. Patients were divided into the training cohort and the validation cohort. Based on the independent factors that influence the early recovery of neurological function and the prognosis, the respective predictive nomograms were established. The predictive accuracy and discrimination ability of the nomograms were evaluated by ROC and calibration curve, while the decision curve and clinical impact curve were adopted to evaluate the clinical applicability of the nomograms. Results: The nomogram constructed based on the factors affecting the prognosis in 3 months had ideal accuracy as the AUC (95% CI) was 0.901 (0.874~0.927) in the training cohort and 0.877 (0.826~0.929) in the validation cohort. The accuracy of the nomogram is required to be improved, since the AUC (95% CI) of the training cohort and the validation cohort was 0.641 (0.597~0.685) and 0.627 (0.559~0.696), respectively. Conclusions: Based on this ideal and practical prediction model, we can early identify and actively intervene in patients with ischemic stroke after IVT to improve their prognosis. Nevertheless, the accuracy of predicting nomograms for the recovery of early neurological function after IVT still needs improvement.

Non-invasive embryo selection strategy for clinical IVF to avoid wastage of potentially competent embryos.

RESEARCH QUESTION: Can a non-invasive embryo transfer strategy provide a reference for embryo selection to be established? DESIGN: Chromosome sequencing of 345 paired blastocyst culture medium and whole blastocyst samples was carried out and a non-invasive embryo grading system was developed based on the random forest machine learning algorithm to predict blastocyst ploidy. The system was validated in 266 patients, and a blinded prospective observational study was conducted to investigate clinical outcomes between machine learning-guided and traditional non-invasive preimplantation genetic testing for aneuploidy (niPGT-A) analyses. Embryos were graded as A, B or C according to their euploidy probability levels predicted by non-invasive chromosomal screening (NICS). RESULTS: Higher live birth rate was observed in A- versus C-grade embryos (50.4% versus 27.1%, P = 0.006) and B- versus C-grade embryos (45.3% versus 27.1%, P = 0.022) and lower miscarriage rate in A- versus C-grade embryos (15.9% versus 33.3%, P = 0.026) and B- versus C-grade embryos (14.3% versus 33.3%, P = 0.021). The embryo utilization rate was significantly higher through the machine learning strategy than the conventional dichotomic judgment of euploidy or aneuploidy in the niPGT-A analysis (78.8% versus 57.9%, P < 0.001). Better outcomes were observed in A- and B-grade embryos versus C-grade embryos and higher embryo utilization rates through the machine learning strategy compared with traditional niPGT-A analysis. CONCLUSION: A machine learning guided embryo grading system can be used to optimize embryo selection and avoid wastage of potential embryos.

Enhancement effect of defoamer additives on photo-fermentation biohydrogen production process.

Foaming is a key issue should be solved in the process of photo-fermentation biohydrogen production (PFHP), since it has negative influence on the hydrogen yield potential, especially when taken straw as substrate. Appropriate foam control measures must be considered for industrialization. Hence, in this work, foam height and biohydrogen yield were selected as index, the effect of defoamer addition on PFHP was investigated. The defoamer has no negative effect on bacterial growth. In the addition range of 0-1 mL/L, the higher addition amount, indicates better foam control effect. The maximum foam height could be reduced by 55% and the foam existence time by 36 h. The reduction of foam was beneficial to biohydrogen production, and the highest cumulative hydrogen yield was increased 23% at the addition level of 0.125 mL/L.

Blastocyst development rate influences singleton gestational age of similarly graded blastocysts after vitrified-warmed single embryo transfer cycles.

RESEARCH QUESTION: Does the development rate of blastocysts influence neonatal outcomes after blastocyst transfer cycles when the morphological score of the transferred blastocysts is similar? DESIGN: A retrospective study involving singleton live births born to 1280 women undergoing single frozen blastocyst transfers (FBTs) between January 2016 and December 2018 at a tertiary care centre. Patients were grouped into day-5 or day-6 groups depending on the development rate of blastocysts. These were further grouped into four groups based on the blastocyst inner cell mass and trophectoderm scoring: excellent (AA); good (AB or BA); average (AC, CA or BB); and poor (BC or CB). The primary outcomes were gestational age and singleton birth weight. RESULTS: Singletons resulting from day-5 single FBT were at a lower risk of preterm birth than those resulting from day-6 single FBT (adjusted OR 0.63, 95% CI 0.41 to 0.97, P = 0.035). In the day-5 good-quality blastocyst group and day-5 average-quality blastocyst group, singletons were at a lower risk of preterm birth than those resulting from day-6 groups, respectively (adjusted OR 0.22, 95% CI 0.08 to 0.63, P = 0.005 and adjusted OR 0.52, 95% CI 0.29 to 0.94, P = 0.03). CONCLUSIONS: Day-6 single FBT was associated with a higher risk of preterm birth compared with day-5 single FBT in good and average morphological scoring blastocysts. Our analysis was restricted to women with singleton births from single FBTs. Future prospective studies are required to confirm the findings.

Enhancing photo-fermentation biohydrogen production from corn stalk by iron ion.

This study aimed to investigate the enhancement of iron ion on growth, metabolic pathway, and biohydrogen production performance of biohydrogen producing bacteria HAU-M1. Different concentrations of Fe2+ and Fe3+ were respectively added into fermentation broth of photo-fermentation biohydrogen production (PFHP) from corn stalk. Regular sampling test was used to measure the characteristics of fermentation broth and gas, metabolic pathway, energy conversion efficiency, and kinetic of PFHP. The analysis of experimental data showed that the maximum hydrogen yield of 70.25 mL/g was observed at 2500 µmol/L Fe2+ addition, with an energy conversion efficiency of 5.21%, which was 19.98% higher over no-addition. However, the maximum hydrogen content of 51.41% and the maximum hydrogen production rate of 17.82 mL/h were observed at 2000 µmol/L Fe2+ addition. The experimental results revealed that iron ion played a key role in PFHP, which provided a technical support for improving the performance of PFHP.

The effects of the day of trophectoderm biopsy and blastocyst grade on the clinical and neonatal outcomes of preimplantation genetic testing-frozen embryo transfer cycles.

This study analyzed the effects of the day of trophectoderm (TE) biopsy and blastocyst grade on clinical and neonatal outcomes. The results showed that the implantation and live birth rates of day 5 (D5) TE biopsy were significantly higher compared with those of D6 TE biopsy. The miscarriage rate of the former was lower than that of the latter, but there was no statistically significant difference. Higher quality blastocysts can achieve better implantation and live birth rates. Among good quality blastocysts, the implantation and live birth rates of D5 and D6 TE biopsy were not significantly different. Among fair quality and poor quality blastocysts, the implantation and live birth rates of D5 TE biopsy were significantly higher compared with those of D6 TE biopsy. Neither blastocyst grade nor the day of TE biopsy significantly affected the miscarriage rate. Neonatal outcomes, including newborn sex, gestational age, preterm birth, birth weight and low birth weight in the D5 and D6 TE biopsies were not significantly different. Both blastocyst grade and the day of TE biopsy must be considered at the same time when performing preimplantation genetic testing-frozen embryo transfer.

Enhancing photo-fermentative biohydrogen production using different zinc salt additives.

The kinetic properties of the hydrogen yield of photosynthetic bacteria were investigated using Han-Levenspiel and modified Gompertz models to determine the effects of different zinc salts on the growth and hydrogen production of the photosynthetic bacterium HAU-M1. Inorganic zinc salts (zinc standard solution and zinc sulfate) inhibited bacterial growth by 1-4-fold higher than organic zinc salts (zinc lactate and zinc gluconate). Among these four zinc salts, 5 mg/L zinc lactate displayed the weakest inhibition performance. This compound increased cumulative hydrogen production by approximately 57.81% (80.44 mL/g) and maximum hydrogen production rate by 58.27% (3.43 mL/[g·h]). The Han-Levenspiel model with parameters m > n > 0 indicated that the addition of zinc salts influenced the hydrogen production process of the bacterium in a noncompetitive manner. Compared with the inorganic zinc, the organic zinc salts were more suitable as exogenous zinc supplements to promote bacterial growth and its hydrogen production.

Quantitative evaluation of drug efficacy in the treatment of myasthenia gravis.

OBJECTIVES: This study aimed to quantitatively evaluate placebo effect and drug efficacy characteristics and identify associated factors that affect quantitative myasthenia gravis (MG) score (QMGs) and MG activities of daily living score (MG-ADLs) in patients with MG. METHODS: Randomized placebo-controlled clinical trials were comprehensively searched in public databases (PubMed, EMBASE, and Cochrane Library databases).A model-based meta-analysis was developed to describe time-course about drug efficacy and placebo effect. RESULTS: Twelve articles including 13 trials (673 participants) that were eligible for this study evaluated four immunosuppressants (tacrolimus, cyclosporine, prednisone, and mycophenolate mofetil) and five targeted therapy drugs (eculizumab, belimumab, zilucoplan, efgartigimod, and iscalimab). The pharmacodynamic model showed that eculizumab had the highest efficacy in reducing QMGs scores (3.66 points), and efgartigimod had the highest efficacy in reducing MG-ADLs scores (1.97 points). The placebo effect of QMGs and MG-ADLs increased apparently with time and reached 52% and 90% of their maximum effect in 12 weeks, respectively. In addition, this study found that the activities of daily living ability increased with the increase of the proportion of patients undergoing thymectomy. CONCLUSION: This study analyzed the efficacy characteristics of nine drugs. The present findings provide necessary quantitative information for drug development of MG.