Storing light near an exceptional point.

Photons with zero rest mass are impossible to be stopped. However, a pulse of light can be slowed down and even halted through strong light-matter interaction in a dispersive medium in atomic systems. Exceptional point (EP), a non-Hermitian singularity point, can introduce an abrupt transition in dispersion. Here we experimentally observe room-temperature storing light near an exceptional point induced by nonlinear Brillouin scattering in a chip-scale 90-µm-radius optical microcavity, the smallest platform up to date to store light. Through nonlinear coupling, a Parity-Time (PT) symmetry can be constructed in optical-acoustical hybrid modes, where Brillouin scattering-induced absorption (BSIA) can lead to both slow light and fast light of incoming pulses. A subtle transition of slow-to-fast light reveals a critical point for storing a light pulse up to half a millisecond. This compact and room-temperature scheme of storing light paves the way for practical applications in all-optical communications and quantum information processing.

Correlation analysis of maternal serum folate and 25(OH)D levels with the incidence of fetal growth restriction in patients with preeclampsia.

BACKGROUND: The purpose of this study was to investigate the effect of folic acid (FA) and vitamin D supplementation on increasing maternal serum folate and 25-hydroxyvitamin D [25(OH)D] concentrations during pregnancy and further reveal its role in reducing the risk of fetal growth restriction (FGR) in patients with preeclampsia (PE). METHODS: A total of 300 preeclamptic patients (treatment group 204 and control group 96) who had undergone routine obstetric examinations were retrospectively analyzed in this study. Data that include maternal serum levels of folate and 25(OH)D detected during early, middle, and late gestational periods from the medical records were analyzed. Multifactorial logistic regression analysis was performed to investigate the correlation of serum folate and 25(OH)D concentrations with the incidence of FGR. RESULTS: Serum folate and 25(OH)D concentrations were similar between the treatment group and control group in the early gestation. During the middle and late gestation, the serum folate and 25(OH)D levels were both continuously increased in the treatment group, but persistently decreased in the control group, leading to significant differences between the two groups (p < .001). In addition, the incidence of FGR was significantly lower in the treatment group than in the control group (p < .001). Logistic regression analysis showed significant correlations of increased serum folate and 25(OH)D levels with lower risk of FGR. CONCLUSIONS: FA and vitamin D supplementations facilitated to lower the risk of FGR in preeclamptic patients. These results would be the solid foundation for the further investigation of approaches to improve adverse outcomes of pregnancy, and have potential guiding implications for clinical practice.

Behcet's Disease Presenting as Pancolonic Ulcerations in a Patient With Kikuchi-Fujimoto Disease: A Rare Gastrointestinal Manifestation.

Kikuchi-Fujimoto disease (KFD) is a rare and self-limiting disorder characterized by cervical lymphadenopathy and fever. In this report, we present a case of a 24-year-old man with known history of KFD who presented with lower gastrointestinal bleeding and acute blood loss anemia. Further evaluation with colonoscopy showed widespread ulcerations in the colon and terminal ileum with suspicion for Behcet's disease. Biopsy from the colonic mucosa and ileocecal valve demonstrated focal ulcer with cryptitis and lymphoid aggregates that can be seen in Behcet's syndrome; however, it lacks specificity and Behcet's disease is a clinical diagnosis. This case emphasizes the importance of including gastrointestinal bleeding as a potential manifestation due to Behcet's disease in patients diagnosed with KFD.

Sharing Our World: Impact of Group Motor Skill Learning on Joint Attention in Children with Autism Spectrum Disorder.

Impaired joint attention is a common feature of autism spectrum disorder (ASD), affecting social interaction and communication. We explored if group basketball learning could enhance joint attention in autistic children, and how this relates to brain changes, particularly white matter development integrity. Forty-nine autistic children, aged 4-12 years, were recruited from special education centers. The experimental group underwent a 12-week basketball motor skill learning, while the control group received standard care. Eye-tracking and brain scans were conducted. The 12-week basketball motor skill learning improved joint attention in the experimental group, evidenced by better eye tracking metrics and enhanced white matter integrity. Moreover, reduced time to first fixation correlated positively with decreased mean diffusivity of the left superior corona radiata and left superior fronto-occipital fasciculus in the experimental group. Basketball-based motor skill intervention effectively improved joint attention in autistic children. Improved white matter fiber integrity related to sensory perception, spatial and early attention function may underlie this effect. These findings highlight the potential of group motor skill learning within clinical rehabilitation for treating ASD.

Activation of D2-like dopamine receptors improves the neuronal network and cognitive function of PPT1KI mice.

Palmitoyl-protein thioesterase 1 (PPT1) is a lysosomal depalmitoylation enzyme that mediates protein posttranslational modifications. Loss-of-function mutation of PPT1 causes a failure of the lysosomal degradation of palmitoylated proteins and results in a congenital disease characterized by progressive neuronal degeneration referred to as infantile neuronal ceroid lipofuscinosis (INCL). A mouse knock-in model of PPT1 (PPT1-KI) was established by introducing the R151X mutation into exon 5 of the PPT1 gene, which exhibited INCL-like pathological lesions. We previously reported that hippocampal γ oscillations were impaired in PPT1 mice. Hippocampal γ oscillations can be enhanced by selective activation of the dopamine D4 receptor (DR4), a dopamine D2-like receptor. In this study, we investigated the changes in DR expression and the effects of dopamine and various DR agonists on neural network activity, cognition and motor function in PPT1KI mice. Cognition and motor defects were evaluated via Y-maze, novel object recognition and rotarod tests. Extracellular field potentials were elicited in hippocampal slices, and neuronal network oscillations in the gamma frequency band (γ oscillations) were induced by perfusion with kainic acid (200 nM). PPT1KI mice displayed progressive impairments in γ oscillations and hippocampus-related memory, as well as abnormal expression profiles of dopamine receptors with preserved expression of DR1 and 3, increased membrane expression of DR4 and decreased DR2 levels. The immunocytochemistry analysis revealed the colocalization of PPT1 with DR4 or DR2 in the soma and large dendrites of both WT and PPT1KI mice. Immunoprecipitation confirmed the interaction between PPT1 and DR4 or DR2. The impaired γ oscillations and cognitive functions were largely restored by the application of exogenous dopamine, the selective DR2 agonist quinpirole or the DR4 agonist A412997. Furthermore, the administration of A412997 (0.5 mg/kg, i.p.) significantly upregulated the activity of CaMKII in the hippocampus of 5-month-old PPT1KI mice. Collectively, these results suggest that the activation of D2-like dopamine receptors improves cognition and network activity in PPT1KI mice and that specific DR subunits may be potential targets for the intervention of neurodegenerative disorders, such as INCL.

Unveiling key impact parameters and mechanistic insights towards activated biochar performance for carbon dioxide reduction.

Chemically activated biochar is effective in supercapacitors and water splitting, but low conductivity hinders its application as a carbon support in carbon dioxide reduction reaction (CO2RR). Based on the observed CO2RR performance from potassium hydroxide (KOH)-activated biochar, increased microporosity was hypothesized to enhance the performance, leading to selection of potassium carbonate (K2CO3) for activation. K2CO3 activation at 600℃ increased microporosity significantly, yielding a total Faradaic efficiency of 72%, compared to 60% with KOH at 800℃. Further refinement of thermal ramping rate enriched micropore content, directly boosting FEC to 82%. Additionally, K2CO3's lower activation temperature could preserve hydroxyl groups to improve ethylene selectivity. These findings demonstrate that optimizing microporosity and surface chemistry is critical for designing activated biochar-based CO2RR electrocatalysts. Despite lower electrical conductivity of activated biochar, selecting the appropriate activating agents and conditions can make it a viable alternative to carbon black-based electrocatalysts.

Effects of Zishen Yutai pills combined with metformin on women with polycystic ovary syndrome undergoing in vitro fertilization.

In this study, we analyzed the clinical efficacy of Zishen Yutai pills (ZSYTP) combined with metformin hydrochloride on infertile women diagnosed with polycystic ovary syndrome (PCOS) undergoing in vitro fertilization and embryo transfer (IVF-ET). Patients were assigned into 3 groups: the ZSYTP group (n = 50), the metformin group (n = 50), and the combination group (ZSYTP combined with metformin hydrochloride, n = 50), based on their respective and the indicated treatments before undergoing IVF-ET. Then, their glucose metabolism indices, sex hormone indices, traditional Chinese medicine (TCM) syndrome scores, and outcomes of IVF-ET were compared. Baseline characteristics were not significantly different between the 2 groups. After treatment, various parameters such as body mass index (BMI), fasting plasma glucose (FPG), fasting insulin (FIN), homeostatic model assessment of insulin resistance (HOMA-IR), luteinizing hormone (LH), estradiol (E2), follicle-stimulating hormone (FSH), testosterone (T) levels, and TCM syndrome scores were found to be reduced compared to pretreatment levels in both groups. Moreover, the improvement observed in the treatment group exceeded that of the control group. Specifically, the observation group displayed significantly lower gonadotropin (Gn) dosage and duration, as well as a reduced abortion rate compared to the control group. Furthermore, the observation group had higher numbers of obtained eggs, high-quality embryos, eggs obtained through IVF-ET, average transferred embryos, clinical pregnancy rate, and embryo implantation rate compared to the control group. Pretreatment with ZSYTP combined with metformin before IVF-ET in PCOS patients improves the outcome of IVF-ET.

Global research trends in the effects of exercise on depression: A bibliometric study over the past two decades.

Introduction: With depression's growing global prevalence and substantial impact, effective prevention and management strategies are imperative. Our study aims to perform a thorough bibliometric analysis of existing research on the impact of exercise on depression. Methods: A comprehensive analysis of Web of Science Core Collection publications from 2000 to 2020 was performed, highlighting trends, themes, and influential authors. The study focused on subject categories, source journals, countries/regions, institutions, and prolific authors. Co-citation and keyword analyses revealed key themes, hotspots and the thematic evolution. Results: The multidisciplinary nature of this research is evident across psychiatry, psychology, neuroscience, and sports science. Specific populations such as women, the elderly, and those with chronic illnesses were targeted. Mind-body exercises like yoga and tai chi gained prominence. Co-citation clusters showcased the evolution from early investigations on exercise's impact to recent dose-response and protocol studies. Conclusions: This bibliometric analysis provides insights into the dynamic field of exercise interventions for depression. It underscores the importance of individual differences, calls for guidelines considering comorbidities, and points towards future directions such as exploring mind-body exercise mechanisms and well-designed clinical trials. This study contributes to a comprehensive understanding of the research landscape and informs future endeavors aimed at refining depression treatment through exercise interventions.

Effect of different treatment protocols on in vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI) outcomes in adenomyosis women: a systematic review and meta-analysis.

OBJECTIVES: Pregnancy outcomes of different ovarian stimulation protocols for in vitro fertilisation/intracytoplasmic sperm injection (IVF/ICSI) in patients with adenomyosis are not explicit. This meta-analysis aimed to systematically evaluate the effects of different IVF/ICSI protocols on pregnancy outcomes. DESIGN: Meta-analysis. DATA SOURCES: PubMed, Web of Science and Cochrane library were searched up to October 2023. ELIGIBILITY CRITERIA: Comparative studies on IVF/ICSI outcomes in the adenomyosis population were eligible. Studies on preimplantation genetic testing, reviews, case reports and animal experiments were excluded. DATA EXTRACTION AND SYNTHESIS: Valid information was extracted by two independent authors according to a standard data format. All analyses were conducted using Review Manager (RevMan, V.5.3). RESULTS: Compared with the non-adenomyosis population, adenomyosis was responsible for a 26% reduction in clinical pregnancy rate (CPR; 42.47% vs 55.89%, OR: 0.74, 95% CI: 0.66 to 0.82, p<0.00001), a 35% reduction in live birth rate (LBR; 30.72% vs 47.77%, OR: 0.65, 95% CI: 0.58 to 0.73, p<0.00001) and a 1.9-fold increase in miscarriage rate (MR; 27.82% vs 13.9%, OR: 1.90, 95% CI: 1.56 to 2.31, p<0.00001). Subgroup analysis suggested that, in fresh embryo transfer (ET) cycles, the CPR (34.4% vs 58.25%) in the long/short/antagonist protocol group was poorer than that in the ultralong protocol group. In frozen ET (FET) cycles, there were no statistical differences in CPR ((GnRHa+FET) AM(adenomyosis) vs non-AM: 51.32% vs 43.48%, p=0.31; (non-GnRHa+FET) AM vs non-AM: 50.25% vs 60.10%, p=0.82), MR ((GnRHa+FET) AM vs non-AM:12.82% vs 12.50%, p=0.97; (non-GnRHa+FET) AM vs non-AM: 30.5% vs 15.54%, p=0.15) and LBR ((GnRHa+FET) AM vs non-AM:44.74% vs 36.96%, p=0.31; (non-GnRHa+FET) AM vs non-AM: 34.42% vs 50.25%, p=0.28). The MR in the adenomyosis group was high in the fresh ET and FET cycles. CONCLUSIONS: FET might be a better choice for women with adenomyosis, especially those pretreated with GnRHa. In fresh ET cycles, pregnancy outcomes of the long/short/antagonist protocols were poorer than those of the ultralong protocol. TRIAL REGISTRATION NUMBER: CRD42022340743.

Enhanced Frequency Conversion in Parity-Time Symmetry Line.

Non-Hermitian degeneracies reveal intriguing and nontrivial behaviors in open physical systems. Examples like parity-time (PT) symmetry breaking, topological encircling chirality, and enhanced sensing near an exceptional point (EP) are often associated with the abrupt nature of the phase transition around these degeneracies. Here we experimentally observe a cavity-enhanced second-harmonic frequency (SHG) conversion on a PT symmetry line, i.e., a set consisting of open-ended isofrequency or isoloss lines, both terminated at EPs on the Riemann surface in parameter space. The enhancement factor can reach as high as 300, depending on the crossing point whether in the symmetry or the broken phase of the PT line. Moreover, such enhancement of SHG enables sensitive distance sensing with a nanometer resolution. Our works may pave the way for practical applications in sensing, frequency conversion, and coherent wave control.

TGF-ß1 mediates hypoxia-preconditioned olfactory mucosa mesenchymal stem cells improved neural functional recovery in Parkinson's disease models and patients.

BACKGROUND: Parkinson's disease (PD) is a neurodegenerative disorder characterized by the degeneration of dopaminergic neurons in the substantia nigra (SN). Activation of the neuroinflammatory response has a pivotal role in PD. Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic approach for various nerve injuries, but there are limited reports on their use in PD and the underlying mechanisms remain unclear. METHODS: We investigated the effects of clinical-grade hypoxia-preconditioned olfactory mucosa (hOM)-MSCs on neural functional recovery in both PD models and patients, as well as the preventive effects on mouse models of PD. To assess improvement in neuroinflammatory response and neural functional recovery induced by hOM-MSCs exposure, we employed single-cell RNA sequencing (scRNA-seq), assay for transposase accessible chromatin with high-throughput sequencing (ATAC-seq) combined with full-length transcriptome isoform-sequencing (ISO-seq), and functional assay. Furthermore, we present the findings from an initial cohort of patients enrolled in a phase I first-in-human clinical trial evaluating the safety and efficacy of intraspinal transplantation of hOM-MSC transplantation into severe PD patients. RESULTS: A functional assay identified that transforming growth factor-ß1 (TGF-ß1), secreted from hOM-MSCs, played a critical role in modulating mitochondrial function recovery in dopaminergic neurons. This effect was achieved through improving microglia immune regulation and autophagy homeostasis in the SN, which are closely associated with neuroinflammatory responses. Mechanistically, exposure to hOM-MSCs led to an improvement in neuroinflammation and neural function recovery partially mediated by TGF-ß1 via activation of the anaplastic lymphoma kinase/phosphatidylinositol-3-kinase/protein kinase B (ALK/PI3K/Akt) signaling pathway in microglia located in the SN of PD patients. Furthermore, intraspinal transplantation of hOM-MSCs improved the recovery of neurologic function and regulated the neuroinflammatory response without any adverse reactions observed in patients with PD. CONCLUSIONS: These findings provide compelling evidence for the involvement of TGF-ß1 in mediating the beneficial effects of hOM-MSCs on neural functional recovery in PD. Treatment and prevention of hOM-MSCs could be a promising and effective neuroprotective strategy for PD. Additionally, TGF-ß1 may be used alone or combined with hOM-MSCs therapy for treating PD.

Targeting transposable elements in cancer: developments and opportunities.

Transposable elements (TEs), comprising nearly 50% of the human genome, have transitioned from being perceived as "genomic junk" to key players in cancer progression. Contemporary research links TE regulatory disruptions with cancer development, underscoring their therapeutic potential. Advances in long-read sequencing, computational analytics, single-cell sequencing, proteomics, and CRISPR-Cas9 technologies have enriched our understanding of TEs' clinical implications, notably their impact on genome architecture, gene regulation, and evolutionary processes. In cancer, TEs, including long interspersed element-1 (LINE-1), Alus, and long terminal repeat (LTR) elements, demonstrate altered patterns, influencing both tumorigenic and tumor-suppressive mechanisms. TE-derived nucleic acids and tumor antigens play critical roles in tumor immunity, bridging innate and adaptive responses. Given their central role in oncology, TE-targeted therapies, particularly through reverse transcriptase inhibitors and epigenetic modulators, represent a novel avenue in cancer treatment. Combining these TE-focused strategies with existing chemotherapy or immunotherapy regimens could enhance efficacy and offer a new dimension in cancer treatment. This review delves into recent TE detection advancements, explores their multifaceted roles in tumorigenesis and immune regulation, discusses emerging diagnostic and therapeutic approaches centered on TEs, and anticipates future directions in cancer research.

Temperature-sensitive metal-enhanced fluorescence and plasmon resonance energy transfer.

Experimental decoupling of the effects of plasmon resonance energy transfer (PRET) and metal-enhanced fluorescence (MEF) within the same nanometal-fluorophore pair is fascinating but challenging. In this study, we presented a possible solution for this by coating plasmonic Au nanoparticles (AuNPs) with temperature-sensitive poly(N-isopropylacrylamide) (pNIPAM) shells and R6G hybrids, termed the Au@p-R nanoplatform, which could reversibly adjust the separation between dyes and the AuNP surface, enabling an ON/OFF switch between MEF and PRET. In our optimization process, we discovered that 20 kDa of pNIPAM causes an MEF effect owing to an appropriate shrinking distance of 6.86 ± 0.85 nm. This dual-model nanoplatform exhibits great potential for tracking temperature-dependent transitions.

Assessing the performance of methods for central statistical monitoring of a binary or continuous outcome in multi-center trials: A simulation study.

BACKGROUND: Quality study monitoring is fundamental to patient safety and data integrity. Regulators and industry consortia have increasingly advocated for risk-based monitoring (RBM) and central statistical monitoring (CSM) for more effective and efficient monitoring. Assessing which statistical methods underpin these approaches can best identify unusual data patterns in multi-center clinical trials that may be driven by potential systematic errors is important. METHODS: We assessed various CSM techniques, including cross-tests, fixed-effects, mixed-effects, and finite mixture models, across scenarios with different sample sizes, contamination rates, and overdispersion via simulation. Our evaluation utilized threshold-independent metrics such as the area under the curve (AUC) and average precision (AP), offering a fuller picture of CSM performance. RESULTS: All CSM methods showed consistent characteristics across center sizes or overdispersion. The adaptive finite mixture model outperformed others in AUC and AP, especially at 30% contamination, upholding high specificity unless converging to a single-component model due to low contamination or deviation. The mixed-effects model performed well at lower contamination rates. However, it became conservative in specificity and exhibited declined performance for binary outcomes under high deviation. Cross-tests and fixed-effects methods underperformed, especially when deviation increased. CONCLUSION: Our evaluation explored the merits and drawbacks of multiple CSM methods, and found that relying on sensitivity and specificity alone is likely insufficient to fully measure predictive performance. The finite mixture method demonstrated more consistent performance across scenarios by mitigating the influence of outliers. In practice, considering the study-specific costs of false positives/negatives with available resources for monitoring is important.

Topological valley Hall polariton condensation.

A photonic topological insulator features robust directional propagation and immunity to defect perturbations of the edge/surface state. Exciton-polaritons, that is, the hybrid quasiparticles of excitons and photons in semiconductor microcavities, have been proposed as a tunable nonlinear platform for emulating topological phenomena. However, mainly due to excitonic material limitations, experimental observations so far have not been able to enter the nonlinear condensation regime or only show localized condensation in one dimension. Here we show a topological propagating edge state with polariton condensation at room temperature and without any external magnetic field. We overcome material limitations by using excitonic CsPbCl3 halide perovskites with a valley Hall lattice design. The polariton lattice features a large bandgap of 18.8 meV and exhibits strong nonlinear polariton condensation with clear long-range spatial coherence across the critical pumping density. The geometric parameters and material composition of our nonlinear many-body photonic system platform can in principle be tailored to study topological phenomena of other interquasiparticle interactions.

Lycorine inhibits migration and proliferation of hepatocellular carcinoma cells by reducing transketonase expression.

Background: Previous studies have showed that lycorine can restrain the development of multiple tumor types, containing hepatocellular carcinoma (HCC), but the underlying mechanisms remain unknown. Methods: We assessed the impact of lycorine on hepatocellular cancer cell proliferation, migration, colony formation, cell cycle, and apoptosis. The possible inhibitory effect of lycorine on the activity of HCC cells was analyzed by RNA-seq, and transketolase (TKT) expression in HCC and nontumorous tissues was detected using RT-PCR. The expression of TKT protein in HCC and tumor adjacent non-cancerous tissues was detected by immunohistochemistry. We evaluated the association of expression of TKT in HCC tissues with prognosis, and investigated the inhibitory effect of lycorine on tumor growth in vivo. Results: Lycorine significantly inhibited the proliferation, invasion, migration, colony formation, cell cycle of HCC cells, but had no obvious impact on apoptosis. Twenty-eight genes were found to be down-regulated in HuH7 and HepG2 cells after lycorine treatment, and the difference of TKT gene expression was significantly. The expression of TKT protein was significantly higher in HCC than in non-tumorous tissues. The expression of TKT was correlated with tumor size, Edmondson grade, AFP, and overall survival. Survival analysis suggested that high expression of TKT was associated with a poor survival. The average tumor volume and weight were significantly reduced in the lycorine injection group, but the body weights of the mice did not change significantly. Conclusion: Lycorine can restrict the migration and proliferation of HCC cells by down-regulating TKT expression, and it may be a potential meaningful drug for the prevention and treatment of HCC.

Two undescribed compounds from Aspergillus Niger, an endophytic fungus isolated from Camellia flavida.

A new naphtho-γ-pyrone dimer, asperosperma A, and a new methyl nicotinate derivative, asperosperma B, with 12 known compounds were isolated from the endophytic fungus Aspergillus niger from the stem of Camellia flavida. Their structure was elucidated by NMR, ECD spectrum, and HR-ESI-MS data. Asperosperma A exhibited a highly cytotoxicity against H460 and 4T1 cancer cells with the IC50 values were 0.37 ± 0.06 and 2.04 ± 0.79 µM, respectively. Moreover, it showed a highly sensitive against Staphylococcus aureus, Escherichia coli, Pseudomonas aeruginosa and methicillin-resistant S. aureus.

The altered volume of striatum: A neuroimaging marker of treatment in first-episode and drug-naïve schizophrenia.

Although schizophrenia patients exhibit structural abnormalities in the striatum, it remains largely unknown for the role of the striatum subregions in the treatment response of antipsychotic drugs. The purpose of this study was to investigate the associations between the striatal subregions and improved clinical symptoms in first-episode drug-naïve (FEDN) schizophrenia. Forty-two FEDN schizophrenia patients and 29 healthy controls (HCs) were recruited. At baseline, the Positive and Negative Syndrome Scale (PANSS) was used to assess the clinical symptoms of patients, MRI scanner was used to obtain anatomical images of patients and HCs. After 12-week stable doses of risperidone treatment, clinical symptoms were obtained in 38 patients and anatomical images in 26 patients. After 12 weeks of treatment, the left nucleus accumbens volume decreased, whereas the left pallidum volume increased in schizophrenia patients. The decreased left nucleus accumbens volume was positively correlated with cognitive factor improvement measured by PANSS. Intriguingly, greater left nucleus accumbens volume at baseline predicted greater cognitive improvements. Furthermore, the responders who had >50 % improvement in cognitive symptoms exhibited significantly greater baseline left nucleus accumbens volume compared to non-responders. The left striatum volume at baseline and after treatment predicted the cognitive improvements in FEDN schizophrenia, which could be a potential biomarker for the development of precision medicine approaches targeting cognitive function.

Quantitative systems pharmacology modeling of HER2-positive metastatic breast cancer for translational efficacy evaluation and combination assessment across therapeutic modalities.

HER2-positive (HER2+) metastatic breast cancer (mBC) is highly aggressive and a major threat to human health. Despite the significant improvement in patients' prognosis given the drug development efforts during the past several decades, many clinical questions still remain to be addressed such as efficacy when combining different therapeutic modalities, best treatment sequences, interindividual variability as well as resistance and potential coping strategies. To better answer these questions, we developed a mechanistic quantitative systems pharmacology model of the pathophysiology of HER2+ mBC that was extensively calibrated and validated against multiscale data to quantitatively predict and characterize the signal transduction and preclinical tumor growth kinetics under different therapeutic interventions. Focusing on the second-line treatment for HER2+ mBC, e.g., antibody-drug conjugates (ADC), small molecule inhibitors/TKI and chemotherapy, the model accurately predicted the efficacy of various drug combinations and dosing regimens at the in vitro and in vivo levels. Sensitivity analyses and subsequent heterogeneous phenotype simulations revealed important insights into the design of new drug combinations to effectively overcome various resistance scenarios in HER2+ mBC treatments. In addition, the model predicted a better efficacy of the new TKI plus ADC combination which can potentially reduce drug dosage and toxicity, while it also shed light on the optimal treatment ordering of ADC versus TKI plus capecitabine regimens, and these findings were validated by new in vivo experiments. Our model is the first that mechanistically integrates multiple key drug modalities in HER2+ mBC research and it can serve as a high-throughput computational platform to guide future model-informed drug development and clinical translation.

Efficacy of acellular fish skin graft in the management of chronic ulcer: a systematic review and meta-analysis.

BACKGROUND: The wounds failing to heal through a timely and orderly standard of care (SOC) treatment are considered as chronic wounds, which add significant burden to healthcare systems around the world. SOC treatment has been commonly applied for management of chronic wounds, but SOC alone may not be adequate to heal all ulcers effectively. Fish skin graft (FSG) is a xenogenic skin substitute which could be used for accelerating skin healing. The current study was performed with the view of evaluating the effectiveness of FSG as an adjuvant treatment of SOC for chronic ulcer treatment. METHODS: Two authors independently searched the following electronic databases: PubMed, Embase, and CENTRAL, using keywords including "diabetic foot ulcer," "fish skin graft," and "wound healing." Clinical studies that evaluated the clinical outcomes of FSG in treatment of chronic ulcers were included in this meta-analysis. Random- or fixed-effect modeled meta-analyses were performed according to the heterogeneity test result (i.e., I2), to analyze the clinical outcome of FSG. RESULTS: A total of 8 studies were included in qualitative synthesis and meta-analysis, with 145 patients treated by SOC and 245 patients treated by SOC plus FSG. There was no significant difference between two groups for time to healing (MD = 1.99, 95% CI: -3.70~7.67, p = 0.493). The complete healing rate was significantly higher in FSG group compared with SOC alone (OR = 3.44, 95% CI: 2.03~5.82, p < 0.001***). Mean percentage area reduction (PAR) was reported in six studies, with a range of 71.6~97.3%. However, many of these studies did not report the value of standard deviation (SD), so we could not pool the data. No significantly different ulcer recurrence rate (RR = 0.60, 95% CI: 0.07~5.27, p = 0.645) and severe adverse events (SAEs) risk (RR = 1.67, 95% CI: 0.42~6.61, p = 0.467) were found between two groups. CONCLUSIONS: The application of FSG treatment for patients with chronic ulcers that do not respond well to SOC management could significantly increase the complete healing rate compared with SOC alone, without increased recurrence rate and SAEs risk.