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1.
medRxiv ; 2024 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-38746245

RESUMO

Background: The incidence and mortality rates of hepatocellular carcinoma (HCC) among Hispanics in the United States are much higher than those of non-Hispanic whites. We conducted comprehensive multi-omics analyses to understand molecular alterations in HCC among Hispanic patients. Methods: Paired tumor and adjacent non-tumor samples were collected from 31 Hispanic HCC in South Texas (STX-Hispanic) for genomic, transcriptomic, proteomic, and metabolomic profiling. Additionally, serum lipids were profiled in 40 Hispanic and non-Hispanic patients with or without clinically diagnosed HCC. Results: Exome sequencing revealed high mutation frequencies of AXIN2 and CTNNB1 in STX Hispanic HCCs, suggesting a predominant activation of the Wnt/ß-catenin pathway. The TERT promoter mutation frequency was also remarkably high in the Hispanic cohort. Cell cycles and liver functions were identified as positively- and negatively-enriched, respectively, with gene set enrichment analysis. Gene sets representing specific liver metabolic pathways were associated with dysregulation of corresponding metabolites. Negative enrichment of liver adipogenesis and lipid metabolism corroborated with a significant reduction in most lipids in the serum samples of HCC patients. Two HCC subtypes from our Hispanic cohort were identified and validated with the TCGA liver cancer cohort. The subtype with better overall survival showed higher activity of immune and angiogenesis signatures, and lower activity of liver function-related gene signatures. It also had higher levels of immune checkpoint and immune exhaustion markers. Conclusions: Our study revealed some specific molecular features of Hispanic HCC and potential biomarkers for therapeutic management of HCC and provides a unique resource for studying Hispanic HCC.

2.
Mol Psychiatry ; 2024 May 08.
Artigo em Inglês | MEDLINE | ID: mdl-38719894

RESUMO

Post-traumatic stress disorder (PTSD) is a hypermnesic condition that develops in a subset of individuals following exposure to severe trauma. PTSD symptoms are debilitating, and include increased anxiety, abnormal threat generalization, and impaired extinction. In developing treatment strategies for PTSD, preclinical studies in rodents have largely focused on interventions that target post-encoding memory processes such as reconsolidation and extinction. Instead, here we focus on forgetting, another post-encoding process that regulates memory expression. Using a double trauma murine model for PTSD, we asked whether promoting neurogenesis-mediated forgetting can weaken trauma memories and associated PTSD-relevant behavioral phenotypes. In the double trauma paradigm, consecutive aversive experiences lead to a constellation of behavioral phenotypes associated with PTSD including increases in anxiety-like behavior, abnormal threat generalization, and deficient extinction. We found that post-training interventions that elevate hippocampal neurogenesis weakened the original trauma memory and decreased these PTSD-relevant phenotypes. These effects were observed using multiple methods to manipulate hippocampal neurogenesis, including interventions restricted to neural progenitor cells that selectively promoted integration of adult-generated granule cells into hippocampal circuits. The same interventions also weakened cocaine place preference memories, suggesting that promoting hippocampal neurogenesis may represent a broadly useful approach in hypermnesic conditions such as PTSD and substance abuse disorders.

3.
Adv Sci (Weinh) ; : e2306217, 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38742466

RESUMO

Radiation proctopathy (RP) is a common complication of radiotherapy for pelvic malignancies with high incidence. RP accompanies by microbial dysbiosis. However, how the gut microbiota affects the disease remains unclear. Here, metabolomics reveals that the fecal and serous concentrations of microbiota-derived 3-hydroxybutyrate (3HB) are significantly reduced in RP mice and radiotherapeutic patients. Moreover, the concentration of 3HB is negatively associated with the expression of proinflammatory IL6 that is increased along with the severity of radiation damage. 3HB treatment significantly downregulates IL6 expression and alleviates IL6-mediated radiation damage. Irradiated cell-fecal microbiota co-culture experiments and in vivo assays show that such a radioprotection of 3HB is mediated by GPR43. Microbiome analysis reveals that radiation leads to a distinct bacterial community compared to untreated controls, in which Akkermansia muciniphila is significantly reduced in RP mice and radiotherapeutic patients and is associated with lower 3HB concentration. Gavage of A. muciniphila significantly increases 3HB concentration, downregulates GPR43 and IL6 expression, and ameliorates radiation damage. Collectively, these results demonstrate that the gut microbiota, including A. muciniphila, induce higher concentrations of 3HB to block GPR43-mediated IL6 signaling, thereby conferring radioprotection. The findings reveal a novel implication of the gut-immune axis in radiation pathophysiology, with potential therapeutic applications.

4.
Bioorg Chem ; 148: 107469, 2024 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-38781669

RESUMO

PARP7 has been proven to play an important role in immunity. Substantial upregulation of PARP7 is observed in numerous cancerous cell types, consequently resulting in the inhibition of type Ⅰ interferon signaling pathways. Therefore, inhibiting the activity of PARP7 can enhance type Ⅰ interferon signaling to exert an anti-tumor immune response. In this study, we reported the identification of a newly found PARP7 inhibitor (XLY-1) with higher inhibitory activity (IC50 = 0.6 nM) than that of RBN-2397 (IC50 = 6.0 nM). Additionally, XYL-1 displayed weak inhibitory activity on PARP1 (IC50 > 1.0 µM). Mechanism studies showed that XYL-1 could enhance the type Ⅰ interferon signaling in vitro. Pharmacodynamic experiments showed that 50 mg/kg XYL-1 could significantly inhibit tumor growth (TGI: 76.5 %) and related experiments showed that XYL-1 could restore type Ⅰ interferon signaling and promote T cell infiltration in tumor tissues. Taken together, XYL-1 shows promise as a potential candidate for developing cancer immunotherapy agents.

5.
Eur J Med Chem ; 272: 116489, 2024 May 16.
Artigo em Inglês | MEDLINE | ID: mdl-38759458

RESUMO

Although three generations of Epidermal growth factor receptor (EGFR) - TK inhibitors have been approved for the treatment of Non-small-cell lung cancers (NSCLC), their clinical application is still largely hindered by acquired drug resistance mediated new EGFR mutations and side effects. The Proteolysis targeting chimera (PROTAC) technology has the potential to overcome acquired resistance from mutant EGFR through a novel mechanism of action. In this study, we developed the candidate degrader IV-3 by structural modifications of the lead compound 13, which exhibited limited antiproliferative activity against HCC-827 cells. Compared to compound 13, IV-3 exhibited remarkable anti-proliferative activity against HCC-827 cells, NCI-H1975 cells, and NCI-H1975-TM cells (IC50 = 0.009 µM, 0.49 µM and 3.24 µM, respectively), as well as significantly inducing degradation of EGFR protein in these cell lines (DC50 = 17.93 nM, 0.25 µM and 0.63 µM, respectively). Further investigations confirmed that IV-3 exhibited superior anti-tumor activity in all xenograft tumor models through the degradation of mutant EGFR protein. Moreover, IV-3 showed no inhibitory activity against A431 and A549 cells expressing wild-type EGFR, thereby eliminating potential toxic side effects emerging from wild-type EGFR inhibition. Overall, our study provides promising insights into EGFR-PROTACs as a potential therapeutic strategy against EGFR-acquired mutation.

6.
Proc Natl Acad Sci U S A ; 121(20): e2306776121, 2024 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-38709933

RESUMO

A high-fat diet (HFD) is a high-risk factor for the malignant progression of cancers through the disruption of the intestinal microbiota. However, the role of the HFD-related gut microbiota in cancer development remains unclear. This study found that obesity and obesity-related gut microbiota were associated with poor prognosis and advanced clinicopathological status in female patients with breast cancer. To investigate the impact of HFD-associated gut microbiota on cancer progression, we established various models, including HFD feeding, fecal microbiota transplantation, antibiotic feeding, and bacterial gavage, in tumor-bearing mice. HFD-related microbiota promotes cancer progression by generating polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs). Mechanistically, the HFD microbiota released abundant leucine, which activated the mTORC1 signaling pathway in myeloid progenitors for PMN-MDSC differentiation. Clinically, the elevated leucine level in the peripheral blood induced by the HFD microbiota was correlated with abundant tumoral PMN-MDSC infiltration and poor clinical outcomes in female patients with breast cancer. These findings revealed that the "gut-bone marrow-tumor" axis is involved in HFD-mediated cancer progression and opens a broad avenue for anticancer therapeutic strategies by targeting the aberrant metabolism of the gut microbiota.


Assuntos
Neoplasias da Mama , Diferenciação Celular , Dieta Hiperlipídica , Progressão da Doença , Microbioma Gastrointestinal , Leucina , Células Supressoras Mieloides , Animais , Dieta Hiperlipídica/efeitos adversos , Leucina/metabolismo , Feminino , Humanos , Camundongos , Células Supressoras Mieloides/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/microbiologia , Neoplasias da Mama/metabolismo , Obesidade/microbiologia , Obesidade/metabolismo , Obesidade/patologia , Linhagem Celular Tumoral
7.
Discov Oncol ; 15(1): 153, 2024 May 10.
Artigo em Inglês | MEDLINE | ID: mdl-38730061

RESUMO

Parthanatos, a cell death mechanism triggered by PARP-1 activation, is implicated in oncogenic processes, yet their role in low-grade gliomas (LGG) remains poorly understood. This research investigates Parthanatos-related miRNAs' prognostic and immunomodulatory potential, alongside their influence on therapeutic outcomes in LGGs. Comprehensive miRNA and mRNA profiles of LGG patients were extracted from TCGA and CGGA databases, integrating clinical parameters to identify Parthanatos-associated miRNAs. IHC data validated the expression levels of Parthanatos-related genes in glioma versus normal brain tissues. Protein-protein interaction networks and Spearman correlation analysis facilitated the identification of key miRNAs. Parthanatos-related miRNA indices (PMI) were screened using Lasso and assessed for their accuracy in predicting prognosis, comparing their associated potential molecular functions and heterogeneity of the immune microenvironment. Drug sensitivity was assessed between different groups and optimal therapeutic agents were predicted. Validate the expression levels of key miRNAs by qPCR. Ninety-one miRNAs significantly associated with Parthanatos were screened, through which a PMI prognosis model of nine miRNAs was constructed. The PMI score was able to independently predict the prognosis of patients with LGG, and the nomogram constructed based on the PMI provided a practical tool for clinical prediction of patient prognosis. The proportion of immune response was lower in patients in the high-risk group, and there were significant differences in drug sensitivity between different risk classes, while drugs such as Fasudil were identified as the most promising therapeutic agents for patients in the high-risk group. Our findings highlight the critical role of Parthanatos-associated miRNAs in the progression and treatment of LGG, offering novel insights into their prognostic value and therapeutic potential.

8.
Pain Manag Nurs ; 2024 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-38609805

RESUMO

OBJECTIVE: To assess the effect of a teach-back educational intervention using Behavior Change Wheel (BCW) framework on perioperative pain among patients with lung cancer. METHODS: A prospective quasi-experimental study was conducted in 88 patients with lung cancer from a tertiary hospital in China. According to the order of admission, they were allocated to either control group or intervention group, with 44 patients in each group. Patients in the control group received routine nursing care, while patients in the intervention group were given a teach-back education program based on BCW framework. The visual analog scale (VAS) was adopted to evaluate patients' pain on the day of surgery (T0), 1 (T1), 2 (T2), and 3 (T3) days after surgery. We also recorded the use of patient-controlled analgesia (PCA), the length of hospital stay, and the degree of patients' satisfaction. RESULTS: Rest pain, pain when coughing, and pain during activity that patients in the intervention group experienced were significantly less severe than those in the control group on T0 and T1. The pain when coughing in the intervention group was also significantly milder on T2 and T3. In addition, the number of self-control time, use duration, and total dose of PCA were significantly lower in the intervention group. Moreover, patients' satisfaction of nursing service was significantly higher in the intervention group. CONCLUSION: A teach-back education program based on BCW framework was effective in pain management among the perioperative patients with lung cancer. This study demonstrates the application of teach-back method and the BCW in the development of patient education intervention to mitigate perioperative pain.

9.
bioRxiv ; 2024 Apr 15.
Artigo em Inglês | MEDLINE | ID: mdl-38659885

RESUMO

Homeostatic plasticity maintains the stability of functional brain networks. The axon initial segment (AIS), where action potentials start, undergoes dynamic adjustment to exert powerful control over neuronal firing properties in response to network activity changes. However, it is poorly understood whether this plasticity involves direct synaptic input to the AIS. Here we show that changes of GABAergic synaptic input from chandelier cells (ChCs) drive homeostatic tuning of the AIS of principal neurons (PNs) in the prelimbic (PL) region, while those from parvalbumin-positive basket cells do not. This tuning is evident in AIS morphology, voltage-gated sodium channel expression, and PN excitability. Moreover, the impact of this homeostatic plasticity can be reflected in animal behavior. Social behavior, inversely linked to PL PN activity, shows time-dependent alterations tightly coupled to changes in AIS plasticity and PN excitability. Thus, AIS-originated homeostatic plasticity in PNs may counteract deficits elicited by imbalanced ChC presynaptic input at cellular and behavioral levels. Teaser: Axon initial segment dynamically responds to changes in local input from chandelier cells to prevent abnormal neuronal functions.

10.
Org Lett ; 26(17): 3597-3601, 2024 May 03.
Artigo em Inglês | MEDLINE | ID: mdl-38661293

RESUMO

Guided by the retrobiosynthesis hypothesis, we characterized a fungal polyketide synthase-nonribosomal peptide synthetase (PKS-NRPS) hybrid megasynthetase pathway to generate 2-trans-4-trans-2-methylsorbyl-d-leucine (1), a polyketide amino acid conjugate that inhibits Arabidopsis root growth. The biosynthesis of 1 includes a PKS-NRPS enzyme to assemble an N-acyl amino alcohol intermediate, which is further oxidized to an N-acyl amino acid (NAAA), demonstrating a new biosynthetic logic for synthesizing NAAAs and expanding the chemical space of products encoded by fungal PKS-NRPS clusters.


Assuntos
Peptídeo Sintases , Policetídeo Sintases , Peptídeo Sintases/metabolismo , Peptídeo Sintases/genética , Policetídeo Sintases/metabolismo , Estrutura Molecular , Aminoácidos/química , Aminoácidos/metabolismo , Arabidopsis , Raízes de Plantas , Leucina/química , Leucina/metabolismo
11.
Angew Chem Int Ed Engl ; 63(22): e202404000, 2024 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-38527935

RESUMO

Cytochrome P450 (CYP450)-catalyzed oxidative coupling is an efficient strategy for using simple building blocks to construct complex structural scaffolds of natural products. Among them, heterodimeric coupling between two different monomers is relatively scarce, and the corresponding CYP450s are largely undiscovered. In this study, we discovered a fungal CYP450 (CpsD) and its associated cps cluster from 37208 CYP450s of Pfam PF00067 family member database and subsequently identified a group of new skeleton indole piperazine alkaloids (campesines A-G) by combination of genome mining and heterologous synthesis. Importantly, CYP450 CpsD mainly catalyzes intermolecular oxidative heterocoupling of two different indole piperazine monomers to generate an unexpected 6/5/6/6/6/6/5/6 eight-ring scaffold through the formation of one C-C bond and two C-N bonds, illuminating its first dimerase role in this family of natural products. The proposed catalytic mechanism of CpsD was deeply investigated by diversified substrate derivatization. Moreover, dimeric campesine G shows good insecticidal activity against the global honeybee pest Galleria mellonella. Our study shows a representative example of discovering new skeleton monomeric and dimeric indole piperazine alkaloids from microbial resources, expands our knowledge of bond formation by CYP450s and supports further development of the newly discovered and engineered campesine family compounds as potential biopesticides.


Assuntos
Sistema Enzimático do Citocromo P-450 , Inseticidas , Oxirredução , Piperazinas , Sistema Enzimático do Citocromo P-450/metabolismo , Sistema Enzimático do Citocromo P-450/química , Piperazinas/química , Piperazinas/metabolismo , Piperazinas/farmacologia , Inseticidas/química , Inseticidas/metabolismo , Inseticidas/farmacologia , Animais , Alcaloides Indólicos/química , Alcaloides Indólicos/metabolismo , Biocatálise , Alcaloides/química , Alcaloides/metabolismo , Alcaloides/farmacologia , Estrutura Molecular , Dimerização
12.
Nano Lett ; 24(13): 3906-3913, 2024 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-38506264

RESUMO

The intriguing and anomalous optical characteristics of exceptional points (EPs) in optical resonators have attracted significant attention. While EP-related phenomena have been observed by perturbing resonators with off-chip components, implementing EPs fully on-chip remains challenging due to their extreme susceptibility to fabrication errors. In this Letter, we propose a succinct and compact approach to reach EP in an on-chip integrated silicon microring resonator by manipulating the evolution of backscatterings with two nanocylinders of disparate diameters. The theoretical analysis unveils that the fabrication constraints could be significantly relieved by increasing the difference in diameters of the nanocylinders. The evolution from non-EP to EP is traced experimentally through the step-by-step tuning of the angular and radial positions of nanocylinders. The proposed method opens a pathway toward the on-chip high-density integration of non-Hermitian devices.

13.
Int Immunopharmacol ; 131: 111888, 2024 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-38522139

RESUMO

OBJECTIVES: Osteoarthritis (OA) is a whole-joint disease in which the role of the infrapatellar fat pad (IFP) in its pathogenesis is unclear. Our study explored the cellular heterogeneity of IFP to understand OA and identify therapeutic targets. METHODS: Single-cell and single-nuclei RNA sequencing were used to analyze 10 IFP samples, comprising 5 from OA patients and 5 from healthy controls. Analyses included differential gene expression, enrichment, pseudotime trajectory, and cellular communication, along with comparative studies with visceral and subcutaneous fats. Key subcluster and pathways were validated using multiplex immunohistochemistry. RESULTS: The scRNA-seq performed on the IFPs of the OA and control group profiled the gene expressions of over 49,674 cells belonging to 11 major cell types. We discovered that adipose stem and progenitor cells (ASPCs), contributing to the formation of both adipocytes and synovial-lining fibroblasts (SLF). Interstitial inflammatory fibroblasts (iiFBs) were a subcluster of ASPCs that exhibit notable pro-inflammatory and proliferative characteristics. We identified four adipocyte subtypes, with one subtype showing a reduced lipid synthesis ability. Furthermore, iiFBs modulated the activities of macrophages and T cells in the IFP. Compared to subcutaneous and visceral adipose tissues, iiFBs represented a distinctive subpopulation of ASPCs in IFP that regulated cartilage proliferation through the MK pathway. CONCLUSION: This study presents a comprehensive single-cell transcriptomic atlas of IFP, uncovering its complex cellular landscape and potential impact on OA progression. Our findings highlight the role of iiFBs in OA, especially through MK pathway, opening new avenues for understanding OA pathogenesis and developing novel targeted therapies.


Assuntos
Osteoartrite do Joelho , Humanos , Osteoartrite do Joelho/patologia , Tecido Adiposo/patologia , Articulação do Joelho/patologia , Perfilação da Expressão Gênica , Fibroblastos/metabolismo
14.
J Med Chem ; 67(6): 4916-4935, 2024 Mar 28.
Artigo em Inglês | MEDLINE | ID: mdl-38477575

RESUMO

The emergence of resistance to PARP1 inhibitors poses a current therapeutic challenge, necessitating the development of novel strategies to overcome this obstacle. The present study describes the design and synthesis of a series of small molecules that target both PARP1 and c-Met. Among them, compound 16 is identified as a highly potent dual inhibitor, exhibiting excellent inhibitory activities against PARP1 (IC50 = 3.3 nM) and c-Met (IC50 = 32.2 nM), as well as demonstrating good antiproliferative effects on HR-proficient cancer cell lines and those resistant to PARP1 inhibitors. Importantly, compound 16 demonstrates superior antitumor potency compared to the PARP1 inhibitor Olaparib and the c-Met inhibitor Crizotinib, either alone or in combination, in MDA-MB-231 and HCT116OR xenograft models. These findings highlight the potential of PARP1/c-Met dual inhibitors for expanding the indications of PARP1 inhibitors and overcoming tumor cells' resistance to them.


Assuntos
Antineoplásicos , Inibidores de Poli(ADP-Ribose) Polimerases , Humanos , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Linhagem Celular Tumoral , Poli(ADP-Ribose) Polimerase-1 , Crizotinibe/farmacologia , Inibidores de Proteínas Quinases/farmacologia , Proliferação de Células , Antineoplásicos/farmacologia
15.
Molecules ; 29(5)2024 Feb 28.
Artigo em Inglês | MEDLINE | ID: mdl-38474565

RESUMO

Based on density functional theory (DFT) and wave function analysis, the ultraviolet and visible spectrophotometry (UV-Vis) spectra and Raman spectra of 1-meso and 1-rac obtained by the chiral separation of chiral nanographenes are theoretically investigated. The electron excitation properties of 1-meso and 1-rac are studied by means of transition density matrix (TDM) and charge density difference (CDD) diagrams. The intermolecular interaction is discussed based on an independent gradient model based on Hirshfeld partition (IGMH). The interaction of 1-meso and 1-rac with the external environment is studied using the electrostatic potential (ESP), and the electron delocalization degree of 1-meso and 1-rac is studied based on the magnetically induced current under the external magnetic field. Through the chiral separation of 1-rac, two enantiomers, 1-(P, P) and 1-(M, M), were obtained. The electrical-magnetic interaction of the molecule is revealed by analyzing the electron circular dichroism (ECD) spectra of 1-meso, 1-(P, P) and 1-(M, M), the transition electric dipole moment (TEDM) and the transition magnetic dipole moment (TMDM). It is found that 1-(P, P) and 1-(M, M) have opposite chiral properties due to the inversion of the structure.

16.
Materials (Basel) ; 17(6)2024 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-38541439

RESUMO

As the lightest structural metal material, magnesium alloys possess good casting properties, high electrical and thermal conductivity, high electromagnetic shielding, and excellent damping properties. With the increasing demand for lightweight, high-strength, and high-damping structural materials in aviation, automobiles, rail transit, and other industries with serious vibration and noise, damping magnesium alloy materials are becoming one of the important development directions of magnesium alloys. A comprehensive review of the progress in this field is conducive to the development of damping magnesium alloys. This review not only looks back on the traditional damping magnesium alloys represented by Mg-Zr alloys, Mg-Cu-Mn alloys, etc. but also introduces the new damping magnesium materials, such as magnesium matrix composites and porous magnesium. But up to now, there have still been some problems in the research of damping magnesium materials. The effect of spiral dislocation on damping is still unknown and needs to be studied; the contradiction between damping performance and mechanical properties still lacks a good balance method. In the future, the introduction of more diversified damping regulating methods, such as adding other elements and reinforcements, optimizing the manufacturing method of damping magnesium alloy, etc., to solve these issues, will be the development trend of damping magnesium materials.

17.
iScience ; 27(4): 109399, 2024 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-38523794

RESUMO

The question of whether serofast status of syphilis patients indicates an ongoing low-grade Treponema pallidum (T. pallidum) infection remains unanswered. To address this, we developed a machine learning model to identify T. pallidum in cell-free DNA (cfDNA) using next-generation sequencing (NGS). Our findings showed that a TP_rate cut-off of 0.033 demonstrated superior diagnostic performance for syphilis, with a specificity of 92.3% and a sensitivity of 71.4% (AUROC = 0.92). This diagnosis model predicted that 20 out of 92 serofast patients had a persistent low-level infection. Based on these predictions, re-treatment was administered to these patients and its efficacy was evaluated. The results showed a statistically significant decrease in RPR titers in the prediction-positive group compared to the prediction-negative group after re-treatment (p < 0.05). These findings provide evidence for the existence of T. pallidum under serofast status and support the use of intensive treatment for serofast patients at higher risk in clinical practice.

18.
JACC Basic Transl Sci ; 9(2): 244-256, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38510719

RESUMO

This study assesses the feasibility, safety, and effectiveness of noninvasive stereotactic body radiotherapy (SBRT) as an approach for pulmonary artery denervation in canine models. SBRT with CyberKnife resulted in reduced mean pulmonary artery pressure, pulmonary capillary wedge pressure, and pulmonary vascular resistance, and insignificantly increased cardiac output. In comparison to the control group, serum norepinephrine levels at 1 month and 6 months were significantly lower in the CyberKnife group. Computed tomography, pulmonary angiography, and histology analysis revealed that SBRT was associated with minimal collateral damage.

19.
Comput Methods Programs Biomed ; 248: 108137, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38520784

RESUMO

BACKGROUND AND OBJECTIVE: Clinical pharmacological modeling and statistical analysis software is an essential basic tool for drug development and personalized drug therapy. The learning curve of current basic tools is steep and unfriendly to beginners. The curve is even more challenging in cases of significant individual differences or measurement errors in data, resulting in difficulties in accurately estimating pharmacokinetic parameters by existing fitting algorithms. Hence, this study aims to explore a new optimized parameter fitting algorithm that reduces the sensitivity of the model to initial values and integrate it into the CPhaMAS platform, a user-friendly online application for pharmacokinetic data analysis. METHODS: In this study, we proposed an optimized Nelder-Mead method that reinitializes simplex vertices when trapped in local solutions and integrated it into the CPhaMAS platform. The CPhaMAS, an online platform for pharmacokinetic data analysis, includes three modules: compartment model analysis, non-compartment analysis (NCA) and bioequivalence/bioavailability (BE/BA) analysis. Our proposed CPhaMAS platform was evaluated and compared with existing WinNonlin. RESULTS: The platform was easy to learn and did not require code programming. The accuracy investigation found that the optimized Nelder-Mead method of the CPhaMAS platform showed better accuracy (smaller mean relative error and higher R2) in two-compartment and extravascular administration models when the initial value was set to true and abnormal values (10 times larger or smaller than the true value) compared with the WinNonlin. The mean relative error of the NCA calculation parameters of CPhaMAS and WinNonlin was <0.0001 %. When calculating BE for conventional, high-variability and narrow-therapeutic drugs. The main statistical parameters of the parameters Cmax, AUCt, and AUCinf in CPhaMAS have a mean relative error of <0.01% compared to WinNonLin. CONCLUSIONS: In summary, CPhaMAS is a user-friendly platform with relatively accurate algorithms. It is a powerful tool for analysing pharmacokinetic data for new drug development and precision medicine.


Assuntos
Algoritmos , Software , Modelos Teóricos , Preparações Farmacêuticas , Projetos de Pesquisa
20.
Heliyon ; 10(5): e26170, 2024 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-38439874

RESUMO

Objective: To analyse and summarise the regularity of acupoint selection in the treatment of opioid-induced constipation (OIC) in patients with cancer pain using a data mining technique and provide a reference for clinical practice and more valuable treatment options. Methods: The acupoint prescription database for the treatment of OIC-related cancer pain was established by searching the relevant literature on randomised controlled trials involving acupoint therapy for OIC-related cancer pain in seven major databases, including the China National Knowledge Infrastructure, Wanfang and VIP Chinese scientific journal databases, from database establishment to December 31, 2022. The main therapeutic measures of acupoint prescription, frequency of acupoint use and its subordinate meridians and subordinate sites were then analysed. Through systematic clustering and association rule analysis, the core acupoint prescriptions and most commonly used acupoint compatibility of acupoint therapy for OIC-related cancer pain were obtained. Results: A total of 649 articles were retrieved, with 72 articles included after screening. The treatment measures were found to be mainly acupoint applications involving 28 acupoints, with a total frequency of 234. The three most frequently used acupoints were Shenque, Tianshu and Zusanli. The number of points used in the Foot-Yangming stomach meridian was the highest. Commonly used acupoints were mainly distributed in the abdomen. The compatibility of two commonly used acupoints was obtained through systematic clustering. Through association rule analysis, it was found that in the compatibility of acupoints, the strongest correlation was between Tianshu and Zusanli, and their frequency of application was the highest. Conclusion: Tianshu and Zusanli are the core acupoints for acupoint therapy in the treatment of OIC-related cancer pain, and the Shangjuxu-Zhigou-Zusanli, Qihai-Guanyuan and Zhongwan-Tianshu acupoints exhibit the highest compatibility. This study provides a reference for the clinical acupoint selection programme of acupuncture and moxibustion in the treatment of OIC-related cancer pain.

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