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1.
Front Pharmacol ; 15: 1463465, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-39421671

RESUMEN

Introduction: Myocardial infarction (MI), a leading cause of heart failure, is characterized by the loss of cardiomyocytes, which severely limits the heart's regenerative capacity. The Hippo pathway, which regulates cell proliferation and apoptosis, presents a therapeutic target for cardiac regeneration. This study explores the efficacy of Lats-IN-1, a LATS1/2 kinase inhibitor targeting the Hippo pathway, as a novel treatment for MI. Methods: Using male C57BL/6 mice subjected to surgically induced MI, we administered Lats-IN-1 and evaluated the effects on cardiac function, infarct size, cardiomyocyte proliferation, and apoptosis through various assays and echocardiographic assessments. Results: Our results demonstrate that Lats-IN-1 significantly improves cardiac function, as evidenced by enhanced ejection fraction and reduced ventricular dimensions. Additionally, Lats-IN-1 decreased infarct size and apoptosis rates while promoting cardiomyocyte proliferation. These findings suggest that Lats-IN-1 promotes cardiac repair and regeneration. Discussion: By modulating the Hippo pathway and reducing apoptosis markers, Lats-IN-1 represents a promising therapeutic strategy for improving outcomes in heart diseases characterized by cardiomyocyte loss. This study highlights the critical role of the Hippo pathway in facilitating cardiac regeneration.

2.
J Thorac Dis ; 16(9): 6064-6080, 2024 Sep 30.
Artículo en Inglés | MEDLINE | ID: mdl-39444865

RESUMEN

Background: The relationship between quality of life and survival outcomes in esophageal cancer patients following curative resection is not well established. This study aimed to longitudinally assess quality of life indicators and their association with overall survival (OS) in these patients. Methods: A total of 232 patients were included in the study, and their quality of life was prospectively assessed at different time points using the European Organisation for Research and Treatment of Cancer (EORTC) 30-item core quality of life questionnaire (QLQ-C30) and the disease-specific esophageal module (QLQ-OES18). The scores of QLQ indicators at each time point were summarized, and changes in postoperative assessment were compared with preoperative assessments. The association of deterioration in certain indicators with OS was evaluated at each time point using Cox univariable analysis. Further confirmation of independent variables was carried out using Cox multivariable analysis. Results: The study cohort comprised 62 females (26.7%), and 113 patients (48.7%) aged over 60 years. The median follow-up time was 80 months (range, 8-118 months). At 24 months after discharge, patients reported improvements in role function, fatigue, cognition function, emotional function, social function, insomnia, appetite loss, nausea and vomiting, constipation, financial status, trouble swallowing saliva, and pain related to esophageal cancer. However, physical function, dyspnea, diarrhea, global health status, choking when swallowing, trouble talking, and reflux remained compromised. Multivariable regression analysis revealed deterioration in role function, emotional function, and coughing difficulty at 6 months, and dyspnea, pain, and cognitive function at 24 months post-discharge were identified as independent prognostic factors for OS. Conclusions: Our findings underscore the importance of monitoring quality of life indicators in esophageal cancer patients as they may significantly influence survival outcomes. The identification of specific quality of life indicators as prognostic factors highlights the need for a patient-centered approach in clinical practice to enhance care and potentially improve survival.

3.
J Biomater Appl ; : 8853282241287916, 2024 Sep 26.
Artículo en Inglés | MEDLINE | ID: mdl-39325858

RESUMEN

The 3D printing of porous titanium scaffolds reduces the elastic modulus of titanium alloys and promotes osteogenic integration. However, due to the biological inertness of titanium alloy materials, the implant-bone tissue interface is weakly bonded. A calcium silicate (CS) coating doped with polymetallic ions can impart various biological properties to titanium alloy materials. In this study, CuO and SrO binary-doped CS coatings were prepared on the surface of 3D-printed porous titanium alloy scaffolds using atmospheric plasma spraying and characterized by SEM, EDS, and XRD. Both CuO and SrO were successfully incorporated into the CS coating. The in vivo osseointegration evaluation of the composite coating-modified 3D-printed porous titanium alloy scaffolds was conducted using a rabbit bone defect model, showing that the in vivo osseointegration of 2% CuO-10% SrO-CS-modified 3D-printed porous titanium alloy was improved. The in vitro antimicrobial properties of the 2% CuO-10% SrO-CS-modified 3D-printed porous titanium alloy were evaluated through bacterial platform coating, co-culture liquid absorbance detection, and crystal violet staining experiments, demonstrating that the composite coating exhibited good antimicrobial properties. In conclusion, the composite scaffold possesses both osteointegration-promoting and antimicrobial properties, indicating a broad potential for clinical applications.

4.
NPJ Regen Med ; 9(1): 22, 2024 Sep 17.
Artículo en Inglés | MEDLINE | ID: mdl-39289387

RESUMEN

Local injection of anti-inflammatory drugs for osteoarthritis emerged as a promising administration in the clinic, and sustained-release dosage forms have great potential for future therapeutic applications. Controlling the response of patients only in the acute inflammatory phase is currently the focus of therapeutic interventions. To relieve acute pain in patients and to improve the long-term prognosis effect of osteoarthritis treatment, we designed a two-pronged approach in this research: an injectable double-layer microsphere containing a "nonsteroidal anti-inflammatory drug - macrophage polarizing factor" was constructed. The results indicated that microspheres could regulate the intra-articular environment by inhibiting local inflammatory cytokine production, promoting macrophage polarization to the M2-phenotype, and increasing the expression of cartilage repair factors. Polymers chosen could govern the biocompatibility of microspheres and control the release sequence of the two drugs. Injection of microspheres into the degenerative articular cavity of rats leads to suppressed inflammation and well-promoted cartilage regeneration.

5.
BMC Pharmacol Toxicol ; 25(1): 62, 2024 Sep 06.
Artículo en Inglés | MEDLINE | ID: mdl-39243062

RESUMEN

Higher olefins (HO) are a category of unsaturated hydrocarbons widely used in industry applications to make products essential for daily human life. Establishing safe exposure limits requires a solid data matrix that facilitates understanding of their toxicological profile. This in turn allows for data to be read across to other members of the category, which are structurally similar and have predictable physico-chemical properties. Five independent subchronic oral toxicity studies were conducted in Wistar rats with Oct-1-ene, Nonene, branched, Octadec-1-ene, Octadecene and hydrocarbon C12-30, olefin-rich, ethylene polymn. by product, at doses ranging from 20 to 1000 mg/kg bw. These HO were selected considering gut absorption, carbon chain length, double-bond position and carbon backbone structural variations. Generally, limited and non-adverse toxicity effects were observed at the end of the treatment for short carbon chain HO. For instance, alpha 2u-globulin nephropathy in the male rats and liver hypertrophy. No clear trend in systemic toxicity was linked to the double-bond position. Key factors for hazard assessment include absorption, carbon chain length, and branching, with Nonene, branched, identified as the worst-case substance. Taken together, the no observed adverse effect level (NOAEL) of each HO in these subchronic studies was set at the highest dose tested.


Asunto(s)
Alquenos , Ratas Wistar , Pruebas de Toxicidad Subcrónica , Animales , Masculino , Alquenos/toxicidad , Femenino , Ratas , Nivel sin Efectos Adversos Observados
6.
Chem Sci ; 2024 Sep 04.
Artículo en Inglés | MEDLINE | ID: mdl-39268204

RESUMEN

The transition metal-catalyzed meta-C-H functionalization of alcohols and their hydroxylamine derivatives remains underdeveloped. Herein, we report an efficient meta-C-H arylation of both phenylethyl and benzylic alcohols and their hydroxylamine derivatives using a readily removable oxime ether directing group. Using electronically activated 2-carbomethoxynorbornene as the transient mediator and 3-trifluoromethyl-2-pyridone as the enabling ligand, this reaction features a broad substrate scope and good functional group tolerance. More importantly, with this oxime-directed meta-C-H functionalization, this method provides a dual approach for efficient access to both meta-substituted alcohols and hydroxylamines using two sets of simple deprotection conditions. This protocol leads to the efficient synthesis of bioactive compounds possessing promising reactivities for the treatment of pulmonary fibrosis.

7.
Sci Rep ; 14(1): 19685, 2024 08 24.
Artículo en Inglés | MEDLINE | ID: mdl-39181964

RESUMEN

Prostate cancer (PRAD) is one of the leading malignancies in men all around the world. Here, we identified Myosin Heavy Chain 6 (MYH6) as a potential tumor suppressor gene in the development of prostate cancer. We found lower expression of MYH6 in prostate cancer tissues, and its lower gene expression was also associated with worse clinical outcomes. In vitro and in vivo assays indicated that overexpressed MYH6 could suppress the proliferation and migration progression of prostate cancer cells. RNA-seq was employed to investigate the mechanism, and KIT Proto-Oncogen (KIT) was determined as the downstream gene of MYH6, which was further confirmed using rescue assays. In all, we provide the evidence that MYH6 could serve as a tumor suppressor in prostate cancer. Our results highlight the potential role of MYH6 in the development of prostate cancer.


Asunto(s)
Movimiento Celular , Proliferación Celular , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Cadenas Pesadas de Miosina , Neoplasias de la Próstata , Proteínas Proto-Oncogénicas c-kit , Masculino , Humanos , Cadenas Pesadas de Miosina/genética , Cadenas Pesadas de Miosina/metabolismo , Neoplasias de la Próstata/genética , Neoplasias de la Próstata/patología , Neoplasias de la Próstata/metabolismo , Proliferación Celular/genética , Línea Celular Tumoral , Proteínas Proto-Oncogénicas c-kit/genética , Proteínas Proto-Oncogénicas c-kit/metabolismo , Movimiento Celular/genética , Animales , Regulación hacia Abajo , Ratones , Miosinas Cardíacas
8.
Parasit Vectors ; 17(1): 298, 2024 Jul 09.
Artículo en Inglés | MEDLINE | ID: mdl-38982497

RESUMEN

BACKGROUND: Angiostrongyliasis is a zoonotic parasitic disease caused by the rat lungworm Angiostrongylus cantonensis. The intermediate hosts of A. cantonensis are gastropods, and snail species such as Pomacea canaliculata play a key role in the transmission of human angiostrongyliasis. Detecting A. cantonensis infection in snails is an important component of epidemiological surveillance and the control of angiostrongyliasis. METHODS: In this study, a new method for diagnosing A. cantonensis infection in gastropods was developed by recovering larvae from the buccal cavity of three snail species. The entire buccal cavity of a snail was extracted, and the tissue was pressed between two microscope slides to observe whether A. cantonensis larvae were present. Our new method was compared with traditional pathogenic detection methods of lung microscopy, tissue homogenization, and artificial digestion. We artificially infected 160 P. canaliculata, 160 Cipangopaludina chinensis, and 160 Bellamya aeruginosa snails with A. cantonensis. Then, the four different detection methods were used to diagnose infection in each snail species at 7, 14, 21, and 28 days post exposure. RESULTS: We found no significant difference in the percentages of infected P. canaliculata snails using the four methods to detect A. cantonensis larvae. The radula pressing method had a mean detection rate of 80%, while the lung microscopy (81.3%), tissue homogenization (83.8%), and artificial digestion (85%) methods had slightly greater detection rates. Similarly, the percentages of infected C. chinensis snails that were detected using the radula pressing (80%), tissue homogenization (82.1%), and artificial digestion (83.8%) methods were not significantly different. Finally, the percentages of infected B. aeruginosa snails that were detected using the radula pressing (81.3%), tissue homogenization (81.9%), and artificial digestion (81.4%) methods were not significantly different. These results showed that the radula pressing method had a similar detection rate to traditional lung microscopy, tissue homogenization, or artificial digestion methods. CONCLUSIONS: This study demonstrates a new method for the qualitative screening of gastropods that act as intermediate hosts of A. cantonensis (and other Angiostrongylus species), provides technical support for the control of human angiostrongyliasis, and furthers research on A. cantonensis.


Asunto(s)
Angiostrongylus cantonensis , Larva , Caracoles , Infecciones por Strongylida , Animales , Caracoles/parasitología , Infecciones por Strongylida/diagnóstico , Infecciones por Strongylida/parasitología , Infecciones por Strongylida/veterinaria , Angiostrongylus cantonensis/aislamiento & purificación , Angiostrongylus cantonensis/fisiología , Boca/parasitología , Angiostrongylus/aislamiento & purificación , Angiostrongylus/fisiología , Ratas , Humanos
9.
J Geriatr Cardiol ; 21(6): 658-668, 2024 Jun 28.
Artículo en Inglés | MEDLINE | ID: mdl-38973822

RESUMEN

BACKGROUND: Stress hyperglycemia ratio (SHR) could provide accurate information on the acute status of hyperglycemia. The relationship between SHR and acute coronary syndrome (ACS) prognosis remains unclear. This study was conducted to identity the association between SHR and in-hospital outcomes in patients with ACS. METHODS: A total of 12,010 patients were eventually enrolled in the study. The relationship between SHR and in-hospital major adverse cardiovascular events (MACEs) was then modeled by restricted cubic spline (RCS) curves, and all patients were divided into three groups according to the results. The multivariate logistic regression analysis was used to determine the associations between the SHR and in-hospital outcomes, described as odds ratios (ORs) and 95% confidence intervals (CIs). Subgroup analyses were also performed on different diseases. RESULTS: The median age of this cohort was 63 (54, 71) years old, and 8942 (74.5%) were male. Group 1 was defined as SHR < 0.6 (n = 426), Group 2 was defined as SHR between 0.6 and 1 (n = 5821), and Group 3 was defined as SHR > 1 (n = 5763). Compared with Group 2, Group 1 (OR = 1.891, 95% CI: 1.028-3.479, P < 0.001) and Group 3 (OR = 1.868, 95% CI: 1.434-2.434, P < 0.001) had higher risks of suffering from in-hospital MACEs. SHR was associated with higher risks of in-hospital MACEs in the subgroups of DM [OR = 2.282, 95% CI: 1.477-3.524). CONCLUSIONS: Both low and high SHR levels were independently associated with in-hospital MACEs. Young males with DM, hypertension, and decreased renal function had much higher risks of suffering from SHR-correlated MACEs.

10.
Nat Commun ; 15(1): 6022, 2024 Jul 17.
Artículo en Inglés | MEDLINE | ID: mdl-39019858

RESUMEN

Electronic skins with deep and comprehensive liquid information detection are desired to endow intelligent robotic devices with augmented perception and autonomous regulation in common droplet environments. At present, one technical limitation of electronic skins is the inability to perceive the liquid sliding information as realistically as humans and give feedback in time. To this critical challenge, in this work, a self-powered bionic droplet electronic skin is proposed by constructing an ingenious co-layer interlaced electrode network and using an overpass connection method. The bionic skin is used for droplet environment reconnaissance and converts various dynamic droplet sliding behaviors into electrical signals based on triboelectricity. More importantly, the two-dimensional sliding behavior of liquid droplets is comprehensively perceived by the e-skin and visually fed back in real-time on an indicator. Furthermore, the flow direction warning and intelligent closed-loop control of water leakage are also achieved by this e-skin, achieving the effect of human neuromodulation. This strategy compensates for the limitations of e-skin sensing droplets and greatly narrows the gap between artificial e-skins and human skins in perceiving functions.


Asunto(s)
Biónica , Robótica , Robótica/instrumentación , Robótica/métodos , Humanos , Biónica/métodos , Dispositivos Electrónicos Vestibles , Electrodos , Piel , Diseño de Equipo
11.
Medicine (Baltimore) ; 103(30): e38776, 2024 Jul 26.
Artículo en Inglés | MEDLINE | ID: mdl-39058801

RESUMEN

Several risk factors were associated with mortality in patients with coronavirus disease 2019 (COVID-19) infection in intensive care units (ICU). We assessed the effect of risk factors related to the characteristics and clinical history of the population, laboratory test results, drug management, and type of ventilation on the probability of survival/discharge from the ICU. A retrospective cohort multicentric study of adults with COVID-19 admitted to the ICU between March 2020 and December 2021. Data were collected from 6 hospitals in 5 cities in Ecuador. The primary outcome was ICU survival/discharge. Survival analysis was conducted using semi-parametric Cox proportional hazards models. Of those admitted to the ICU with COVID-19, (n = 991), mean age was 56.76 ±â€…13.14, and 65.9% were male. Regarding the primary outcome, 51.1% (n = 506) died and 48.9% (n = 485) survived. Of the group that died, their mean age was higher than the survivors (60.7 vs 52.60 years, respectively), and they had a higher prevalence of comorbidities such as arterial hypertension (37.2% vs 20.4%, respectively) and diabetes mellitus (26.9% vs 15.7%, respectively), with P < .001. In ventilatory management, 32.7% of patients used noninvasive ventilation and high-flow nasal cannula, and 67.3% required invasive ventilatory support. After adjusting for confounders, Cox regression analysis showed that patients were less likely to be discharged alive from the ICU if they met the following conditions: arterial hypertension (hazard ratio [HR] = 0.83 95% CI 0.723-0.964), diabetes mellitus (HR = 0.80 95% CI 0.696-0.938), older than 62 years (HR = 0.86 95% CI 0.790-0.956), obese (body mass index ≥ 30) (HR = 0.78 95% CI 0.697-0.887), 1 unit increase in SOFA score (HR = 0.94 95% CI 0.937-0.961), PaO2/FiO2 ratio <100 mm Hg (HR = 0.84 95% CI 0.786-0.914), and the use of invasive mechanical ventilation (HR = 0.68 95% CI 0.614-0.769). Risk factors associated with increased mortality were older age, obesity, arterial hypertension, and diabetes. Factors such as male gender, chronic obstructive pulmonary disease, acute kidney injury, and cancer reported in other investigations did not have the same effect on mortality in our study.


Asunto(s)
COVID-19 , Unidades de Cuidados Intensivos , Humanos , Masculino , COVID-19/mortalidad , COVID-19/epidemiología , Persona de Mediana Edad , Femenino , Ecuador/epidemiología , Estudios Retrospectivos , Unidades de Cuidados Intensivos/estadística & datos numéricos , Factores de Riesgo , Anciano , Adulto , Comorbilidad , Mortalidad Hospitalaria , SARS-CoV-2 , Respiración Artificial/estadística & datos numéricos , Modelos de Riesgos Proporcionales
12.
Sci Rep ; 14(1): 17625, 2024 07 31.
Artículo en Inglés | MEDLINE | ID: mdl-39085273

RESUMEN

Aortic valve replacement (AVR) is a critical procedure for patients with aortic valve diseases. This study compares the effectiveness of three minimally-invasive surgical approaches for AVR: totally thoracoscopic (TT), right anterior mini-thoracotomy, and upper mini-sternotomy. We analyzed retrospective data from 130 patients who underwent one of these surgeries, focusing on various factors such as duration of hospital stay, operation time, times for cardiopulmonary bypass and aortic cross-clamping, postoperative complications, levels of cardiac biomarkers, pain intensity using the Visual Analog Scale, and mid-term survival rates. Results show that while the TT method had the longest operation times, it also had the shortest hospital stays and faster pain reduction post-surgery. Although the TT group initially showed higher cardiac biomarker levels after surgery, these levels normalized by the third day, similar to the other groups. There were no significant differences in mid-term survival and major adverse cardiac and cerebrovascular event (MACCE) rates among the groups. These findings suggest that the TT method, despite longer surgical times, offers a quicker initial recovery, making it a viable option for AVR.


Asunto(s)
Válvula Aórtica , Implantación de Prótesis de Válvulas Cardíacas , Esternotomía , Toracoscopía , Toracotomía , Humanos , Masculino , Femenino , Toracotomía/métodos , Esternotomía/métodos , Válvula Aórtica/cirugía , Persona de Mediana Edad , Anciano , Implantación de Prótesis de Válvulas Cardíacas/métodos , Implantación de Prótesis de Válvulas Cardíacas/efectos adversos , Estudios Retrospectivos , Toracoscopía/métodos , Resultado del Tratamiento , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Tempo Operativo , Tiempo de Internación , Procedimientos Quirúrgicos Mínimamente Invasivos/métodos
13.
Asian J Pharm Sci ; 19(3): 100925, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38966285

RESUMEN

Despite standard treatment for non-small cell lung cancer (NSCLC) being surgical resection, cancer recurrence and complications, such as induction of malignant pleural effusion (MPE) and significant postoperative pain, usually result in treatment failure. In this study, an alginate-based hybrid hydrogel (SOG) is developed that can be injected into the resection surface of the lungs during surgery. Briefly, endoplasmic reticulum-modified liposomes (MSLs) pre-loaded with the signal transducer and activator of transcription 3 (STAT3) small interfering RNA and lidocaine hydrochloride are encapsulated in SOG. Once applied, MSLs strongly downregulated STAT3 expression in the tumor microenvironment, resulting in the apoptosis of lung cancer cells and polarization of tumor-associated macrophages towards the M1-like phenotype. Meanwhile, the release of lidocaine hydrochloride (LID) was beneficial for pain relief and natural killer cell activation. Our data demonstrated MSL@LID@SOG not only efficiently inhibited tumor growth but also potently improved the quality of life, including reduced MPE volume and pain relief in orthotopic NSCLC mouse models, even with a single administration. MSL@LID@SOG shows potential for comprehensive clinical management upon tumor resection in NSCLC, and may alter the treatment paradigms for other cancers.

14.
Transl Oncol ; 48: 102065, 2024 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-39053343

RESUMEN

Numerous recent studies have underscored the indispensable roles of long non-coding RNAs (lncRNAs) in various diseases. However, their precise mechanisms in urinary bladder cancer (UBC) remain to be further elucidated. To delve into this inquiry, online databases were analyzed to identify differentially expressed lncRNAs in UBC, followed by the functional experiments in vivo and in vitro functional experiments. GAS6-AS1 exhibited high expression levels in UBC tissues and was shown to regulate the proliferation, migration, invasion, and cell cycle progression of UBC cells in vitro and in vivo. Then, a series of molecular biology experiments, including RNA pull-down, dual-luciferase reporter gene assays, RNA immunoprecipitation (RIP) assays, fluorescent in situ hybridization (FISH), and the triplex-capture assay demonstrated its interaction with miR-367-3p and PRC1. Mechanistically, GAS6-AS1 was found to enhance MMP7 expression by sequestering miR-367-3p. Moreover, GAS6-AS1 inhibited APC transcription by binding with PRC1, thereby activating several oncogenes downstream of the WNT pathway. To sum up, GAS6-AS1 promotes UBC progression through two distinct axes: the GAS6-AS1/miR-367-3p/MMP7 axis and the GAS6-AS1/PRC1/APC/Wnt/MMP7 axis, respectively. As a potential biomarker for UBC, GAS6-AS1 holds promising prospects for the diagnosis, treatment, and prognosis of UBC.

15.
RSC Adv ; 14(28): 20020-20031, 2024 Jun 18.
Artículo en Inglés | MEDLINE | ID: mdl-38911829

RESUMEN

The structure and properties of graphene/alumina composites are affected by the interface interaction. To demonstrate the influence of interface interaction on the structure of composite materials, a composite without graphene/matrix alumina interface was designed and prepared. We introduced a nano transition layer into the composite by pre-fabricating nano alumina coating on the surface of graphene, thus regulating the influence of interface interaction on the structure of the composite. According to the analysis of laser micro Raman spectroscopy, the structure of graphene was not seriously damaged during the modification process, and graphene was subjected to tensile or compressive stress along the 2D plane. The fracture behavior of the modified graphene/alumina composites is similar to that of pure alumina, but significantly different from that of pure graphene/alumina composites. The elastic modulus and hardness of composite material G/A/A are higher, while its microstructure has better density and uniformity. In situ HRSEM observation showed that there was a transition layer of alumina in the modified graphene/alumina composite. The transition layer blocks or buffers the interfacial stress interaction, therefore, the composite material exhibits a fracture behavior similar to that of pure alumina at this time. This work demonstrates that interface interactions have a significant impact on the structure and fracture behavior of graphene/alumina composites.

16.
medRxiv ; 2024 Mar 18.
Artículo en Inglés | MEDLINE | ID: mdl-38562723

RESUMEN

Comprehending the mechanism behind human diseases with an established heritable component represents the forefront of personalized medicine. Nevertheless, numerous medically important genes are inaccurately represented in short-read sequencing data analysis due to their complexity and repetitiveness or the so-called 'dark regions' of the human genome. The advent of PacBio as a long-read platform has provided new insights, yet HiFi whole-genome sequencing (WGS) cost remains frequently prohibitive. We introduce a targeted sequencing and analysis framework, Twist Alliance Dark Genes Panel (TADGP), designed to offer phased variants across 389 medically important yet complex autosomal genes. We highlight TADGP accuracy across eleven control samples and compare it to WGS. This demonstrates that TADGP achieves variant calling accuracy comparable to HiFi-WGS data, but at a fraction of the cost. Thus, enabling scalability and broad applicability for studying rare diseases or complementing previously sequenced samples to gain insights into these complex genes. TADGP revealed several candidate variants across all cases and provided insight into LPA diversity when tested on samples from rare disease and cardiovascular disease cohorts. In both cohorts, we identified novel variants affecting individual disease-associated genes (e.g., IKZF1, KCNE1). Nevertheless, the annotation of the variants across these 389 medically important genes remains challenging due to their underrepresentation in ClinVar and gnomAD. Consequently, we also offer an annotation resource to enhance the evaluation and prioritization of these variants. Overall, we can demonstrate that TADGP offers a cost-efficient and scalable approach to routinely assess the dark regions of the human genome with clinical relevance.

17.
Mol Pharm ; 21(5): 2415-2424, 2024 May 06.
Artículo en Inglés | MEDLINE | ID: mdl-38606663

RESUMEN

Chemokines and chemokine receptors are indispensable to play a key role in the development of malignant tumors. As one of the most widely expressed chemokine receptors, chemokine (C-X-C motif) receptor 4 (CXCR4) has been a popular research focus. In most tumors, CXCR4 expression is significantly upregulated. Moreover, integrated nuclide diagnosis and therapy targeting CXCR4 show great potential. [68Ga]Ga-pentixafor, a radioligand targeting CXCR4, exhibits a strong affinity for CXCR4 both in vivo and in vitro. However, [177Lu]Lu-pentixather, the therapeutic companion of [68Ga]Ga-pentixafor, requires significant refinement to mitigate its pronounced hepatic biodistribution. The objective of this study was to synthesize theranostic molecular tracers with superior CXCR4 targeting functions. The Daudi cell line, which highly expressed CXCR4, and the MM.1S cell line, which weakly expressed CXCR4, were used in this study. Based on the pharmacophore cyclo (-d-Tyr-n-me-d-Orn-l-Arg-L-2-NAL-Gly-) (CPCR4) of pentixafor, six tracers were synthesized: [124I]I-1 ([124I]I-CPCR4), [99mTc]Tc-2 ([99mTc]Tc-HYNIC-CPCR4), [124I]I-3 ([124I]I-pentixafor), [18F]AlF-4 ([18F]AlF-NETA-CPCR4), [99mTc]Tc-5 ([99mTc]Tc-MAG3-CPCR4) and [124I]I-6 ([124I]I-pentixafor-Ga) and their radiochemical purities were all higher than 95%. After positron emission tomography (PET)/single-photon emission computed tomography (SPECT) imaging, the [124I]I-6 group exhibited the best target-nontarget ratio. At the same time, comparing the [68Ga]Ga-pentixafor group with the [124I]I-6 group, we found that the [124I]I-6 group had a better target-nontarget ratio and lower uptake in nontarget organs. Therefore, compound 6 was selected for therapeutic radionuclide (131I) labeling, and the tumor-bearing animal models were treated with [131I]I-6. The volume of the tumor site was significantly reduced in the treatment group compared with the control group, and no significant side effects were found. [124I]I-6 and [131I]I-6 showed excellent affinity for targeting CXCR4, and they showed great potential for the integrated diagnosis and treatment of tumors with high CXCR4 expression.


Asunto(s)
Complejos de Coordinación , Receptores CXCR4 , Receptores CXCR4/metabolismo , Receptores CXCR4/genética , Animales , Humanos , Ratones , Línea Celular Tumoral , Distribución Tisular , Radiofármacos/farmacocinética , Radiofármacos/farmacología , Radiofármacos/química , Péptidos Cíclicos/química , Péptidos Cíclicos/farmacología , Sondas Moleculares/química , Sondas Moleculares/farmacocinética , Radioisótopos de Galio , Ratones Desnudos , Nanomedicina Teranóstica/métodos , Femenino
18.
J Cardiothorac Surg ; 19(1): 233, 2024 Apr 16.
Artículo en Inglés | MEDLINE | ID: mdl-38627773

RESUMEN

OBJECTIVE: This study aimed to confirm the safety and feasibility of totally endoscopic repair for mitral regurgitation (MR) in Barlow's disease. METHODS: From June 2018 to December 2022, 21 consecutive Barlow's disease patients (aged 33 ± 12 years; 57.1% male) underwent totally endoscopic mitral valve (MV) repair with leaflets folding, multiple artificial chordae implantation and ring annuloplasty. The safety and feasibility of this technique was evaluated by its mid-term clinical outcomes. RESULTS: There was no operative death or complications. The mean cardiopulmonary bypass (CPB) time was 190 ± 41 (128-267) min, and the aortic cross-clamp time was 145 ± 32 (66-200) min. The average number of artificial chordae implantation was 2.9 ± 0.7 (1-4) pairs. The mean MV coaptation length was 1.4 ± 0.3 (0.8-1.8) cm, and the median transvalvular gradient was 1 [interquartile range (IQR), 1-2] mmHg. During a median follow-up time of 24 (IQR, 10-38) months, all patients showed persistent effective valve function with no significant MR or systolic anterior motion. CONCLUSIONS: Totally endoscopic repair was a safe, effective, and reproducible procedure with satisfied mid-term clinical outcomes for MR in Barlow's disease. However, further randomized and long-term follow-up studies were warranted to determine its clinical effects.


Asunto(s)
Procedimientos Quirúrgicos Cardíacos , Anuloplastia de la Válvula Mitral , Insuficiencia de la Válvula Mitral , Prolapso de la Válvula Mitral , Humanos , Masculino , Femenino , Insuficiencia de la Válvula Mitral/cirugía , Prolapso de la Válvula Mitral/cirugía , Resultado del Tratamiento , Válvula Mitral/cirugía , Procedimientos Quirúrgicos Cardíacos/métodos , Anuloplastia de la Válvula Mitral/métodos
19.
Gland Surg ; 13(3): 383-394, 2024 Mar 27.
Artículo en Inglés | MEDLINE | ID: mdl-38601277

RESUMEN

Background: In postoperative setting, breast cancer (BC) patients can experience adverse effects, including fatigue, sleep disorders, and pain, which substantially affect their health-related quality of life (HRQoL). This study sought to assess the effectiveness of a WeChat-based multimodal nursing program (WCBMNP) that was specifically designed for the rehabilitation of women following BC surgery. Methods: BC patients were randomly, single-blinded allocated to either the intervention (n=62) or control (n=63) cohorts. Over a period of 6 months (24 weeks), the intervention cohort received a WCBMNP in addition to routine nursing care, while the control cohort received routine nursing care only. To evaluate patients' fear of cancer recurrence (FCR), their overall fear score was assessed using the Japanese version of the Concerns About Recurrence Scale (CARS-J) for primary outcome. The initial outcome (HRQoL) and secondary results, such as fatigue, sleep, and pain, were examined using the Functional Assessment of Cancer Therapy-Breast (FACT-B, version 4.0) and Nursing Rating Scale (NRS), respectively. Results: Two hundred and ten participants, 85 participants were excluded. Compared to the controls (n=63), the intervention cohort (n=62) showed statistically significant improvements in their CARS-J scores. The intervention cohort aggregate scores on the FACT-B improved significantly but were affected by the compounding influences of cohort dynamics, temporal progression, and their interaction. Similar improvements were observed in the social/family and functional well-being domains. Emotional well-being was improved based on the effects of time and group-time interaction. In the intervention cohort, the "BC-specific subscale for additional concerns" was affected by group and time, whereas physical well-being was only affected by time. Conversely, there were no statistically significant changes in the variables of fatigue, sleep, and pain. Conclusions: The WCBMNP reduced FCR and significantly increased the HRQoL of female patients with BC postoperatively. The WCBMNP could be implemented as a postoperative rehabilitation intervention in this patient population to improve outcomes. Trial Registration: Chinese Clinical Trial Registry (ChiCTR2400081557).

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