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The E-twenty-six variant 1 (ETV1)-dependent transcriptome plays an important role in atrial electrical and structural remodelling and the occurrence of atrial fibrillation (AF), but the underlying mechanism of ETV1 in AF is unclear. In this study, cardiomyocyte-specific ETV1 knockout (ETV1f/fMyHCCre/+, ETV1-CKO) mice were constructed to observe the susceptibility to AF and the underlying mechanism in AF associated with ETV1-CKO mice. AF susceptibility was examined by intraesophageal burst pacing, induction of AF was increased obviously in ETV1-CKO mice than WT mice. Electrophysiology experiments indicated shortened APD50 and APD90, increased incidence of DADs, decreased density of ICa,L in ETV1-CKO mice. There was no difference in VINACT,1/2 and VACT,1/2, but a significantly longer duration of the recovery time after inactivation in the ETV1-CKO mice. The recording of intracellular Ca2+ showed that there was significantly increased in the frequency of calcium spark, Ca2+ transient amplitude, and proportion of SCaEs in ETV1-CKO mice. Reduction of Cav1.2 rather than NCX1 and SERCA2a, increase RyR2, p-RyR2 and CaMKII was reflected in ETV1-CKO group. This study demonstrates that the increase in calcium spark and SCaEs corresponding to Ca2+ transient amplitude may trigger DAD in membrane potential in ETV1-CKO mice, thereby increasing the risk of AF.
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Fibrilación Atrial , Calcio , Atrios Cardíacos , Ratones Noqueados , Miocitos Cardíacos , Factores de Transcripción , Animales , Miocitos Cardíacos/metabolismo , Ratones , Fibrilación Atrial/metabolismo , Fibrilación Atrial/genética , Calcio/metabolismo , Atrios Cardíacos/metabolismo , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Proteínas de Unión al ADN/metabolismo , Proteínas de Unión al ADN/genética , Señalización del Calcio , Potenciales de Acción , Potenciales de la Membrana , MasculinoRESUMEN
This review offers a comprehensive analysis of the intricate relationship between the gut virome and diabetes, elucidating the mechanisms by which the virome engages with both human cells and the intestinal bacteriome. By examining a decade of scientific literature, we provide a detailed account of the distinct viral variations observed in type 1 diabetes (T1D) and type 2 diabetes (T2D). Our synthesis reveals that the gut virome significantly influences the development of both diabetes types through its interactions, which indirectly modulate immune and inflammatory responses. In T1D, the focus is on eukaryotic viruses that stimulate the host's immune system, whereas T2D is characterized by a broader spectrum of altered phage diversities. Promisingly, in vitro and animal studies suggest fecal virome transplantation as a potential therapeutic strategy to alleviate symptoms of T2D and obesity. This study pioneers a holistic overview of the gut virome's role in T1D and T2D, its interplay with host immunity, and the innovative potential of fecal transplantation therapy in clinical diabetes management.
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Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Trasplante de Microbiota Fecal , Microbioma Gastrointestinal , Viroma , Humanos , Diabetes Mellitus Tipo 1/terapia , Diabetes Mellitus Tipo 1/virología , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 2/terapia , Diabetes Mellitus Tipo 2/virología , Animales , Bacteriófagos/genética , Bacteriófagos/fisiología , Virus/genética , Virus/clasificaciónAsunto(s)
Glucemia , Control Glucémico , Humanos , China/epidemiología , Glucemia/análisis , Glucemia/metabolismo , Femenino , Masculino , Control Glucémico/métodos , Persona de Mediana Edad , Diabetes Mellitus/sangre , Anciano , Diabetes Mellitus Tipo 2/sangre , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Adulto , Hipoglucemiantes/uso terapéutico , Hemoglobina Glucada/análisis , Hemoglobina Glucada/metabolismo , Servicios de Salud Comunitaria/métodosRESUMEN
Purpose: This study analyzed the biomechanical responses of different corneal cap thicknesses after small incision lenticule extraction (SMILE). Methods: Individual finite element models of myopic eyes were constructed based on the clinical data. Then, four types of corneal cap thicknesses after SMILE were included for each model. The biomechanical effects of material parameters and intraocular pressure on corneas with different cap thicknesses were analyzed. Results: When the cap thickness increased, the vertex displacements of the anterior and posterior corneal surfaces decreased slightly. The corneal stress distributions demonstrated little change. Regarding wave-front aberrations caused by the displacements of the anterior surface, the absolute defocus value decreased slightly, but the magnitude of primary spherical aberration increased slightly. The horizontal coma increased, and the levels of other low-order and high-order aberrations were small and demonstrated little change. The corneal vertex displacement and wave-front aberration were significantly affected by elastic modulus and intraocular pressure, whereas the corneal stress distribution was greatly affected by intraocular pressure. There were obvious individual differences in the biomechanical responses of human eyes. Conclusions: The biomechanical difference of different corneal cap thicknesses after SMILE was small. The effect of corneal cap thickness was significantly less than that resulting from material parameters and intraocular pressure. Translational Relevance: Individual models were constructed based on the clinical data. The elastic modulus was controlled by programming to simulate its heterogeneous distribution in the actual human eye. The simulation was improved to bridge the gap between basic research and clinical care.
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Cirugía Laser de Córnea , Miopía , Humanos , Análisis de Elementos Finitos , Agudeza Visual , Cirugía Laser de Córnea/métodos , Córnea , Miopía/cirugíaRESUMEN
Streptococcus suis serotype 2 (SS2) is an important zoonotic pathogen that can infect humans in contact with infected pigs or their byproducts. It can employ different types of genes to defend against oxidative stress and ensure its survival. The thioredoxin (Trx) system is a key antioxidant system that contributes adversity adaptation and pathogenicity. SS2 has been shown to encode putative thioredoxin genes, but the biological roles, coding sequence, and underlying mechanisms remains uncharacterized. Here, we demonstrated that SSU05_0237-ORF, from a clinical SS2 strain, ZJ081101, encodes a protein of 104 amino acids with a canonical CGPC active motif and an identity 70-85% similar to the thioredoxin A (TrxA) in other microorganisms. Recombinant TrxA efficiently catalyzed the thiol-disulfide oxidoreduction of insulin. The deletion of TrxA led to a significantly slow growth and markedly compromised tolerance of the pathogen to temperature stress, as well as impaired adhesion ability to pig intestinal epithelial cells (IPEC-J2). However, it was not involved in H2O2 and paraquat-induced oxidative stress. Compared with the wild-type strain, the ΔTrxA strain was more susceptible to killing by macrophages through increasing NO production. Treatment with TrxA mutant strain also significantly attenuated cytotoxic effects on RAW 264.7 cells by inhibiting inflammatory response and apoptosis. Knockdown of pentraxin 3 in RAW 264.7 cells was more vulnerable to phagocytic activity, and TrxA promoted SS2 survival in phagocytic cells depending on pentraxin 3 activity compared with the wild-type strain. Moreover, a co-inoculation experiment in mice revealed that TrxA mutant strain is far more easily cleared from the body than the wild type strain in the period from 8-24 h, and exhibits significantly attenuated oxidative stress and liver injury. In summary, we reveal the important role of TrxA in the pathogenesis of SS2.
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Macrófagos , Infecciones Estreptocócicas , Streptococcus suis , Animales , Humanos , Ratones , Proteínas Bacterianas/metabolismo , Peróxido de Hidrógeno/farmacología , Peróxido de Hidrógeno/metabolismo , Macrófagos/metabolismo , Macrófagos/microbiología , Serogrupo , Streptococcus suis/metabolismo , Streptococcus suis/patogenicidad , Porcinos , Tiorredoxinas/genética , Tiorredoxinas/metabolismo , Tiorredoxinas/farmacología , VirulenciaRESUMEN
To examine wavefront aberrations induced by biomechanical effects after Small Incision Lenticule Extraction (SMILE) surgery. The three-dimensional (3D) finite element models of the human eye were established. By loading the intraocular pressure (IOP), the displacement of the anterior and posterior surface of the cornea was calculated. Then the displacement was converted into the wavefront aberrations by wave-surface fitting. The results showed that the induced wavefront aberrations were noticeable from biomechanical effects after SMILE surgery. The induced higher-order aberrations from the anterior corneal surface included spherical aberration, y-Trefoil, and x-Tetrafoil. Spherical aberration was positively correlated with corrected diopter (D), but x-Tetrafoil and y-Trefoil remained stable. The induced wavefront aberrations from the posterior corneal surface were smaller than those from the anterior corneal surface, and some of the aberrations compensated each other. With IOP increased, defocus and x-Tetrafoil from the anterior corneal surface increased, while y-Trefoil and spherical aberration decreased. The IOP only affected defocus from the posterior corneal surface. In addition, the incision size also had a distinct impact on primary x-astigmatism and x-Trefoil from the anterior corneal surface, and it had a smaller effect on the aberrations from the posterior corneal surface. Therefore, the biomechanical effects increased residual wavefront aberrations after SMILE refractive surgery.
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Aberración de Frente de Onda Corneal , Miopía , Humanos , Agudeza Visual , Análisis de Elementos Finitos , Miopía/cirugía , Miopía/complicaciones , Aberración de Frente de Onda Corneal/etiología , Córnea/cirugíaRESUMEN
Graves' disease, characterized by hyperthyroidism resulting from loss of immune tolerance to thyroid autoantigens, may be attributable to both genetic and environmental factors. Allogeneic hematopoietic stem cell transplantation (HSCT) represents a means to induce immunotolerance via an artificial immune environment. We present a male patient with severe aplastic anemia arising from a germline SAMD9L missense mutation who successfully underwent HSCT from his HLA-haploidentical SAMD9L non-mutated father together with nonmyeloablative conditioning and post-transplant cyclophosphamide at 8 years of age. He did not suffer graft-versus-host disease, but Graves' disease evolved 10 months post-transplant when cyclosporine was discontinued for one month. Reconstitution of peripheral lymphocyte subsets was found to be transiently downregulated shortly after Graves' disease onset but recovered upon antithyroid treatment. Our investigation revealed the presence of genetic factors associated with Graves' disease, including HLA-B*46:01 and HLA-DRB1*09:01 haplotypes carried by the asymptomatic donor and germline FLT3 c.2500C>T mutation carried by both the patient and the donor. Given his current euthyroid state with normal hematopoiesis, the patient has returned to normal school life. This rare event of Graves' disease in a young boy arising from special HSCT circumstances indicates that both the genetic background and the HSCT environment can prompt the evolution of Graves' disease.
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Enfermedad Injerto contra Huésped , Enfermedad de Graves , Trasplante de Células Madre Hematopoyéticas , Reconstitución Inmune , Trasplante de Células Madre de Sangre Periférica , Células Germinativas , Enfermedad Injerto contra Huésped/genética , Enfermedad de Graves/genética , Enfermedad de Graves/terapia , Trasplante de Células Madre Hematopoyéticas/métodos , Humanos , Masculino , Tirosina Quinasa 3 Similar a fmsRESUMEN
Primary mediastinal non-seminomatous germ cell tumors (PMNSGCT) are rare but life-threatening thoracic cancers. We report our experience from eight patients with peri-treatment adverse events. By analyzing changes in tumor extent, serum tumor markers, and pathologies between diagnosis and transfer, those events could be attributed to postbiopsy respiratory insufficiency, growing teratoma syndrome, secondary histiocytic malignancy, and PMNSGCT progression. Subjecting patients to respiratory therapy, conventional or high-dose chemotherapy, and surgery controlled the disease, with five of the eight patients surviving disease free. These outcomes indicate that integrated appropriate and timely approaches are important in tackling peri-treatment adverse events.
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Neoplasias del Mediastino , Neoplasias de Células Germinales y Embrionarias , Neoplasias Testiculares , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Humanos , Masculino , Neoplasias del Mediastino/patología , Neoplasias de Células Germinales y Embrionarias/tratamiento farmacológico , Neoplasias Testiculares/patologíaRESUMEN
PURPOSE: A customized myopic refractive surgery was simulated by establishing a finite element model of the human eye, after which we studied the wave front aberrations induced by biomechanical effects and ablation profile after wave front-guided LASIK surgery. METHODS: Thirty myopia patients (i.e., 60 eyes) without other eye diseases were selected. Their ages, preoperative spherical equivalent, astigmatism, and wave front aberration were then obtained, in addition to the mean spherical equivalent error range - 4 to - 8D. Afterward, wave front-guided customized LASIK surgery was simulated by establishing a finite element eye model, followed by the analysis of the wave front aberrations induced by the surface displacement from corneal biomechanical effects, as well as customized ablation profile. Finally, the preoperative and induced aberrations were statistically analyzed. RESULTS: Comatic aberrations were the main wave front abnormality induced by biomechanical effects, and the wave front aberrations induced by the ablation profile mainly included coma and secondary coma, as well as sphere and secondary-sphere aberrations. Overall, the total high-order aberrations (tHOAs), total coma (C31), and sphere ([Formula: see text]) increased after wave front-guided customized LASIK surgery. According to our correlation analyses, coma, sphere, and tHOAs were significantly correlated with decentration. Additionally, the material parameters of ocular tissue were found to affect the postoperative wave front aberrations. When the material parameters of the sclera remained constant but those of cornea increased, the induced wave front aberrations were reduced. CONCLUSION: All biomechanical effects of cornea and ablation profile had significant effects on postoperative wave front aberrations after customized LASIK refractive surgery; however, the effects of the ablation profile were more notorious. Additionally, the characteristics of biomechanical materials have influence on the clinical correction effect.
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Astigmatismo , Queratomileusis por Láser In Situ , Miopía , Astigmatismo/etiología , Astigmatismo/cirugía , Córnea/cirugía , Topografía de la Córnea , Análisis de Elementos Finitos , Humanos , Queratomileusis por Láser In Situ/efectos adversos , Rayos Láser , Miopía/cirugía , Refracción OcularRESUMEN
Chondrocyte apoptosis contributes to osteoarthritis, while miR-146a is a critical player in chondrocyte apoptosis. Our bioinformatics analysis showed that miR-146a may bind with long non-coding RNA (lncRNA) CALML3 antisense RNA 1 (CALML3-AS1). Our study was therefore carried out to investigate the interactions between lncRNA CALML3-AS1 and miR-146a in osteoarthritis. This study included 66 osteoarthritis patients who were admitted at Shanxi People's Hospital from July 2016 to June 2019. Transfections were performed to analyse gene interactions. RT-qPCR and Western blot were performed to determine the expression levels of gene and protein, respectively. Cell apoptosis of chondrocytes induced by lipopolysaccharide (LPS) was analysed by cell apoptosis assay. We found that CALML3-AS1 was downregulated, while miR-146a was upregulated in osteoarthritis. However, no significant correlation was found between them. In addition, overexpression of CALML3-AS1 or miR-146a did not affect the expression of each other. However, overexpression of CALML3-AS1 resulted in the upregulation of Smad family member 4 (Smad4), a downstream target of miR-146a. We also found that the expression of miR-146a and Smad4 were negatively correlated, while the correlation between CALML3-AS1 and smad4 was not significant. In cell apoptosis assay, overexpression of CALML3-AS1 and Smad4 resulted in decreased proliferation of chondrocytes. MiR-146a played an opposite role and reduced the effects of overexpression of CALML3-AS1 and Smad4. Therefore, CALML3-AS1 may regulate chondrocyte apoptosis by acting as a sponge for miR-146a to upregulate Smad4.
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Apoptosis , Condrocitos , MicroARNs , ARN Largo no Codificante , Apoptosis/genética , Proliferación Celular/genética , Condrocitos/citología , Humanos , MicroARNs/genética , MicroARNs/metabolismo , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismoRESUMEN
(1) Background: Busulfan has been used as a conditioning regimen in allogeneic hematopoietic cell stem transplantation (HSCT). Owing to a large inter-individual variation in pharmacokinetics, therapeutic drug monitoring (TDM)-guided busulfan dosing is necessary to reduce graft failure and relapse rate. As there exists no TDM of busulfan administration for HCT in Taiwan, we conducted a pilot study to assess the TDM-dosing of busulfan in the Taiwanese population; (2) Methods: Seven patients with HCT from The Koo Foundation Sun Yat-Sen Cancer Center, Taipei, Taiwan, received conditioning regimens consisting of intravenous busulfan and other chemotherapies. After the initial busulfan dose, blood samples were collected for busulfan TDM at 5 min, 1 h, 2 h, and 3 h. Busulfan was extracted and detected by performing stable-isotope dilution LC-MS/MS. Plasma busulfan concentration was quantified and used for dose adjustment. Potential adverse effects of busulfan, such as mucositis and hepatic veno-occlusive disease (VOD), were also evaluated; (3) Results: The LC-MS/MS method was validated with an analyte recovery of 88-99%, within-run and between-run precision of <15%, and linearity ranging from 10 to 10,000 ng/mL. Using TDM-guided busulfan dosing, dose adjustment was necessary and performed in six out of seven patients (86%) with successful engraftments in all patients (100%). Mild mucositis was observed, and VOD was diagnosed in only one patient; (4) Conclusions: This single-center study in Taiwan demonstrated the importance of busulfan TDM in increasing the success rate of HCT transplantation. It is also necessary to further investigate the optimal busulfan target value in the Taiwanese population in the future.
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PURPOSE: To investigate the biomechanical responses of the human cornea after small incision lenticule extraction (SMILE) procedures, especially their effects of SMILE surgery on stress and strain. METHODS: Based on finite element analysis, a three-dimensional (3D) model of the human eye was established to simulate SMILE refractive surgery procedures. Stress and strain values were calculated by inputting the intraocular pressure (IOP). RESULTS: After SMILE refractive surgery procedures, the stress and strain of the anterior and posterior corneal surfaces were significantly increased. The equivalent stress and strain on the anterior and posterior corneal surfaces increased with increasing diopter and were concentrated in the central area, whereas the values of stress and strain at the incision site on the anterior surface of the cornea were approximately 0. Compared with the anterior corneal surface, the stress and strain of the posterior surface were larger. Increasing IOP caused an approximately linear change in stress and a nonlinear increase in corneal strain. In addition, we found that the incision sizes and direction had less of an influence on stress and strain. In summary, SMILE surgery increased the equivalent stress and strain on the human cornea. CONCLUSIONS: The equivalent stress and strain of the anterior and posterior human corneal surfaces increased after SMILE refractive surgery; these increases were particularly noticeable on the posterior surface of the cornea.
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Miopía , Procedimientos Quirúrgicos Refractivos , Fenómenos Biomecánicos , Córnea/cirugía , Análisis de Elementos Finitos , Humanos , Miopía/cirugía , Agudeza VisualRESUMEN
AIM: The aim was to study the effect of Allitridum (Allicin) on the heterologous expression of the late sodium current on the ΔKPQ-SCN5A mutations in HEK293 cells, with a view to screening new drugs for the treatment of long QT syndrome type 3 (LQT3). METHODS AND RESULTS: The ΔKPQ-SCN5A plasmid was transiently transferred into HEK293 cells by liposome technology and administered by extracellular perfusion, and the sodium current was recorded by whole-cell patch-clamp technology. Application of Allicin 30 µM reduced the late sodium current (I Na,L ) of the Nav1.5 channel current encoded by ΔKPQ-SCN5A from 1.92 ± 0.12 to 0.65 ± 0.03 pA/pF (P < 0.01, n = 15), which resulted in the decrease of I Na,L /I Na,P (from 0.94% ± 0.04% to 0.32% ± 0.02%). Furthermore, treatment with Allicin could move the steady-state inactivation of the channel to a more negative direction, resulting in an increase in channel inactivation at the same voltage, which reduced the increase in the window current and further increased the inactivation of the channel intermediate state. However, it had no effect on channel steady-state activation (SSA), inactivation mechanics, and recovery dynamics after inactivation. What's more, the Nav1.5 channel protein levels of membrane in the ΔKPQ-SCN5A mutation were enhanced from 0.49% ± 0.04% to 0.76% ± 0.02% with the effect of 30 mM Allicin, close to 0.89% ± 0.02% of the WT. CONCLUSION: Allicin reduced the late sodium current of ΔKPQ-SCN5A, whose mechanism may be related to the increase of channel steady-state inactivation (SSI) and intermediate-state inactivation (ISI) by the drug, thus reducing the window current.
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We studied the effects of the aspheric transition zone on the optical wavefront aberrations, corneal surface displacement, and stress induced by the biomechanical properties of the cornea after conventional laser in situ keratomileusis (LASIK) refractive surgery. The findings in this study can help improve visual quality after refractive surgery. Hyperopia correction in 1-5D was simulated using five types of aspheric transition zones with finite element modeling. The algorithm for the simulations was designed according to the optical path difference. Wavefront aberrations were calculated from the displacements on the anterior and posterior corneal surfaces. The vertex displacements and stress on the corneal surface were also evaluated. The results showed that the aspheric transition zone has an effect on the postoperative visual quality. The main wavefront aberrations on the anterior corneal surface are defocus, y-primary astigmatism, x-coma, and spherical aberrations. The wavefront aberrations on the corneal posterior surface were relatively small and vertex displacements on the posterior corneal surface were not significantly affected by the aspheric transition zone. Stress analysis revealed that the stress on the cutting edge of the anterior corneal surface decreased with the number of aspheric transition zone increased, and profile #1 resulted in the maximum stress. The stress on the posterior surface of the cornea was more concentrated in the central region and was less than that on the anterior corneal surface overall. The results showed that the aspheric transition zone has an effect on postoperative aberrations, but wavefront aberrations cannot be eliminated. In addition, the aspheric transition zone influences the postoperative biomechanical properties of the cornea, which significantly affect the postoperative visual quality.
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Astigmatismo , Hiperopía , Queratomileusis por Láser In Situ , Miopía , Astigmatismo/cirugía , Humanos , Hiperopía/cirugía , Miopía/cirugía , Agudeza VisualRESUMEN
The edible silver carp (Hypophthalmichthys molitrix) and bighead carp (H. nobilis), which are two of the "Four Domesticated Fish" of China, are cultivated intensively worldwide. Here, we constructed 837- and 845-Mb draft genome assemblies for the silver carp and the bighead carp, respectively, including 24,571 and 24,229 annotated protein-coding genes. Genetic maps, anchoring 71.7% and 83.8% of all scaffolds, were obtained for the silver and bighead carp, respectively. Phylogenetic analysis showed that the bighead carp formed a clade with the silver carp, with an estimated divergence time of 3.6 million years ago; the time of divergence between the silver carp and zebrafish was 50.7 million years ago. An East Asian cyprinid genome-specific chromosome fusion took place ~9.2 million years after this clade diverged from the clade containing the common carp and Sinocyclocheilus. KEGG and GO analyses indicated that the expanded gene families in the silver and bighead carp were associated with diseases, the immune system and environmental adaptations. Genomic regions differentiating the silver and bighead carp populations were detected based on the whole-genome sequences of 42 individuals. Genes associated with the divergent regions were associated with reproductive system development and the development of primary female sexual characteristics. Thus, our results provided a novel systematic genomic analysis of the East Asian cyprinids, as well as the evolution and speciation of the silver carp and bighead carp.
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Evolución Biológica , Carpas , Especiación Genética , Animales , Carpas/clasificación , Carpas/genética , China , Mapeo Cromosómico , Femenino , Filogenia , Secuenciación Completa del Genoma , Pez CebraRESUMEN
PURPOSE: Although chimeric antigen receptor T-cell (CAR-T) therapy development for B-cell malignancies has made significant progress in the last decade, broadening the success to treating T-cell acute lymphoblastic leukemia (T-ALL) has been limited. We conducted two clinical trials to verify the safety and efficacy of GC027, an "off-the-shelf" allogeneic CAR-T product targeting T-cell antigen, CD7. Here, we report 2 patients as case reports with relapsed/refractory T-ALL who were treated with GC027. PATIENTS AND METHODS: Both the trials reported here were open-label and single-arm. A single infusion of GC027 was given to each patient after preconditioning therapy. RESULT: Robust expansion of CAR-T cells along with rapid eradication of CD7+ T lymphoblasts were observed in the peripheral blood, bone marrow, and cerebrospinal fluid. Both patients achieved complete remission with no detectable minimal residual disease. At data cutoff, 30 September 2020, 1 of the 2 patients remains in ongoing remission for over 1 year after CAR T-cell infusion. Grade 3 cytokine release syndrome (CRS) occurred in both patients and was managed by a novel approach with a ruxolitinib-based CRS management. Ruxolitinib showed promising activity in a preclinical study conducted at our center. No graft-versus-host disease was observed. CONCLUSIONS: The two case reports demonstrate that a standalone therapy with this novel CD7-targeted "off-the-shelf" allogeneic CAR-T therapy may provide deep and durable responses in select patients with relapsed/refractory T-ALL. GC027 might have a potential to be a promising new approach for treating refractory/relapsed T-ALL. Further studies are warranted.
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Antígenos CD7/inmunología , Síndrome de Liberación de Citoquinas/tratamiento farmacológico , Inmunoterapia Adoptiva/efectos adversos , Nitrilos/uso terapéutico , Leucemia-Linfoma Linfoblástico de Células T Precursoras/terapia , Pirazoles/uso terapéutico , Pirimidinas/uso terapéutico , Adulto , Ensayos Clínicos como Asunto , Síndrome de Liberación de Citoquinas/etiología , Síndrome de Liberación de Citoquinas/patología , Humanos , Masculino , Leucemia-Linfoma Linfoblástico de Células T Precursoras/inmunología , Leucemia-Linfoma Linfoblástico de Células T Precursoras/patología , Pronóstico , Adulto JovenRESUMEN
Emerging evidence suggests that the gut microbiome actively regulates cognitive functions and that gut microbiome imbalance is associated with Alzheimer's disease (AD), the most prevalent neurodegenerative disorder. However, the changes in gut microbiome composition in AD and their association with disease pathology, especially in the early stages, are unclear. Here, we compared the profiles of gut microbiota between APP/PS1 transgenic mice (an AD mouse model) and their wild-type littermates at different ages by amplicon-based sequencing of 16S ribosomal RNA genes. Microbiota composition started diverging between the APP/PS1 and wild-type mice at young ages (i.e., 1-3 months), before obvious amyloid deposition and plaque-localized microglial activation in the cerebral cortex in APP/PS1 mice. At later ages (i.e., 6 and 9 months), there were distinct changes in the abundance of inflammation-related bacterial taxa including Escherichia-Shigella, Desulfovibrio, Akkermansia, and Blautia in APP/PS1 mice. These findings suggest that gut microbiota alterations precede the development of key pathological features of AD, including amyloidosis and plaque-localized neuroinflammation. Thus, the investigation of gut microbiota might provide new avenues for developing diagnostic biomarkers and therapeutic targets for AD.
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Enfermedad de Alzheimer , Amiloidosis , Encefalopatías , Microbioma Gastrointestinal/genética , Microglía/patología , Factores de Edad , Enfermedad de Alzheimer/genética , Enfermedad de Alzheimer/patología , Amiloidosis/genética , Amiloidosis/patología , Animales , Encéfalo/patología , Encefalopatías/genética , Encefalopatías/patología , Modelos Animales de Enfermedad , Inflamación/patología , Masculino , Ratones , Ratones TransgénicosRESUMEN
PURPOSE: Doublet combination chemotherapy is commonly considered a second-line treatment for advanced non-small cell lung cancer (NSCLC) in China. This multi-institutional retrospective analysis evaluated and compared the efficacy between combination and mono-therapy after platinum-based first-line chemotherapy in Chinese patients with advanced NSCLC. METHODS: We retrospectively reviewed 335 patients who received second-line chemotherapy for advanced NSCLC. The primary endpoint was overall survival (OS), and the secondary endpoints were progression-free survival (PFS), response rate (RR) and toxicity. Treatment-free interval (TFI) was used for further stratification analysis. The Cox proportional hazards model was used for multivariate analysis. RESULTS: Two hundred and fifty-three patients received doublet combination chemotherapy and 82 received single-agent chemotherapy. PFS was significantly prolonged in combination group compared to single-agent group (median 5.70 vs 3.70 months; HR 0.62; 95% CI 0.45-0.85; p < 0.001). The RR was significantly higher in the combination group than in the single-agent group (29.25% vs. 10.98%; p = 0.001). OS was also prolonged in combination group versus single-agent group (median 13.30 vs. 11.45 months, respectively; HR 0.70; 95% CI 0.52-0.95; p = 0.023). Among patients with TFI of ≥ 6 months, PFS and OS of the combination group were significantly increased than the single-agent group (median PFS, 6.67 vs. 3.80 months, p = 0.002; median OS, 13.60 vs. 11.45 months, p = 0.013). Grade III/IV toxicity was similar between the two groups (p = 0.113). Through multivariate analyses, we found that Eastern Cooperative Oncology Group (ECOG) score (p < 0.001), further-line treatment (p < 0.001) and combination chemotherapy (p = 0.024) were the independent prognostic factors. CONCLUSION: Compared with mono-therapy, combination chemotherapy was a better second-line option for Chinese patients with good performance status, especially in those with TFI of ≥ 6 months.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Docetaxel/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Pemetrexed/uso terapéutico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Pueblo Asiatico , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Carcinoma de Pulmón de Células no Pequeñas/patología , Femenino , Humanos , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/patología , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
Purpose: To examine the biomechanical effects-induced wave-front aberrations after conventional laser refractive surgery. Methods: A finite element model of the human eye was established to simulate conventional laser refractive surgery with corrected refraction from -1 to -15 diopters (D). The deformation of the anterior and posterior corneal surfaces was obtained under the intraocular pressure (IOP). Then, the surface displacement was converted to wave-front aberrations. Results: Following conventional refractive surgery, significant deformation of the anterior and posterior corneal surfaces occurred because of the corneal biomechanical effects, resulting in increased residual wave-front aberrations. Deformation of the anterior surface resulted in a hyperopic shift, which was significantly increased with the increasing refractive correction. The residual high-order aberrations consisted of spherical aberration, vertical coma, and y-trefoil. Spherical aberration was significantly positively correlated to enhanced refraction correction. The effect of posterior corneal surface on induced wave-front aberration was less than the anterior corneal surface. The IOP slightly affects the postoperative defocus, coma, and spherical aberration. When treatment decentration occurred during the procedure, the hyperopic shift decreased as the eccentricity increased. Treatment decentration had a significant impact on the spherical aberration and the coma. In addition, the ocular tissue elasticity played a key role in hyperopic shift, whereas it had little effect on the other aberrations. Conclusions: Among the many factors that affect high-order aberrations after conventional laser refractive surgery, the alterations in corneal morphology caused by biomechanical effects must be considered, as they can lead to an increase in postoperative residual wave-front aberrations.
Asunto(s)
Córnea/fisiopatología , Cirugía Laser de Córnea/efectos adversos , Aberración de Frente de Onda Corneal/etiología , Análisis de Elementos Finitos , Modelos Teóricos , Miopía/cirugía , Fenómenos Biomecánicos , Aberración de Frente de Onda Corneal/fisiopatología , Elasticidad/fisiología , Humanos , Presión Intraocular/fisiología , Miopía/fisiopatología , Refracción Ocular/fisiología , Agudeza Visual/fisiologíaRESUMEN
Of the different types of lung cancer, lung squamous cell cancer (LUSC) has the second highest rates of morbidity and mortality, which have been increasing in recent years. Epigenetic abnormalities may serve as potential biomarkers and diagnostic and/or therapeutic targets, which may help to monitor and improve the prognosis of patients with cancer. In the present study, data were obtained from The Cancer Genome Atlas database and survival and joint survival analyses were conducted using the R MethylMix package. Peptidase, mitochondrial processing a subunit pseudogene 1 (PMPCAP1), sosondowah ankyrin repeat domain family member C (SOWAHC) and zinc finger protein (ZNF) 454 were identified as independent prognosisrelated hub methylationdriven genes (MDGs). Of these three genes, PMPCAP1 and SOWAHC, characterized by hypomethylation and high expression levels, were associated with poor prognosis in patients with LUSC, whilst ZNF454 was associated with an improved prognosis. In addition, pathway enrichment analysis suggested that PMPCAP1, SOWAHC and ZNF454 were primarily involved in gene expression or transcription pathways. Furthermore, 5, 1 and 10 key methylation sites of PMPCAP1, SOWAHC and ZNF454, respectively, were confirmed to be significantly relevant to gene expression, establishing a basis for further investigation into the mechanisms and more precise targets of these 3 genes. In conclusion, the MDGs PMPCAP1, SOWAHC and ZNF454 may be potential prognostic biomarkers of LUSC for guiding diagnosis and therapy options, as well as providing a theoretical basis for further investigation.