RESUMEN

BACKGROUND: We investigated the proper timing, efficacy and safety of tacrolimus for juvenile myasthenia gravis (JMG). METHODS: We conducted a retrospective cohort study for JMG patients treated with tacrolimus at Xiangya Hospital, Central South University, Changsha, China from 2010 to 2023. The clinical information of patients with a follow-up of more than 1 year was collected. Comparisons of clinical features between groups of patients who achieved therapeutic goal and those who did not achieve therapeutic goal as well as between groups of patients treated with tacrolimus within or after 1 year from JMG onset was carried out. RESULTS: Forty-three patients were enrolled, of whom 28 achieved therapeutic goal. Tacrolimus reduced glucocorticoids (GC) dosages for the 28 cases and 15 cases discontinued GC completely. Generalized myasthenia gravis (GMG) subtype had an association with a group of patients who achieved therapeutic goal (p = 0.001). Median duration from JMG onset to tacrolimus use was 10.50 months for those who achieved therapeutic goal and 36.00 months for those who did not achieve therapeutic goal (p = 0.010). The median Myasthenia Gravis Activities of Daily Living (MG-ADL) score improved significantly (p = 0.003). The initiation of tacrolimus within 1 year of JMG onset showed an association with achievement of therapeutic goal (p = 0.026). GMG subtype showed an association with a group of patients who received tacrolimus within 1 year (p = <0.001). Tacrolimus side effects were tolerable. CONCLUSION: The provision of tacrolimus within 1 year of JMG onset is effective and safe.

RESUMEN

Electrochemiluminescence (ECL) is a powerful tool for clinical diagnosis due to its exceptional sensitivity. However, the standard tripropylamine (TPrA) coreactant for Ru(bpy)3Cl2, the most widely studied and used ECL system, is highly toxic. Despite extensive research on alternative coreactants, they often fall short in poor efficiency. From a reaction kinetics perspective, accelerating electrooxidation rate of Ru(bpy)3Cl2 is an essential way to compensate the efficiency limitation of coreactants, but is rarely reported. Here, a hybrid electrocatalyst@coreactant dots for the ECL of Ru(bpy)3Cl2 is reported. The as-prepared WSe2@bovine serum albumin (WSe2@BSA) dots is biocompatible, and demonstrate dual functions, i.e., the BSA shell works as a coreactant, meanwhile, the WSe2 core effectively catalyzes Ru(bpy)3Cl2 oxidation. As a result, WSe2@BSA dots exhibit an exceptionally high efficiency comparable to TPrA for the ECL of Ru(bpy)3Cl2. In addition, the procedure for synthesizing WSe2@BSA dots is facile (room temperature, atmospheric conditions), rapid (5 min), and scalable (for millions of bioassays). A biosensor utilizing WSe2@BSA dots shows promise for highly sensitive detecting glypican-3 in clinical liver cancer serum samples, especially for alpha-fetoprotein-negative patients. This work opens a new avenue for developing a highly efficient ECL system for biosensing and clinical diagnosis.

RESUMEN

Background and objective: The use of sizable dorsal flaps for webspace reconstruction without skin grafting can minimize complications in syndactyly correction. We report the technique and results of a cross-shaped advancement flap for reconstruction of the webspace and coverage of the lateral sides of the bases of the separated fingers in congenital syndactyly. Methods: From June 2018 to July 2020, 15 patients with simple or complex syndactyly for webspace reconstruction with a dorsal cross-shaped advancement flap were retrospectively studied. The patients' ages ranged from 5 to 144 months, with a median age of 12 months. Out of these 15 patients, six patients were suffering from bilateral involvement. Withey grading of web creep was used for postoperative evaluation. Scar hyperplasia was assessed using the Vancouver Scar Scale, and Visual Analogue Scale was applied to evaluate the subjective satisfaction of the children's families with the reconstructed finger appearance, pain and function. Results: There was no perioperative complication in the group. During an 8-17 months follow-up period, no secondary correction was needed in this group. The average score of Withey scale was 0.1, and Vancouver Scar Scale was 1.5. The Visual Analogue Scale score of appearance, pain and function was 1.8, 0.2 and 1.1, respectively. Conclusion: This technique can reconstruct the webspace and cover the lateral wall of the fingers for syndactyly correction without the risk for web creep or hypertrophic scar.

RESUMEN

Flow cytometry is a vital tool in biomedical research and laboratory medicine. However, its accuracy is often compromised by undesired fluctuations in fluorescence intensity. While fluorescence lifetime imaging microscopy (FLIM) bypasses this challenge as fluorescence lifetime remains unaffected by such fluctuations, the full integration of FLIM into flow cytometry has yet to be demonstrated due to speed limitations. Here we overcome the speed limitations in FLIM, thereby enabling high-throughput FLIM flow cytometry at a high rate of over 10,000 cells per second. This is made possible by using dual intensity-modulated continuous-wave beam arrays with complementary modulation frequency pairs for fluorophore excitation and acquiring fluorescence lifetime images of rapidly flowing cells. Moreover, our FLIM system distinguishes subpopulations in male rat glioma and captures dynamic changes in the cell nucleus induced by an anti-cancer drug. FLIM flow cytometry significantly enhances cellular analysis capabilities, providing detailed insights into cellular functions, interactions, and environments.

Asunto(s)

Citometría de Flujo , Glioma , Citometría de Flujo/métodos , Animales , Ratas , Glioma/diagnóstico por imagen , Glioma/patología , Glioma/metabolismo , Masculino , Microscopía Fluorescente/métodos , Línea Celular Tumoral , Imagen Óptica/métodos , Humanos , Núcleo Celular/metabolismo , Ensayos Analíticos de Alto Rendimiento/métodos , Colorantes Fluorescentes/química

RESUMEN

Detoxification genes are crucial to insect resistance against chemical pesticides, yet their expression may be altered by exposure to biopesticides such as spores and insecticidal proteins of Bacillus thuringiensis (Bt). Increased enzymatic levels of selected detoxification genes, including glutathione S-transferase (GST), cytochrome P450 (CYP450), and carboxylesterase (CarE), were detected in chlorantraniliprole (CAP)-resistant strains of the diamondback moth (DBM, Plutella xylostella) from China when compared to a reference susceptible strain. These CAP-resistant DBM strains displayed distinct expression patterns of GST 1, CYP6B7, and CarE-6 after treatment with CAP and a Bt pesticide (Bt-G033). In particular, the gene expression analysis demonstrated significant upregulation of the CYP6B7 gene in response to the CAP treatment, while the same gene was downregulated following the Bt-G033 treatment. Downregulation of CYP6B7 using RNAi resulted in increased susceptibility to CAP in resistant DBM strains, suggesting a role of this gene in the resistant phenotype. However, pretreatment with a sublethal dose of Bt-G033 inducing the downregulation of CYP6B7 did not significantly increase CAP potency against the resistant DBM strains. These results identify the DBM genes involved in the metabolic resistance to CAP and demonstrate how their expression is affected by exposure to Bt-G033.

RESUMEN

We examined the function of heparan-sulfate-modified proteoglycans (HSPGs) in pathways affecting Alzheimer disease (AD)-related cell pathology in human cell lines and mouse astrocytes. Mechanisms of HSPG influences on presenilin-dependent cell loss were evaluated in Drosophila using knockdown of the presenilin homolog, Psn, together with partial loss-of-function of sulfateless (sfl), a gene specifically affecting HS sulfation. HSPG modulation of autophagy, mitochondrial function, and lipid metabolism were shown to be conserved in human cell lines, Drosophila, and mouse astrocytes. RNA interference (RNAi) of Ndst1 reduced intracellular lipid levels in wild-type mouse astrocytes or those expressing humanized variants of APOE, APOE3, and APOE4. Neuron-directed knockdown of Psn in Drosophila produced apoptosis and cell loss in the brain, phenotypes suppressed by reductions in sfl expression. Abnormalities in mitochondria, liposomes, and autophagosome-derived structures in animals with Psn knockdown were also rescued by reduction of sfl. These findings support the direct involvement of HSPGs in AD pathogenesis.

RESUMEN

BACKGROUND: Depression has been found to be associated with cognitive decline, but whether longer depressive durations lead to more severe cognitive declines has not been investigated. We aimed to estimate the association between depressive duration and cognitive decline in middle-aged and older Americans based on a large-scale representative population study. METHODS: We included 27,886 participants from the Health and Retirement Study (HRS) in 2010-2018. Four datasets with 2-, 4-, 6-, and 8-year consecutive interviews were further derived which involving persistent depressed and persistent depression-free individuals. Multiple linear regressions were constructed to estimate the effects of each depressive duration on the decline in global cognition, memory and mental status. Meta-regressions were performed to test the linear trends and to explore the heterogeneity between sex, age and baseline cognitive function along with subgroup analyses. RESULTS: Depressive durations of 2, 4, 6, and 8 years were associated with reductions in global cognitive scores of 0.62 points (95% CI: 0.51-0.73), 0.77 points (95% CI: 0.60-0.94), 0.83 points (95% CI: 0.55-1.10), and 1.09 points (95% CI: 0.63-1.55), respectively, indicating a linear trend (P = 0.016). More pronounced associations were observed in middle-aged adults and females. Similar patterns were found in the associations between depressive duration and two subdomains, i.e., memory and mental health. LIMITATIONS: This study is essentially a cross-sectional study and therefore cannot provide causal associations. CONCLUSIONS: Longer depressive durations were linearly related to more severe cognitive declines. Timely intervention for depression targeted middle-aged adults can more effectively alleviate cognition-related burdens.

Asunto(s)

Disfunción Cognitiva , Depresión , Humanos , Femenino , Masculino , Disfunción Cognitiva/epidemiología , Persona de Mediana Edad , Anciano , Depresión/epidemiología , Factores de Tiempo , Estados Unidos/epidemiología , Jubilación/estadística & datos numéricos , Jubilación/psicología

RESUMEN

BACKGROUND: Contactin-associated protein-2(CASPR2) antibody-associated autoimmune encephalitis(AE) is rare in children. This study aimed to report the clinical characteristics and long-term outcome of CASPR2 autoimmunity in children to expand the disease spectrum. METHODS: Children who were hospitalized in our hospital with clinically suspected AE from May 2015 to April 2022 and underwent neuronal surface antibodies detections were retrospectively analyzed. Clinical data of patients with CASPR2 autoimmunity were collected. RESULTS: Patients who were positive for NMDAR-IgG, CASPR2-IgG, LGI1-IgG and IgLON5-IgG occupied 95.2%(119/125),3.2%(4/125),0.8%(1/125) and 0.8%(1/125), respectively.The median onset age of the 4 patients with CASPR2-IgG was 5.6 years. The most common symptoms were psychiatric symptoms/abnormal behavior(3/4) and sleep dysfunction(3/4). One patient developed a phenotype of Rasmussen encephalitis(RE). Tumor was absent in our patients. Two patients showed abnormal findings on initial brain magnetic resonance imaging(MRI) scans. All the patients showed favorable response to immunotherapy except the patient with RE experienced recurrent symptoms who finally achieved remission after surgery. All the patients had a favorable long-term outcome at the last follow-up(33-58months). CONCLUSIONS: CASPR2 autoimmunity may be the second most common anti-neuronal surface antibodies associated neurological disease in children. Psychiatric symptoms/abnormal behavior and sleep disorder were common in children with CASPR2-associated AE. Tumor was rare in those patients. Most pediatric patients had a favorable long-term outcome.

Asunto(s)

Autoanticuerpos , Encefalitis , Proteínas de la Membrana , Proteínas del Tejido Nervioso , Humanos , Masculino , Femenino , Niño , Encefalitis/inmunología , Encefalitis/diagnóstico , Estudios Retrospectivos , Proteínas del Tejido Nervioso/inmunología , Proteínas de la Membrana/inmunología , Preescolar , Enfermedad de Hashimoto/inmunología , Enfermedad de Hashimoto/diagnóstico , Adolescente

RESUMEN

Pseudomonas plecoglossicida is one of most important pathogenic bacterial species in large yellow croaker and several other commercially valuable fish species. In our previous study, a GacS deficient mutant (ΔgacS) was constructed and its virulence showed substantially attenuated. In present study, the safety, immunogenicity and protective effect of the ΔgacS were evaluated in large yellow croaker as a live-attenuated vaccine candidate. It was shown that the ΔgacS strain exhibited good safety to large yellow croaker and there was no mortality or clinical symptoms observed in all fish that infected by ΔgacS strain with the doses range from 2 × 105～107 CFU per fish via intraperitoneal injection (IP) or immersion (IM), and almost all bacteria were cleaned up in the spleen of the fish at 14-day post infection. Specific antibodies could be detected at 7-day and 14-day post infection by direct agglutination method, and the valences of antibodies and bactericidal activities of the serum were significant increased with vaccination doses and vaccination time. Moreover, the expressions of some molecules and cytokines involved in specific immune responses were detected in the ΔgacS strain immunization group and control group. After challenged by the wild-type (WT) strain XSDHY-P, the relative percentage survival (RPS) showed highly correlated with the immunized dosage regardless of vaccination methods. It showed that the RPS of the IP groups were 39.47 %, 57.89 %, 71.05 % with the immune dosage in a descending order, respectively, and the RPS of the IM groups were 26.31 %, 36.84 %, 76.31 % with the immune dosage in a descending order, respectively. In summary, the ΔgacS strain exhibited safety and good protective effect to large yellow croaker and was a potential live vaccine candidate.

Asunto(s)

Enfermedades de los Peces , Perciformes , Infecciones por Pseudomonas , Pseudomonas , Vacunas Atenuadas , Animales , Enfermedades de los Peces/inmunología , Enfermedades de los Peces/prevención & control , Perciformes/inmunología , Vacunas Atenuadas/inmunología , Vacunas Atenuadas/administración & dosificación , Infecciones por Pseudomonas/veterinaria , Infecciones por Pseudomonas/prevención & control , Infecciones por Pseudomonas/inmunología , Pseudomonas/inmunología , Vacunas Bacterianas/inmunología , Vacunas Bacterianas/administración & dosificación , Vacunas contra la Infección por Pseudomonas/inmunología , Vacunas contra la Infección por Pseudomonas/genética , Inmunogenicidad Vacunal

RESUMEN

BACKGROUND: Cognitive decline, a heavy burden on middle-aged and older adults as global aging is aggravated, was found to be associated with sleep quality. However, the country-between heterogeneity of the association prevented us from quantifying underlying relationship and identifying potential effect modifiers for vulnerable populations and targeted interventions. METHODS: We collected data from 79,922 eligible adults in five nationwide cohorts, examined the respective relationships between cognitive function and sleep quality, synthesized underlying average relationships by meta-analysis, and explored effect modifiers by meta-regressions. Additionally, we conducted subgroup and interaction analyses to identify vulnerable populations and to determine their disparities in vulnerability. RESULTS: Although country-between disparities exist, cognitive function is robustly associated with sleep quality in middle-aged and older adults worldwide, with an effect (ß) of 0.015 [0.003, 0.027]. Executive function is the subdomain most relevant to sleep quality. Disparities in the effects of sleep quality on subdomains exist in populations with different sexes (orientation: ßfemale/ßmale = 1.615, P = 0.020), marital statuses (orientation: ßunmarried/ßmarried = 2.074, P < 0.001), education levels (orientation:ßuneducated/ßeducated = 2.074, P < 0.001) and chronic disease statuses (memory: ßunhealthy/ßhealthy = 1.560, P = 0.005). CONCLUSIONS: Cognitive function decreases with worsening sleep quality in middle-aged and older adults. Vulnerability to poor sleep generally persists in singles, females, the uneducated and people with chronic diseases. To minimize disparities and achieve health equity, we advocate for targeted interventions, i.e., encouraging socialization in singles, confirming effectiveness of hormone replacement therapy in females, employing compulsory education in middle-aged and older adults.

Asunto(s)

Cognición , Disfunción Cognitiva , Calidad del Sueño , Humanos , Anciano , Persona de Mediana Edad , Masculino , Femenino , Disfunción Cognitiva/epidemiología , Estudios de Cohortes , Equidad en Salud , Disparidades en el Estado de Salud , Función Ejecutiva

RESUMEN

OBJECTIVE: This study aims to evaluate the clinical application efficacy of the ultrasound-guided Joystick technique for percutaneous leverage reduction in conjunction with Kirschner wires and external fixator in the treatment of difficult-to-reduce pediatric Salter-Harris II type proximal humerus fractures. METHODS: A retrospective analysis was conducted on children with Salter-Harris II type proximal humerus fractures, who failed manual closed reduction from January 2018 to March 2022. The group consisted of 7 males and 2 females, aged between 10 and 14 years. The surgical method involved percutaneous leverage reduction using the ultrasound-guided Joystick technique, combined with Kirschner wires and external fixation. Throughout the procedure, ultrasound is used for monitoring, with the fracture condition being determined before surgery. An external support screw is inserted into the distal end of the humerus as an operating lever, along with 3.5 mm Kirschner wire for ultrasound-guided reduction and maintenance of position during the operation. Following fixation with Kirschner wire, a combination external fixator is applied. After fixation is completed, ultrasound is used once more to assess the quality of fracture reduction, followed by verification of the reduction status using a C-arm X-ray machine. RESULTS: All surgeries were successfully completed with a 100 % success rate in resetting. Notably, there were no postoperative complications like nerve or vascular injury, malunion, nonunion, or bone bridge formation in the proximal humeral physis. Three cases experienced minor complications (redness and swelling at the screw sites), which improved with conservative management. The follow-up period ranged from 6 to 18 months, averaging 10.6 months, with fracture clinical healing occurring within 6 to 8 weeks (average 6.3 weeks). The final follow-up revealed excellent functional outcomes, with Neer scores ranging from 90 to 100 (average 96.3 points). CONCLUSION: The ultrasound-guided Joystick technique for percutaneous leverage reduction in conjunction with Kirschner wires and external fixator can effectively treat difficult-to-reduce Salter-Harris II proximal humeral fractures in children, avoiding open reduction and minimizing intraoperative radiation exposure. This approach offers good stability and facilitates early rehabilitation, aligning with the ERAS (Enhanced Recovery After Surgery) concept in fracture management, thus warranting clinical promotion.

RESUMEN

A boy, aged 7 months, presented with severe global developmental delay (GDD), refractory epilepsy, hypotonia, nystagmus, ocular hypertelorism, a broad nasal bridge, everted upper lip, a high palatal arch, and cryptorchidism. Genetic testing revealed a de novo heterozygous missense mutation of c.364G>A(p.E122K) in the EEF1A2 gene, and finally the boy was diagnosed with autosomal dominant developmental and epileptic encephalopathy 33 caused by the EEF1A2 gene mutation. This case report suggests that for children with unexplained infancy-onset severe to profound GDD/intellectual disability and refractory epilepsy, genetic testing for EEF1A2 gene mutations should be considered. This is particularly important for those exhibiting hypotonia, nonverbal communication, and craniofacial deformities, to facilitate a confirmed diagnosis.

Asunto(s)

Discapacidades del Desarrollo , Factor 1 de Elongación Peptídica , Humanos , Masculino , Lactante , Discapacidades del Desarrollo/genética , Factor 1 de Elongación Peptídica/genética , Epilepsia/genética , Mutación , Mutación Missense

RESUMEN

Given its antioxidant, anti-inflammatory, and antiapoptotic properties, melatonin (MEL), a health-caring food to improve sleep disorders, is hypothesized to protect against nanomaterial exposure-induced toxicity. However, the conclusion derived from different studies seemed inconsistent. A meta-analysis of all available preclinical studies was performed to examine the effects of MEL on nanomaterial-induced damages. Eighteen relevant studies were retrieved through searching five electronic databases up to December 2023. The meta-analysis showed that relative to control, MEL treatment significantly increased cell viability (standardized mean difference [SMD = 1.27]) and alleviated liver function (lowered AST [SMD = -3.89] and ALT [SMD = -5.89]), bone formation (enhanced BV/TV [SMD = 4.13] and lessened eroded bone surface [SMD = -5.40]), and brain nerve (inhibition of AChE activity [SMD = -3.60]) damages in animals. The protective mechanisms of MEL against damages caused by nanomaterial exposure were associated with its antiapoptotic (decreased Bax/Bcl-2 ratio [SMD = -4.50] and caspase-3 levels [dose <100 µM: SMD = -3.66]), antioxidant (decreased MDA [in vitro: SMD = -2.84; in vivo: SMD = -4.27]), and anti-inflammatory (downregulated TNF-α [in vitro: SMD = -5.41; in vivo: SMD = -3.21] and IL-6 [in vitro: SMD = -5.90; in vivo: SMD = -2.81]) capabilities. In conclusion, our study suggests that MEL should be supplemented to prevent damages in populations exposed to nanomaterials.

RESUMEN

BACKGROUND: Describing the transmission dynamics of infectious diseases across different regions is crucial for effective disease surveillance. The multivariate time series (MTS) model has been widely adopted for constructing cross-regional infectious disease transmission networks due to its strengths in interpretability and predictive performance. Nevertheless, the assumption of constant parameters frequently disregards the dynamic shifts in disease transmission rates, thereby compromising the accuracy of early warnings. This study investigated the applicability of time-varying MTS models in multi-regional infectious disease monitoring and explored strategies for model selection. METHODS: This study focused on two prominent time-varying MTS models: the time-varying parameter-stochastic volatility-vector autoregression (TVP-SV-VAR) model and the time-varying VAR model using the generalized additive framework (tvvarGAM), and intended to explore and verify their applicable conditions for the surveillance of infectious diseases. For the first time, this study proposed the time delay coefficient and spatial sparsity indicators for model selection. These indicators quantify the temporal lags and spatial distribution of infectious disease data, respectively. Simulation study adopted from real-world infectious disease surveillance was carried out to compare model performances under various scenarios of spatio-temporal variation as well as random volatility. Meanwhile, we illustrated how the modelling process could help the surveillance of infectious diseases with an application to the influenza-like case in Sichuan Province, China. RESULTS: When the spatio-temporal variation was small (time delay coefficient: 0.1-0.2, spatial sparsity:0.1-0.3), the TVP-SV-VAR model was superior with smaller fitting residuals and standard errors of parameter estimation than those of the tvvarGAM model. In contrast, the tvvarGAM model was preferable when the spatio-temporal variation increased (time delay coefficient: 0.2-0.3, spatial sparsity: 0.6-0.9). CONCLUSION: This study emphasized the importance of considering spatio-temporal variations when selecting appropriate models for infectious disease surveillance. By incorporating our novel indicators-the time delay coefficient and spatial sparsity-into the model selection process, the study could enhance the accuracy and effectiveness of infectious disease monitoring efforts. This approach was not only valuable in the context of this study, but also has broader implications for improving time-varying MTS analyses in various applications.

Asunto(s)

Enfermedades Transmisibles , Humanos , Enfermedades Transmisibles/epidemiología , Enfermedades Transmisibles/transmisión , China/epidemiología , Modelos Estadísticos , Factores de Tiempo , Monitoreo Epidemiológico , Análisis Multivariante , Gripe Humana/epidemiología , Simulación por Computador

RESUMEN

OBJECTIVE: Since in the cancer setting, tumor cells may use cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) to evade the immune system. This study aimed to identify CTLA-4-related long non-coding RNAs (lncRNAs) and assess their roles in lung adenocarcinoma (LUAD) development. METHODS: Clinical and genomic data were obtained from The Cancer Genome Atlas (TCGA), MSigDB and Gene Weaver. CTLA-4-related lncRNA-based gene signatures (CTLA4LncSigs) were identified using Cox regression, establishing a risk score model and an independent prognostic model. Enrichment analysis (GO/KEGG) was performed. Mendelian randomization (MR) analysis investigated the nitrogen metabolism and lung cancer relationship, with Bayesian weighted MR (BWMR) addressing uncertainties. Correlations with tumor microenvironment and drug sensitivity were explored. RESULTS: Nineteen CTLA4LncSigs significantly influenced LUAD prognosis. The risk score demonstrated independence as a prognostic factor. Functional analysis revealed lncRNAs' impact on nitrogen metabolism. MR and BWMR confirmed the protective role of the nitrogen metabolism pathway in lung cancer. CONCLUSION: Our study identifies CTLA-4-related lncRNAs associated with LUAD prognosis and uncovers a previously undiscovered protective role of the nitrogen metabolism pathway in combating LUAD development, providing new insights into potential therapeutic targets and prognostic biomarkers for this aggressive cancer subtype.

Asunto(s)

Adenocarcinoma del Pulmón , Biomarcadores de Tumor , Antígeno CTLA-4 , Neoplasias Pulmonares , Nitrógeno , ARN Largo no Codificante , Humanos , ARN Largo no Codificante/genética , Antígeno CTLA-4/genética , Antígeno CTLA-4/metabolismo , Pronóstico , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/patología , Adenocarcinoma del Pulmón/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Nitrógeno/metabolismo , Transcriptoma , Regulación Neoplásica de la Expresión Génica , Femenino , Masculino , Análisis de la Aleatorización Mendeliana , Microambiente Tumoral/genética , Microambiente Tumoral/inmunología , Persona de Mediana Edad , Perfilación de la Expresión Génica

RESUMEN

BACKGROUND: The long-term survival benefit of immune checkpoint inhibitors (ICIs) in neoadjuvant and adjuvant settings is unclear for colorectal cancers (CRC) and gastric cancers (GC) with deficiency of mismatch repair (dMMR) or microsatellite instability-high (MSI-H). METHODS: This retrospective study enrolled patients with dMMR/MSI-H CRC and GC who received at least one dose of neoadjuvant ICIs (neoadjuvant cohort, NAC) or adjuvant ICIs (adjuvant cohort, AC) at 17 centers in China. Patients with stage IV disease were also eligible if all tumor lesions were radically resectable. RESULTS: In NAC (n = 124), objective response rates were 75.7% and 55.4%, respectively, in CRC and GC, and pathological complete response rates were 73.4% and 47.7%, respectively. The 3-year disease-free survival (DFS) and overall survival (OS) rates were 96% (95%CI 90-100%) and 100% for CRC (median follow-up [mFU] 29.4 months), respectively, and were 84% (72-96%) and 93% (85-100%) for GC (mFU 33.0 months), respectively. In AC (n = 48), the 3-year DFS and OS rates were 94% (84-100%) and 100% for CRC (mFU 35.5 months), respectively, and were 92% (82-100%) and 96% (88-100%) for GC (mFU 40.4 months), respectively. Among the seven patients with distant relapse, four received dual blockade of PD1 and CTLA4 combined with or without chemo- and targeted drugs, with three partial response and one progressive disease. CONCLUSION: With a relatively long follow-up, this study demonstrated that neoadjuvant and adjuvant ICIs might be both associated with promising DFS and OS in dMMR/MSI-H CRC and GC, which should be confirmed in further randomized clinical trials.

Asunto(s)

Neoplasias Colorrectales , Inhibidores de Puntos de Control Inmunológico , Inestabilidad de Microsatélites , Terapia Neoadyuvante , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/mortalidad , Neoplasias Gástricas/patología , Femenino , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Masculino , Terapia Neoadyuvante/métodos , Persona de Mediana Edad , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/mortalidad , Neoplasias Colorrectales/patología , Estudios Retrospectivos , Anciano , Adulto , Reparación de la Incompatibilidad de ADN , Quimioterapia Adyuvante/métodos , Estudios de Seguimiento

RESUMEN

Even though some recent research revealed individuals with HSA typically display enhanced processing in the early stages of emotional information processing due to hypervigilance and vulnerability to negative stimuli, it is still unclear whether social anxiety affects the time course underlying processing bias for emotional stimuli. Therefore, the present study aimed to explore the early stage of processing social threat stimuli in high social anxiety (HSA) individuals by recording RTs and EEG data in the emotional Stroop task. Behavioral data showed that the HSA group responded to the threat words faster than neutral words (i.e. negative bias), but no emotional effects in the low social anxiety (LSA) group. Although the P1 component did not show any early effects, ERP data exhibited an enhanced N170 for HSA than for LSA groups. Threat words elicited larger N170 than neutral words in the LSA group only; this emotion effect was not evident in the HSA group. These findings indicated that social anxiety modulates early processing for social threat words. This study revealed the neural mechanisms underlying early emotional processing in individuals with social anxiety, providing insights for the evaluation and intervention of social anxiety.

RESUMEN

Calmodulin-like proteins (CMLs) are an essential family of calcium sensors involved in multiple Ca2+-mediated cellular processes in plants. Rosa roxburghii Tratt, known for the abundance of L-ascorbic acid (AsA) in its fruits, is widely distributed in calcium-rich soil of the karst region in southwestern China. The aim of this study was to identify key CMLs that respond to exogenous Ca2+ levels and regulate AsA biosynthesis in R. roxburghii. A genome-wide scan revealed the presence of 41 RrCML genes with 1-4 EF-hand motif (s) unevenly distributed across the 7 chromosomes of R. roxburghii. qRT-PCR analysis revealed that RrCML13, RrCML10, and RrCML36 responded significantly to exogenous Ca2+ treatment, and RrCML13 was positively correlated with GDP-L-galactose phosphorylase encoding gene (RrGGP2) expression and AsA content in the developing fruit. Overexpression of RrCML13 in fruits and roots significantly promoted the transcription of RrGGP2 and the accumulation of AsA, while virus-induced silencing of RrCML13 reduced the transcription of RrGGP2 and the content of AsA. Furthermore, Moreover, the yeast two-hybrid and bimolecular fluorescence complementation (BiFC) analysis confirmed the interaction between RrCML13 and RrGGP2 proteins, indicating that RrCML13 plays a regulatory role in calcium-mediated AsA biosynthesis. This study enhances our understanding of R. roxburghii CMLs and sheds light on the calcium-mediated regulation of AsA biosynthesis.

Asunto(s)

Ácido Ascórbico , Calcio , Calmodulina , Proteínas de Plantas , Rosa , Rosa/genética , Rosa/metabolismo , Ácido Ascórbico/metabolismo , Ácido Ascórbico/biosíntesis , Calcio/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Calmodulina/metabolismo , Calmodulina/genética , Regulación de la Expresión Génica de las Plantas , Familia de Multigenes , Frutas/metabolismo , Frutas/genética , Genoma de Planta , Estudio de Asociación del Genoma Completo , Genes de Plantas

RESUMEN

Dysregulation of apoptosis occurs in different types of malignant tumors and is likely to influence the tumor evolution, as well as clinical prognosis. However, the limited number of studies investigating the predictive power of apoptosis-related genes (ARGs) in gastric cancer indicates a gap in the current research. 174 ARGs who differentially expressed were screened using public databases, including the Gene Expression Omnibus and the Molecular Signatures Database. Univariate and LASSO regression analyses were rigorous approaches to recognize the 12 optimal genes (CTHRC1, PDGFRL, VCAN, GJA1, LOX, UPP1, ANGPT2, CRIM1, HIF1A, APOD, RNase1, and ID1) that make up the prognostic risk model. Molecular mutations, related signaling pathways, and immune system characteristics in different subgroups defined by the risk model were analyzed using different R packages. Moreover, based on the database of Genomics of Drug Sensitivity in Cancer, chemotherapy sensitivity was predicted among the risk subgroups. As a result, there were differences in mutation profiles, signaling pathways, and infiltrated immune cells between patients in various risk groups. Moreover, the low-risk group displayed greater sensitivity to chemotherapy than the high-risk group. Risk model provided a better prognostic value than the T, N, and M stages, according to the receiver operating characteristic curve. Finally, in a nomogram, the risk model and clinical factors were combined to visualize the survival rates of patients with GC. In response to the differential expression of apoptosis-related genes, a novel model for predicting the prognosis of GC patients was developed. This model may be highly valuable for guiding doctors to deliver treatment plans tailored to the need of patients with GC.