RESUMEN

This paper reports the results of a hybrid effectiveness-implementation randomized trial that systematically varied levels of human oversight required to support the implementation of a digital medicine intervention for persons with mild-to-moderate alcohol use disorder (AUD). Participants were randomly assigned to three groups representing possible digital health support models within a health system: self-monitored use (SM; n = 185), peer-supported use (PS; n = 186), or a clinically integrated model CI; (n = 187). Across all three groups, the percentage of self-reported heavy drinking days dropped from 38.4% at baseline (95% CI [35.8%, 41%]) to 22.5% (19.5%, 25.5%) at 12 months. The clinically integrated group showed significant improvements in mental health and quality of life compared to the self-monitoring group (p = 0.011). However, higher attrition rates in the clinically integrated group warrant consideration in interpreting this result. Results suggest that making a self-guided digital intervention available to patients may be a viable option for health systems looking to promote alcohol risk reduction. This study was prospectively registered at clinicaltrials.gov on 7/03/2019 (NCT04011644).

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Pulmonary hypertension (PH) is a progressive cardiopulmonary disorder characterized by pulmonary vascular remodeling (PVR), primarily due to the excessive proliferation of pulmonary artery smooth muscle cells (PASMCs). This study aimed to investigate the role and molecular mechanism of SOX9 in hypoxic PH in rats. The findings revealed that SOX9 was upregulated in the pulmonary arteries and PASMCs of hypoxia-exposed rats. SOX9 knockdown inhibited hypoxia-induced proliferation and migration of PASMCs, reduced PVR, and subsequently alleviated hypoxia-induced PH in rats, suggesting that SOX9 plays a critical role in PH. Further investigation demonstrated that SOX9 interacted with DPP4, preventing its ubiquitin degradation in hypoxia-exposed PASMCs. DPP4 knockdown inhibited hypoxia-induced PASMC proliferation and migration, and administration of the DPP4 inhibitor sitagliptin (5 mg/kg) significantly reduced PVR and alleviated hypoxia-induced PH in rats, indicating that SOX9 contributes to PH by stabilizing DPP4. The results also showed that hypoxia induced YAP1 expression and dephosphorylation, leading to YAP1 nuclear localization. YAP1 knockdown promoted the degradation of HIF-1α in hypoxia-exposed PASMCs and inhibited hypoxia-induced proliferation and migration of PASMCs. Additionally, HIF-1α, as a transcription factor, promoted SOX9 expression by binding to the SOX9 promoter in hypoxia-exposed PASMCs. In conclusion, hypoxia promotes the proliferation and migration of PASMCs through the regulation of the YAP1/HIF-1α/SOX9/DPP4 signaling pathway, leading to PH in rats. These findings suggest that SOX9 may serve as a potential prognostic marker and therapeutic target for PH.

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Piezoelectric ceramics with high electrical performances and high Curie temperature (Tc) act as key materials for numerous electromechanical devices such as transducers and actuators. Herein, we report a systematic investigation on the crystal structure, microstructure and electrical properties of Sr and La co-doped Pb(Mg1/3Nb2/3)O3-PbZrO3-PbTiO3 ceramics with a low Pb(Mg1/3Nb2/3)O3 content, namely, (Pb1-ySry)(Mg1/3Nb2/3)0.07ZrxTi0.93-xO3:zLa. With an increase in the Zr content (x value) from 0.49 to 0.53, its crystal structure evolved from a tetragonal phase to a rhombohedral phase, leading to not only a morphotropic phase boundary (MPB) at around x = 0.51 but also a monotonously decreasing Tc. Meanwhile, a change in either the Sr- or La-doping content (y and z values, respectively) in the range of y = 0.03-0.07 and z = 0.01-0.03 can slightly deviate the structure of MPB, resulting in a significant effect on its electrical properties. As the best results, the optimal composition of x = 0.51, y = 0.05, and z = 0.02 yielded peak electrical performance, with a related room temperature piezoelectric coefficient (d33) of 645 pC N-1, remanent polarization (Pr) of 33.5 µC cm-2, coercive field (Ec) of 8.6 kV cm-1, and Tc of 242 °C. Especially, its piezoelectric properties showed excellent temperature stability, and its d33 value decreased by only 3% from room temperature to 150 °C. This work not only provides an alternative piezoelectric ceramic with outstanding electrical performance for industrial applications, but also reveals a comprehensive perspective on the composition-structure-property relationship of doped Pb[(Mg1/3Nb2/3),Zr,Ti]O3, which is helpful for further work on piezoelectric ceramics.

RESUMEN

Alteration of synaptic function in the dorsal horn (DH) has been implicated as a cellular substrate for the development of neuropathic pain, but certain details remain unclear. In particular, the lack of information on the types of synapses that undergo functional changes hinders the understanding of disease pathogenesis from a synaptic plasticity perspective. Here, we addressed this issue by using optogenetic and retrograde tracing ex vivo to selectively stimulate first-order nociceptors expressing Nav1.8 (NRsNav1.8) and record the responses of spinothalamic tract neurons in spinal lamina I (L1-STTNs). We found that spared nerve injury (SNI) increased excitatory postsynaptic currents (EPSCs) in L1-STTNs evoked by photostimulation of NRsNav1.8 (referred to as Nav1.8-STTN EPSCs). This effect was accompanied by a significant change in the failure rate and paired-pulse ratio of synaptic transmission from NRsNav1.8 to L1-STTN and in the frequency (not amplitude) of spontaneous EPSCs recorded in L1-STTNs. However, no change was observed in the ratio of AMPA to NMDA receptor-mediated components of Nav1.8-STTN EPSCs or in the amplitude of unitary EPSCs constituting Nav1.8-STTN EPSCs recorded with extracellular Ca2+ replaced by Sr2+ In addition, there was a small increase (approximately 10%) in the number of L1-STTNs showing immunoreactivity for phosphorylated extracellular signal-regulated kinases in mice after SNI compared with sham. Similarly, only a small percentage of L1-STTNs showed a lower action potential threshold after SNI. In conclusion, our results show that SNI induces presynaptic modulation at NRNav1.8 (consisting of both peptidergic and nonpeptidergic nociceptors) synapses on L1-STTNs forming the lateral spinothalamic tract.

Asunto(s)

Potenciales Postsinápticos Excitadores , Canal de Sodio Activado por Voltaje NAV1.8 , Nociceptores , Tractos Espinotalámicos , Transmisión Sináptica , Animales , Canal de Sodio Activado por Voltaje NAV1.8/metabolismo , Canal de Sodio Activado por Voltaje NAV1.8/genética , Nociceptores/metabolismo , Nociceptores/fisiología , Tractos Espinotalámicos/metabolismo , Potenciales Postsinápticos Excitadores/fisiología , Masculino , Transmisión Sináptica/fisiología , Ratones , Optogenética , Ratones Endogámicos C57BL , Ratones Transgénicos

RESUMEN

BACKGROUND: This study aims to facilitate parental identification of designated emergency facilities for expeditious pediatric care within the framework of Taiwan's newly implemented "regional joint defense" approach to pediatric emergency services. The research seeks to elucidate the mechanisms by which this novel system can enhance timely access to appropriate emergency care for children, potentially improving health outcomes and resource utilization in acute pediatric situations. METHODS: Factor analysis (FA) and triangular entropy matrix (TEM) analyzed the appearance, breathing and skin of pediatric assessment triangle (ABC of PAT), three types of prehospital pediatric emergence condition (PPEC), five levels of Taiwan's pediatric emergency triage (TPET), and applied the social learning theory (SLT) in educational doctrine, using experts' weighted questionnaires. RESULTS: Firstly, to address deficiencies in Taiwan's pediatric prehospital emergency medicine (PEM) system, integrating emergency medical knowledge (EMK) and pediatric life support (PLS) into medical education, staff training, and the national handbook for new parents is crucial. This equips parents to manage children's illnesses and prevent emergencies. Then, in life-threatening situations, immediate emergency room (ER) transport is vital for symptoms like whitish or purple lips, cold limbs, mottled skin, cold sweat, convulsions, dyspnea, chest dimples, weak consciousness, and oxygen saturation below 94%. Finally, for non-life-threatening emergencies, seek medical evaluation if symptoms include wheezing, chest tightness, chest pain, persistent high fever over 39 degrees with convulsions, chills, cold sweats, not eating or urinating for over 12 hours, or fever lasting more than 48 hours. CONCLUSION: Parents must remain calm and provide their baby with a sense of security while observing the development of physical symptoms. This approach enables them to effectively determine the most appropriate time to take their children to the emergency room, thereby avoiding life-threatening emergencies. Prompt and proper measures and treatments not only alleviate various discomforts caused by illness or medical emergencies but also reduce systemic distress, life-threatening situations, and unfortunate incidents before hospitalization.

Asunto(s)

Servicios Médicos de Urgencia , Humanos , Taiwán/epidemiología , Niño , Medicina de Emergencia/educación , Medicina de Emergencia/organización & administración , Cuidados para Prolongación de la Vida/métodos , Pediatría/métodos , Pediatría/organización & administración , Triaje/métodos , Medicina de Urgencia Pediátrica/métodos , Medicina de Urgencia Pediátrica/estadística & datos numéricos , Preescolar , Encuestas y Cuestionarios , Lactante

RESUMEN

Proteolysis-targeting chimeras (PROTACs) selectively eliminate detrimental proteins by exploiting the ubiquitin-proteasome system (UPS), representing a promising therapeutic strategy against various diseases. Effective adaptations of degradation signal sequences and E3 ligases for PROTACs remain limited. Here, we employed three amino acids─Gly, Pro, and Lys─as the ligand to recruit the corresponding E3 ligases: CRL2ZYG11B/ZER1, GID4, and UBRs, to degrade EML4-ALK and mutant EGFR, two oncogenic drivers in NSCLC. We found that the extent of EML4-ALK and EGFR reduction can be easily fine-tuned by using different degradation signals. These amino acid-based PROTACs, termed AATacs, hindered proliferation and induced cell cycle arrest and apoptosis of NSCLC cells in vitro. Compared to other PROTACs, AATacs are small, interchangeable but with different degradation efficiency. Our study further expands the repertoire of E3 ligases and their ligands for PROTAC application, improving the versatility and utility of targeted protein degradation for therapeutic purposes.

Asunto(s)

Aminoácidos , Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Proteolisis , Ubiquitina-Proteína Ligasas , Humanos , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Carcinoma de Pulmón de Células no Pequeñas/metabolismo , Proteolisis/efectos de los fármacos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/metabolismo , Ubiquitina-Proteína Ligasas/metabolismo , Aminoácidos/farmacología , Aminoácidos/metabolismo , Aminoácidos/química , Antineoplásicos/farmacología , Antineoplásicos/química , Antineoplásicos/síntesis química , Proliferación Celular/efectos de los fármacos , Línea Celular Tumoral , Receptores ErbB/metabolismo , Receptores ErbB/antagonistas & inhibidores , Apoptosis/efectos de los fármacos , Quimera Dirigida a la Proteólisis

RESUMEN

Among the many adverse geological disasters, the surge water disaster in karst areas causes the greatest loss to underground engineering construction, so it is necessary to carry out relevant research on the management of surge water disaster in karst pipelines. This study presents the creation of an oily epoxy resin magnetic convergence grouting material (OEMS) specifically developed to prevent water infiltration in pipelines. A self-designed visual karst pipeline grouting simulation system was used to conduct an experimental study on the diffusion and plugging behavior of magnetic slurry grouting. A model was constructed to simulate the migration of a magnetic slurry in water inrush circumstances. The model is based on the theory of slurry diffusion and the concept of magnetic adsorption. The results suggest that:(i) The best performance in grouting sealing is achieved when the ratio of new OEMS epoxy resin A liquid to B liquid is 2:1, and the blending ratio of flyash and Fe3O4 powder falls between 25 and 55%. (ii) The primary and secondary correlations among the parameters that affect the rate of change in flow rate, plugging pressure, and slurry retention rate are as follows: Hydrodynamic velocity has the greatest correlation, followed by plugging length, Fe3O4 power ratio, and flyash mixture ratio. (iii) The validity of the model is verified by comparing empirical observations with calculated theoretical values.

RESUMEN

Over the years, microbiome research has achieved tremendous advancements driven by culture-independent meta-omics approaches. Despite extensive research, our understanding of the functional roles and causal effects of the microbiome on phenotypes remains limited. In this study, we focused on the rumen metaproteome, combining it with metatranscriptome and metabolome data to accurately identify the active functional distributions of rumen microorganisms and specific functional groups that influence feed efficiency. By integrating host genetics data, we established the potentially causal relationships between microbes-proteins/metabolites-phenotype, and identified specific patterns in which functional groups of rumen microorganisms influence host feed efficiency. We found a causal link between Selenomonas bovis and rumen carbohydrate metabolism, potentially mediated by bacterial chemotaxis and a two-component regulatory system, impacting feed utilization efficiency of dairy cows. Our study on the nutrient utilization functional groups in the rumen of high-feed-efficiency dairy cows, along with the identification of key microbiota functional proteins and their potentially causal relationships, will help move from correlation to causation in rumen microbiome research. This will ultimately enable precise regulation of the rumen microbiota for optimized ruminant production.

RESUMEN

Cancer is the disease that poses the greatest threat to human health today. Among them, hepatocellular carcinoma (HCC) is particularly prominent due to its high recurrence rate and extremely low five-year postoperative survival rate. In addition to surgical treatment, radiotherapy, chemotherapy, and immunotherapy are the main methods for treating HCC. Due to the natural drug resistance of chemoradiotherapy and targeted drugs, satisfactory results have not been achieved in terms of therapeutic efficacy and cost. AMP-Activated Protein Kinase (AMPK) is a serine/threonine protein kinase. It mainly coordinates the metabolism and transformation of energy between cells, which maintaining a balance between energy supply and demand. The processes of cell growth, proliferation, autophagy, and survival all involve various reaction of cells to energy changes. The regulatory role of AMPK in cellular energy metabolism plays an important role in the occurrence, development, treatment, and prognosis of HCC. Here, we reviewed the latest progress on the regulatory role of AMPK in the occurrence and development of HCC. Firstly, the molecular structure and activation mechanism of AMPK were introduced. Secondly, the emerging regulator related to AMPK and tumors were elaborated. Next, the multitasking roles of AMPK in the occurrence and development mechanism of HCC were discussed separately. Finally, the translational implications and the challenges of AMPK-targeted therapies for HCC treatment were elaborated. In summary, these pieces of information suggest that AMPK can serve as a promising specific therapeutic target for the treatment of HCC.

RESUMEN

Two-dimensional (2D) transition metal dichalcogenides (TMDs) allow for atomic-scale manipulation, challenging the conventional limitations of semiconductor materials. This capability may overcome the short-channel effect, sparking significant advancements in electronic devices that utilize 2D TMDs. Exploring the dimension and performance limits of transistors based on 2D TMDs has gained substantial importance. This review provides a comprehensive investigation into these limits of the single 2D-TMD transistor. It delves into the impacts of miniaturization, including the reduction of channel length, gate length, source/drain contact length, and dielectric thickness on transistor operation and performance. In addition, this review provides a detailed analysis of performance parameters such as source/drain contact resistance, subthreshold swing, hysteresis loop, carrier mobility, on/off ratio, and the development of p-type and single logic transistors. This review details the two logical expressions of the single 2D-TMD logic transistor, including current and voltage. It also emphasizes the role of 2D TMD-based transistors as memory devices, focusing on enhancing memory operation speed, endurance, data retention, and extinction ratio, as well as reducing energy consumption in memory devices functioning as artificial synapses. This review demonstrates the two calculating methods for dynamic energy consumption of 2D synaptic devices. This review not only summarizes the current state of the art in this field but also highlights potential future research directions and applications. It underscores the anticipated challenges, opportunities, and potential solutions in navigating the dimension and performance boundaries of 2D transistors.

RESUMEN

Prader-Willi syndrome (PWS) is a multisystemic disorder. Notably, many characteristic symptoms of PWS are correlated with locus coeruleus norepinephrine system (LC-NE) dysfunction, including impairment in arousal, learning, pain modulation, and stress-induced negative affective states. Although electrophysiological experiments in necdin-deficient mice, an established PWS animal model, have revealed decreased spontaneous neuronal firing activity in the LC and impaired excitability, the behavioral phenotypes related to LC-NE dysfunction remain unexplored. In this study, heterozygous necdin-deficient mice (B6.Cg-Ndntm1ky) were bred from wild-type (WT) females to generate WT (+m/+p) and heterozygous (+m/-p) animals. Compared to WT mice, Ndn + m/-p mice demonstrated impaired visual-spatial memory in the Y-maze test, reduced social interaction, impaired sexual recognition, and shorter falling latency on the Rotarod. Using the open field test (OFT) and elevated plus maze (EPM), we observed similar locomotion activity of Ndn + m/-p and WT mice, but Ndn + m/-p mice were less anxious. After acute restraint, Ndn + m/-p mice exhibited significant impairment in stress-induced anxiety. Additionally, the plasma norepinephrine surge following exposure to acute restraint stress was also impaired. Pretreatment with atomoxetine, a norepinephrine reuptake inhibitor aimed to enhance LC function, restored Ndn + m/-p mice to exhibit a normal response to acute restraint stress. Furthermore, by employing chemogenetic approaches to facilitate LC neuronal firing, post-stress anxious responses were also partially rescued in Ndn + m/-p mice. These data strongly suggest that LC dysfunction is implicated in the pathogenesis of stress-related neuropsychiatric symptoms in PWS. Manipulation of LC activity may hold therapeutic potential for patients with PWS.

Asunto(s)

Modelos Animales de Enfermedad , Locus Coeruleus , Síndrome de Prader-Willi , Animales , Locus Coeruleus/fisiopatología , Ratones , Síndrome de Prader-Willi/fisiopatología , Femenino , Masculino , Proteínas del Tejido Nervioso/genética , Norepinefrina/metabolismo , Ansiedad/fisiopatología , Ansiedad/etiología , Ratones Endogámicos C57BL , Aprendizaje por Laberinto/fisiología , Estrés Psicológico/fisiopatología , Estrés Psicológico/psicología , Interacción Social , Proteínas Nucleares

RESUMEN

Plant-derived ß-glucosidases hold promise for glycoside biosynthesis via reverse hydrolysis because of their excellent glucose tolerance and robust stability. However, their poor heterologous expression hinders the development of large-scale production and applications. In this study, we overexpressed apple seed ß-glucosidase (ASG II) in Komagataella phaffii and enhanced its production from 289 to 4322 U L-1 through expression cassette engineering and protein engineering. Upon scaling up to a 5-L high cell-density fermentation, the resultant mutant ASG IIV80A achieved a maximum protein concentration and activity in the secreted supernatant of 2.3 g L-1 and 41.4 kU L-1, respectively. The preparative biosynthesis of salidroside by ASG IIV80A exhibited a high space-time yield of 33.1 g L-1 d-1, which is so far the highest level by plant-derived ß-glucosidase. Our work addresses the long-standing challenge of the heterologous expression of plant-derived ß-glucosidase in microorganisms and presents new avenues for the efficient production of salidroside and other natural glycosides.

Asunto(s)

Glucósidos , Malus , Fenoles , Semillas , beta-Glucosidasa , Fenoles/metabolismo , beta-Glucosidasa/genética , beta-Glucosidasa/metabolismo , Glucósidos/biosíntesis , Glucósidos/metabolismo , Glucósidos/química , Semillas/genética , Semillas/metabolismo , Saccharomycetales/genética , Saccharomycetales/metabolismo , Saccharomycetales/enzimología , Fermentación , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Ingeniería de Proteínas/métodos

RESUMEN

Substituting electrochemically active elements such as Li and Mg in P2-type layered sodium oxide is an effective strategy for developing competitive cathode materials for sodium-ion batteries. However, the lack of atomic-level understanding regarding the distribution of substitution positions complicates the comprehension of the roles of substituting atoms and the mechanism of sodium-ion intercalation. In this study, we identified the stable configurations of Na in Na0.75Ni0.3Mn0.7O2 and Na0.75Li0.15Mg0.05Ni0.1Mn0.7O2 materials using the site exclusion method. Through simulating the complete charging process for both materials, the structure evolution of the cathodes during the cycling and the impact of the partial substitution of Ni elements by Li and Mg atoms were comprehensively elucidated. Our findings revealed that Mg atoms effectively regulate the distribution of forces within the materials, essentially serving as supportive pillars within the cathode. Meanwhile, Li atoms efficiently mitigated electron localization, consequently diminishing volume fluctuations during the charging process. More importantly, the substitution with Li and Mg atoms could synergistically reduce the interaction between transition metals and sodium ions, thereby reducing the diffusion energy barrier of Na ions. This study not only enhances the comprehension of substituted metal atoms in P2 layered oxides but also offers new insights for the development of sodium-ion cathode materials.

RESUMEN

Sepsis-related brain injury (SRBI) refers to brain dysfunction and structural damage caused by sepsis, which is characterized by inflammation, oxidative stress, and destruction of the blood-brain barrier. Pioglitazone is a PPAR-γ agonist in which PPAR-γ acts as an inflammatory modulator, determining the relationship between PPAR-γ and SRBI and inflammatory state is critical for the disease. This study aimed to construct a drug-target-disease network for SRBI and Pioglitazone based on network pharmacology, and to investigate the therapeutic effect and potential mechanism of Pioglitazone in SRBI induced by lipopolysaccharide (LPS) in rats through transcriptomics. To establish a rat Model of SRBI by intraperitoneal injection of LPS (10 mg/kg): SD rats were divided into Control, Model (LPS), Pioglitazone, (LPS + Pioglitazone) and GW9662 group (LPS+GW9662). The effects and potential mechanisms of Pioglitazone in the treatment of SRBI were studied using biochemical indexes, pathological changes and transcriptome-sequencing (RNA-seq). RNA-seq results showed 620 DEGs between the Model and the Pioglitazone groups. Enrichment analysis involved multiple inflammatory response processes and chemokine receptor binding functions. TLR4 and CXCL10 in the Toll signaling pathway may play an important role in SRBI as important targets. Pioglitazone may ameliorate SRBI through the PPAR-γ/TLR4/CXCL10 pathway.

Asunto(s)

Lipopolisacáridos , PPAR gamma , Pioglitazona , Ratas Sprague-Dawley , Sepsis , Transcriptoma , Pioglitazona/farmacología , Animales , Ratas , PPAR gamma/metabolismo , PPAR gamma/genética , Masculino , Transcriptoma/efectos de los fármacos , Sepsis/tratamiento farmacológico , Sepsis/genética , Sepsis/complicaciones , Sepsis/metabolismo , Receptor Toll-Like 4/metabolismo , Receptor Toll-Like 4/genética , Quimiocina CXCL10/genética , Quimiocina CXCL10/metabolismo , Modelos Animales de Enfermedad , Transducción de Señal/efectos de los fármacos , Anilidas/farmacología , Lesiones Encefálicas/tratamiento farmacológico , Lesiones Encefálicas/metabolismo , Lesiones Encefálicas/genética , Lesiones Encefálicas/etiología , Perfilación de la Expresión Génica , Encefalopatía Asociada a la Sepsis/tratamiento farmacológico , Encefalopatía Asociada a la Sepsis/genética , Encefalopatía Asociada a la Sepsis/metabolismo

RESUMEN

BACKGROUND: Keratinizing squamous cell carcinoma (KSCC) is recognized as WHO I nasopharyngeal carcinoma (NPC). Current guidelines for treating nasopharyngeal cancer do not delineate specific strategies for individual pathologic subtypes. OBJECTIVES: To explore the optimal treatment for KSCC of the nasopharynx. MATERIAL AND METHODS: Data on patients were extracted from the SEER database. Survival differences between patients treated with radiotherapy alone and combined surgery were assessed using Kaplan-Meier and Cox regression models and compared using propensity score matching (PSM). In addition, we explored the survival differences between the two groups of patients in different risk stratifications. RESULTS: In our study, 165 patients underwent surgical intervention, while 1238 patients did not. In both univariate (CSS: p = .001, HR = 0.612; OS: p < .001, HR = 0.623) and multivariate (CSS: p = .004, HR = 0.655; OS: p < .001, HR = 0.655) analyses, combined surgery was identified as a significant prognostic factor. These findings were consistent after PSM. Using RPA, patients were categorized into two groups. CSS improved in the high-risk group, whereas the difference in low-risk patients was not significant. CONCLUSIONS AND SIGNIFICANCE: For patients diagnosed with WHO I nasopharyngeal carcinoma, the combination of radiotherapy and surgery has significant clinical advantages, especially for patients at high risk.

Asunto(s)

Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Humanos , Masculino , Femenino , Persona de Mediana Edad , Neoplasias Nasofaríngeas/radioterapia , Neoplasias Nasofaríngeas/mortalidad , Neoplasias Nasofaríngeas/cirugía , Carcinoma Nasofaríngeo/radioterapia , Carcinoma Nasofaríngeo/mortalidad , Carcinoma Nasofaríngeo/cirugía , Anciano , Adulto , Terapia Combinada , Estudios Retrospectivos , Programa de VERF , Estimación de Kaplan-Meier

RESUMEN

Locally recurrent nasopharyngeal carcinoma (NPC) presents substantial challenges in clinical management. Although postoperative re-irradiation (re-RT) has been acknowledged as a potential treatment option, standardized guidelines and consensus regarding the use of re-RT in this context are lacking. This article provides a comprehensive review and summary of international recommendations on postoperative management for potentially resectable locally recurrent NPC, with a special focus on postoperative re-RT. A thorough search was conducted to identify relevant studies on postoperative re-RT for locally recurrent NPC. Controversial issues, including resectability criteria, margin assessment, indications for postoperative re-RT, and the optimal dose and method of re-RT, were addressed through a Delphi consensus process. The consensus recommendations emphasize the need for a clearer and broader definition of resectability, highlighting the importance of achieving clear surgical margins, preferably through an en bloc approach with frozen section margin assessment. Furthermore, these guidelines suggest considering re-RT for patients with positive or close margins. Optimal postoperative re-RT doses typically range around 60 Gy, and hyperfractionation has shown promise in reducing toxicity. These guidelines aim to assist clinicians in making evidence-based decisions and improving patient outcomes in the management of potentially resectable locally recurrent NPC. By addressing key areas of controversy and providing recommendations on resectability, margin assessment, and re-RT parameters, these guidelines serve as a valuable resource for clinical experts involved in the treatment of locally recurrent NPC.

RESUMEN

BACKGROUND: Pancreatic cancer is one of the most lethal malignancies and the lack of treatment options makes it more deadly. Chimeric Antigen Receptor T-cell (CAR-T) immunotherapy has revolutionized cancer treatment and made great breakthroughs in treating hematological malignancies, however its success in treating solid cancers remains limited mainly due to the lack of tumor-specific antigens. On the other hand, the prolonged traditional manufacturing process poses challenges, taking 2 to 6 weeks and impacting patient outcomes. CD276 has recently emerged as a potential therapeutic target for anti-solid cancer therapy. Here, we investigated the efficacy of CD276 CAR-T and rapidly-manufactured CAR-T against pancreatic cancer. METHODS: In the present study, CD276 CAR-T was prepared by CAR structure carrying 376.96 scFv sequence, CD8 hinge and transmembrane domain, 4-1BB and CD3ζ intracellular domains. Additionally, CD276 rapidly-manufactured CAR-T (named CD276 Dash CAR-T) was innovatively developed by shortening the duration of ex vitro culture to reduce CAR-T manufacturing time. We evaluated the anti-tumor efficacy of CD276 CAR-T and further compared the functional assessment of Dash CAR-T and conventional CAR-T in vitro and in vivo by detecting the immunophenotypes, killing ability, expansion capacity and tumor-eradicating effect of CAR-T. RESULTS: We found that CD276 was strongly expressed in multiple solid cancer cell lines and that CD276 CAR-T could efficiently kill these solid cancer cells. Moreover, Dash CAR-T was successfully manufactured within 48-72 h and the functional validation was carried out subsequently. In vitro, CD276 Dash CAR-T possessed a less-differentiated phenotype and robust proliferative ability compared to conventional CAR-T. In vivo xenograft mouse model, CD276 Dash CAR-T showed enhanced anti-pancreatic cancer efficacy and T cell expansion. Besides, except for the high-dose group, the body weight of mice was maintained stable, and the state of mice was normal. CONCLUSIONS: In this study, we proved CD276 CAR-T exhibited powerful activity against pancreatic cancer cells in vitro and in vivo. More importantly, we demonstrated the manufacturing feasibility, acceptable safety and superior anti-tumor efficacy of CD276 Dash CAR-T generated with reduced time. The results of the above studies indicated that CD276 Dash CAR-T immunotherapy might be a novel and promising strategy for pancreatic cancer treatment.

Asunto(s)

Antígenos B7 , Inmunoterapia Adoptiva , Neoplasias Pancreáticas , Receptores Quiméricos de Antígenos , Neoplasias Pancreáticas/terapia , Neoplasias Pancreáticas/inmunología , Neoplasias Pancreáticas/patología , Humanos , Animales , Línea Celular Tumoral , Receptores Quiméricos de Antígenos/metabolismo , Receptores Quiméricos de Antígenos/inmunología , Inmunoterapia Adoptiva/métodos , Antígenos B7/metabolismo , Antígenos B7/inmunología , Ensayos Antitumor por Modelo de Xenoinjerto , Ratones , Proliferación Celular , Linfocitos T/inmunología

RESUMEN

Despite significant progress in treating chronic lymphocytic leukaemia (CLL), resistance to therapy remains challenging. NOTCH1 activation, common in CLL, confers adverse prognosis. This study explores the impact of NOTCH1 signalling on venetoclax sensitivity in vitro. Although NOTCH1 activation minimally impaired the susceptibility of CLL cells to venetoclax, ex vivo cell competition studies reveal that cells with constitutive NOTCH1 activation outgrew their wild-type counterparts in the presence of ongoing venetoclax exposure. Our findings suggest that while NOTCH1 activation is insufficient to confer venetoclax refractoriness, there is enhanced potential for cells with NOTCH1 activation to escape and thus become fully resistant to venetoclax.

RESUMEN

BACKGROUND: In recent years, compression therapy has attracted gradually increasing clinical attention in lower extremity venous diseases. However, basic concepts and clear nomenclature, standard treatment methods, and consistent product standards for pressure equipment are lacking. Therefore, developing clinical guidelines for compression therapy is essential to improving the treatment of venous diseases. METHODS: Our panel generated strong (grade I), moderate (grade IIa and IIb), and weak (grade III) recommendations based on high-quality (class A), moderate-quality (class B), and low-quality (class C) evidence, using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach and the European Society of Cardiology (ESC) grading system. RESULTS: The panels made 30 recommendations from current evidence, focusing on 7 fields of lower extremity venous disease (venous thromboembolism, post-thrombotic syndrome (PTS), chronic venous insufficiency (CVI), varicose veins, hemangioma and vascular malformations, lymphedema, and venous ulcers) and 18 topics. CONCLUSIONS: Of the 30 recommendations made across the 18 topics, 7 were strong (grade I) and 17 were based on high-quality (class A) evidence, highlighting the need for further research of the use of compression therapy.