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1.
Cardiovasc Diabetol ; 23(1): 232, 2024 Jul 04.
Artículo en Inglés | MEDLINE | ID: mdl-38965572

RESUMEN

BACKGROUND: The prognostic value of triglyceride-glucose (TyG) related indices in non-alcoholic fatty liver disease (NAFLD) or metabolic dysfunction-associated steatotic liver disease (MASLD) is still unclear. This study aimed to determine the associations between TyG-related indices and long-term mortality in this population. METHODS: The data came from the National Health and Nutrition Examination Survey (NHANES III) and National Death Index (NDI). Baseline TyG, TyG combining with body mass index (TyG-BMI), and TyG combining with waist circumference (TyG-WC) indices were calculated, and mortality status was determined through 31 December 2019. Multivariate Cox and restricted cubic spline (RCS) regression models were performed to evaluate the relationship between TyG-related indices and long-term mortality among participants with NAFLD/MASLD. In addition, we examined the association between TyG-related indices and all-cause mortality within subgroups defined by age, sex, race/ethnicity, and fibrosis-4 index (FIB-4). RESULTS: There were 10,390 participants with completed ultrasonography and laboratory data included in this study. NAFLD was diagnosed in 3672/10,390 (35.3%) participants, while MASLD in 3556/10,390 (34.2%) amongst the overall population. The multivariate Cox regression analyses showed high levels of TyG-related indices, particularly in TyG-BMI and TyG-WC indices were significantly associated with the all-cause mortality, cardiovascular mortality, and diabetes mortality in either NAFLD or MASLD. The RCS curves showed a nonlinear trend between three TyG-related indices with all-cause mortality in either NAFLD or MASLD. Subgroup analyses showed that TyG-BMI and TyG-WC indices were more suitable for predicting all-cause mortality in patients without advanced fibrosis. CONCLUSION: Our study highlights the clinical value of TyG-related indices in predicting the survival of the NAFLD/MASLD population. TyG-BMI and TyG-WC indices would be the surrogate biomarkers for the follow-up of the population without advanced fibrosis.


Asunto(s)
Biomarcadores , Glucemia , Enfermedad del Hígado Graso no Alcohólico , Encuestas Nutricionales , Triglicéridos , Humanos , Enfermedad del Hígado Graso no Alcohólico/sangre , Enfermedad del Hígado Graso no Alcohólico/mortalidad , Enfermedad del Hígado Graso no Alcohólico/diagnóstico , Masculino , Femenino , Persona de Mediana Edad , Triglicéridos/sangre , Medición de Riesgo , Glucemia/metabolismo , Biomarcadores/sangre , Adulto , Pronóstico , Factores de Riesgo , Factores de Tiempo , Anciano , Estados Unidos/epidemiología , Causas de Muerte , Valor Predictivo de las Pruebas , Índice de Masa Corporal , Hígado Graso/mortalidad , Hígado Graso/sangre , Hígado Graso/diagnóstico , Circunferencia de la Cintura
2.
Langmuir ; 2024 Jul 16.
Artículo en Inglés | MEDLINE | ID: mdl-39013153

RESUMEN

Challenges including rapid capacity degradation and reduced Coulombic efficiency due to the shuttle effect have hindered the commercial viability of lithium-sulfur (Li-S) batteries. A novel sandwich-structured electrode with an optimized electrode structure and current collector interface design was presented as a free-standing positive electrode for Li-S batteries. Fabricated via a simple slurry coating process, the electrode embedded multiwalled carbon nanotubes within carbon nanofiber composite films (PCNF/T). Owing to the superior conductivity and reduced weight in comparison to both carbon nanofibers (PCNF) and the conventional aluminum foil current collector (Al), the PCNF/T electrode exhibited diminished polarization and accelerated redox reaction kinetics. Thus, it delivers an initial discharge capacity of 990.23 mA h g-1 at 0.5 C. Even after 400 cycles, while retains a reversible capacity of 707.45 mA h g-1, corresponding to a minimal capacity degradation rate of merely 0.07% per cycle. Notably, the electrode exhibits a capacity retention of 619.81 mA h g-1 after 400 cycles at 1 C, with a capacity decay rate of only 0.08% per cycle. This study presents an innovative approach to developing a new free-standing cathode for high-performance Li-S batteries.

3.
Transl Lung Cancer Res ; 13(6): 1307-1317, 2024 Jun 30.
Artículo en Inglés | MEDLINE | ID: mdl-38973954

RESUMEN

Background: Immunotherapy functions by leveraging immunoregulation drugs to bolster the immune system's capacity to identify and eliminate cancerous cells. In contrast to radiotherapy and chemotherapy, immunotherapy exhibits diminished side effects, heightened efficacy, and prolonged survival rates. Nevertheless, meticulous exploration into the determinants governing the advantageous effects of immunotherapy among patients who have previously undergone multiple prior therapies has yet to be conducted. Albumin (ALB) as a nutritional indicator has not been thoroughly studied for its prognostic effect on efficacy or survival. This study aims to identify factors that influence treatment outcomes among patients undergoing third-line or later immunological therapies. Methods: A cohort of 250 lung cancer patients undergoing toripalimab or tislelizumab immunotherapy was the focal point of data collection. The determination of the median value facilitated the establishment of a cut-off point, enabling the categorization of continuous variables. After data collection, a series of statistical analyses of various clinical factors at baseline were performed, including nonparametric tests, logistic regression, and Cox proportional risk modeling. The last follow-up was in May 2022. The primary study endpoint was overall survival (OS). Results: A total of 250 patients were enrolled in the study, of which 129 patients received first- or second-line immunotherapy and 121 patients received third-line or subsequent immunotherapy. According to Cox multifactor regression analysis, in patients receiving either first- or second-line therapy, the ALB level exhibited negligible prognostic relevance (P>0.05). However, in patients subjected to immunotherapy beyond the second line, the ALB level manifested significant prognostic importance (P=0.039). Notably, patients demonstrating elevated ALB levels achieved a higher disease control rate (DCR) (70.0% vs. 52.5%, P=0.05) and displayed a tendency towards a heightened objective response rate (ORR) (20.0% vs. 16.4%, P=0.61) in comparison to those with lower ALB levels. Conclusions: Among patients undergoing immunotherapy in the third line or subsequent treatment phases, elevated ALB levels in baseline correlated with DCR and OS. Thus, the pre-immunotherapy ALB level emerges as an autonomous predictor of OS in patients subjected to third- or later line immunotherapy interventions.

4.
J Pharm Pharmacol ; 2024 Apr 18.
Artículo en Inglés | MEDLINE | ID: mdl-38635883

RESUMEN

AIM: To understand the regulatory roles of miR-1972 and GZMH in hepatocellular carcinoma (HCC) and explore their potential as therapeutic biomarkers. METHODS: In vitro verification of the regulation of malignant cell behavior by differential expression of miR-1972 in HCC cells. The GSE113996 dataset was studied using weighted gene co-expression network analysis (WGCNA) and differential expressed genes respectively to identify the key prognostic gene GZMH and assess the effect of its differential expression on the prognosis of the patient. Finally, the regulation of GZMH expression by miR-1972 was verified, and the effect of their combination on HCC cell behavior was analyzed. RESULTS: Inhibition of miR-1972 can reduce cell proliferation, migration, and invasion, while overexpression of miR-1972 has the opposite effect in HCC cells. According to the data, a positive prognosis for HCC was linked with higher GZMH expression. Interestingly, miR-1972 was observed to reverse-regulate the expression of GZMH. Besides, the combined regulation of GZMH and miR-1972 has been discovered to affect the cell growth, invasive capacity, and migratory potential of HCC cells, especially the cell cycle arrest in the G2 phase. CONCLUSIONS: miR-1972 regulates the malignant behavior of HCC cells, especially cell proliferation, by regulating GZMH expression.

5.
IEEE Trans Biomed Eng ; 71(9): 2663-2677, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38683702

RESUMEN

OBJECTIVE: Intraoperative liver deformation poses a considerable challenge during liver surgery, causing significant errors in image-guided surgical navigation systems. This study addresses a critical non-rigid registration problem in liver surgery: the alignment of intrahepatic vascular trees. The goal is to deform the complete vascular shape extracted from preoperative Computed Tomography (CT) volume, aligning it with sparse vascular contour points obtained from intraoperative ultrasound (iUS) images. Challenges arise due to the intricate nature of slender vascular branches, causing existing methods to struggle with accuracy and vascular self-intersection. METHODS: We present a novel non-rigid sparse-dense registration pipeline structured in a coarse-to-fine fashion. In the initial coarse registration stage, we introduce a parametrization deformation graph and a Welsch function-based error metric to enhance convergence and robustness of non-rigid registration. For the fine registration stage, we propose an automatic curvature-based algorithm to detect and eliminate overlapping regions. Subsequently, we generate the complete vascular shape using posterior computation of a Gaussian Process Shape Model. RESULTS: Experimental results using simulated data demonstrate the accuracy and robustness of our proposed method. Evaluation results on the target registration error of tumors highlight the clinical significance of our method in tumor location computation. Comparative analysis against related methods reveals superior accuracy and competitive efficiency of our approach. Moreover, Ex vivo swine liver experiments and clinical experiments were conducted to evaluate the method's performance. CONCLUSION: The experimental results emphasize the accurate and robust performance of our proposed method. SIGNIFICANCE: Our proposed non-rigid registration method holds significant application potential in clinical practice.


Asunto(s)
Algoritmos , Hígado , Cirugía Asistida por Computador , Tomografía Computarizada por Rayos X , Hígado/diagnóstico por imagen , Hígado/cirugía , Hígado/irrigación sanguínea , Cirugía Asistida por Computador/métodos , Humanos , Tomografía Computarizada por Rayos X/métodos , Animales , Neoplasias Hepáticas/diagnóstico por imagen , Neoplasias Hepáticas/cirugía , Porcinos , Procesamiento de Imagen Asistido por Computador/métodos , Hepatectomía/métodos , Ultrasonografía/métodos
6.
Clin Transl Oncol ; 26(9): 2339-2350, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-38598001

RESUMEN

BACKGROUND: The application of immune checkpoint inhibitors (ICIs) in treating patients with extensive-stage small-cell lung cancer (ES-SCLC) has brought us new hope, but the real-world outcome is relatively lacking. Our aim was to investigate the clinical use, efficacy, and survival benefit of ICIs in ES-SCLC from real-world data analysis. METHODS: A retrospective analysis of ES-SCLC patients was conducted between 2012 and 2022. Progression-free survival (PFS) and overall survival (OS) were assessed between groups to evaluate the value of ICIs at different lines of treatment. PFS1 was defined as the duration from initial therapy to disease progression or death. PFS2 was defined as the duration from the first disease progression to the second disease progression or death. RESULTS: One hundred and eighty patients with ES-SCLC were included. We performed landmark analysis, which showed that compared to the second-line and subsequent-lines ICIs-combined therapy group (2SL-ICIs) and non-ICIs group, the first-line ICIs-combined therapy group (1L-ICIs) prolonged OS and PFS1. There was a trend toward prolonged OS in the 2SL-ICIs group than in the non-ICIs group, but the significance threshold was not met (median OS 11.94 months vs. 11.10 months, P = 0.14). A longer PFS2 was present in the 2SL-ICIs group than in the non-ICIs group (median PFS2 4.13 months vs. 2.60 months, P < 0.001). CONCLUSION: First-line ICIs plus chemotherapy should be applied in clinical practice. If patients did not use ICIs plus chemotherapy in first-line therapy, the use of ICIs in the second line or subsequent lines of treatment could prolong PFS2.


Asunto(s)
Inhibidores de Puntos de Control Inmunológico , Neoplasias Pulmonares , Supervivencia sin Progresión , Carcinoma Pulmonar de Células Pequeñas , Humanos , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Neoplasias Pulmonares/mortalidad , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/patología , Carcinoma Pulmonar de Células Pequeñas/mortalidad , Estudios Retrospectivos , Masculino , Femenino , Anciano , Persona de Mediana Edad , Pronóstico , Factores de Tiempo , Estadificación de Neoplasias , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Anciano de 80 o más Años , Adulto , Tasa de Supervivencia
7.
Surg Laparosc Endosc Percutan Tech ; 34(2): 129-135, 2024 Apr 01.
Artículo en Inglés | MEDLINE | ID: mdl-38444073

RESUMEN

OBJECTIVE: The purpose of this study is to evaluate the safety and efficacy of linaclotide and polyethylene glycol (PEG) electrolyte powder in patients with chronic constipation undergoing colonoscopy preparation. PATIENTS AND METHODS: We included 260 patients with chronic constipation who were scheduled to undergo a colonoscopy. They were equally divided into 4 groups using a random number table: 4L PEG, 3L PEG, 3L PEG+L, and 2L PEG+L. The 4 groups were compared based on their scores on the Boston Bowel Preparation Scale (BBPS) and Ottawa Bowel Preparation Quality Scale (OBPQS), adverse reactions during the bowel preparation procedure, colonoscope insertion time, colonoscope withdrawal time, detection rate of adenomas, and their willingness to repeat bowel preparation. RESULTS: In terms of the score of the right half of the colon, the score of the transverse colon, the total score using BBPS, and the total score using OBPQS, the 3L PEG (polyethylene glycol)+L group was superior to groups 3L PEG and 2L PEG+L ( P <0.05), but comparable to the 4L PEG group ( P >0.05). The incidence rate of vomiting was higher in the 4L PEG group than in the 2L PEG+L group ( P <0.05). There was no statistically significant difference in the insertion time of the colonoscope between the 4 groups. The colonoscope withdrawal time in the 3L PEG+L group was shorter than in groups 4L PEG and 3L PEG ( P <0.05) and comparable to that in the 4L PEG group ( P >0.05). There was no statistically significant difference in the rate of adenoma detection among the 4 groups ( P >0.05). The 4L PEG group was the least willing of the 4 groups to undergo repeated bowel preparation ( P <0.05). CONCLUSION: The 3L PEG+L is optimal among the 4 procedures. It can facilitate high-quality bowel preparation, reduce the incidence of nausea during the bowel preparation procedure, and encourage patients to undertake repeated bowel preparation.


Asunto(s)
Catárticos , Estreñimiento , Péptidos , Humanos , Catárticos/efectos adversos , Polvos , Estreñimiento/diagnóstico , Estreñimiento/inducido químicamente , Polietilenglicoles , Colonoscopía/métodos , Electrólitos
8.
Free Radic Biol Med ; 212: 284-294, 2024 02 20.
Artículo en Inglés | MEDLINE | ID: mdl-38163553

RESUMEN

BACKGROUND AND AIM: Sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2 (SERCA2) is critical in maintaining Ca2+ homeostasis. The cysteine 674 (C674) is the key redox regulatory cysteine in regulating SERCA2 activity, which is irreversibly oxidized in the renal cortex of hypertensive mice. We have reported that the substitution of C674 by serine causes SERCA2 dysfunction and increases blood pressure by induction of endoplasmic reticulum stress (ERS). This study is to explore whether the dysfunction of SERCA2 causes hypertension by interrupting mitochondrial homeostasis and inducing oxidative stress. METHODS & RESULTS: We used heterozygous SERCA2 C674S gene mutation knock-in (SKI) mice, where one copy of C674 was substituted by serine to represent partial C674 oxidation. In renal proximal tubule (RPT) cells, the substitution of C674 by serine decreased mitochondrial Ca2+ content, increased mitochondrial membrane potential, ATP content, and reactive oxygen species (ROS), which could be reversed by ERS inhibitor 4-phenylbutyric acid or SERCA2 agonist CDN1163. In SKI RPT cells, the redox modulator Tempol alleviated oxidative stress, downregulated the protein expression of ERS markers and soluble epoxide hydrolase, upregulated the protein expression of dopamine D1 receptor, and reduced Na+/K+- ATPase activity. In SKI mice, SERCA2 agonists CDN1163 and [6]-Gingerol, or the redox modulator Tempol increased urine output and lowered blood pressure. CONCLUSION: The irreversible oxidation of C674 is not only an indicator of increased ROS, but also further inducing oxidative stress to cause hypertension. Activation of SERCA2 or inhibition of oxidative stress is beneficial to alleviate hypertension caused by SERCA2 dysfunction.


Asunto(s)
Aminoquinolinas , Benzamidas , Óxidos N-Cíclicos , Cisteína , Hipertensión , Marcadores de Spin , Ratones , Animales , Especies Reactivas de Oxígeno/metabolismo , Cisteína/metabolismo , Hipertensión/genética , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/genética , ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico/metabolismo , Estrés Oxidativo , Homeostasis , Serina/metabolismo
9.
Cancer Manag Res ; 16: 23-35, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38230351

RESUMEN

Background: Radiation therapy (RT) can cause changes in peripheral blood immune cells. The relationship between the efficacy of radiation therapy for non-small cell lung cancer (NSCLC) and immune cell changes and the study of how mediastinal radiation dose parameters affect immune cell changes is still unclear. This study aims to analyze the relationship between immune cell changes induced by radiotherapy and the efficacy of NSCLC radiotherapy, as well as the relationship between radiotherapy dose parameters and immune cell changes. Materials and Methods: We retrospectively analyzed the data of NSCLC patients receiving mediastinal radiation therapy from 2020 to 2022. Collect lymphocytes and circulating immune cells within one week before and after radiotherapy and collect the dose-volume parameters of the whole mediastinum in the patient's RT planning system. Analyze the changes in lymphocytes and radiotherapy effects after radiotherapy, and explore the relationship between radiotherapy dose parameters and immune cell changes. Results: A total of 72 patients were enrolled. Compared with before radiotherapy, the proportion of CD3+T cells, CD8+T cells, and CD8/Treg in peripheral blood significantly increased after radiotherapy (P<0.05). The increase in CD8+T cells and CD8/Treg after radiotherapy was correlated with Objective response rate (ORR) (P<0.05). Based on binary logistic univariate and multivariate regression analysis, an increase in CD8+T cells after radiotherapy is an independent predictor of objective tumor response after radiotherapy (OR=12.71, 95% CI=3.64-44.64, P=0.01), and Volume of 200 cGy irradiation (V2) is an independent positive predictor of an increase in CD8+T lymphocyte ratio after radiotherapy (high group, OR=3.40, 95% CI=1.13-10.36, P=0.03). Conclusion: The increase in CD8+T cells after radiotherapy can positively predict the short-term efficacy of radiotherapy. Mediastinal low-dose radiation therapy can increase CD8+T cells, thereby improving the short-term efficacy of radiotherapy. These potentially related mechanisms are worth further verification and exploration.

10.
Clin Lung Cancer ; 25(1): 18-28.e3, 2024 01.
Artículo en Inglés | MEDLINE | ID: mdl-37612176

RESUMEN

BACKGROUND: With the widespread application of immune checkpoint inhibitor (ICI) combined with radiotherapy (RT) for the treatment of lung cancer, increasing attention has been paid to treatment-related pneumonitis. The effect of the treatment sequence on the incidence of pneumonitis remains unclear. METHODS: We searched databases including PubMed, Embase, and ClinicalTrials.gov, meeting abstracts, and reference lists of relevant review articles for literature published on radio- and immunotherapy in lung cancer. Stata software (version 16.0) was used for meta-analysis. Data on the incidence of any grade and ≥ grade 3 pneumonitis was pooled using the random effects model. Bayesian network meta-analysis was used for arm-based pairwise comparisons. Subgroup analyses were performed to identify the potential influencing factors. RESULTS: Thirty-eight studies met our inclusion criteria. The network meta-analysis showed no significant difference between the incidence of pneumonitis in concurrent ICI with RT (concurrent arm) and RT followed by ICI (RT-first arm) (odds ratio [OR]: 0.71, 95% confidence interval [CI]: 0.10-4.81). In the meta-analysis of single group rates, RT following ICI (ICI-first arm) exhibited higher incidence of any grade pneumonitis compared with concurrent- and RT-first arms, with 0.321 (95% CI: 0.260-0.386) for programmed cell death protein 1 (PD-1) inhibitors from clinical trials, and 0.480 (95% CI: 0.363-0.598) for PD-1 inhibitors from real-world retrospective data, respectively. CONCLUSION: No significant difference in the incidence of any grade and grade ≥ 3 pneumonitis was found between RT-first and concurrent arms. The ICI-first arm exhibited a higher incidence of pneumonitis, which needs to be further confirmed by follow-up studies.


Asunto(s)
Neoplasias Pulmonares , Neumonía , Humanos , Teorema de Bayes , Inmunoterapia/efectos adversos , Incidencia , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/radioterapia , Metaanálisis en Red , Neumonía/epidemiología , Neumonía/etiología , Estudios Retrospectivos
11.
Cancer Biol Ther ; 24(1): 2285367, 2023 12 31.
Artículo en Inglés | MEDLINE | ID: mdl-38031846

RESUMEN

Immunotherapy of lung cancer has achieved promising clinical results. However, it is urgent to develop predictive biomarkers for effective immunotherapy. While ferroptosis plays a critical role in immunotherapy efficacy, ferritin is an important regulatory factor. We, therefore, hypothesize that basal serum ferritin levels before immunotherapy and their corresponding changes during immunotherapy can be useful predictors of immunotherapy response in patients with lung cancer. We measured serum ferritin levels in 107 patients with lung cancer before and during immune checkpoint blockade treatments and studied the correlation between ferritin levels, response rate, and survival. Moreover, the correlation between basal ferritin and PD-L1 expression, tumor stages and pathological types was also analyzed. Patients with lower basal serum ferritin levels before immunotherapy had longer progression-free survival (PFS) (median 7 vs 4 months, P = .023) and higher disease control rate (DCR) (X2 = 4.837, P = .028), those with downregulated serum ferritin levels during immunotherapy correlated with longer PFS (median 9.5 vs 4 months, P < .001) and higher DCR (X2 = 6.475, P = .011). However, the "integrated factor", which was calculated as the combination of lower basal serum ferritin levels before immunotherapy and downregulated serum ferritin levels during immunotherapy, correlated with prolonged PFS (P < .001). Multivariate analyses revealed that the basal serum ferritin levels before immunotherapy and the corresponding changes during immunotherapy were both strong independent prognostic factors (hazard ratio (HR) = 1.60, P = .041; HR = 2.65, P = .001). These findings suggest that serum ferritin levels can be used as a prognostic biomarker for lung cancer in predicting immunotherapy efficacy.


Asunto(s)
Carcinoma de Pulmón de Células no Pequeñas , Neoplasias Pulmonares , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Carcinoma de Pulmón de Células no Pequeñas/patología , Pronóstico , Biomarcadores de Tumor/metabolismo , Inmunoterapia/métodos , Antígeno B7-H1/metabolismo , Ferritinas/uso terapéutico
12.
Clin Exp Hypertens ; 45(1): 2272062, 2023 Dec 31.
Artículo en Inglés | MEDLINE | ID: mdl-37899350

RESUMEN

BACKGROUND AND PURPOSE: Substitution of Cys674 (C674) in the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2 (SERCA2) causes SERCA2 dysfunction which leads to activated inositol requiring enzyme 1 alpha (IRE1α) and spliced X-box binding protein 1 (XBP1s) pathway accelerating cell proliferation of pulmonary artery smooth muscle cells (PASMCs) followed by significant pulmonary vascular remodeling resembling human pulmonary hypertension. Based on this knowledge, we intend to investigate other potential mechanisms involved in SERCA2 dysfunction-induced pulmonary vascular remodeling. EXPERIMENTAL APPROACH: Heterozygous SERCA2 C674S knock-in (SKI) mice of which half of cysteine in 674 was substituted by serine to mimic the partial irreversible oxidation of C674 were used. The lungs of SKI mice and their littermate wild-type mice were collected for PASMC culture, protein expression, and pulmonary vascular remodeling analysis. RESULTS: SERCA2 dysfunction increased intracellular Ca2+ levels, which activated Ca2+-dependent calcineurin (CaN) and promoted the nuclear translocation and protein expression of the nuclear factor of activated T-lymphocytes 4 (NFAT4) in an IRE1α/XBP1s pathway-independent manner. In SKI PASMCs, the scavenge of intracellular Ca2+ by BAPTA-AM or inhibition of CaN by cyclosporin A can prevent PASMC phenotypic transition. CDN1163, a SERCA2 agonist, suppressed the activation of CaN/NFAT4 and IRE1α/XBP1s pathways, reversed the protein expression of PASMC phenotypic transition markers and cell cycle-related proteins, and inhibited cell proliferation and migration when given to SKI PASMCs. Furthermore, CDN1163 ameliorated pulmonary vascular remodeling in SKI mice. CONCLUSIONS AND IMPLICATIONS: SERCA2 dysfunction promotes PASMC phenotypic transition and pulmonary vascular remodeling by multiple mechanisms, which could be improved by SERCA2 agonist CDN1163.


'What is already known' l The dysfunction of SERCA2 promotes PASMC hyperproliferation and pulmonary vascular remodeling through activation of the IRE1α/XBP1s pathway.'What this study adds' l The dysfunction of SERCA2 activates the Ca2+-dependent CaN-mediated NFAT4 pathway to promote the PASMC phenotypic transition.l Revitalization of SERCA2 suppresses PASMC phenotypic transition and pulmonary vascular remodeling caused by SERCA2 dysfunction.'Clinical significance' l SERCA2 dysfunction-induced pulmonary vascular remodeling involves more than one mechanism, implicating that more drugable targets are to be discovered.l SERCA2 is a potential therapeutic target for preventing pulmonary vascular remodeling.


Asunto(s)
Hipertensión Pulmonar , Hipertensión Arterial Pulmonar , Ratones , Humanos , Animales , Arteria Pulmonar , Endorribonucleasas/metabolismo , Remodelación Vascular , Proteínas Serina-Treonina Quinasas/metabolismo , Hipertensión Arterial Pulmonar/metabolismo , Proliferación Celular , Miocitos del Músculo Liso/metabolismo , Células Cultivadas
13.
Oncology ; 2023 Oct 30.
Artículo en Inglés | MEDLINE | ID: mdl-37903484

RESUMEN

Background Since the success of the PACIFIC trial, durvalumab has become the clear standard of care for many patients with stage III non-small cell lung cancer (NSCLC) after concurrent chemoradiotherapy (CRT). However, the duration of immune consolidation and the efficacy and safety of different immune agents remain unclear. We conducted a systematic review of relevant studies. Methods We searched all the relevant studies in PubMed, Embase and Cochrane Library databases. We also reviewed abstracts of relevant conferences, to prevent omissions. The meta-analysis was performed using Stata version 16.0. Results Chemoradiotherapy combined with immunotherapy can improve PFS (HR: 0.60, 95%CI :0.55-0.60) and OS (HR: 0.59, 95%CI :0.53-0.66) compared with no immunotherapy. The pooled 24-month PFS and 24-month OS rates were 48.1% (95% CI, 43.5%-52.7%) and 71.3% (95% CI, 67.3%-75.2%), respectively. Subgroup analysis showed that 24-month OS rates were 60.7% (95%CI, 51.0%-70.3%) and 77.4% (95%CI, 73.2%-81.7%) at 1 year and 2 years of immune consolidation, respectively. The pooled 1-year completion rate for immune consolidation was 35.6% (95%CI, 31.3%-39.8%). The pooled rate of pneumonitis for all grades was 41.7% (95%CI, 31.9%-51.9%). The pooled rate of pneumonitis ≥ grade 3 was 6.7% (95%CI, 5.0%-8.5%). The incidence of pneumonitis ≥ grade 3 after 1 year of immunotherapy is 4.8% (95%CI, 3.1%-6.5%). The incidence of pneumonitis ≥ grade 3 after 2 years of immunotherapy is 5.1% (95%CI, 2.9%-7.3%). Conclusions Prolonging the duration of immunotherapy consolidation increases survival benefits in patients with stage III NSCLC without causing higher side effects. Older patients, due to high incidence of pneumonia and low immunotherapy completion rate, have less survival benefit.

14.
Front Bioeng Biotechnol ; 11: 1286502, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37854883

RESUMEN

Cancer therapies, such as chemotherapy and radiotherapy, are often unsatisfactory due to several limitations, including drug resistance, inability to cross biological barriers, and toxic side effects on the body. These drawbacks underscore the need for alternative treatments that can overcome these challenges and provide more effective and safer options for cancer patients. In recent years, the use of live bacteria, engineered bacteria, or bacterial derivatives to deliver antitumor drugs to specific tumor sites for controlled release has emerged as a promising therapeutic tool. This approach offers several advantages over traditional cancer therapies, including targeted drug delivery and reduced toxicity to healthy tissues. Ongoing research in this field holds great potential for further developing more efficient and personalized cancer therapies, such as E. coli, Salmonella, Listeria, and bacterial derivatives like outer membrane vesicles (OMVs), which can serve as vehicles for drugs, therapeutic proteins, or antigens. In this review, we describe the advances, challenges, and future directions of research on using live bacteria or OMVs as carriers or components derived from bacteria of delivery systems for cancer therapy.

15.
Mediators Inflamm ; 2023: 2546278, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37396299

RESUMEN

Methods: Using a CRISPR/Cas9 gene-editing system, EFTUD2 single allele knockout HepG2.2.15 cells were constructed. Subsequently, the HBV biomarkers in EFTUD2+/- HepG2.2.15 cells and wild-type (WT) cells with or without IFN-α treatment were detected. And the EFTUD2-regulated genes were then identified using mRNA sequence. Selected gene mRNA variants and their proteins were examined by qRT-PCR and Western blotting. To confirm the effects of EFTUD2 on HBV replication and IFN-stimulated gene (ISG) expression, a rescue experiment in EFTUD2+/- HepG2.2.15 cells was performed by EFTUD2 overexpression. Results: IFN-induced anti-HBV activity was found to be restricted in EFTUD2+/- HepG2.2.15 cells. The mRNA sequence showed that EFTUD2 could regulate classical IFN and virus response genes. Mechanistically, EFTUD2 single allele knockout decreased the expression of ISG-encoded proteins, comprising Mx1, OAS1, and PKR (EIF2AK2), through mediated gene splicing. However, EFTUD2 did not affect the expression of Jak-STAT pathway genes. Furthermore, EFTUD2 overexpression could restore the attenuation of IFN anti-HBV activity and the reduction of ISG resulting from EFTUD2 single allele knockout. Conclusion: EFTUD2, the spliceosome factor, is not IFN-inducible but is an IFN effector gene. EFTUD2 mediates IFN anti-HBV effect through regulation of gene splicing for certain ISGs, including Mx1, OAS1, and PKR. EFTUD2 does not affect IFN receptors or canonical signal transduction components. Therefore, it can be concluded that EFTUD2 regulates ISGs using a novel, nonclassical mechanism.


Asunto(s)
Quinasas Janus , Empalmosomas , Humanos , Células Hep G2 , Virus de la Hepatitis B/genética , ARN Mensajero/genética , Transducción de Señal , Factores de Transcripción STAT , Replicación Viral
16.
Transl Lung Cancer Res ; 12(5): 1093-1107, 2023 May 31.
Artículo en Inglés | MEDLINE | ID: mdl-37323177

RESUMEN

Background: Tumor local and distant relapse recurrence after radiotherapy (RT) is one of the critical factors leading to poor prognosis. The effective antitumor effects of RT are dependent upon the participation of innate and adaptive components of the immune system. C5a/C5aR1 signaling can regulate antitumor immune effect in the tumor microenvironment (TME). Thus, exploring the changes and mechanism in the TME induced by RT-mediated complement activation may provide a novel perspective for reversing radioresistance. Methods: First, fractionated radiation of 8 Gy ×3 fractions were targeted at Lewis lung carcinoma (LLC) tumor-bearing female mice to measure the infiltration of CD8+ T cell and analyze the RNA sequencing (RNA-seq) in RT-recruited CD8+ T cells. Second, tumor growth was measured in LLC tumor-bearing mice treated with RT either with or without C5aR1 inhibitor to clarify the antitumor effect of RT combined with C5aR1 inhibitor. Third, we detected the expression of C5a/C5aR1 and their signaling pathways on radiated tumor tissues. Furthermore, we investigated the expression of C5a in tumor cells at different time points after different doses of RT. Results: In our system, RT induced the increased infiltration of CD8+ T cells and local activation of complement C5a/C5aR. Concurrent administration of RT and blocking of C5aR improved radiosensitivity and tumor-specific immune response, which was reflected by high C5aR expression in CD8+ T cells. The AKT/NF-κB pathway was found to be an important signaling pathway in C5a/C5aR axis mediation by RT. Conclusions: RT promotes the release of C5a from tumor cells and leads to up-regulation of C5aR1 expression via the AKT/NF-κB pathway. Inhibition of the combination of complement C5a and C5aR could improve RT sensitivity. Our work provides evidence that the combination of RT and C5aR blockade opens a new window of opportunity to promote anti-tumor therapeutic effects in lung cancer.

17.
Transl Oncol ; 33: 101687, 2023 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-37182510

RESUMEN

BACKGROUND: Although immunotherapy greatly extends overall survival (OS) of patients with extensive-stage small cell lung cancer (ES-SCLC), a number of patients develop immunotherapy resistance (IR). Patterns of failure in ES-SCLC are not clarified. Our study aims to explore the clinical pattern of IR and prognostic factors for these patients. METHODS: The study was conducted from 117 ES-SCLC patients with immunotherapy between 2018 and 2022. Chi-square tests and Fishers' exact tests was used to explore failure patterns in different populations. Survival analyses of different progression patterns and subsequent treatment regimens were conducted by Kaplan-Meier curves and log-rank test. RESULTS: 86 (73.5%) patients experienced IR. The patients with smoking (never smoker vs. current or ex-smoker, 59.5 % vs. 81.3%, P = 0.010), liver metastasis (extrahepatic metastasis vs. intrahepatic metastasis, 73.6 % vs. 90.9%, P = 0.050), and distant metastasis status (no distant metastasis vs. distant metastasis, 39.1 % vs. 81.9%, P<0.001) were associated with IR rates. Liver progression had a lower incidence in 1st line immunotherapy (1st line vs. ≥2nd lines, 14.0 % vs. 41.7%, P = 0.004) and a higher incidence in multiple progression (multiple progression vs. Oligo-progression, 39.4 % vs. 17.0%, P = 0.021). Cranial (41.7 % vs. 16.1%, P = 0.012) and distant lymph node (16.7 % vs. 3.2%, P = 0.049) progression were the main failure model for acquired IR in comparison to primary IR. Patients with new lesion progression only (17.73 vs. 9.17 months, P = 0.013) and non-hepatic progression (14.23 vs. 11.67 months, P = 0.042) had a longer OS. Patients in cross-line immunotherapy after IR had a favourable prognosis (17.07 vs. 11.93 months, P = 0.007). CONCLUSION: The most common failure pattern of immunotherapy for ES-SCLC was lung and regional lymph node progression. Brain and liver progression were the most common extra thoracic failure sites for 1st line and 2nd and more lines immunotherapy, respectively. There was a higher probability of primary IR in 2 lines and above immunotherapy. Patients with new only progression site and cross-line rechallenge immunotherapy had a better prognosis.

18.
J Cancer Res Ther ; 19(1): 144-149, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-37006055

RESUMEN

Immunotherapy is a novel treatment option for various types of cancers. However, the optimal timing for response evaluation has not been well defined. Here, we present a gastric cancer (GC) patient with microsatellite instability-high who experienced recurrence 5 years and 11 months after radical gastrectomy. Then, the patient was treated with radiotherapy, targeted drugs, and immunotherapy. Immunotherapy resulted in 5 months of continuous progression, accompanied by significantly increased tumor marker CA19-9. However, the patient exhibited a satisfactory response without altering the treatment. Based on this, we hypothesized that some persistent progression with elevated tumor markers, known as pseudoprogression (PsP), might be observed in patients with recurrent GC during immunotherapy. This process might be prolonged, but if the treatment is continued, it will eventually produce remarkable therapeutic effects. PsP might challenge the globally accepted immune response evaluation criteria for solid tumors.


Asunto(s)
Adenocarcinoma , Neoplasias Gástricas , Humanos , Neoplasias Gástricas/terapia , Progresión de la Enfermedad , Recurrencia Local de Neoplasia/terapia , Adenocarcinoma/terapia , Inmunoterapia/métodos
19.
Heliyon ; 9(3): e14309, 2023 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-36938447

RESUMEN

Metastasis is a major obstacle in the treatment of hepatocellular carcinoma (HCC). Microtubule-associated protein 4 (MAP4) plays an important role as a coordinator between microtubules and microfilaments. However, the role of MAP4 in HCC migration and epithelial mesenchymal transition (EMT) is unclear. We compared the protein and mRNA levels of MAP4 in human HCC and adjacent normal tissues using western blotting, immunohistochemistry and RT-qPCR. The migration and invasion abilities and the levels of EMT markers (E-Cadherin, N-Cadherin, Vimentin, and Snail) were compared between MAP4-knockdown and MAP4-overexpressed HCC cells. Finally, we examined whether ß-catenin and glycogen synthase kinase 3ß (GSK3ß) are involved in the stimulatory effects of MAP4 on HCC migration, invasion and EMT. The results revealed that MAP4 levels were higher in the HCC tissues than in the normal hepatic tissues. More importantly, MAP4 knockdown suppressed migration and invasion abilities and EMT processes in HCC cells, which were confirmed by the stimulatory effects of MAP4 overexpression on EMT processes in HCC cells. Further evidence demonstrated that the up-regulation of ß-catenin activity induced by the interaction between MAP4 and GSK3ß possibly accounted for the pro-migration and pro-EMT effects of MAP4 on HCC cells. Taken together, these results suggest that MAP4 promotes migration, invasion, and EMT in HCC cells by regulating the GSK3ß/ß-catenin pathway.

20.
Adv Healthc Mater ; 12(21): e2300102, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-36988195

RESUMEN

Cell signal transduction mediated by cell surface ligand-receptor is crucial for regulating cell behavior. The oligomerization or hetero-aggregation of the membrane receptor driven by the ligand realizes the rearrangement of apoptotic signals, providing a new ideal tool for tumor therapy. However, the construction of a stable model of cytomembrane receptor aggregation and the development of a universal anti-tumor therapy model on the cellular surface remain challenging. This work describes the construction of a "multi-catcher" flexible structure GC-chol-apt-cDNA with a suitable integration of the oligonucleotide aptamer (apt) and cholesterol (chol) on a polymer skeleton glycol chitosan (GC), for the regulation of the nucleolin cluster through strong polyvalent binding and hydrophobic membrane anchoring on the cell surface. This oligonucleotide aptamer shows nearly 100-fold higher affinity than that of the monovalent aptamer and achieves stable anchoring to the plasma membrane for up to 6 h. Moreover, it exerts a high tumor inhibition both in vitro and in vivo by activating endogenous mitochondrial apoptosis pathway through the cluster of nucleolins on the cell membrane. This multi-catcher nano-platform combines the spatial location regulation of cytomembrane receptors with the intracellular apoptotic signaling cascade and represents a promising strategy for antitumor therapy.


Asunto(s)
Aptámeros de Nucleótidos , Neoplasias , Humanos , Polímeros/metabolismo , Ligandos , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Membrana Celular/metabolismo , Receptores de Superficie Celular/metabolismo , Oligonucleótidos , Línea Celular Tumoral , Aptámeros de Nucleótidos/farmacología , Aptámeros de Nucleótidos/química , Nucleolina
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