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1.
Heart Rhythm ; 2024 Feb 14.
Artigo em Inglês | MEDLINE | ID: mdl-38365127

RESUMO

BACKGROUND: Female sex has long been recognized to present higher risk of stroke and atrial fibrillation (AF) recurrence after circumferential pulmonary vein isolation (CPVI) than male. However, the underlying mechanisms and benefits of additional low-voltage area (LVA) modification in women remain unknown. OBJECTIVE: To investigate differences in atrial substrate and efficacy of additive LVA ablation between sex subgroups. METHODS: Patients with paroxysmal AF (PAF) aged 65-80 years were randomly assigned to either CPVI plus LVA modification (STABLE-SR) group or CPVI alone group. The primary outcome was freedom from atrial arrhythmias after a single ablation procedure. RESULTS: Of 414 patients included in the STABLE-SR-III, 204 (49.3%) were women, mean age was 70.5±4.7 years. Women demonstrated significantly higher LVA prevalence (51.5% vs. 32.9%, P<0.001) and LVA burden (6.5% vs. 2.9%, P<0.001) than men. In STABLE-SR group, additional LVA ablation was associated with a 63% reduction in recurrence for women compared with CPVI alone group (10.8% vs. 29.4%, adjusted HR 0.37; 95% CI 0.18-0.75, P for interaction=0.040). However, this finding was not observed in men (18.7% vs. 18.5%). In female subgroup, both Group 1 (CPVI + LVA modification) and Group 3 (CPVI alone in females without LVA) had similar clinical outcomes, which were much better than Group 2 (CPVI alone in women with LVA) (90% vs. 83.8% vs. 63.6%, P=0.003). CONCLUSIONS: In older patients with PAF, women demonstrated more advanced atrial substrate, including higher prevalence and burden of LVA compared with men. Women may receive greater benefit from additional LVA modification than men.

2.
Adv Mater ; : e2312014, 2024 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-38380583

RESUMO

Perovskite photovoltaics have emerged as the most promising candidates for next-generation light-to-electricity technology. However, their practical application still suffers from energy loss induced by intrinsic defects within the perovskite lattice. We here design a refined defect passivation in perovskite films, which shows a multi-interaction mechanism between the perovskite and passivator. Interestingly, we observed a shift of molecular bonding upon cooling down the film, leading to a stronger passivation of iodine/formamidine vacancies. We further leverage such mechanism on device under low-light and low-temperature conditions and obtained a record efficiency over 45% with durable ambient stability (T90 >4000 h). The pioneer application of perovskite solar cells in above dual extreme conditions in this work reveals the key principles of designing functional groups for the passivators, and also demonstrates the capability of perovskites for diverse terrestrial energy conversion applications in demanding environments such as polar regions and outer space. This article is protected by copyright. All rights reserved.

3.
Cell Rep ; 43(2): 113821, 2024 Feb 17.
Artigo em Inglês | MEDLINE | ID: mdl-38368611

RESUMO

The titer of viruses that persist and propagate in their insect vector must be high enough for transmission yet not harm the insect, but the mechanism of this dynamic balance is unclear. Here, expression of inosine monophosphate dehydrogenase (LsIMPDH), a rate-limiting enzyme for guanosine triphosphate (GTP) synthesis, is shown to be downregulated by increased levels of N6-methyladenosine (m6A) on LsIMPDH mRNA in rice stripe virus (RSV)-infected small brown planthoppers (SBPHs; Laodelphax striatellus), the RSV vector, which decreases GTP content, thus limiting viral proliferation. Moreover, planthopper methyltransferase-like protein 3 (LsMETTL3) and m6A reader protein LsYTHDF3 are found to catalyze and recognize the m6A on LsIMPDH mRNA, respectively, and cooperate in destabilizing LsIMPDH transcripts. Co-silencing assays show that negative regulation of viral proliferation by both LsMETTL3 and LsYTHDF3 is partially dependent on LsIMPDH. This distinct mechanism limits virus replication in an insect vector, providing a potential gene target to block viral transmission.

4.
Food Funct ; 2024 Feb 16.
Artigo em Inglês | MEDLINE | ID: mdl-38362628

RESUMO

Peptides in milk fermented with Lactobacillus delbrueckii QS306 before and after ultrahigh pressure treatment were identified using proteomics. Subsequently, 16 stable tripeptides were screened out based on activity score prediction, PeptideCutter analysis, and hydrophobicity calculations. Among them, WRP, WSR, and YRP showed the best angiotensin-converting enzyme (ACE) inhibitory activity, and their semi-inhibitory concentrations were 46.707, 300.121, and 89.555 µM, respectively. WRP and WSR were competitive inhibitors, whereas YRP was non-competitive. Gastrointestinal simulation revealed that WRP and YRP had better gastrointestinal stability. The values of RMSD, ΔGbind, ΔGpol, and RSMF obtained from molecular dynamics simulation indicated that the interaction of WRP and ACE was stable. Thus, Lactobacillus delbrueckii QS306-fermented milk can serve as an important source of ACE inhibitory peptides both before and after ultrahigh pressure treatment. The strategy of in silico screening, activity evaluation, and molecular dynamics simulation adopted in this study can be applied to the large-scale screening of novel peptides with high ACE inhibitory activity.

5.
Nat Commun ; 15(1): 1125, 2024 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-38321032

RESUMO

Congenital vertebral malformation, affecting 0.13-0.50 per 1000 live births, has an immense locus heterogeneity and complex genetic architecture. In this study, we analyze exome/genome sequencing data from 873 probands with congenital vertebral malformation and 3794 control individuals. Clinical interpretation identifies Mendelian etiologies in 12.0% of the probands and reveals a muscle-related disease mechanism. Gene-based burden test of ultra-rare variants identifies risk genes with large effect sizes (ITPR2, TBX6, TPO, H6PD, and SEC24B). To further investigate the biological relevance of the genetic association signals, we perform single-nucleus RNAseq on human embryonic spines. The burden test signals are enriched in the notochord at early developmental stages and myoblast/myocytes at late stages, highlighting their critical roles in the developing spine. Our work provides insights into the developmental biology of the human spine and the pathogenesis of spine malformation.


Assuntos
Anormalidades Musculoesqueléticas , Coluna Vertebral , Humanos , Coluna Vertebral/anormalidades , Anormalidades Musculoesqueléticas/genética , Alelos , Exoma , Proteínas com Domínio T/genética
6.
Research (Wash D C) ; 7: 0303, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38323094

RESUMO

Recent studies have highlighted the pivotal roles of circular RNAs (circRNAs) in cardiovascular diseases. Through high-throughput circRNA sequencing of both normal myocardial tissues and hypertrophic patients, we unveiled 32,034 previously undiscovered circRNAs with distinct cardiac expression patterns. Notably, circITGa9, a circRNA derived from integrin-α9, exhibited substantial up-regulation in cardiac hypertrophy patients. This elevation was validated across extensive sample pools from cardiac patients and donors. In vivo experiments revealed heightened cardiac fibrosis in mice subjected to transverse aortic constriction (TAC) after circITGa9 injection. We identified circITGa9 binding proteins through circRNA precipitation followed by liquid chromatography tandem-mass spectrometry. Furthermore, circRNA pull-down/precipitation assays demonstrated that increased circITGa9 expression facilitated binding with tropomyosin 3 (TPM3). Specific binding sites between circITGa9 and TPM3 were identified through computational algorithms and further validated by site-directed mutagenesis. We further showed that circITGa9 induced actin polymerization, characteristic of tissue fibrosis. Finally, we developed approaches that improved cardiac function and decreased fibrosis by delivering small interfering RNA targeting circITGa9 or blocking oligo inhibiting the interaction of circITGa9 and TPM3 into TAC mice, which is amenable for further preclinical and translational development. We conclude that elevated circITGa9 levels drive cardiac remodeling and fibrosis. By pinpointing circITGa9 as a therapeutic target, we open doors to innovative interventions for mitigating cardiac remodeling and fibrosis.

7.
J Ethnopharmacol ; 325: 117840, 2024 Feb 03.
Artigo em Inglês | MEDLINE | ID: mdl-38316219

RESUMO

ETHNOPHARMACOLOGICAL RELEVANCE: Lysimachiae Herba (LH), called Jinqiancao in Chinese, is a commonly used traditional Chinese medicine in clinical practice. Doctors in the Qing Dynasty recorded that it tastes bitter, sour, and slightly cold, and it belongs to the liver, gallbladder, kidney, and bladder meridians. It has the effects of removing dampness and jaundice, eliminating gallstones, and reducing blood stasis. Because of its potent pharmacological effects, it is extensively utilized in the treatment of hepatobiliary and urinary system stones, jaundice, hepatitis, and cholecystitis. Although LH is included in "Sichuan authentic Chinese herbal medicine records", the quality of it from different origins still lacks reliable evaluation methods, which is difficult to reflect the high quality of LH from Sichuan. AIMS OF THE STUDY: This study aimed to establish a fingerprint-activity relationship model between the fingerprint of LH and its protective effect on cholestatic liver injury, and to evaluate the quality of LH from Sichuan and Guizhou by multivariate statistical analysis. MATERIALS AND METHODS: 20 batches of LH samples were collected from Sichuan and Guizhou. Characteristic fingerprints of samples were established by UHPLC-Triple TOF-MS/MS and the chemical pattern recognition analysis was carried out by HCA. Then, a rat model of cholestatic liver injury was established by intragastric administration of ANIT. Combined with the common peak information of fingerprint and pharmacodynamic index results, GCA and BCA were used to screen the efficacy markers. Finally, based on UHPLC-QTRAP-MS/MS, the content of efficacy markers was simultaneously determined, and the overall quality of LH from two origins was evaluated by PCA and TOPSIS. RESULTS: In the fingerprint of 20 batches of LH, 15 common peaks were identified in the negative ion mode, and the similarity was between 0.887 and 0.981. Pharmacological results showed that, compared with the control group, the content of AST, ALT, ALP, TBA, TBIL, and MDA in serum increased, and the content of GSH and SOD activity decreased after 48 h of ANIT administration. In addition, compared to the model group, different doses of LH from the two origins could decrease the serum levels of AST, ALT, ALP, TBA, TBIL, and MDA, raise the levels of GSH and SOD activity, reduce the infiltration range of inflammatory cells, and improve the cholestatic liver injury in rats. Among them, the pharmacodynamic indices of the SCHD group were significantly better. GCA and BCA showed that a total of 7 constituents related to the efficacy were screened, which were proanthocyanidin B1, ferulic acid, hyperoside, astragalin, nicotiflorin, afzelin, and kaempferol. Besides, the content of 7 active constituents in samples from Sichuan was higher than that from Guizhou, indicating that the quality of samples from Sichuan may be better, consistent with the result of the pharmacological experiment. CONCLUSION: The quality and efficacy of LH from different origins were stable, and all of them had protective effects on cholestatic liver injury in rats. The method established in this study is accurate and reliable, and it can be used to comprehensively evaluate the internal quality of LH.

8.
Integr Zool ; 2024 Feb 13.
Artigo em Inglês | MEDLINE | ID: mdl-38348491

RESUMO

Mining can significantly alter landscapes, impacting wildlife and ecosystem functionality. Natural recovery in open-pit mines is vital for habitat restoration and ecosystem re-establishment, although few empirical studies have examined this process. Here, we assessed temporal and spatial responses of small rodents at the community, population, and individual levels during natural mine recovery. We examined the abundance, reproductive potential, and individual health of small rodents at active mines and at former mine sites left to recover naturally for approx. 10 and 20 years. We also assessed the effects of disturbance on rodent recovery processes at three distances from the mine boundary. Rodent numbers peaked after 10-13 years of recovery and exhibited the strongest male bias in the sex ratio. The Chinese white-bellied rat (Niviventer confucianus) was the most abundant species, achieving its highest population abundance at sites abandoned for 10-13 years and thriving at locations closer to the mine boundary. Only Chevrier's field mouse exhibited morphological responses to the mine recovery category. Ectoparasite load was unaffected by mine or distance-disturbance categories. Both Chevrier's field mouse (Apodemus chevrieri) and the South China field mouse (Apodemus draco) were affected significantly by vegetation layer cover during recovery succession. Our study highlights the complexities of ecological succession, with a peak in abundance as pioneer communities transition toward a climax seral stage. Careful prior planning and active site management are necessary to optimize abandoned mine recovery. Efforts to accelerate mine recovery through technical restoration should promote conditions that initiate and perpetuate the establishment and succession of wildlife assemblages.

9.
J Cancer Res Clin Oncol ; 150(2): 65, 2024 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-38300308

RESUMO

BACKGROUND: Extramedullary plasmacytoma (EMP) is a rare plasma cell malignancy, especially when the tumor originates in skeletal muscle. Plasmablastic plasmacytoma is an anaplastic round cell tumor with highly malignancy and poor prognosis. To date, there have been no reports on the transformation of skeletal muscle EMP into plasmablastic plasmacytoma. Therefore, the diagnosis, treatment, and prognosis of cases of this pathologic transformation are unclear. CASE PRESENTATION: This article reports a case of an elderly male patient who presented with a painless mass in the right calf and was diagnosed with EMP by puncture pathology. Complete remission was obtained after sequential chemoradiotherapy. 6 months later, another puncture was performed due to plasmablastic plasmacytoma multiple distant metastases, and the pathology showed that EMP was transformed to plasmablastic plasmacytoma. Despite aggressive antitumor therapy, the disease continued to deteriorate, and the patient ultimately died of respiratory failure. CONCLUSION: The transformation of EMP into plasmablastic plasmacytoma is very rare, and its diagnosis and treatment require the participation of both experienced pathologists and clinicians. We report this case in order to raise clinicians' awareness of the diagnosis and treatment of EMP and its transformation to plasmablastic plasmacytoma, and to avoid misdiagnosis and underdiagnosis.


Assuntos
Plasmocitoma , Idoso , Masculino , Humanos , Plasmocitoma/diagnóstico , Plasmocitoma/terapia , Quimiorradioterapia , Morte , Músculo Esquelético
11.
Cell Death Differ ; 2024 Feb 08.
Artigo em Inglês | MEDLINE | ID: mdl-38332049

RESUMO

The appropriate transcriptional activity of PPARγ is indispensable for controlling inflammation, tumor and obesity. Therefore, the identification of key switch that couples PPARγ activation with degradation to sustain its activity homeostasis is extremely important. Unexpectedly, we here show that acetyl-CoA synthetase short-chain family member 2 (ACSS2) critically controls PPARγ activity homeostasis via SIRT1 to enhance adipose plasticity via promoting white adipose tissues beiging and brown adipose tissues thermogenesis. Mechanistically, ACSS2 binds directly acetylated PPARγ in the presence of ligand and recruits SIRT1 and PRDM16 to activate UCP1 expression. In turn, SIRT1 triggers ACSS2 translocation from deacetylated PPARγ to P300 and thereafter induces PPARγ polyubiquitination and degradation. Interestingly, D-mannose rapidly activates ACSS2-PPARγ-UCP1 axis to resist high fat diet induced obesity in mice. We thus reveal a novel ACSS2 function in coupling PPARγ activation with degradation via SIRT1 and suggest D-mannose as a novel adipose plasticity regulator via ACSS2 to prevent obesity.

12.
Photodiagnosis Photodyn Ther ; 45: 104010, 2024 Feb 07.
Artigo em Inglês | MEDLINE | ID: mdl-38336147

RESUMO

BACKGROUND: Brain tumors have serious adverse effects on public health and social economy. Accurate detection of brain tumor types is critical for effective and proactive treatment, and thus improve the survival of patients. METHODS: Four types of brain tumor tissue sections were detected by Raman spectroscopy. Principal component analysis (PCA) has been used to reduce the dimensionality of the Raman spectra data. Linear discriminant analysis (LDA) and quadratic discriminant analysis (QDA) methods were utilized to discriminate different types of brain tumors. RESULTS: Raman spectra were collected from 40 brain tumors. Variations in intensity and shift were observed in the Raman spectra positioned at 721, 854, 1004, 1032, 1128, 1248, 1449 cm-1 for different brain tumor tissues. The PCA results indicated that glioma, pituitary adenoma, and meningioma are difficult to differentiate from each other, whereas acoustic neuroma is clearly distinguished from the other three tumors. Multivariate analysis including QDA and LDA methods showed the classification accuracy rate of the QDA model was 99.47 %, better than the rate of LDA model was 95.07 %. CONCLUSIONS: Raman spectroscopy could be used to extract valuable fingerprint-type molecular and chemical information of biological samples. The demonstrated technique has the potential to be developed to a rapid, label-free, and intelligent approach to distinguish brain tumor types with high accuracy.

13.
Zhongguo Shi Yan Xue Ye Xue Za Zhi ; 32(1): 269-273, 2024 Feb.
Artigo em Chinês | MEDLINE | ID: mdl-38387933

RESUMO

OBJECTIVE: To study the correlation between the number of hemophagocytes and peripheral blood cells in bone marrow of patients with fever of unknown origin. METHODS: A total of 465 patients with fever of unknown origin in our hospital from January 2019 to December 2021 were selected as the research objects, which was to reviewed retrospectively the correlation between the number of hemophagocytes and peripheral blood cells in bone marrow. RESULTS: The positive rates of hemophagocytes detected in the three lines decreased group, the two lines decreased group, the one line decreased group, normal group of the three lines and at least one of the three lines increased group were 86.4%, 62.1%, 38.3%, 34.6% and 33.3%, respectively. The number of hemophagocytes per unit area in the three lines decreased group was significantly higher than that in the other four groups ( P < 0.001). The number of hemophagocytes per unit area in the two lines decreased group was higher than that in the one line decreased group, normal group of three lines and at least one of the three lines increased group ( P < 0.01). There was no significant difference in the number of hemophagocytes per unit area between the group with a decreased number of one line and the other two groups with a normal number of three lines and the group with at least one increased number of three lines (P >0.05). The missed rates of hemophagocytes in the five groups were 15.78%, 22.03%, 62.22%, 77.78% and 53.84%, respectively. CONCLUSION: For patients with fever of unknown origin, especially those with obvious decrease in the number of three lines and two lines in peripheral blood cells, which should pay attention to the detection of hemophagocytes in bone marrow. Meanwhile, if the number of three lines was normal even at least one of the three lines increased, the presence of hemophagocytes in the bone marrow slice should be also carefully observed.

14.
STAR Protoc ; 5(1): 102853, 2024 Jan 30.
Artigo em Inglês | MEDLINE | ID: mdl-38294911

RESUMO

Superhydrophobic surfaces face challenges in comprehensive durability when used in extreme outdoor environments. Here, we present a protocol for preparing nanocomposite bulks with hierarchical structures using the template technique. We describe steps for using hybrid nanoparticles of polytetrafluoroethylene and multi-walled carbon nanotube to fill inside and dip on the polyurethane (PU) foam. We then detail procedures for its removal by sintering treatment. The extra accretion layer on the PU foam surface was highlighted to construct hierarchical porous structures. For complete details on the use and execution of this protocol, please refer to Wu et al.1.

15.
Clin Pharmacokinet ; 63(2): 227-239, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-38184489

RESUMO

OBJECTIVE: HSK7653 is a novel, ultralong-acting dipeptidyl peptidase-4 (DPP-4) inhibitor, promising for type 2 diabetes mellitus with a dosing regimen of once every 2 weeks. This trial investigates the pharmacokinetics (PKs), pharmacodynamics (PDs),and safety of HSK7653 in outpatients with normal or impaired renal function. METHODS: This is a multicenter, open-label, nonrandomized, parallel-controlled phase I clinical study that investigates the pharmacokinetic profiles of HSK7653 after a single oral administration in 42 subjects with mild (n = 8), moderate (n = 10), severe renal impairment (n = 10), and end-stage renal disease (without dialysis, n = 5) compared with matched control subjects with normal renal function (n = 9). Safety was evaluated throughout the study, and the pharmacodynamic effects were assessed on the basis of a DPP-4 inhibition rate. RESULTS: HSK7653 exposure levels including the maximum plasma concentration (Cmax), area under the plasma concentration-time curve from zero to last time of quantifiable concentration (AUC0-t), and area under the plasma concentration-time curve from zero to infinity (AUC0-inf) showed no significant differences related to the severity of renal impairment. Renal clearance (CLR) showed a certain downtrend along with the severity of renal impairment. The CLR of the group with severe renal impairment and the group with end-stage renal disease were basically similar. The DPP-4 inhibition rate-time curve graph was similar among the renal function groups. All groups had favorable safety, and no serious adverse events occurred. CONCLUSIONS: HSK7653 is a potent oral DPP-4 inhibitor with a long plasma half-life, supporting a dosing regimen of once every 2 weeks. Impaired renal function does not appear to impact the pharmacokinetic and pharmacodynamic properties of HSK7653 after a single administration in Chinese subjects. HSK7653 is also well tolerated without an increase in adverse events with increasing renal impairment. These results indicate that dose adjustment of HSK7653 may not be required in patients with renal impairment. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05497297.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Falência Renal Crônica , Insuficiência Renal , Humanos , Área Sob a Curva , China , Diabetes Mellitus Tipo 2/tratamento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Inibidores da Dipeptidil Peptidase IV/farmacocinética , Hipoglicemiantes/farmacocinética , Rim
16.
Stud Health Technol Inform ; 310: 906-910, 2024 Jan 25.
Artigo em Inglês | MEDLINE | ID: mdl-38269940

RESUMO

Lymph node metastasis is of paramount importance for patient treatment decision-making, prognosis evaluation, and clinical trial enrollment. However, accurate preoperative diagnosis remains challenging. In this study, we proposed a multi-task network to learn the primary tumor pathological features using the pT stage prediction task and leverage these features to facilitate lymph node metastasis prediction. We conducted experiments using electronic medical record data from 681 patients with non-small cell lung cancer. The proposed method achieved a 0.768 area under the receiver operating characteristic curve (AUC) value with a 0.073 standard deviation (SD) and a 0.448 average precision (AP) value with a 0.113 SD for lymph node metastasis prediction, which significantly outperformed the baseline models. Based on the results, we can conclude that the proposed multi-task method can effectively learn representations about tumor pathological conditions to support lymph node metastasis prediction.


Assuntos
Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Humanos , Metástase Linfática , Aprendizagem , Registros Eletrônicos de Saúde
17.
Inflamm Bowel Dis ; 2024 Jan 19.
Artigo em Inglês | MEDLINE | ID: mdl-38244236

RESUMO

BACKGROUND: Emulsifiers are implicated in the pathogenesis of inflammatory bowel disease (IBD). Few studies have examined emulsifier intake in people with existing IBD. We aimed to describe the frequency of exposure to 6 selected emulsifiers in a contemporary cohort of people with IBD and compare intake with healthy controls (HCs). METHODS: Baseline food records from participants in an Australian prospective cohort study examining the microbiome of IBD patients and HCs were analyzed. Exposure to inflammatory emulsifiers polysorbate-80 (P80); carboxymethylcellulose (CMC); carrageenan; xanthan gum (XG); lecithin (soy and sunflower) and mono- and diglycerides of fatty acids (MDGs) were determined by examining ingredient lists. Frequency of emulsifier exposure between groups (IBD vs HC, Crohn's disease [CD] vs ulcerative colitis [UC], IBD children vs adults, active disease vs remission) was examined after controlling for confounders. RESULTS: Records from 367 participants were analyzed (n = 176 IBD, of which there were 101 CD, 75 UC, and 191 HC patients). In total, 5022 unique food items were examined, with 18% containing 1 or more emulsifier of interest. Inflammatory bowel disease participants had significantly higher total daily emulsifier exposure compared with HCs (2.7 ±â€…1.8 vs 2.3 ±â€…1.6, P = .02). In IBD participants, emulsifiers with the highest daily exposure were MDGs (1.2 ±â€…0.93), lecithin (0.85 ±â€…0.93), and XG (0.38 ±â€…0.42). There were no recorded exposures to P80. CONCLUSIONS: Inflammatory bowel disease participants were exposed to more emulsifiers than HCs. Intake of inflammatory emulsifiers were low or nonexistent, suggesting their presence in the food supply are not as common as frequently stated.

18.
JAMA ; 331(3): 201-211, 2024 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-38227033

RESUMO

Importance: Adjuvant and neoadjuvant immunotherapy have improved clinical outcomes for patients with early-stage non-small cell lung cancer (NSCLC). However, the optimal combination of checkpoint inhibition with chemotherapy remains unknown. Objective: To determine whether toripalimab in combination with platinum-based chemotherapy will improve event-free survival and major pathological response in patients with stage II or III resectable NSCLC compared with chemotherapy alone. Design, Setting, and Participants: This randomized clinical trial enrolled patients with stage II or III resectable NSCLC (without EGFR or ALK alterations for nonsquamous NSCLC) from March 12, 2020, to June 19, 2023, at 50 participating hospitals in China. The data cutoff date for this interim analysis was November 30, 2022. Interventions: Patients were randomized in a 1:1 ratio to receive 240 mg of toripalimab or placebo once every 3 weeks combined with platinum-based chemotherapy for 3 cycles before surgery and 1 cycle after surgery, followed by toripalimab only (240 mg) or placebo once every 3 weeks for up to 13 cycles. Main Outcomes and Measures: The primary outcomes were event-free survival (assessed by the investigators) and the major pathological response rate (assessed by blinded, independent pathological review). The secondary outcomes included the pathological complete response rate (assessed by blinded, independent pathological review) and adverse events. Results: Of the 501 patients randomized, 404 had stage III NSCLC (202 in the toripalimab + chemotherapy group and 202 in the placebo + chemotherapy group) and 97 had stage II NSCLC and were excluded from this interim analysis. The median age was 62 years (IQR, 56-65 years), 92% of patients were male, and the median follow-up was 18.3 months (IQR, 12.7-22.5 months). For the primary outcome of event-free survival, the median length was not estimable (95% CI, 24.4 months-not estimable) in the toripalimab group compared with 15.1 months (95% CI, 10.6-21.9 months) in the placebo group (hazard ratio, 0.40 [95% CI, 0.28-0.57], P < .001). The major pathological response rate (another primary outcome) was 48.5% (95% CI, 41.4%-55.6%) in the toripalimab group compared with 8.4% (95% CI, 5.0%-13.1%) in the placebo group (between-group difference, 40.2% [95% CI, 32.2%-48.1%], P < .001). The pathological complete response rate (secondary outcome) was 24.8% (95% CI, 19.0%-31.3%) in the toripalimab group compared with 1.0% (95% CI, 0.1%-3.5%) in the placebo group (between-group difference, 23.7% [95% CI, 17.6%-29.8%]). The incidence of immune-related adverse events occurred more frequently in the toripalimab group. No unexpected treatment-related toxic effects were identified. The incidence of grade 3 or higher adverse events, fatal adverse events, and adverse events leading to discontinuation of treatment were comparable between the groups. Conclusions and Relevance: The addition of toripalimab to perioperative chemotherapy led to a significant improvement in event-free survival for patients with resectable stage III NSCLC and this treatment strategy had a manageable safety profile. Trial Registration: ClinicalTrials.gov Identifier: NCT04158440.


Assuntos
Anticorpos Monoclonais Humanizados , Antineoplásicos , Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Compostos de Platina , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Neoplasias Pulmonares/cirurgia , Antineoplásicos/uso terapêutico , Terapia Combinada , Compostos de Platina/administração & dosagem , Compostos de Platina/uso terapêutico , Idoso
19.
Int J Biol Sci ; 20(2): 664-679, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38169590

RESUMO

Myeloid derived suppressor cells (MDSCs) are known to accumulate in cancer patients and tumor-bearing mice, playing a significant role in promoting tumor growth. Depleting MDSCs has emerged as a potential therapeutic strategy for cancer. Here, we demonstrated that a fungal polysaccharide, extracted from Grifola frondosa, can effectively suppress breast tumorigenesis in mice by reducing the accumulation of MDSCs. Treatment with Grifola frondosa polysaccharide (GFI) leads to a substantial decrease in MDSCs in the blood and tumor tissue, and a potent inhibition of tumor growth. GFI treatment significantly reduces the number and proportion of MDSCs in the spleen, although this effect is not observed in the bone marrow. Further analysis reveals that GFI treatment primarily targets PMN-MDSCs, sparing M-MDSCs. Our research also highlights that GFI treatment has the dual effect of restoring and activating CD8+T cells, achieved through the downregulation of TIGIT expression and the upregulation of Granzyme B. Taken together, our findings suggest that GFI treatment effectively eliminates PMN-MDSCs in the spleen, leading to a reduction in MDSC numbers in circulation and tumor tissues, ultimately enhancing the antitumor immune response of CD8+T cells and inhibiting tumor growth. This study introduces a promising therapeutic agent for breast cancer.


Assuntos
Neoplasias da Mama , Grifola , Células Supressoras Mieloides , Humanos , Camundongos , Animais , Feminino , Células Supressoras Mieloides/metabolismo , Neoplasias da Mama/metabolismo , Linfócitos T CD8-Positivos/metabolismo , Polissacarídeos/farmacologia
20.
World J Clin Cases ; 12(1): 86-94, 2024 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-38292647

RESUMO

BACKGROUND: The obesity rate of adolescents is gradually increasing, which seriously affects their mental health, and sleep plays an important role in adolescent obesity. AIM: To investigate the relationship between sleep rhythm and obesity among adolescents and further explores the interactive effect of sleep rhythm and gender on adolescent obesity, providing a theoretical basis for developing interventions for adolescent obesity. METHODS: Research data source Tianjin Mental Health Promotion Program for Students. From April to June 2022, this study selected 14201 students from 13 middle schools in a certain district of Tianjin as the research subject using the convenient cluster sampling method. Among these students, 13374 accepted and completed the survey, with an effective rate of 94.2%.The demographic data and basic information of adolescents, such as height and weight, were collected through a general situation questionnaire. The sleep rhythm of adolescents was evaluated using the reduced version of the morningness-eveningness questionnaire. RESULTS: A total of 13374 participants (6629 females, accounting for 49.56%; the average age is 15.21 ± 1.433 years) were analyzed. Among them, the survey showed that 2942 adolescent were obesity, accounting for 22% and 2104 adolescent were overweight, accounting for 15.7%. Among them, 1692 male adolescents are obese, with an obesity rate of 25.1%, higher than 18.9% of female adolescents. There is a statistically significant difference between the three groups (χ2 = 231.522, P < 0.000). The obesity group has the smallest age (14.94 ± 1.442 years), and there is a statistical difference in age among the three groups (F = 69.996, P < 0.000).Obesity rates are higher among individuals who are not-only-child, have residential experience within six months, have family economic poverty, and have evening-type sleep (P < 0.05). Logistic regression analysis shows a correlation between sleep rhythm and adolescent obesity. Evening-type sleep rhythm can increase the risk of obesity in male adolescents [1.250 (1.067-1.468)], but the effect on female obesity is not remarkable. Further logistic regression analysis in the overall population demonstrates that the interaction between evening-type sleep rhythm and the male gender poses a risk of adolescent obesity [1.122 (1.043-1.208)]. CONCLUSION: Among adolescents, the incidence of obesity in males is higher than in females. Evening-type sleep rhythm plays an important role in male obesity but has no significant effect on female obesity. Progressive analysis suggests an interactive effect of sleep rhythm and gender on adolescent obesity, and the combination of evening-type sleep and the male gender promotes the development of adolescent obesity. In formulating precautions against adolescent obesity, obesity in male adolescents with evening-type sleep should be a critical concern.

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