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Biallelic mutations in the GBA1 gene result in Gaucher disease (GD), and both patients with GD and carriers of a single GBA1 mutation have an increased susceptibility to Parkinson's disease (PD), but the underlying mechanisms of this association are not yet clear. In previous studies, we established Gba1 F213I point mutation mice and found that homozygous Gba1 F213I mutant mice died shortly after birth, while heterozygous mice could survive normally. In this study, we investigated the transcriptomic changes in the brain tissue of Gba1 F213I heterozygous mice, identifying 138 differentially expressed genes. Among them, Nfe2l1 was the most significantly downregulated gene. Inhibition or knockdown of GBA1 in BE(2)-M17 cells resulted in decreased expression levels of NFE2L1. Knockdown of GBA1 or NFE2L1 could lead to an elevation in intracellular aggregation of α-synuclein (α-syn) and reactive oxygen species (ROS) levels, while upregulation of NFE2L1 effectively mitigated those cellular manifestations induced by GBA1 knockdown. In summary, our in vitro results showed that upregulation of NFE2L1 may provide a therapeutic benefit for cellular phenotypes resulting from GBA1 knockdown, providing new insights for future research on GD and GBA1-associated PD.
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The stable isotope analysis of black powder (BP) is of great significance for its comparison and source inference. Previous studies have verified the feasibility of distinguishing different BP samples through stable isotopes. However, the impact of raw materials and synthesis processes on the stable isotopes of BP remains unclear. On the one hand, the raw materials of BP are widely sourced, and whether stable isotopes can distinguish different source materials remains to be studied. On the other hand, the synthesis of BP involves the physical mixing of raw materials, and whether this process leads to isotope fractionation also needs further investigation. To address these problems, stable isotope ratios of 27 charcoals, 15 potassium nitrates, 6 self-made and 10 commercial BP samples were analyzed. The results showed that the stable isotope ratios can be utilized to distinguish charcoals and potassium nitrates from different manufacturers and batches. No significant differences in the nitrogen and oxygen stable isotope ratios between the self-made BP and its raw materials were observed, indicating that the physical mixing process does not induce significant fractionation of stable isotopes. However, the carbon stable isotope ratios of charcoal increased (within 2SD) after being synthesized into BP. Due to the utilization of additives and variations in the synthesis process, the correlation between the stable isotope ratios of commercial BP and its raw materials was complex. The findings of this study provide a scientific reference for tracing the source of BP.
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Radiotherapy, a precise modality for treating malignant tumors, has undergone rapid advancements in primary and clinical research. The mechanisms underlying tumor radioresistance have become significant research. With the introduction and in-depth study of cancer stem cells (CSCs) theory, CSCs have been identified as the primary factor contributing to the development of tumor radioresistance. The "stemness" of CSCs is a biological characteristic of a small subset of cells within tumor tissues, characterized by self-renewal solid ability. This characteristic leads to resistance to radiotherapy, chemotherapy, and targeted therapies, driving tumor recurrence and metastasis. Another study revealed that cellular autophagy plays a pivotal role in maintaining the "stemness" of CSCs. Autophagy is a cellular mechanism that degrades proteins and organelles to generate nutrients and energy in response to stress. This process maintains cellular homeostasis and contributes to CSCs radioresistance. Furthermore, ionizing radiation (IR) facilitates epithelial-to-mesenchymal transition (EMT), vascular regeneration, and other tumor processes by influencing the infiltration of M2-type tumor-associated macrophages (TAMs). IR promotes the activation of the classical immunosuppressive "switch," PD-1/PD-L1, which diminishes T-cell secretion, leading to immune evasion and promoting radioresistance. Interestingly, recent studies have found that the immune pathway PD-1/PD-L1 is closely related to cellular autophagy. However, the interrelationships between immunity, autophagy, and radioresistance of CSCs and the regulatory mechanisms involved remain unclear. Consequently, this paper reviews recent research to summarize these potential connections, aiming to establish a theoretical foundation for future studies and propose a new model for the network regulation of immunity, autophagy, and radioresistance of tumor cells.
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The inflammation causes the destroyed osseointegration at the implant-bone interface, significantly increasing the probability of implant loosening in osteoporotic patients. Currently, inhibiting the differentiation of M1 macrophages and the inflammatory response could be a solution to stabilize the microenvironment of implants. Interestingly, some natural products have anti-inflammatory and anti-polarization effects, which could be a promising candidate for stabilizing the implants' microenvironment in osteoporotic patients. This research aims to explore the inhibitory effect of Urolithin B(UB) on macrophage M1 polarization, which ameliorates inflammation, thus alleviating implant instability. We established an osteoporosis mouse model of implant loosening. The mouse tissues were taken out for morphological analysis, staining analysis, and bone metabolic index analysis. In in vitro experiments, RAW264.7 cells were polarized to M1 macrophages using lipopolysaccharide (LPS) and analyzed by immunofluorescence (IF) staining, Western blot (WB), and flow cytometry. The CSP100 plus chip experiments were used to explore the potential mechanisms behind the inhibiting effects of UB. Through observation of these experiments, UB can improve the osseointegration between the implants and femurs in osteoporotic mice and enhance the stability of implants. The UB can inhibit the differentiation of M1 macrophages and local inflammation via inhibiting the phosphorylation of VEGFR2, which can be further proved by the weakened inhibited effects of UB in macrophages with lentivirus-induced overexpression of VEGFR2. Overall, UB can specifically inhibit the activation of VEGFR2, alleviate local inflammation, and improve the stability of implants in osteoporotic mice.
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Diferenciación Celular , Cumarinas , Macrófagos , Osteoporosis , Receptor 2 de Factores de Crecimiento Endotelial Vascular , Animales , Ratones , Cumarinas/farmacología , Cumarinas/uso terapéutico , Macrófagos/inmunología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Diferenciación Celular/efectos de los fármacos , Células RAW 264.7 , Fosforilación/efectos de los fármacos , Osteoporosis/tratamiento farmacológico , Osteoporosis/inmunología , Receptor 2 de Factores de Crecimiento Endotelial Vascular/metabolismo , Femenino , Ratones Endogámicos C57BL , Regulación hacia Abajo/efectos de los fármacos , Oseointegración/efectos de los fármacos , Antiinflamatorios/farmacología , Antiinflamatorios/uso terapéutico , Humanos , Inflamación/tratamiento farmacológico , Modelos Animales de Enfermedad , Prótesis e ImplantesRESUMEN
The WD40 domain is one of the most abundant domains and is among the top interacting domains in eukaryotic genomes. The WD40 domain of ATG16L1 is essential for LC3 recruitment to endolysosomal membranes during non-canonical autophagy, but dispensable for canonical autophagy. Canonical autophagy was utilized by FMDV, while the relationship between FMDV and non-canonical autophagy is still elusive. In the present study, WD40 knockout (KO) PK15 cells were successfully generated via CRISPR/cas9 technology as a tool for studying the effect of non-canonical autophagy on FMDV replication. The results of growth curve analysis, morphological observation and karyotype analysis showed that the WD40 knockout cell line was stable in terms of growth and morphological characteristics. After infection with FMDV, the expression of viral protein, viral titers, and the number of copies of viral RNA in the WD40-KO cells were significantly greater than those in the wild-type PK15 cells. Moreover, RNAâseq technology was used to sequence WD40-KO cells and wild-type cells infected or uninfected with FMDV. Differentially expressed factors such as Mx1, RSAD2, IFIT1, IRF9, IFITM3, GBP1, CXCL8, CCL5, TNFRSF17 were significantly enriched in the autophagy, NOD-like receptor signaling pathway, RIG-I-like receptor signaling pathway, Toll-like receptor signaling pathway, cytokine-cytokine receptor interaction and TNF signaling pathway, etc. The expression levels of differentially expressed genes were detected via qRTâPCR, which was consistent with the RNAâseq data. Here, we experimentally demonstrate for the first time that knockout of the WD40 domain of ATG16L1 enhances FMDV replication by downregulation innate immune factors. In addition, this result also indicates non-canonical autophagy inhibits FMDV replication. In total, our results play an essential role in regulating the replication level of FMDV and providing new insights into virus-host interactions and potential antiviral strategies.
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Proteínas Relacionadas con la Autofagia , Autofagia , Virus de la Fiebre Aftosa , Técnicas de Inactivación de Genes , Replicación Viral , Virus de la Fiebre Aftosa/genética , Virus de la Fiebre Aftosa/fisiología , Proteínas Relacionadas con la Autofagia/genética , Proteínas Relacionadas con la Autofagia/metabolismo , Animales , Autofagia/genética , Línea Celular , Repeticiones WD40/genética , Sistemas CRISPR-Cas , Fiebre Aftosa/virologíaRESUMEN
Starch biosynthesis involves numerous enzymes and is a crucial metabolic activity in plant storage organs. Sucrose non-fermenting related protein kinase 2 (SnRK2) is an abscisic acid (ABA)-dependent kinase and a significant regulatory enzyme in the ABA signaling pathway. However, whether SnRK2 kinases regulate starch biosynthesis is unclear. In this study, we identified that MeSnRK2.3, an ABA-dependent kinase, was highly expressed in the storage roots of cassava and was induced by ABA. Overexpression of MeSnRK2.3 in cassava significantly increased the starch content in the storage roots and promoted plant growth. MeSnRK2.3 was further found to interact with the cassava basic helix-loop-helix 68 (MebHLH68) transcription factor in vivo and in vitro. MebHLH68 directly bound to the promoters of sucrose synthase 1 (MeSUS1), granule-bound starch synthase I a (MeGBSSIa), and starch-branching enzyme 2.4 (MeSBE2.4), thereby upregulating their transcriptional activities. Additionally, MebHLH68 negatively regulated the transcriptional activity of sucrose phosphate synthase B (MeSPSB). Moreover, phosphorylated MebHLH68 by MeSnRK2.3 up-regulated the transcription activity of MeSBE2.4. These findings demonstrated that the MeSnRK2.3-MebHLH68 module connects the ABA signaling pathway and starch biosynthesis in cassava, thereby providing direct evidence of ABA-mediated participation in the sucrose metabolism and starch biosynthesis pathway.
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It is unknown why roses are terpene-rich, what the terpene biosynthetic pathways in roses are, and why only a few rose species produce the major components of rose essential oil. Here, we assembled two high-quality chromosome-level genomes for Rosa rugosa and Rosa multiflora. We also re-sequenced 132 individuals from the F1 progeny of Rosa chinensis and Rosa wichuraiana and 36 of their related species. Comparative genomics revealed that expansions of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGR) and terpene synthases (TPSs) gene families led to the enrichment of terpenes in rose scent components. We constructed a terpene biosynthesis network and discovered a TPS-independent citronellol biosynthetic pathway in roses through gene functional identification, genome-wide association studies (GWASs), and multi-omic analysis. Heterologous co-expression of rose citronellol biosynthetic genes in Nicotiana benthamiana led to citronellol production. Our genomic and metabolomic analyses suggested that the copy number of NUDX1-1a determines the citronellol content in different rose species. Our findings not only provide additional genome and gene resources and reveal the evolution of the terpene biosynthetic pathways but also present a nearly complete scenario for terpenoid metabolism that will facilitate the breeding of fragrant roses and the production of rose oil.
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Vías Biosintéticas , Rosa , Terpenos , Rosa/genética , Rosa/metabolismo , Terpenos/metabolismo , Vías Biosintéticas/genética , Transferasas Alquil y Aril/genética , Transferasas Alquil y Aril/metabolismo , Estudio de Asociación del Genoma Completo , Odorantes , Evolución Molecular , Genoma de Planta , Monoterpenos Acíclicos/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismoRESUMEN
Tomatoes are prone to mechanical damage due to improper gripping forces during automated harvest and postharvest processes. To reduce this damage, a dynamic viscoelastic model based on long short-term memory (LSTM) is proposed to fit the dynamic compression stress relaxation characteristics of the individual fruit. Furthermore, the classical stress relaxation models involved, the triple-element Maxwell and Caputo fractional derivative models, are compared with the LSTM model to validate its performance. Meanwhile, the LSTM and classical stress relaxation models are used to predict the stress relaxation characteristics of tomato fruit with different fruit sizes and compression positions. The results for the whole test dataset show that the LSTM model achieves a RMSE of 2.829×10-5 Mpa and a MAPE of 0.228%. It significantly outperforms the Caputo fractional derivative model by demonstrating a substantial enhancement with a 37% decrease in RMSE and a 36% reduction in MAPE. Further analysis of individual tomato fruit reveals the LSTM model's performance, with the minimum RMSE recorded at the septum position being 3.438×10-5 Mpa, 31% higher than the maximum RMSE at the locule position. Similarly, the lowest MAPE at the septum stands at 0.375%, outperforming the highest MAPE at the locule position by a significant margin of 90%. Moreover, the LSTM model consistently reports the smallest discrepancies between the predicted and observed values compared to classical stress relaxation models. This accuracy suggests that the LSTM model could effectively supplant classical stress relaxation models for predicting stress relaxation changes in individual tomato fruit.
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Mesenchymal stem cells (MSCs) possess significant differentiation potential, making them highly promising in medicine and immunotherapy due to their regenerative capabilities and exosome secretion. However, challenges such as limited cell divisions and complex testing hinder large-scale MSC production. In this study, we successfully established an immortalized MSC line by transfecting the human telomerase reverse transcriptase (TERT) gene into MSCs isolated from pregnant sheep umbilical cords. This approach effectively inhibits cell senescence and promotes cell proliferation, enabling the generation of umbilical cord mesenchymal stem cells (UCMSCs) on a larger scale. Our findings demonstrate that these transfected TERT-UCMSCs exhibit enhanced proliferative capacity and a reduced aging rate compared to regular UCMSCs while maintaining their stemness without tumorigenicity concerns. Consequently, they hold great potential for medical applications requiring large quantities of functional MSCs.
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BACKGROUND: Foot-and-mouth disease (FMD) is a devastating disease affecting cloven-hoofed animals, that leads to significant economic losses in affected countries and regions. Currently, there is an evident inclination towards the utilization of nanoparticles as powerful platforms for innovative vaccine development. Therefore, this study developed a ferritin-based nanoparticle (FNP) vaccine that displays a neutralizing epitope of foot-and-mouth disease virus (FMDV) VP1 (aa 140-158) on the surface of FNP, and evaluated the immunogenicity and protective efficacy of these FNPs in mouse and guinea pig models to provide a strategy for developing potential FMD vaccines. RESULTS: This study expressed the recombinant proteins Hpf, HPF-NE and HPF-T34E via an E. coli expression system. The results showed that the recombinant proteins Hpf, Hpf-NE and Hpf-T34E could be effectively assembled into nanoparticles. Subsequently, we evaluated the immunogenicity of the Hpf, Hpf-NE and Hpf-T34E proteins in mice, as well as the immunogenicity and protectiveness of the Hpf-T34E protein in guinea pigs. The results of the mouse experiment showed that the immune efficacy in the Hpf-T34E group was greater than the Hpf-NE group. The results from guinea pigs immunized with Hpf-T34E showed that the immune efficacy was largely consistent with the immunogenicity of the FMD inactivated vaccine (IV) and could confer partial protection against FMDV challenge in guinea pigs. CONCLUSIONS: The Hpf-T34E nanoparticles stand out as a superior choice for a subunit vaccine candidate against FMD, offering effective protection in FMDV-infected model animals. FNP-based vaccines exhibit excellent safety and immunogenicity, thus representing a promising strategy for the continued development of highly efficient and safe FMD vaccines.
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Epítopos , Ferritinas , Virus de la Fiebre Aftosa , Fiebre Aftosa , Nanopartículas , Vacunas Virales , Animales , Cobayas , Fiebre Aftosa/prevención & control , Fiebre Aftosa/inmunología , Virus de la Fiebre Aftosa/inmunología , Ferritinas/inmunología , Vacunas Virales/inmunología , Epítopos/inmunología , Ratones , Femenino , Ratones Endogámicos BALB C , Proteínas Recombinantes/inmunología , Proteínas de la CápsideRESUMEN
Objective: To investigate the effect of self-developed Ye'an Analgetic Decoction/Jiawei Shaoyao Gancao Decoction on Traditional Chinese Medicine (TCM) symptom scores and RLS Severity of patients with restless legs syndrome (RLS). Methods: This was a clinical comparative study. Eighty patients with RLS admitted to Baoding No.1 Central Hospital from January 2022 to December 2022 were randomly divided into observation group and control group(n=40). Patients in the control group were given basic and oral tramadol treatment, while those in the observation group were given self-developed Ye'an Analgetic Decoction/Jiawei Shaoyao Gancao Decoction based on the treatment in the control group. The differences of TCM symptom scores, RLS severity (IRLS), quality of life (QOL-RLS), sleep quality (PSQI) and clinical efficacy between the two groups were compared. Results: Before treatment, no statistically significant differences were observed in the TCM symptom scores, IRLS scores, QOL-RLS scores and PSQI scores between the two groups (p>0.05). After treatment, the above scores decreased significantly in both groups, with a higher degree of decrease in the observation group than in the control group, indicating statistically significant differences (p<0.05). The QOL-RLS scores were significantly higher in the observation group than in the control group, with a statistically significant difference (p<0.05). The overall response rate in the observation group was 95.00%, which was higher than that in the control group (80.00%), with a statistically significant difference (p<0.05). Conclusion: Self-developed Ye'an Analgetic Decoction/Jiawei Shaoyao Gancao Decoction leads to numerous benefits in the treatment of RLS, such as obviously ameliorating patients' clinical symptoms, reducing RLS severity, and improving their quality of life and sleep quality.
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Depressive symptoms and aggression frequently occur together, and this co-occurrence may result in more severe developmental problems. However, it is unclear if there are distinct patterns of co-occurrence. This study investigated the co-occurrence patterns of depressive symptoms and aggression, and examined their stability and demographic characteristics. A total of 1010 Chinese adolescents (50.6% girls; mean age at T1 = 12.54 years, SD = 0.42) participated in annual surveys over three years (2019-2021). Three different patterns of co-occurrence were found except for the normal group: depression-dominant co-occurrence (13.6%), aggression-dominant co-occurrence (3.2%), and moderate co-occurrence (6.0%) (T1). In these co-occurrence patterns, adolescents classified as aggression-dominant co-occurrence exhibited the most instability and frequent changes, while adolescents classified as depression-dominant co-occurrence exhibited the most stability. Boys or younger adolescents were more likely to exhibit the aggression-dominant co-occurrence, while girls or older adolescents were more likely to exhibit the depression-dominant co-occurrence. The findings indicate that the co-occurrence patterns observed are distinct and are dominated by aggression or depression, which implies the need for targeted intervention practices.
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BACKGROUND: Nitzschia closterium f. minutissima is a commonly available diatom that plays important roles in marine aquaculture. It was originally classified as Nitzschia (Bacillariaceae, Bacillariophyta) but is currently regarded as a heterotypic synonym of Phaeodactylum tricornutum. The aim of this study was to obtain the draft genome of the marine microalga N. closterium f. minutissima to understand its phylogenetic placement and evolutionary specialization. Given that the ornate hierarchical silicified cell walls (frustules) of diatoms have immense applications in nanotechnology for biomedical fields, biosensors and optoelectric devices, transcriptomic data were generated by using reference genome-based read mapping to identify significantly differentially expressed genes and elucidate the molecular processes involved in diatom biosilicification. RESULTS: In this study, we generated 13.81 Gb of pass reads from the PromethION sequencer. The draft genome of N. closterium f. minutissima has a total length of 29.28 Mb, and contains 28 contigs with an N50 value of 1.23 Mb. The GC content was 48.55%, and approximately 18.36% of the genome assembly contained repeat sequences. Gene annotation revealed 9,132 protein-coding genes. The results of comparative genomic analysis showed that N. closterium f. minutissima was clustered as a sister lineage of Phaeodactylum tricornutum and the divergence time between them was estimated to be approximately 17.2 million years ago (Mya). CAFF analysis demonstrated that 220 gene families that significantly changed were unique to N. closterium f. minutissima and that 154 were specific to P. tricornutum, moreover, only 26 gene families overlapped between these two species. A total of 818 DEGs in response to silicon were identified in N. closterium f. minutissima through RNA sequencing, these genes are involved in various molecular processes such as transcription regulator activity. Several genes encoding proteins, including silicon transporters, heat shock factors, methyltransferases, ankyrin repeat domains, cGMP-mediated signaling pathways-related proteins, cytoskeleton-associated proteins, polyamines, glycoproteins and saturated fatty acids may contribute to the formation of frustules in N. closterium f. minutissima. CONCLUSIONS: Here, we described a draft genome of N. closterium f. minutissima and compared it with those of eight other diatoms, which provided new insight into its evolutionary features. Transcriptome analysis to identify DEGs in response to silicon will help to elucidate the underlying molecular mechanism of diatom biosilicification in N. closterium f. minutissima.
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Diatomeas , Perfilación de la Expresión Génica , Filogenia , Diatomeas/genética , Diatomeas/metabolismo , Diatomeas/clasificación , Genoma , Transcriptoma , Anotación de Secuencia MolecularRESUMEN
The aroma of Sichuan Xiaoqu Baijiu (SXB) greatly benefits from the use of sorghum as its primary brewing ingredient. Nevertheless, the impact of different sorghum variety on the primary aroma compounds of SXB has not been thoroughly investigated. Gas chromatography-mass spectrometry (GC-MS) in conjunction with headspace solid phase microextraction (HS-SPME) and liquid-liquid extraction (LLE) were employed in this investigation. Using 5 sorghum varieties as raw materials, five different types of SXB were analysed for their aroma compounds using GC-MS, GC-O, AEDA, aroma recombination, and aroma omission. Key aroma compounds of SXB were successfully identified as ethyl acetate, ethyl 2-methylbutyrate, isoamyl acetate, ethyl hexanoate, ethyl heptanoate, ethyl lactate, ethyl octanoate, ethyl decanoate, phenylethyl acetate, ethyl laurate, ethyl palmitate, isoamyl alcohol, phenylethanol, 1,1-diethoxyethane, 3-hydroxy-2- butanone, furfural, and glacial acetic acid. Glacial acetic acid, ethyl acetate, ethyl lactate, phenylethyl acetate, acetoin, phenylethanol, and ethyl caproate were found to be the seven major aroma compounds that had the biggest impact on the variations of the five SXB aroma properties, according to partial least squares regression (PLS-R) analysis. The collinear network analysis also revealed that the largest positive correlation weight was discovered between the protein and furfural content, tannin content and cereal-like aroma profile while the highest negative correlation weight was found between the moisture and acetoin content. This study is a valuable resource for understanding how raw materials control the directional regulation of the sensory quality of the SXB liquor body.
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This paper introduces two cases of multiple myeloma, COVID-19 infection during autologous stem cell transplantation, the treatment process, and different results of the two patients, which provides a reference for how to carry out ASCT safely during the COVID-19 normalization stage.
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Improving access to HIV/AIDS healthcare services is of great concern to government and policymakers striving to strengthen overall public health. How to reasonably allocate HIV/AIDS healthcare resources and maximize the equality of access to healthcare services across subdistrict areas has become an urgent problem to be solved. However, there is limited research on this topic in China. It is necessary to evaluate spatial accessibility to improve the accessibility and equity of HIV/AIDS healthcare services. In this study, the improved multi-modal two-step floating catchment area (2SFCA) and inverted 2SFCA (i2SFCA) methods are used to measure the spatial accessibility of HIV/AIDS healthcare services and the crowdedness of the healthcare sites in Shandong Province, China. Then, the theoretical supply and the optimal spatial distribution of resources are calculated and visualized by minimizing the accessibility gaps between demand locations. This study showed that the spatial accessibility of HIV/AIDS service resources in Shandong Province was concentrated and unevenly distributed, and the accessibility scores in the marginal areas of prefecture-level cities were significantly lower than those in other areas. Regions with a large number of doctors had significantly higher levels of spatial accessibility. The ART accessibility scores in the southwest of Shandong Province were higher than those in other regions. As the travel friction coefficient increased, the accessibility scores formed an approximately circular cluster distribution centered on the healthcare sites in geographical distribution. More ART drugs needed to be supplied in marginal areas and more doctors were needed to work on HIV/AIDS in urban areas to address the spatial distribution imbalance of HIV/AIDS healthcare services. This study profoundly analyzed the spatial accessibility of HIV/AIDS healthcare services and provided essential references for decision-makers. In addition, it gives a significant exploration for achieving the goal of equal access to HIV/AIDS healthcare services in the future.
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Síndrome de Inmunodeficiencia Adquirida , Infecciones por VIH , Accesibilidad a los Servicios de Salud , China/epidemiología , Humanos , Infecciones por VIH/epidemiología , Infecciones por VIH/terapia , Síndrome de Inmunodeficiencia Adquirida/epidemiología , Síndrome de Inmunodeficiencia Adquirida/terapia , Análisis Espacial , Áreas de Influencia de SaludRESUMEN
BACKGROUND: Cadonilimab (AK104) is a bispecific IgG-single-chain Fv fragment (ScFv) antibody that binds to PD-1 and CTLA-4. Cadonilimab has shown encouraging anti-tumour activity and a favourable safety profile in several tumour types. In second-line treatment, there is no defined standard of care for patients with extensive-stage small-cell lung cancer (ES-SCLC). Cadonilimab is expected to show substantial clinical efficacy. OBJECTIVE: To assess the antitumor activity and safety of cadonilimab monotherapy or combination with conventional therapy in ES-SCLC patients who failed first-line treatment. METHODS: In this multicenter, open-label, phase II study, ES-SCLC patients who had failed first-line treatment, also aged 18 years to 70 years with histologically or cytologically confirmed ES-SCLC, and an Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0-2 were eligible. Patients will receive cadonilimab 10 mg/kg every three weeks (Q3 W) among 24 months until progressive disease (PD) or adverse events (AE) discovery. The primary endpoint is progression-free survival (PFS). TRIAL REGISTRATION: NCT05901584.
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Antígeno CTLA-4 , Neoplasias Pulmonares , Receptor de Muerte Celular Programada 1 , Carcinoma Pulmonar de Células Pequeñas , Humanos , Neoplasias Pulmonares/tratamiento farmacológico , Neoplasias Pulmonares/patología , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Carcinoma Pulmonar de Células Pequeñas/patología , Masculino , Antígeno CTLA-4/antagonistas & inhibidores , Femenino , Persona de Mediana Edad , Anciano , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Estadificación de Neoplasias , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Resultado del Tratamiento , Adulto Joven , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/administración & dosificación , AdolescenteRESUMEN
Immunotherapy with programmed cell death 1 ligand 1 (PD-L1) blockade was effective in patients with NK/T-cell lymphoma. In addition to PD-L1, indoleamine 2,3-dioxygenase-1 (IDO1) is one of the most promising immunotherapeutic targets. High proportions of PD-L1 and IDO1 proteins were observed by immunohistochemistry (IHC) from 230 newly diagnosed patients with NK/T lymphoma with tissue samples from three cancer centers and were associated with poor overall survival (OS) in patients with NK/T lymphoma. Importantly, the coexpression of PD-L1 and IDO1 was related to poor OS and short restricted mean survival time in patients with NK/T lymphoma and was an independent prognostic factor in the training cohorts, and which was also validated in 58 NK/T lymphoma patients (GSE90597). Moreover, a nomogram model constructed with PD-L1 and IDO1 expression together with age could provide concise and precise predictions of OS rates and median survival time. The high-risk group in the nomogram model had a positive correlation with CD4 + T-cell infiltration in the validation cohort, as did the immunosuppressive factor level. Therefore, high PD-L1 and IDO1 expression was associated with poor OS in patients with NK/T lymphoma. PD-L1 and IDO1 might be potential targets for future immune checkpoint blockade (ICB) therapy for NK/T lymphoma.
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Antígeno B7-H1 , Biomarcadores de Tumor , Indolamina-Pirrol 2,3,-Dioxigenasa , Linfoma Extranodal de Células NK-T , Humanos , Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo , Antígeno B7-H1/metabolismo , Masculino , Femenino , Linfoma Extranodal de Células NK-T/mortalidad , Linfoma Extranodal de Células NK-T/metabolismo , Linfoma Extranodal de Células NK-T/patología , Linfoma Extranodal de Células NK-T/tratamiento farmacológico , Persona de Mediana Edad , Pronóstico , Adulto , Anciano , Biomarcadores de Tumor/metabolismo , Tasa de Supervivencia , Adulto Joven , Nomogramas , Estudios de Seguimiento , Anciano de 80 o más AñosRESUMEN
Cassava, a pivotal tropical crop, exhibits rapid growth and possesses a substantial biomass. Its stem is rich in cellulose and serves as a crucial carbohydrate storage organ. The height and strength of stems restrict the mechanised operation and propagation of cassava. In this study, the triple helix transcription factor MeGT2.6 was identified through yeast one-hybrid assay using MeCesA1pro as bait, which is critical for cellulose synthesis. Over-expression and loss-of-function lines were generated, and results revealed that MeGT2.6 could promote a significant increase in the plant height, stem diameter, cell size and thickness of SCW of cassava plant. Specifically, MeGT2.6 upregulated the transcription activity of MeGA20ox1 and downregulated the expression level of MeGA2ox1, thereby enhancing the content of active GA3, resulting in a large cell size, high plant height and long stem diameter in cassava. Moreover, MeGT2.6 upregulated the transcription activity of MeCesA1, which promoted the synthesis of cellulose and hemicellulose and produced a thick secondary cell wall. Finally, MeGT2.6 could help supply additional substrates for the synthesis of cellulose and hemicellulose by upregulating the invertase genes (MeNINV1/6). Thus, MeGT2.6 was found to be a multiple regulator; it was involved in GA metabolism and sucrose decomposition and the synthesis of cellulose and hemicellulose.
Asunto(s)
Celulosa , Regulación de la Expresión Génica de las Plantas , Giberelinas , Manihot , Proteínas de Plantas , Manihot/genética , Manihot/metabolismo , Celulosa/metabolismo , Celulosa/biosíntesis , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Giberelinas/metabolismo , Pared Celular/metabolismo , Aumento de la Célula , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Tallos de la Planta/genética , Tallos de la Planta/metabolismo , Tallos de la Planta/crecimiento & desarrollo , Polisacáridos/metabolismoRESUMEN
Matrix Metalloproteinases (MMPs) have been demonstrated to be essential in facilitating the migration and metastasis of clear cell renal cell carcinoma (ccRCC). However, the ability of the MMP family to predict clinical outcomes and guide optimal therapeutic strategies for ccRCC patients remains incompletely understood. In this investigation, we initially conducted a thorough examination of the MMP family in pan-cancer. Notably, MMPs exhibited distinctive significance in ccRCC. Following this, we undertook an extensive analysis to evaluate the clinical value of MMPs and potential mechanisms by which MMPs contribute to the progression of ccRCC. A novel stratification method and prognostic model were developed based on MMPs in order to enhance the accuracy of prognosis prediction for ccRCC patients and facilitate personalized treatment. By conducting multi-omics analysis and transcriptional regulation analysis, it was hypothesized that SAA1 plays a crucial role in promoting ccRCC migration through MMPs. Subsequently, in vitro experiments confirmed that SAA1 regulates ccRCC cell migration via the ERK-AP1-MMPs axis. In conclusion, our study has explored the potential value of the MMP family as prognostic markers for ccRCC and as guides for medication regimens. Additionally, we have identified SAA1 as a crucial factor in the migration of ccRCC.