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p53 is a frequent target for mutation in human tumors, and mutant p53 proteins can actively contribute to tumorigenesis. We employed a three-dimensional culture model in which nonmalignant breast epithelial cells form spheroids reminiscent of acinar structures found in vivo, whereas breast cancer cells display highly disorganized morphology. We found that mutant p53 depletion is sufficient to phenotypically revert breast cancer cells to a more acinar-like morphology. Genome-wide expression analysis identified the mevalonate pathway as significantly upregulated by mutant p53. Statins and sterol biosynthesis intermediates reveal that this pathway is both necessary and sufficient for the phenotypic effects of mutant p53 on breast tissue architecture. Mutant p53 associates with sterol gene promoters at least partly via SREBP transcription factors. Finally, p53 mutation correlates with highly expressed sterol biosynthesis genes in human breast tumors. These findings implicate the mevalonate pathway as a therapeutic target for tumors bearing mutations in p53.
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Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Ácido Mevalónico/metabolismo , Proteína p53 Supresora de Tumor/genética , Línea Celular Tumoral , Femenino , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Redes y Vías Metabólicas/efectos de los fármacos , Mutación , Prenilación , Regiones Promotoras Genéticas , Simvastatina/farmacología , Proteínas de Unión a los Elementos Reguladores de Esteroles/metabolismoRESUMEN
Alternative polyadenylation (APA) produces mRNA isoforms with different 3' UTR lengths. Previous studies indicated that 3' end processing and mRNA export are intertwined in gene regulation. Here, we show that mRNA export factors generally facilitate usage of distal cleavage and polyadenylation sites (PASs), leading to long 3' UTR isoform expression. By focusing on the export receptor NXF1, which exhibits the most potent effect on APA in this study, we reveal several gene features that impact NXF1-dependent APA, including 3' UTR size, gene size, and AT content. Surprisingly, NXF1 downregulation results in RNA polymerase II (Pol II) accumulation at the 3' end of genes, correlating with its role in APA regulation. Moreover, NXF1 cooperates with CFI-68 to facilitate nuclear export of long 3' UTR isoform with UGUA motifs. Together, our work reveals important roles of NXF1 in coordinating transcriptional dynamics, 3' end processing, and nuclear export of long 3' UTR transcripts, implicating NXF1 as a nexus of gene regulation.
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Núcleo Celular/metabolismo , Proteínas de Transporte Nucleocitoplasmático/metabolismo , Poliadenilación , ARN Mensajero/biosíntesis , Proteínas de Unión al ARN/metabolismo , Transcripción Genética , Regiones no Traducidas 3' , Transporte Activo de Núcleo Celular , Sitios de Unión , Núcleo Celular/genética , Células HEK293 , Células HeLa , Humanos , Cinética , Proteínas de Transporte Nucleocitoplasmático/genética , Unión Proteica , ARN Polimerasa II/metabolismo , ARN Mensajero/genética , Proteínas de Unión al ARN/genéticaRESUMEN
Duchenne muscular dystrophy (DMD) is a progressive disabling X-linked recessive disorder that causes gradual and irreversible loss of muscle, resulting in early death. The corticosteroids prednisone/prednisolone and deflazacort are used to treat DMD as the standard of care; however, only deflazacort is FDA approved for DMD. The novel atypical corticosteroid vamorolone is being investigated for treatment of DMD. We compared the pharmaceutical properties as well as the efficacy and safety of the three corticosteroids across multiple doses in the B10-mdx DMD mouse model. Pharmacokinetic studies in the mouse and evaluation of p-glycoprotein (P-gP) efflux in a cellular system demonstrated that vamorolone is not a strong P-gp substrate resulting in measurable central nervous system (CNS) exposure in the mouse. In contrast, deflazacort and prednisolone are strong P-gp substrates. All three corticosteroids showed efficacy, but also side effects at efficacious doses. After dosing mdx mice for two weeks, all three corticosteroids induced changes in gene expression in the liver and the muscle, but prednisolone and vamorolone induced more changes in the brain than did deflazacort. Both prednisolone and vamorolone induced depression-like behavior. All three corticosteroids reduced endogenous corticosterone levels, increased glucose levels, and reduced osteocalcin levels. Using micro-computed tomography, femur bone density was decreased, reaching significance with prednisolone. The results of these studies indicate that efficacious doses of vamorolone, are associated with similar side effects as seen with other corticosteroids. Further, because vamorolone is not a strong P-gp substrate, vamorolone distributes into the CNS increasing the potential CNS side-effects.
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Distrofia Muscular de Duchenne , Prednisolona , Pregnadienodioles , Pregnenodionas , Animales , Ratones , Prednisolona/uso terapéutico , Microtomografía por Rayos X , Ratones Endogámicos mdx , Distrofia Muscular de Duchenne/tratamiento farmacológico , Distrofia Muscular de Duchenne/genética , Corticosterona/uso terapéutico , Preparaciones FarmacéuticasRESUMEN
Immune checkpoint blockade has been used to treat breast cancer, but the clinical responses remain relatively poor. We have used the CRISPR-Cas9 kinome knockout library consisting of 763 kinase genes to identify tumor-intrinsic kinases conferring resistance to anti-PD-1 immune checkpoint blockade. We have identified the CDC42BPB kinase as a potential target to overcome the resistance to anti-PD-1 immune checkpoint blockade immunotherapy. We found that CDC42BPB is highly expressed in breast cancer patients who are non-responsive to immunotherapy. Furthermore, a small-molecule pharmacological inhibitor, BDP5290, which targets CDC42BPB, synergized with anti-PD-1 and enhanced tumor cell killing by promoting T cell proliferation in both in vitro and in vivo assays. Moreover, anti-PD-1-resistant breast cancer cells showed higher expression of CDC42BPB, and its inhibition rendered the resistant cells more susceptible to T cell killing in the presence of anti-PD-1. We also found that CDC42BPB phosphorylated AURKA, which in turn upregulated PD-L1 through cMYC. Our results have revealed a robust link between tumor-intrinsic kinase and immunotherapy resistance and have provided a rationale for a unique combination therapy of CDC42BPB inhibition and anti-PD-1 immunotherapy for breast cancer.
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Many long noncoding RNAs (lncRNAs) are unstable and rapidly degraded in the nucleus by the nuclear exosome. An exosome adaptor complex called NEXT (nuclear exosome targeting) functions to facilitate turnover of some of these lncRNAs. Here we show that knockdown of one NEXT subunit, Mtr4, but neither of the other two subunits, resulted in accumulation of two types of lncRNAs: prematurely terminated RNAs (ptRNAs) and upstream antisense RNAs (uaRNAs). This suggested a NEXT-independent Mtr4 function, and, consistent with this, we isolated a distinct complex containing Mtr4 and the zinc finger protein ZFC3H1. Strikingly, knockdown of either protein not only increased pt/uaRNA levels but also led to their accumulation in the cytoplasm. Furthermore, all pt/uaRNAs examined associated with active ribosomes, but, paradoxically, this correlated with a global reduction in heavy polysomes and overall repression of translation. Our findings highlight a critical role for Mtr4/ZFC3H1 in nuclear surveillance of naturally unstable lncRNAs to prevent their accumulation, transport to the cytoplasm, and resultant disruption of protein synthesis.
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Transporte Activo de Núcleo Celular/genética , Citoplasma/metabolismo , Regulación de la Expresión Génica/genética , ARN Helicasas/metabolismo , ARN Nuclear/metabolismo , Factores de Transcripción/metabolismo , Técnicas de Silenciamiento del Gen , Células HEK293 , Células HeLa , Humanos , ARN Helicasas/genética , Estabilidad del ARN , Factores de Transcripción/genéticaRESUMEN
The advent of wearable sensors heralds a transformation in the continuous, noninvasive analysis of biomarkers critical for disease diagnosis and fitness management. Yet, their advancement is hindered by the functional challenges affiliated with their active sensing analysis layer. Predominantly due to suboptimal intrinsic material properties and inconsistent dispersion leading to aggregation, thus compromising sensor repeatability and performance. Herein, an innovative approach to the functionalization of wearable electrochemical sensors was introduced, specifically addressing these limitations. The method involves a proton-induced self-assembly technique at the organic-water (O/W) interface, facilitating the generation of biomarker-responsive films. This research offers flexible, breathable sensor capable of real-time precision tracking l-cysteine (l-Cys) precision tracking. Utilizing an activation mechanism for Prussian blue nanoparticles by hydrogen peroxide, the catalytic core exhibits a specific response to l-Cys. The implications of this study refine the fabrication of film-based analysis electrodes for wearable sensing applications and the broader utilization of two-dimensional materials in functional-specific response films. Findings illuminate the feasibility of this novel strategy for precise biomarker tracking and extend to pave the way for constructing high-performance electrocatalytic analytical interfaces.
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Cisteína , Técnicas Electroquímicas , Ferrocianuros , Dispositivos Electrónicos Vestibles , Cisteína/análisis , Cisteína/química , Humanos , Técnicas Electroquímicas/instrumentación , Técnicas Electroquímicas/métodos , Ferrocianuros/química , Peróxido de Hidrógeno/análisis , Peróxido de Hidrógeno/química , Electrodos , Técnicas Biosensibles , Biomarcadores/análisis , Nanopartículas/químicaRESUMEN
Cross-linking with functional molecular species in polymeric carbon nitride (PCN) could offer a positive strategy that tunes its molecular structure with excellent conductivity to improve photocatalytic activity. Herein, the benzene ring-cross-linked photocatalyst is obtained via the polymerization of urea, melamine, and trimesic acid. Benzene ring-cross-linked PCN narrows the band gap and augments the push-pull effect of carriers, thus enhancing visible light harvesting and transfer easiness of photogenerated electron/hole pairs. Notably, the amount of trimesic acid was optimized during the benzene ring-cross-linked photocatalyst preparation (marked as 01T/A-CN, 02T/A-CN, and 03T/A-CN). Among them, 02T/A-CN photocatalyst achieved an excellent hydrogen production rate of 1931 µmol/h·g, which is higher than that of CN under visible light and beyond most reported. Theoretical calculations further confirmed that the introduction of benzene ring significantly reduces the band gap of PCN, bringing the delocalized electron, a longer intramolecular electron transition distance, and molecular bending. All those factors made benzene ring-cross-linked PCN with improved photocatalytic hydrogen production under visible light irradiation.
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Alternative polyadenylation (APA) is an important post-transcriptional regulatory mechanism in cancer development and progression. Poly(A) binding protein nuclear 1 (PABPN1) is a gene that encodes abundant nuclear protein, binds with high affinity to nascent poly(A) tails, and is crucial for 3'-UTR (3'-untranslated region) APA. Although PABPN1 has been recently reported as a dominant master APA regulator in clear cell renal cell carcinoma (ccRCC), the underlying functional mechanism remain unclear and the genes subject to PABPN1 regulation that contribute to ccRCC progression have not been identified. Here, we found that PABPN1 is upregulated in ccRCC, and its expression is highly associated with the clinical prognosis of ccRCC patients. PABPN1 promotes ccRCC cell proliferation, migration, invasion, and exerts an influence on sphingolipid metabolism and cell cycle. Moreover, PABPN1 depletion significantly suppressed cancer cell growth via induction of cell cycle arrest and apoptosis. In particular, we characterized PABPN1-regulated 3'-UTR APA of sphingosine-1-phosphate lyase 1 (SGPL1) and cellular repressor of E1A stimulated genes 1 (CREG1), which contribute to ccRCC progression. Collectively, our data revealed that PABPN1 promotes ccRCC progression at least in part, by suppressing SGPL1 and CREG1. Thus, PABPN1 may be a potential therapeutic target in ccRCC.
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Alternative polyadenylation (APA) is emerging as a major posttranscriptional mechanism for gene regulation in cancer. A prevailing hypothesis is that shortening of the 3' untranslated region (3'UTR) increases oncoprotein expression because of the loss of miRNA-binding sites (MBSs). We showed that the longer 3'UTR is associated with a more advanced tumor stage in patients with clear cell renal cell carcinoma (ccRCC). More surprisingly, 3'UTR shortening is correlated with better overall survival in patients with ccRCC. Furthermore, we identified a mechanism by which longer transcripts lead to increased oncogenic protein and decreased tumor-suppressive protein expression compared to the shorter transcripts. In our model, shortening of 3'UTRs by APA may increase the mRNA stability of the majority of the potential tumor-suppressor genes due to the loss of MBSs and AU-rich elements (AREs). Unlike potential tumor-suppressor genes, the potential oncogenes display much lower MBS and ARE density and globally much higher m6A density in distal 3'UTRs. As a result, 3'UTRs shortening decreases the mRNA stability of potential oncogenes and enhances the mRNA stability of potential tumor-suppressor genes. Our findings highlight the cancer-specific pattern of APA regulation and extend our understanding of the mechanism of APA-mediated 3'UTR length changes in cancer biology.
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Carcinoma de Células Renales , Neoplasias Renales , MicroARNs , Humanos , Poliadenilación/genética , Regiones no Traducidas 3'/genética , ARN Mensajero/genética , ARN Mensajero/metabolismo , Carcinoma de Células Renales/genética , MicroARNs/genética , MicroARNs/metabolismo , Proteínas Oncogénicas/genética , Neoplasias Renales/genética , PronósticoRESUMEN
Endometrial stromal tumors (ESTs) are uncommon uterine mesenchymal lesions. Nuclear expression of ß-catenin, an indication of activated Wnt/ß-catenin signaling pathway, was described in 50% to 92% of low-grade ESTs, including endometrial stromal nodule and low-grade endometrial stromal sarcoma. Activation of the Wnt/ß-catenin signaling pathway leads to the translocation of ß-catenin into the nucleus and interaction with the T-cell factor/lymphoid enhancer-binding factor-1 (LEF1) family of transcription factors to regulate cell proliferation, differentiation, migration, and survival. Immunohistochemical analysis of ß-catenin and LEF1 was performed in 2 endometrial stromal nodules and 20 low-grade endometrial stromal sarcomas and demonstrated 90.9% and 81.8% positive rates for ß-catenin and LEF1, respectively. The sensitivity, specificity, positive predictive value, and negative predictive value of ß-catenin and LEF1 were 90.9% versus 81.8%, 81.0% versus 85.7%, 83.3% versus 85.7%, 89.5% versus 81.8%, respectively, in the diagnosis of low-grade ESTs. There is no statistical significance of the performance of ß-catenin and LEF1 in all ESTs (P = 0.664) or in primary or metastatic/recurrent settings (P = 0.515 and 0.999, respectively). Only 3 smooth muscle tumors showed focal and weak positivity for LEF1. Our results indicate LEF1 can be a useful marker in aiding a diagnosis of low-grade EST and differentiating from smooth muscle tumors alone or in combination with ß-catenin.
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(1) Lipoprotein-associated phospholipase A2 (Lp-PLA2) is a risk factor for predicting cardiovascular diseases. Metabolic syndrome is characterized by a state of chronic inflammation that is related to an increased risk of cardiovascular events and death. In the present study, we aimed to analyze the correlation between cardiometabolic risk factors and Lp-PLA2 levels. (2) We collected the related retrospective medical data of Chinese adults, of which 3983 were men and 2836 were women (aged ≥ 18 years), who underwent health check-ups, and discussed the sex and age-related differences. (3) Data analysis showed that Lp-PLA2 was significantly related to lipoproteins and glutamic pyruvic transaminase (GPT), and that a linear trend was observed with increasing Lp-PLA2 levels for all ages and sexes. However, fasting glucose was significantly related to Lp-PLA2 only in the younger population. The two obesity-related parameters (waist-to-height ratio and waist circumference) also had a greater correlation with Lp-PLA2 levels in the younger groups; however, the correlation weakened in the elderly population. Meanwhile, the correlation between mean arterial pressure and creatinine level and Lp-PLA2 was significant only in younger men. (4) The results show that the expression patterns of Lp-PLA2 differ between sexes and across age groups.
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1-Alquil-2-acetilglicerofosfocolina Esterasa , Factores de Riesgo Cardiometabólico , Adulto , Masculino , Humanos , Anciano , Femenino , 1-Alquil-2-acetilglicerofosfocolina Esterasa/metabolismo , Estudios Retrospectivos , Factores de Riesgo , Lipoproteínas , BiomarcadoresRESUMEN
INTRODUCTION: Sarcoma clinical outcomes have been stagnant for decades due to heterogeneity of primaries, lack of comprehensive preclinical models, and rarity of disease. We hypothesized that engineering hydrogel-based sarcoma organoids directly from the patient without xenogeneic extracellular matrices (ECMs) or growth factors is routinely feasible and allows rare tumors to remain viable as avatars for personalized research. METHODS: Surgically resected sarcomas (angiosarcomas, leiomyosarcoma, gastrointestinal stromal tumor, liposarcoma, myxofibrosarcoma, dermatofibrosarcoma protuberans [DFSP], and pleiomorphic abdominal sarcoma) were dissociated and incorporated into a hyaluronic acid and collagen-based ECM hydrogel and screened for chemotherapy efficacy. A subset of organoids was enriched with a patient-matched immune system for screening of immunotherapy efficacy (iPTOs). Response to treatment was assessed using LIVE/DEAD staining and metabolic assays. RESULTS: Sixteen sarcomas were biofabricated into three-dimensional (3D) patient-specific sarcoma organoids with a 100% success rate. Average time from organoid development to initiation of drug testing was 7 days. Enrichment of organoids with immune system components derived from either peripheral blood mononuclear cells or lymph node cells was performed in 10/16 (62.5%) patients; 4/12 (33%) organoids did not respond to chemotherapy, while response to immunotherapy was observed in 2/10 (20%) iPTOs. CONCLUSIONS: A large subset of sarcoma organoids does not exhibit response to chemotherapy or immunotherapy, as currently seen in clinical practice. Routine development of sarcoma hydrogel-based organoids directly from the operating room is a feasible platform, allowing for such rare tumors to remain viable for personalized translational research.
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Sarcoma , Neoplasias de los Tejidos Blandos , Adulto , Humanos , Ácido Hialurónico/metabolismo , Hidrogeles , Leucocitos Mononucleares , Quirófanos , Organoides/patología , Sarcoma/patología , Neoplasias de los Tejidos Blandos/patología , Investigación Biomédica TraslacionalRESUMEN
Alternative polyadenylation (APA) is emerging as a crucial regulatory mechanism in bladder cancer (BC), while it remains elusive whether APA influences the tumor immune microenvironment (TIME) in BC. We identified two distinct subtypes of BC by APA-related regulatory genes expression profiles. The two subtypes have different pathological grades, prognostic outcomes, tumor immune infiltration characteristics, and pathway enrichment. Subsequently, CPSF3 was identified as a potential immune infiltration-related gene in BC. Highly expressed CPSF3 was positively correlated with unfavorable prognosis and high CD276 expression in BC. Moreover, we verified the expression of CPSF3 in BC tissues and cell lines by qRT-PCR. In conclusion, the study indicates that APA regulatory factors play an important role in immune infiltration of BC, and that CPSF3 was a potentially prognostic marker and immunotherapy target for BC.
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Poliadenilación , Neoplasias de la Vejiga Urinaria , Antígenos B7/metabolismo , Genes Reguladores , Humanos , Pronóstico , Microambiente Tumoral/genética , Neoplasias de la Vejiga Urinaria/patologíaRESUMEN
INTRODUCTION AND HYPOTHESIS: To determine whether delayed administration of CXCL12 alters anorectal manometric pressures and histology in rats following anal sphincterotomy compared to primary surgical repair alone. METHODS: Adult female rats were divided into three groups: A, a control group that did not undergo surgery; B, anal sphincterotomy with primary surgical repair; C, anal sphincterotomy with primary surgical repair and intra-sphincteric injection of CXCL12 at 6 weeks post-injury. All rats underwent anal manometry measurements at baseline and at 6 and 12 weeks post-injury. Histologic analysis of the anal sphincters was also performed. RESULTS: At baseline and 6 weeks, there were no statistically significant differences among D, Tmax and P∆ of Groups A, B and C. At 12-week manometry, the total duration of contractions on anal manometry was significantly less in Group C compared to Groups A and B (3.65, 5.5, 5.3 p < 0.01) as was time to peak of contraction at 12 weeks (1.6, 2.1, 3.1, p < 0.01); however, group C had a significantly higher P∆ at 12 weeks compared to Groups A and B (2.25, 1.4, 0.34, p < 0.01). There were no statistically significant differences in the ratio of muscle to collagen at the site of injury; however, muscle fibers were significantly smaller in group C and less per bundle than the other groups. CONCLUSIONS: Administration of chemokine therapy at 6 weeks post-repair using CXCL12 enhanced the magnitude of anal sphincter contractions in a rat model of anal sphincter injury but decreased overall duration of contraction. Increased anal sphincter contraction magnitude was not explained by histologic differences in explanted specimens.
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Canal Anal , Canal Anal/patología , Animales , Femenino , Manometría , Proyectos Piloto , Presión , RatasRESUMEN
Polyadenylation of mRNA precursors is mediated by a large multisubunit protein complex. Here we show that RBBP6 (retinoblastoma-binding protein 6), identified initially as an Rb- and p53-binding protein, is a component of this complex and functions in 3' processing in vitro and in vivo. RBBP6 associates with other core factors, and this interaction is mediated by an unusual ubiquitin-like domain, DWNN ("domain with no name"), that is required for 3' processing activity. The DWNN is also expressed, via alternative RNA processing, as a small single-domain protein (isoform 3 [iso3]). Importantly, we show that iso3, known to be down-regulated in several cancers, competes with RBBP6 for binding to the core machinery, thereby inhibiting 3' processing. Genome-wide analyses following RBBP6 knockdown revealed decreased transcript levels, especially of mRNAs with AU-rich 3' untranslated regions (UTRs) such as c-Fos and c-Jun, and increased usage of distal poly(A) sites. Our results implicate RBBP6 and iso3 as novel regulators of 3' processing, especially of RNAs with AU-rich 3' UTRs.
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Regiones no Traducidas 3'/genética , Proteínas Portadoras/genética , Proteínas Portadoras/metabolismo , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Regulación de la Expresión Génica , ARN Mensajero/genética , Factor de Especificidad de Desdoblamiento y Poliadenilación/metabolismo , Técnicas de Silenciamiento del Gen , Humanos , Poliadenilación/genética , Unión Proteica , Isoformas de Proteínas , Estructura Terciaria de Proteína , ARN Mensajero/metabolismo , Ubiquitina-Proteína LigasasRESUMEN
Nonsense-mediated mRNA decay (NMD) controls the quality of eukaryotic gene expression and also degrades physiologic mRNAs. How NMD targets are identified is incompletely understood. A central NMD factor is the ATP-dependent RNA helicase upframeshift 1 (UPF1). Neither the distance in space between the termination codon and the poly(A) tail nor the binding of steady-state, largely hypophosphorylated UPF1 is a discriminating marker of cellular NMD targets, unlike for premature termination codon (PTC)-containing reporter mRNAs when compared with their PTC-free counterparts. Here, we map phosphorylated UPF1 (p-UPF1)-binding sites using transcriptome-wide footprinting or DNA oligonucleotide-directed mRNA cleavage to report that p-UPF1 provides the first reliable cellular NMD target marker. p-UPF1 is enriched on NMD target 3' untranslated regions (UTRs) along with suppressor with morphogenic effect on genitalia 5 (SMG5) and SMG7 but not SMG1 or SMG6. Immunoprecipitations of UPF1 variants deficient in various aspects of the NMD process in parallel with Förster resonance energy transfer (FRET) experiments reveal that ATPase/helicase-deficient UPF1 manifests high levels of RNA binding and disregulated hyperphosphorylation, whereas wild-type UPF1 releases from nonspecific RNA interactions in an ATP hydrolysis-dependent mechanism until an NMD target is identified. 3' UTR-associated UPF1 undergoes regulated phosphorylation on NMD targets, providing a binding platform for mRNA degradative activities. p-UPF1 binding to NMD target 3' UTRs is stabilized by SMG5 and SMG7. Our results help to explain why steady-state UPF1 binding is not a marker for cellular NMD substrates and how this binding is transformed to induce mRNA decay.
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Estabilidad del ARN/genética , Transactivadores/genética , Transactivadores/metabolismo , Adenosina Trifosfatasas/metabolismo , Sitios de Unión , Células HEK293 , Células HeLa , Humanos , Unión Proteica , Proteína Fosfatasa 2/metabolismo , Procesamiento Proteico-Postraduccional , Estabilidad Proteica , ARN Helicasas/metabolismo , Transcriptoma , Regulación hacia ArribaRESUMEN
Climate change and human activities have seriously degraded alpine grassland, potentially affecting soil particle size distribution (PSD) and further influencing the nutrient levels and erodibility of soil. Predicting the fertility and erodibility of alpine soil using multifractal dimensions of soil PSD could be used to enhance the management and restoration of degraded alpine grasslands. In the present study, we evaluated three types of alpine grasslands: alpine meadow (AM), alpine steppe (AS), and alpine desert steppe (ADS). Fencing and grazing management measures were conducted at sites containing each grassland type. Then, we analyzed the PSDs, erodibility, and other properties of soil in the 0-20 cm soil layer. Multifractal characterization of soil PSD was calculated using the fractal scale theory. The findings showed that grassland type significantly impacted soil nutrients and the multifractal dimensions of soil PSDs, whereas management measures affected soil erodibility significantly. The proportion of finer particles decreased as follows: AM > AS > ADS. Compared to grazing, fencing enhanced clay content and reduced the proportion of coarser particles under all three grassland types. AM had higher organic carbon and nitrogen levels than AS and ADS. Multifractal dimensions were highest for AM, with ADS having higher erodibility than AM and AS. Multifractal dimensions (except for correlation dimension) also had significantly positive relationships with soil organic carbon and available nutrient content and soil erodibility, but had significantly negative correlations with soil pH, bulk density, and electrical conductivity. Thus, the multifractal dimensions of soil PSDs could be used to characterize the erodibility and fertility characteristics of soil in alpine regions, providing a reference for assessing vegetation restoration measures in the Northern Tibet Plateau.
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Pradera , Suelo , Carbono/análisis , Fertilidad , Humanos , Tamaño de la Partícula , Suelo/química , TibetRESUMEN
PURPOSE: 68Ga-prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) is valuable for detecting primary and recurrent prostatic lesions. This study aimed to evaluate the efficacy of 68Ga-PSMA-11 PET/CT as a triage tool for prostate biopsy (PSMA-TB) and compare with transrectal ultrasound-guided biopsy (TRUS-GB) for the diagnosis of clinically significant prostate cancer (csPCa). METHODS: This single-centre study randomly allocated 120 patients with elevated serum prostate-specific antigen (PSA) levels (> 4 ng/ml) to PSMA-PET or TRUS group. Patients with PSMA-avid lesions (SUVmax ≥ 8.0) underwent PSMA-TB via a single-puncture percutaneous transgluteal approach (n = 25), whilst patients with negative PSMA-PET underwent systematic TRUS-GB (n = 35). All patients in the TRUS group underwent TRUS-GB directly (n = 60). RESULTS: PCa and csPCa were detected in 26/60 (43.3%) and 24/60 (40.0%) patients in the PSMA-PET group and 19/60 (31.6%) and 15/60 (25.0%) in the TRUS group, respectively. In the PSMA-PET group, the detection rate of PCa and csPCa were significantly higher in PSMA-PET-positive than negative patients (PCa, 23/25 (92.0%) vs 3/35 (8.6%), P < 0.01; csPCa, 22/25 (88.0%) vs 2/35 (5.7%), P < 0.01). PSMA-TB detected significantly more PCa and csPCa than TRUS-GB in the TRUS controls (PCa, 21/25 (84.0%) vs 19/60 (31.6%), P < 0.01; csPCa, 20/25 (80.0%) vs 15/60 (25.0%), P < 0.01). PSMA-PET detected significantly more cases of csPCa amongst patients with PSA 4.0-20.0 ng/ml than TRUS (27.02% vs 8.82%, P < 0.05). No haematuria, urinary retention or pelvic infection was observed after PSMA-TB compare with TRUS-GB. CONCLUSIONS: 68Ga-PSMA-11 PET/CT is a feasible imaging technique that may serve as a triage tool for prostate biopsy, and may improve the detection rate of csPCa compared with TRUS-GB, especially in patients with serum PSA 4.0-20.0 ng/ml.
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Tomografía Computarizada por Tomografía de Emisión de Positrones , Neoplasias de la Próstata , Ácido Edético/análogos & derivados , Isótopos de Galio , Radioisótopos de Galio , Humanos , Masculino , Oligopéptidos , Estudios Prospectivos , Antígeno Prostático Específico , Neoplasias de la Próstata/diagnóstico por imagen , Ultrasonografía IntervencionalRESUMEN
OBJECTIVE: We aim to evaluate the impact of ThyroSeq® in the management of indeterminate thyroid nodules (ITN), including Bethesda III and IV nodules. METHODS: ITNs that underwent ThyroSeq testing between 2016 and 2019 were retrospectively reviewed. A control cohort included ITNs without molecular testing. Cytological, molecular, and histological data were collected. RESULTS: We identified 202 ITNs that underwent molecular testing (128 in Bethesda III and 74 in Bethesda IV). Mutations were found in 58 nodules with mutation rates of 21.9% in Bethesda III and 40.5% in Bethesda IV. In this cohort, 49 cases had surgical resection with a resection rate of 24.3% (49/202, 15.6% in Bethesda III and 39.2% in Bethesda IV). Among the resected cases, 42 cases had positive molecular results. Thyroid cancer was diagnosed in 21 nodules with a malignancy detection rate of 10.4%. In the other cohort, we identified 236 ITNs (158 in Bethesda III and 78 in Bethesda IV). Surgical resection was performed in 127 cases, with a resection rate of 53.8% (127/236, 46.2% in Bethesda III and 69.2% in Bethesda IV). Thyroid cancer was diagnosed in 21 nodules, with a malignancy detection rate of 8.9%. The risk of malignancy (ROM) recalculated based on positive ThyroSeq results was significantly higher (21.4%-35.5% in Bethesda III and 50%-60% in Bethesda IV) than that without molecular testing (4.4%-9.6% in Bethesda III and 17.9%-25.9% in Bethesda IV). CONCLUSION: We concluded that ThyroSeq significantly decreased the surgical resection rate (from 53.8% to 24.3%) without significantly affecting the malignancy detection rate in ITNs. Furthermore, positive molecular testing significantly increased ROM in ITNs. We believe that the recalculated ROM should be incorporated into the management of ITNs.
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Mutación , Nódulo Tiroideo , Adulto , Biopsia con Aguja Fina , Análisis Mutacional de ADN , Reacciones Falso Positivas , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Nódulo Tiroideo/diagnóstico , Nódulo Tiroideo/genética , Nódulo Tiroideo/patologíaRESUMEN
The purpose of this study was to investigate how pre-hypoxia exposure affected the mitochondrial structure and bioenergetic function of large yellow croaker in responding to Cu stress. Fish were acclimated to normoxia and 3.0 mg DO L-1 for 48 h, then subjected to 0 and 120 µg Cu L-1 for another 48 h. Hypoxic acclimation did not affect mitochondrial ultrastructure and reactive oxygen species (ROS), but reduced oxidative phosphorylation (OXPHOS) efficiency. Cu exposure impaired mitochondrial ultrastructure, increased ROS generation and inhibited OXPHOS efficiency. Compared with Cu exposure alone, hypoxic acclimation plus Cu exposure reduced ROS production and improved OXPHOS efficiency by enhancing mitochondrial respiratory control ratio, mitochondrial membrane potential, and activities and gene expressions of electron transport chain enzymes. In conclusion, hypoxic acclimation improved the mitochondrial energy metabolism of large yellow croaker under Cu stress, facilitating our understanding of the molecular mechanisms regarding adaptive responses of hypoxia-acclimated fish under Cu stress.