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Anaplastic thyroid cancer (ATC) is among the most aggressive and metastatic malignancies, often resulting in fatal outcomes due to the lack of effective treatments. Prosapogenin A (PA), a bioactive compound prevalent in traditional Chinese herbs, has shown potential as an antineoplastic agent against various human tumors. However, its effects on ATC and the underlying mechanism remain unclear. Here, we demonstrate that PA exhibits significant anti-ATC activity both in vitro and in vivo by inducing GSDME-dependent pyroptosis in ATC cells. Mechanistically, PA promotes lysosomal membrane permeabilization (LMP), leading to the release of cathepsins that activate caspase 8/3 to cleave GSDME. Remarkably, PA significantly upregulates three key functional subunits of V-ATPase-ATP6V1A, ATP6V1B2, and ATP6V0C-resulting in lysosomal over-acidification. This over-acidification exacerbates LMP and subsequent lysosomal damage. Neutralization of lysosomal lumen acidification or inhibition/knockdown of these V-ATPase subunits attenuates PA-induced lysosomal damage, pyroptosis and growth inhibition of ATC cells, highlighting the critical role for lysosomal acidification and LMP in PA's anticancer effects. In summary, our findings uncover a novel link between PA and lysosomal damage-dependent pyroptosis in cancer cells. PA may act as a V-ATPase agonist targeting lysosomal acidification, presenting a new potential therapeutic option for ATC treatment.
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Lisossomos , Piroptose , Carcinoma Anaplásico da Tireoide , ATPases Vacuolares Próton-Translocadoras , Lisossomos/metabolismo , Lisossomos/efeitos dos fármacos , Humanos , Piroptose/efeitos dos fármacos , ATPases Vacuolares Próton-Translocadoras/metabolismo , Carcinoma Anaplásico da Tireoide/metabolismo , Carcinoma Anaplásico da Tireoide/patologia , Carcinoma Anaplásico da Tireoide/tratamento farmacológico , Animais , Linhagem Celular Tumoral , Sapogeninas/farmacologia , Camundongos , Camundongos Nus , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/tratamento farmacológico , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Endogâmicos BALB C , GasderminasRESUMO
Purpose: This study aimed to investigate the possible relationship between retinal vascular abnormalities and amblyopia by analyzing vascular structures of fundus images. Methods: In this observational study, retinal fundus images were collected from 36 patients with unilateral amblyopia, 33 patients with bilateral amblyopia, and 36 healthy control volunteers. We developed a customized training algorithm based on U-Net to digitalize the vasculature in the fundus images to quantify vascular density (area and fractal dimension), skeleton length, and number of bifurcation points. For statistical comparisons, this study divided participants into two groups. The amblyopic eyes and the fellow eyes of patients with unilateral amblyopia formed the paired group, while bilateral amblyopic patients and healthy controls formed the independent group. Results: In the paired group, the vascular area (P = 0.007), vascular fractal dimension (P = 0.007), and vascular skeleton length (P = 0.002) of the amblyopic eyes were significantly smaller than those of the fellow eyes. In the independent group, significant decreases in the vascular fractal dimension (P = 0.006) and skeleton length (P = 0.048) were observed in bilateral amblyopia compared to control. The vascular area was also significantly correlated with best-corrected visual acuity in amblyopic eyes. Conclusions: This study demonstrated that retinal vascular density and skeleton length in amblyopic eyes were significantly smaller compared to control, indicating an association between the changes in retinal vascular features and the state of amblyopia. Translational Relevance: Our algorithm presents amblyopic retinal vascular changes that are more biologically interpretable for both clinicians and researchers.
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Algoritmos , Ambliopia , Vasos Retinianos , Acuidade Visual , Humanos , Ambliopia/fisiopatologia , Ambliopia/patologia , Feminino , Masculino , Vasos Retinianos/diagnóstico por imagem , Vasos Retinianos/patologia , Acuidade Visual/fisiologia , Adulto , Adulto Jovem , Adolescente , Criança , Fractais , Densidade MicrovascularRESUMO
Anaplastic thyroid cancer (ATC) is one of the most lethal malignant tumors for which there is no effective treatment. There are an increasing number of studies on herbal medicine for treating malignant tumors, and the classic botanical medicine Digitalis and its active ingredients for treating heart failure and arrhythmias have been revealed to have significant antitumor efficacy against a wide range of malignant tumors. However, the main components of Digitalis and the molecular mechanisms of its anti-ATC effects have not been extensively studied. Here, we screened the main components and core targets of Digitalis and verified the relationship between the active components and targets through network pharmacology, molecular docking, and experimental validation. These experiments showed that the active ingredients of Digitalis inhibit ATC cell activity and lead to ATC cell death through the apoptotic pathway.
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AIM: To describe the clinical, electrophysiological, and genetic features of an unusual case with an RDH12 homozygous pathogenic variant and reviewed the characteristics of the patients reported with the same variant. METHODS: The patient underwent a complete ophthalmologic examination including best-corrected visual acuity, anterior segment and dilated fundus, visual field, spectral-domain optical coherence tomography (OCT) and electroretinogram (ERG). The retinal disease panel genes were sequenced through chip capture high-throughput sequencing and Sanger sequencing was used to confirm the result. Then we reviewed the characteristics of the patients reported with the same variant. RESULTS: A 30-year male presented with severe early retinal degeneration who complained night blindness, decreased visual acuity, vitreous floaters and amaurosis fugax. The best corrected vision was 0.04 OD and 0.12 OS, respectively. The fundus photo and OCT showed bilateral macular atrophy but larger areas of macular atrophy in the left eye. Autofluorescence shows bilateral symmetrical hypo-autofluorescence. ERG revealed that the amplitudes of a- and b-wave were severely decreased. Multifocal ERG showed decreased amplitudes in the local macular area. A homozygous missense variant c.146C>T (chr14:68191267) was found. The clinical characteristics of a total of 13 patients reported with the same pathologic variant varied. CONCLUSION: An unusual patient with a homozygous pathogenic variant in the c.146C>T of RDH12 which causes late-onset and asymmetric retinal degeneration are reported. The clinical manifestations of the patient with multimodal retinal imaging and functional examinations have enriched our understanding of this disease.
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Anaplastic thyroid carcinoma (ATC) has a 100% disease-specific mortality rate. The JAK1/2-STAT3 pathway presents a promising target for treating hematologic and solid tumors. However, it is unknown whether the JAK1/2-STAT3 pathway is activated in ATC, and the anti-cancer effects and the mechanism of action of its inhibitor, ruxolitinib (Ruxo, a clinical JAK1/2 inhibitor), remain elusive. Our data indicated that the JAK1/2-STAT3 signaling pathway is significantly upregulated in ATC tumor tissues than in normal thyroid and papillary thyroid cancer tissues. Apoptosis and GSDME-pyroptosis were observed in ATC cells following the in vitro and in vivo administration of Ruxo. Mechanistically, Ruxo suppresses the phosphorylation of STAT3, resulting in the repression of DRP1 transactivation and causing mitochondrial fission deficiency. This deficiency is essential for activating caspase 9/3-dependent apoptosis and GSDME-mediated pyroptosis within ATC cells. In conclusion, our findings indicate DRP1 is directly regulated and transactivated by STAT3; this exhibits a novel and crucial aspect of JAK1/2-STAT3 on the regulation of mitochondrial dynamics. In ATC, the transcriptional inhibition of DRP1 by Ruxo hampered mitochondrial division and triggered apoptosis and GSDME-pyroptosis through caspase 9/3-dependent mechanisms. These results provide compelling evidence for the potential therapeutic effectiveness of Ruxo in treating ATC.
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Nitrilas , Pirazóis , Pirimidinas , Carcinoma Anaplásico da Tireoide , Neoplasias da Glândula Tireoide , Humanos , Carcinoma Anaplásico da Tireoide/tratamento farmacológico , Carcinoma Anaplásico da Tireoide/genética , Carcinoma Anaplásico da Tireoide/metabolismo , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Dinâmica Mitocondrial , Piroptose , Caspase 9/metabolismo , Proliferação de Células , Linhagem Celular Tumoral , ApoptoseRESUMO
Inflammasome activity is important for the immune response and is instrumental in numerous clinical conditions. Here we identify a mechanism that modulates the central Caspase-1 and NLR (Nod-like receptor) adaptor protein ASC (apoptosis-associated speck-like protein containing a CARD). We show that the function of ASC in assembling the inflammasome is controlled by its modification with SUMO (small ubiquitin-like modifier) and identify that the nuclear ZBTB16 (zinc-finger and BTB domain-containing protein 16) promotes this SUMOylation. The physiological significance of this activity is demonstrated through the reduction of acute inflammatory pathogenesis caused by a constitutive hyperactive inflammasome by ablating ZBTB16 in a mouse model of Muckle-Wells syndrome. Together our findings identify an further mechanism by which ZBTB16-dependent control of ASC SUMOylation assembles the inflammasome to promote this pro-inflammatory response.
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Inflamassomos , Proteína 3 que Contém Domínio de Pirina da Família NLR , Animais , Camundongos , Proteínas Adaptadoras de Sinalização CARD/genética , Proteínas Adaptadoras de Sinalização CARD/metabolismo , Caspase 1/metabolismo , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Ligação Proteica , SumoilaçãoRESUMO
BACKGROUND: Inflammatory bowel disease (IBD) is a global health concern with varying levels and trends across countries and regions. Understanding these differences is crucial for effective prevention and treatment strategies. METHODS: Using data from the 2019 Global Burden of Disease study, we examine IBD incidence, mortality, and disability-adjusted life years (DALYs) rates in 198 countries from 1990 to 2019. To assess changes in the burden of IBD, estimated annual percentage changes (EAPC) were calculated, and a Bayesian age-period-cohort model was used to predict the future 30-year trends of IBD. RESULTS: In 2019, there were 405,000 new IBD cases globally (95% uncertainty interval (UI) 361,000 to 457,000), with 41,000 deaths (95% UI 35,000 to 45,000) and 1.62million DALYs (95% UI 1.36-1.92million). The global age-standardized incidence rate in 2019 was 4.97 per 100,000 person-years (95% UI 4.43 to 5.59), with a mortality rate of 0.54 (95% UI 0.46 to 0.59) and DALYs rate of 20.15 (95% UI 16.86 to 23.71). From 1990 to 2019, EAPC values for incidence, mortality, and DALYs rates were - 0.60 (95% UI - 0.73 to - 0.48), - 0.69 (95% UI - 0.81 to - 0.57), and - 1.04 (95% UI - 1.06 to - 1.01), respectively. Overall, the burden of IBD has shown a slow decline in recent years. In SDI stratification, regions with higher initial SDI (high-income North America and Central Europe) witnessed decreasing incidence and mortality rates with increasing SDI, while regions with lower initial SDI (South Asia, Oceania, and Latin America) experienced a rapid rise in incidence but a decrease in mortality with increasing SDI. Predictions using a Bayesian model showed lower new cases and deaths from 2020 to 2050 than reference values, while the slope of the predicted incidence-time curve closely paralleled that of the 2019 data. CONCLUSION: Increasing cases, deaths, and DALYs highlight the sustained burden of IBD on public health. Developed countries have stabilized or declining incidence rates but face high prevalence and societal burden. Emerging and developing countries experience rising incidence. Understanding these changes aids policymakers in effectively addressing IBD challenges in different regions and economic contexts.
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Carga Global da Doença , Doenças Inflamatórias Intestinais , Humanos , Teorema de Bayes , Anos de Vida Ajustados por Qualidade de Vida , Prevalência , Incidência , Saúde Global , Doenças Inflamatórias Intestinais/epidemiologiaRESUMO
Background: Flat foot deformity is a prevalent and challenging condition often leading to various clinical complications. Accurate identification of abnormal foot types is essential for appropriate interventions. Method: A dataset consisting of 1573 plantar pressure images from 125 individuals was collected. The performance of the You Only Look Once v5 (YOLO-v5) model, improved YOLO-v5 model, and multi-label classification model was evaluated for foot type identification using the collected images. A new dataset was also collected to verify and compare the models. Results: The multi-label classification algorithm based on ResNet-50 outperformed other algorithms. The improved YOLO-v5 model with Squeeze-and-Excitation (SE), the improved YOLO-v5 model with Convolutional Block Attention Module (CBAM), and the multilabel classification model based on ResNet-50 achieved an accuracy of 0.652, 0.717, and 0.826, respectively, which is significantly higher than those obtained using the ordinary plantar-pressure system and the standard YOLO-v5 model. Conclusion: These results indicate that the proposed DL-based multilabel classification model based on ResNet-50 is superior in flat foot type detection and can be used to evaluate the clinical rehabilitation status of patients with abnormal foot types and various foot pathologies when more data on patients with various diseases are available for training.
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An increasing body of evidence has suggested that reprogrammed metabolism plays a critical role in the progression of pancreatic ductal adenocarcinoma (PDAC) by affecting the tumor and stromal cellular components in the tumor microenvironment (TME). By analyzing the KRAS pathway and metabolic pathways, we found that calcium and integrin-binding protein 1 (CIB1) corresponded with upregulation of glucose metabolism pathways and was associated with poor prognosis in patients with PDAC from The Cancer Genome Atlas (TCGA). Elevated CIB1 expression combined with upregulated glycolysis, oxidative phosphorylation (Oxphos), hypoxia pathway activation, and cell cycle promoted PDAC tumor growth and increased tumor cellular com-ponents. Furthermore, we confirmed the mRNA overexpression of CIB1 and co-expression of CIB1 and KRAS mutation in cell lines from the Expression Atlas. Subsequently, immunohistochemistry staining from the Human Protein Atlas (HPA) showed that high expression of CIB1 in tumor cells was associated with an increased tumor compartment and reduced stromal cellular abundance. Furthermore, using multiplexed immunohistochemistry (mIHC), we verified that low stromal abundance was correlated with low infiltration of CD8+ PD-1- T cells which led to suppressed anti-tumor immunity. Overall, our findings identify CIB1 as a metabolic pathway-mediated factor for the restriction of immune cell infiltration in the stromal compartment of PDAC and highlight the potential value of CIB1 as a prognostic biomarker involved in metabolic reprogramming and immune modulation.
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Carcinoma Ductal Pancreático , Neoplasias Pancreáticas , Humanos , Cálcio/metabolismo , Carcinoma Ductal Pancreático/patologia , Glucose , Integrinas/metabolismo , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas p21(ras)/genética , Microambiente Tumoral , Neoplasias PancreáticasRESUMO
Fecal microbiota transplantation (FMT) can induce clinical remission in ulcerative colitis (UC) patients. Enemas, nasoduodenal tubes, and colonoscopies are the most common routes for FMT administration. However, there is a lack of definitive evidence regarding the effectiveness of capsulized FMT treatment in UC patients. In this study, we administered capsulized FMT to 22 patients with active UC to assess the efficiency of capsulized FMT and determine the specific bacteria and metabolite factors associated with the response to clinical remission. Our results showed that the use of capsulized FMT was successful in the treatment of UC patients. Capsulized FMT induced clinical remission and clinical response in 57.1% (12 of 21) and 76.2% (16 of 21) of UC patients, respectively. Gut bacterial richness was increased after FMT in patients who achieved remission. Patients in remission after FMT exhibited enrichment of Alistipes sp. and Odoribacter splanchnicus, along with increased levels of indolelactic acid. Patients who did not achieve remission exhibited enrichment of Escherichia coli and Klebsiella and increased levels of biosynthesis of 12,13-DiHOME (12,13-dihydroxy-9Z-octadecenoic acid) and lipopolysaccharides. Furthermore, we identified a relationship between specific bacteria and metabolites and the induction of remission in patients. These findings may provide new insights into FMT in UC treatment and provide reference information about therapeutic microbial manipulation of FMT to enhance its effects. (This study has been registered at ClinicalTrails.gov under registration no. NCT03426683). IMPORTANCE Fecal microbiota transplantation has been successfully used in patients. Recently, capsulized FMT was reported to induce a response in patients with UC. However, limited patients were enrolled in such studies, and the functional factors of capsulized FMT have not been reported in the remission of patients with UC. In this study, we prospectively recruited patients with UC to receive capsulized FMT. First, we found that capsulized FMT could induce clinical remission in 57.1% of patients and clinical response in 76.2% after 12 weeks, which was more acceptable. Second, we found a relationship between the decrease of opportunistic pathogen and lipopolysaccharide synthesis in patients in remission after capsulized FMT. We also identified an association between specific bacteria and metabolites and remission induction in patients after capsulized FMT. These findings put forward a possibility for patients to receive FMT at home and provide reference information about therapeutic microbial manipulation of FMT to enhance its effects.
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Colite Ulcerativa , Doenças Transmissíveis , Microbioma Gastrointestinal , Humanos , Bactérias , Colite Ulcerativa/terapia , Colite Ulcerativa/microbiologia , Transplante de Microbiota Fecal/métodos , Fezes/microbiologia , Resultado do TratamentoRESUMO
PURPOSE: Most differentiated thyroid cancer (DTC) patients have a good prognosis after surgery, but radioiodine refractory differentiated thyroid cancer (RAIR-DTC) patients have a significantly reduced 5-year survival rate (<60%) and a significantly increased recurrence rate (>30%). This study aimed to clarify the tescalcin (TESC) role in promoting the malignant PTC progression and providing a potential target for RAIR-DTC treatment. METHODS: We analyzed TESC expression and clinicopathological characteristics using the Cancer Genome Atlas (TCGA) and performed qRT-PCR on tissue samples. TPC-1 and IHH-4 proliferation, migration, and invasion were detected after transfection with TESC-RNAi. Using Western blot (WB), several EMT-related indicators were detected. Moreover, iodine uptake of TPC-1 and IHH-4 after transfection with TESC-RNAi was detected. Finally, NIS, ERK1/2, and p-ERK1/2 levels were determined by WB. RESULTS: TESC was significantly upregulated in DTC tissues and positively correlated with BRAF V600E mutation based on data analysis from TCGA and our center. Reduced expression of TESC in both IHH-4 (BRAF V600E mutation) and TPC-1 (BRAF V600E wild type) cells significantly inhibited cell proliferation, migration, and invasion. It downregulated the EMT pathway markers Vimentin and N-cadherin, and increased E- cadherin. Moreover, TESC knockdown significantly inhibited ERK1/2 phosphorylation and decreased NIS expression in DTC cells, with a remarkably increased iodine uptake rate. CONCLUSIONS: TESC was highly expressed in DTC tissues and may have promoted metastasis through EMT and induced iodine resistance by downregulating NIS in DTC cells.
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Adenocarcinoma , Iodo , Neoplasias da Glândula Tireoide , Humanos , Radioisótopos do Iodo/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/radioterapia , Neoplasias da Glândula Tireoide/metabolismoRESUMO
Immune complexity status in the TME has been linked to clinical outcomes in pancreatic ductal adenocarcinoma (PDAC) patients. TME assessments with current cell marker and cell density-based analyses do not identify the original phenotypes of single cells with multilineage selectivity, the functional status of the cells, or cellular spatial information in the tissues. Here, we describe a method that circumvents these problems. The combined strategy of multiplexed IHC with computational image cytometry and multiparameter cytometric quantification allows us to assess multiple lineage-selective and functional phenotypic biomarkers in the TME. Our study revealed that the percentage of CD8+ T lymphoid cells expressing the T cell exhaustion marker PD-1 and the high expression of the checkpoint PD-L1 in CD68+ cells are associated with a poor prognosis. The prognostic value of this combined approach is more significant than that of lymphoid and myeloid cell density analyses. In addition, a spatial analysis revealed a correlation between the abundance of PD-L1+CD68+ tumor-associated macrophages and PD-1+CD8+T cell infiltration, indicating pro-tumor immunity associated with a poor prognosis. These data highlight the implications of practical monitoring for understanding the complexity of immune cells in situ. Digital imaging and multiparameter cytometric processing of cell phenotypes in the TME and tissue architecture can reveal biomarkers and assessment parameters for patient stratification.
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OBJECTIVE: To evaluate cumulative and incremental changes in penile curvature after each treatment cycle of collagenase clostridium histolyticum (CCH) in men with Peyronie's disease (PD). METHODS: Data from 2 phase 3, randomized, placebo-controlled trials were analyzed post hoc. Treatment was administered in up to 4 treatment cycles (per cycle: 2 injections, 1-3 days apart, of CCH 0.58 mg or placebo; subsequent penile modeling) at 6-week intervals. Penile curvature was measured at baseline and after each treatment cycle (weeks 6, 12, 18, and 24). Successful response was defined as ≥20% reduction from baseline penile curvature. RESULTS: Overall, 832 men (CCH, nâ¯=â¯551; placebo, nâ¯=â¯281) were included in the analysis. After each cycle, mean cumulative percent reduction from baseline penile curvature was significantly greater with CCH vs placebo (P <.001). Following one cycle, 29.9% of CCH recipients exhibited a successful response. Among nonresponders, additional cycles of injections led to further successful responses: 60.8% of first cycle failures achieved response after fourth cycle (8 injections), 42.7% of cycle 1-2 failures achieved response after fourth cycle, and 23.5% of cycle 1-3 failures achieved response after fourth cycle. CONCLUSION: Data showed incremental benefits from each of the 4 CCH treatment cycles. Completion of a full series of 4 CCH treatment cycles may optimize improvements in penile curvature in men with PD, including among those who did not clinically respond to previous treatment cycles.
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Colagenase Microbiana , Induração Peniana , Adulto , Idoso , Humanos , Pessoa de Meia-Idade , Colagenase Microbiana/administração & dosagem , Induração Peniana/tratamento farmacológico , Resultado do Tratamento , Ensaios Clínicos Controlados Aleatórios como Assunto , Ensaios Clínicos Fase III como AssuntoRESUMO
BACKGROUND: Anaplastic thyroid cancer (ATC) is one of the fatal cancers and has not effective treatments. Alantolactone (ATL), a terpenoid extracted from traditional Chinese medicinal herb Inula helenium L., confers significant anti-inflammatory, antibacterial and antitumor activity. However, the activity and mechanisms of ATL in ATC remain unclear. PURPOSE: To investigate the potential anti-ATC effects in vitro and in vivo and the mechanisms involved. METHODS: The anti-proliferative activity of Alantolactone (ATL) against ATC cells was analyzed through CCK-8 and colony formation assays. Flow cytometry assay was performed to assess the cell cycle, cell apoptosis, ROS, and mitochondrial membrane potential (ΔΨm), whereas the cellular localization of cytochrome c and calreticulin were determined using cellular immunofluorescence assays. The lactate dehydrogenase (LDH) enzyme activity in the cell culture medium was measured using a commercial LDH kit, whereas ELISA was conducted to assess the secretory function of IL-1ß. Western blot assays were conducted to determine the expression or regulation of proteins associated with apoptosis and pyroptosis. Subcutaneous tumor model of nude mice was established to evaluate the anticancer activity of ATL in vivo. The expression of Ki67, cyclin B1, cleaved-PARP, cleaved-caspase 3, and IL-1ß in the animal tumor tissues was profiled using immunohistochemistry analyses. RESULTS: Our data showed that ATL significantly inhibited the proliferation and colony formation activity of ATC cells. ATL induced ATC cell cycle arrest at G2/M phase, and downregulated the expression of cyclin B1 and CDC2. Furthermore, ATL induced concurrent apoptosis and pyroptosis in the ATC cells, and the cleavage of PARP and GSDME. It also significantly increased the release of LDH and IL-1ß. Mechanically, ATL-mediated increase in ROS suppressed the Bcl-2/Bax ratio, downregulated the mitochondrial membrane potential and increased the release of cytochrome c, leading to caspase 9 and caspase 3 cleavage. We also found that ATL induced the translocation of an immunogenic cell death marker (calreticulin) to the cell membrane. In addition, it inhibited the growth of the ATC subcutaneous xenograft model, and activated proteins associated with apoptosis and pyroptosis, with a high safety profile. CONCLUSION: Taken together, these results firstly demonstrated that ATL exerted an anti-ATC activity by inducing concurrent apoptosis and GSDME-dependent pyroptosis through ROS-mediated mitochondria-dependent caspase activation. Meanwhile, these cell deaths exhibited obvious characteristics of immunogenic cell death, which may synergistically increase the potential of cancer immunotherapy in ATC. Further studies are needed to explore deeper mechanisms for the anti- ATC activity of ATL.
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Carcinoma Anaplásico da Tireoide , Neoplasias da Glândula Tireoide , Camundongos , Animais , Humanos , Caspase 3/metabolismo , Piroptose , Caspases/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Ciclina B1/metabolismo , Calreticulina/metabolismo , Calreticulina/farmacologia , Citocromos c/metabolismo , Camundongos Nus , Carcinoma Anaplásico da Tireoide/tratamento farmacológico , Carcinoma Anaplásico da Tireoide/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Apoptose , Mitocôndrias , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/metabolismo , Linhagem Celular TumoralRESUMO
BACKGROUND AND AIMS: Endoscopy is increasingly performed for evaluating patients with ulcerative colitis (UC). However, its diagnostic accuracy is largely affected by the subjectivity of endoscopists' experience and scoring methods, and scoring of selected endoscopic images cannot reflect the inflammation of the entire intestine. We aimed to develop an automatic scoring system using deep-learning technology for consistent and objective scoring of endoscopic images and full-length endoscopic videos of patients with UC. METHODS: We collected 5875 endoscopic images and 20 full-length videos from 332 patients with UC who underwent colonoscopy between January 2017 and March 2021. We trained the artificial intelligence (AI) scoring system using these images, which was then used for full-length video scoring. To more accurately assess and visualize the full-length intestinal inflammation, we divided the large intestine into a fixed number of "areas" (cecum, 20; transverse colon, 20; descending colon, 20; sigmoid colon, 15; rectum, 10). The scoring system automatically scored inflammatory severity of 85 areas from every video and generated a visualized result of full-length intestinal inflammatory activity. RESULTS: Compared with endoscopist scoring, the trained convolutional neural network achieved 86.54% accuracy in the Mayo-scored task, whereas the kappa coefficient was .813 (95% confidence interval [CI], .782-.844). The metrics of the Ulcerative Colitis Endoscopic Index of Severity-scored task were encouraging, with accuracies of 90.7%, 84.6%, and 77.7% and kappa coefficients of .822 (95% CI, .788-.855), .784 (95% CI, .744-.823), and .702 (95% CI, .612-.793) for vascular pattern, erosions and ulcers, and bleeding, respectively. The AI scoring system predicted each bowel segment's score and displayed distribution of inflammatory activity in the entire large intestine using a 2-dimensional colorized image. CONCLUSIONS: We established a novel deep learning-based scoring system to evaluate endoscopic images from patients with UC, which can also accurately describe the severity and distribution of inflammatory activity through full-length intestinal endoscopic videos.
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Colite Ulcerativa , Aprendizado Profundo , Humanos , Colite Ulcerativa/diagnóstico por imagem , Inteligência Artificial , Colonoscopia , Inflamação , Computadores , Índice de Gravidade de Doença , Mucosa IntestinalRESUMO
Collagenase clostridium histolyticum (CCH) is an injectable therapy targeting collagen present in penile plaques in Peyronie's disease (PD). Data comparing CCH to penile surgery are limited, and long-term therapeutic outcomes are unknown. This retrospective analysis used a US claims database (January 2014-June 2017) to determine the percentage of men with subsequent penile surgery among those who initially received CCH (n = 1227) or surgery (index treatment; n = 620) for PD. Eligible patients were aged ≥18 years with continuous enrollment ≥6 months before and ≥12 months after index treatment date. During 12 months of post-index treatment follow-up, fewer patients with PD initially treated with CCH (4.6% [56/1227]) had subsequent penile surgery versus those initially treated with penile surgery (10.3% [64/620]; p < 0.0001). Mean ± SD time to first subsequent surgery after initial PD treatment was longer in the CCH versus surgery cohort (7.7 ± 3.0 vs 1.7 ± 3.2 months). The likelihood of subsequent surgery varied by initial surgery type: 18.2% after plaque incision or excision with grafting; 11.6% after penile implant; and 8.2% after tunical plication. Patients with PD who received CCH first were less likely to undergo subsequent surgery compared with those who received surgery first within a 12-month post-treatment follow-up.
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Induração Peniana , Masculino , Humanos , Adolescente , Adulto , Induração Peniana/tratamento farmacológico , Induração Peniana/cirurgia , Induração Peniana/induzido quimicamente , Colagenase Microbiana/uso terapêutico , Estudos Retrospectivos , Resultado do Tratamento , Injeções Intralesionais , Pênis/cirurgiaRESUMO
Background: Grading of endoscopic lesions is important for determining the severity of ulcerative colitis and developing treatment strategies, but the commonly used methods are not sufficient. Objectives: This study aimed to investigate whether new endoscopic scoring systems incorporating lesions and disease extent are associated with clinical disease severity and maintainable remission. Design: This was a retrospective study. In all, 110 patients with ulcerative colitis were included and 87 completed 12-month follow-up. Methods: Colonoscopy was performed within 1 week before blood samples were taken. Degree of ulcerative colitis burden of luminal inflammation (DUBLIN) scores were calculated as the product of Mayo endoscopic score (MES) by disease extent and ulcerative colitis endoscopic index of severity was used to replace MES when calculating modified DUBLIN scores. Results: DUBLIN and modified DUBLIN scores were increased in the moderate and severe groups significantly (p < 0.05). Both of increased scores contributed to the detection of serious diseases, and the clinical cutoff values of DUBLIN and modified DUBLIN were 3[area under the curve (AUC) = 0.809, p = 0.001) and 7(AUC = 0.815, p = 0.001), respectively. They were with high sensitivity, but the specificity of DUBLIN was lower. Both scores were correlated to partial Mayo scores, C-reactive protein and erythrocyte sedimentation rate positively, and they were correlated to the albumin negatively (p < 0.05). Higher modified DUBLIN scores (>7) were associated with an increased risk of treatment failure (hazard ratio = 4.96, 95% confidence interval: 1.17-21.00, p = 0.03), but there were no association between DUBLIN scores and long-term remission (p > 0.05). Conclusion: Increased DUBLIN and modified DUBLIN scores were conducive to screening serious disease, but only modified DUBLIN scores had the potential to assist in making an upgraded therapeutic schedule.
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Nanoscale cold welding is a promising method in the bottom-up fabrication of nanodevices. Herein, cold welding mechanisms of Cu50Zr50 nanoporous amorphous alloys (NPAAs) are investigated by molecular dynamics simulations, along with the mechanical properties of the welded products. Effects of welding conditions and microstructural parameters are considered. Our results demonstrate that the welded joint has superior mechanical properties. The ultimate strength of the welded NPAAs can be as high as 94-99% that of the original NPAAs but 62-75% for the yield strength and elastic modulus. Voronoi analysis declares that the changes in atomic clusters of NPAAs caused by cold welding are mild. The welding conditions do not have remarkable influences on the mechanical responses of the welded structure. The NPAAs with smaller ligament sizes are more suitable for cold welding, benefiting from the size effect of amorphous alloys. We also successfully use cold welding to fabricate gradient NPAAs and repair fractured NPAAs. It is found that the ultimate tensile strength of the NPAAs changes very little with each successful cold welding. After ten fracture-welding cycles, the ultimate strength of the as-welded specimen is slightly lower than that of the raw materials.
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Nanoindentation tests are performed by molecular dynamics simulation to explore the mechanical properties of nanocrystalline B2 CuZr shape memory alloys with average grain sizes ranging from 6 to 18 nm. Some paramount aspects are monitored, including indentation force-depth curve, hardness, yield strength, and elastic recovery. The results demonstrate an inverse Hall-Petch effect, i.e., the hardness decreases with the decrease in grain size. For the single crystalline B2 CuZr, dislocation nucleation and propagation are the major plastic mechanisms. However, grain cleavage, grain boundary compression, and grain rotation prevail over the plastic behaviors of nanocrystalline B2 CuZr alloys. The elastic recovery becomes stronger with the increase in grain size. Besides, the effects of temperature, indenter size, and indenter speed on the nanoindentation responses are evaluated quantitively.
RESUMO
Gastric cancer is one of the deadliest cancers worldwide. An accurate prognosis is essential for effective clinical assessment and treatment. Spatial patterns in the tumor microenvironment (TME) are conceptually indicative of the staging and progression of gastric cancer patients. Using spatial patterns of the TME by integrating and transforming the multiplexed immunohistochemistry (mIHC) images as Cell-Graphs, we propose a graph neural network-based approach, termed Cell-Graph Signature or CGSignature, powered by artificial intelligence, for the digital staging of TME and precise prediction of patient survival in gastric cancer. In this study, patient survival prediction is formulated as either a binary (short-term and long-term) or ternary (short-term, medium-term, and long-term) classification task. Extensive benchmarking experiments demonstrate that the CGSignature achieves outstanding model performance, with Area Under the Receiver Operating Characteristic curve of 0.960 ± 0.01, and 0.771 ± 0.024 to 0.904 ± 0.012 for the binary- and ternary-classification, respectively. Moreover, Kaplan-Meier survival analysis indicates that the "digital grade" cancer staging produced by CGSignature provides a remarkable capability in discriminating both binary and ternary classes with statistical significance (P value < 0.0001), significantly outperforming the AJCC 8th edition Tumor Node Metastasis staging system. Using Cell-Graphs extracted from mIHC images, CGSignature improves the assessment of the link between the TME spatial patterns and patient prognosis. Our study suggests the feasibility and benefits of such an artificial intelligence-powered digital staging system in diagnostic pathology and precision oncology.