RESUMO
OBJECTIVES: This study aimed to compare the intestinal and pancreatobiliary subtypes of ampullary adenocarcinoma in a large patient group due to limited data on survival and risk factors. METHODS: A retrospective analysis of the clinical and pathological findings and the survival of 184 patients with ampullary adenocarcinoma who underwent curative operation between 2007 and 2018 was performed. RESULTS: Pancreatobiliary subtype had a higher prevalence of jaundice before operation than the intestinal subtype (p < 0.05). Pancreatobiliary subtype had a larger tumor size (> 2 mm) (p < 0.01) and poorer differentiation (p < 0.05) than the intestinal subtype. Perineural invasion more frequently occurred in pancreatobiliary subtype than the intestinal subtype (p < 0.01) and pancreatobiliary subtype had a higher prevalence of positive dissected lymph nodes (p < 0.05) with an advanced disease stage (p < 0.01) than the intestinal subtype. Patients of the pancreatobiliary subtype had poorer disease-free and overall survival than patients of the intestinal subtype. No survival benefit of adjuvant chemotherapy was found in either patients of the intestinal subtype or pancreatobiliary subtype. No significant difference was found in any subtypes regarding the recurrent regions. CONCLUSIONS: Pancreatobiliary subtype exhibited a higher recurrence rate and a poorer overall survival rate with more unfavorable pathological characteristics than the intestinal subtype.
OBJETIVOS: Los datos sobre la supervivencia y los factores de riesgo del adenocarcinoma ampular son limitados debido a su rareza. Este estudio buscó comparar el subtipo intestinal y el subtipo pancreático-biliar en pacientes con adenocarcinoma ampular. MÉTODOS: Análisis retrospectivo de hallazgos clínicos y patológicos y la supervivencia de 184 pacientes con adenocarcinoma ampular tratados entre 2007 y 2018. RESULTADOS: El subtipo pancreático-biliar tuvo una mayor prevalencia de ictericia antes de la operación y un tamaño de tumor mayor, y una peor diferenciación, que el subtipo intestinal. La invasión perineural fue más frecuente en el subtipo pancreático-biliar, con una mayor prevalencia de linfonodos disecados positivos y un estadio avanzado de la enfermedad. Los pacientes del subtipo pancreático-biliar tuvieron una supervivencia libre de enfermedad y una supervivencia general peores que los pacientes del subtipo intestinal. No se encontró ningún beneficio de la quimioterapia adyuvante en pacientes del subtipo intestinal o pancreático-biliar. No hubo diferencia significativa en las regiones recurrentes. CONCLUSIÓN: El subtipo pancreático-biliar mostró una tasa de recurrencia y una tasa de supervivencia general peores, con características patológicas más desfavorables que el subtipo intestinal.
Assuntos
Adenocarcinoma , Ampola Hepatopancreática , Neoplasias do Ducto Colédoco , Humanos , Estudos Retrospectivos , Ampola Hepatopancreática/patologia , Masculino , Feminino , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Adenocarcinoma/mortalidade , Adenocarcinoma/classificação , Neoplasias do Ducto Colédoco/patologia , Neoplasias do Ducto Colédoco/cirurgia , Neoplasias do Ducto Colédoco/mortalidade , Neoplasias do Ducto Colédoco/classificação , Pessoa de Meia-Idade , Idoso , Quimioterapia Adjuvante , Adulto , Invasividade Neoplásica , Idoso de 80 Anos ou mais , Recidiva Local de Neoplasia , Metástase Linfática , Carga Tumoral , Intervalo Livre de DoençaRESUMO
PURPOSE: Machine learning (ML) models presented an excellent performance in the prognosis prediction. However, the black box characteristic of ML models limited the clinical applications. Here, we aimed to establish explainable and visualizable ML models to predict biochemical recurrence (BCR) of prostate cancer (PCa). MATERIALS AND METHODS: A total of 647 PCa patients were retrospectively evaluated. Clinical parameters were identified using LASSO regression. Then, cohort was split into training and validation datasets with a ratio of 0.75:0.25 and BCR-related features were included in Cox regression and five ML algorithm to construct BCR prediction models. The clinical utility of each model was evaluated by concordance index (C-index) values and decision curve analyses (DCA). Besides, Shapley Additive Explanation (SHAP) values were used to explain the features in the models. RESULTS: We identified 11 BCR-related features using LASSO regression, then establishing five ML-based models, including random survival forest (RSF), survival support vector machine (SSVM), survival Tree (sTree), gradient boosting decision tree (GBDT), extreme gradient boosting (XGBoost), and a Cox regression model, C-index were 0.846 (95%CI 0.796-0.894), 0.774 (95%CI 0.712-0.834), 0.757 (95%CI 0.694-0.818), 0.820 (95%CI 0.765-0.869), 0.793 (95%CI 0.735-0.852), and 0.807 (95%CI 0.753-0.858), respectively. The DCA showed that RSF model had significant advantages over all models. In interpretability of ML models, the SHAP value demonstrated the tangible contribution of each feature in RSF model. CONCLUSIONS: Our score system provide reference for the identification for BCR, and the crafting of a framework for making therapeutic decisions for PCa on a personalized basis.
Assuntos
Aprendizado de Máquina , Recidiva Local de Neoplasia , Neoplasias da Próstata , Humanos , Masculino , Neoplasias da Próstata/sangue , Neoplasias da Próstata/patologia , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/patologia , Estudos Retrospectivos , Idoso , Pessoa de Meia-Idade , Prognóstico , Árvores de Decisões , Modelos de Riscos Proporcionais , Algoritmos , Máquina de Vetores de Suporte , Antígeno Prostático Específico/sangueRESUMO
PURPOSE: Small bowel adenocarcinoma (SBA) is a rare malignancy of the gastrointestinal tract, and its unique location within the small intestine presents difficulties in obtaining tissue samples from the lesions. This limitation hinders the research and development of effective clinical treatment methods. Circulating tumor DNA (ctDNA) analysis holds promise as an alternative approach for investigating SBA and guiding treatment decisions, thereby improving the prognosis of SBA. METHODS: Between January 2017 and August 2021, a total of 336 tissue or plasma samples were obtained and the corresponding mutation status in tissue or blood was evaluated with NGS. RESULTS AND CONCLUSIONS: The study found that in SBA tissues, the most commonly alternated genes were TP53, KRAS, and APC, and the most frequently affected pathways were RTK-RAS-MAPK, TP53, and WNT. Notably, the RTK-RAS-MAPK pathway was identified as a potential biomarker that could be targeted for treatment. Then, we validated the gene mutation profiling of ctDNA extracted from SBA patients exhibited the same characteristics as tissue samples for the first time. Subsequently, we applied ctDNA analysis on a terminal-stage patient who had shown no response to previous chemotherapy. After detecting alterations in the RTK-RAS-MAPK pathway in the ctDNA, the patient was treated with MEK + EGFR inhibitors and achieved a tumor shrinkage rate of 76.33%. Our study utilized the largest Chinese SBA cohort to uncover the molecular characteristics of this disease, which might facilitate clinical decision making for SBA patients.
Assuntos
Adenocarcinoma , DNA Tumoral Circulante , Neoplasias Intestinais , Mutação , Humanos , Adenocarcinoma/genética , Adenocarcinoma/patologia , Adenocarcinoma/tratamento farmacológico , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Neoplasias Intestinais/genética , Neoplasias Intestinais/patologia , DNA Tumoral Circulante/genética , DNA Tumoral Circulante/sangue , Biomarcadores Tumorais/genética , Intestino Delgado/patologia , Adulto , Proteínas Proto-Oncogênicas p21(ras)/genética , Proteína Supressora de Tumor p53/genética , Proteína da Polipose Adenomatosa do Colo/genética , China , Prognóstico , População do Leste AsiáticoRESUMO
Urban soils host diverse bacteria crucial for ecosystem functions and urban health. As urbanization rises, artificial light at night (ALAN) imposes disturbances on soil ecosystems, yet how ALAN affects the structure and stability of soil bacterial community remains unclear. Here we coupled a short-term incubation experiment, community profiling, network analysis, and in situ field survey to assess the ecological impacts of ALAN. We showed that ALAN influenced bacterial compositions and shifted the bacterial network to a less stable phase, altering denitrification potential. Such transition in community stability probably resulted from an ALAN-induced decrease in competition and/or an increase in facilitation, in line with the Stress Gradient Hypothesis. Similar destabilizing effects were also detected in bacterial networks in multiple urban soils subjected to different levels of ALAN stress, supporting the action of ALAN on naturally-occurring soil bacterial communities. Overall, our findings highlight ALAN as a new form of anthropogenic stress that jeopardizes the stability of soil bacterial community, which would facilitate ecological projection of expanding ALAN exposure.
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Ecossistema , Solo , Poluição Luminosa , Meio Ambiente , Bactérias , LuzRESUMO
Background: Previous studies demonstrated that induction chemotherapy (IC) followed by de-escalated chemoradiotherapy adapted to tumor response was effective in treating childhood nasopharyngeal carcinoma (NPC), but the toxicity profile of this treatment strategy, and whether childhood patients with advanced stages can obtain enough benefits from it requires further investigation. Methods: We conducted a single-center phase II trial (NCT03020329). All participants received 3 cycles of paclitaxel liposome, cisplatin and 5-fluorouracil (TPF)-based IC. Patients who showed complete or partial response received de-escalated radiotherapy of 60 Gy with 3 cycles of concurrent cisplatin, and those who showed stable or progressive disease received standard-dose radiotherapy of 70 Gy with concurrent cisplatin. The primary endpoint was the complete response (CR) rate at the end of concurrent chemoradiotherapy (CCRT). Findings: From November 2016 to March 2021, 44 patients were recruited in the cohort. The CR rate was 80% (35/44, 95% CI, 65-90) of the whole cohort. All patients achieved CR 3 months after CCRT. By the last follow-up, the 3-year progression-free survival and overall survival were 91% (95% CI, 82-99) and 100% respectively. Dry mouth was the most common late toxicity, with an incidence of 41% (18/44), followed by skin fibrosis and hearing impairment. No patient suffered from severe late toxicity and growth retardation. Interpretation: Our results proved the efficacy and safety of TPF regimen followed by de-escalated radiotherapy with concurrent cisplatin in treating stage IVa-b childhood NPC patients. Funding: A full list of funding bodies that contributed to this study can be found in the Acknowledgements section.
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Powdery mildew severely affects several important crops and cash plants. Disruption of mildew resistance locus O (MLO) genes elevates resistance against powdery mildew in several plants. However, whether rubber tree (Heveae brasiliensis) MLO proteins are linked to susceptibility remains unknown, owing to technical limitations in the genetic manipulation of this woody plant. A previous study showed that the H. brasiliensis MLO-like protein HbMLO12 demonstrates high amino acid sequence similarity with the known Arabidopsis MLO protein AtMLO12. In this study, we investigated whether HbMLO12 regulates susceptibility to powdery mildew. H. brasiliensis leaves take up exogenously synthesized double-stranded RNAs (dsRNAs), and foliar application of dsRNA homologous to HbMLO12 gene specifically induces HbMLO12 silencing in H. brasiliensis leaf tissues. Notably, HbMLO12 silencing inhibited fungal infection and elevated the immune response during interaction with the rubber tree powdery mildew fungus. Furthermore, the heterologous expression of HbMLO12 suppressed bacterial flg22- and fungal chitin-induced immune responses and enhanced bacterial infection in Arabidopsis. Our study provides evidence that HbMLO12 contributes to susceptibility to powdery mildew. [Formula: see text] Copyright © 2023 The Author(s). This is an open access article distributed under the CC BY-NC-ND 4.0 International license.
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Proteínas de Arabidopsis , Arabidopsis , Ascomicetos , Hevea , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Hevea/genética , Hevea/metabolismo , Ascomicetos/fisiologia , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Doenças das Plantas/microbiologia , Resistência à Doença/genéticaRESUMO
Abstract Voriconazole increases tacrolimus blood concentration significantly when coadministrated. The recommendation of reducing tacrolimus to 1/3 in voriconazole package insert seems not to be satisfactory in clinical practice. In vitro studies demonstrated that the magnitude of inhibition depends on the concentration of voriconazole, while voriconazole exposure is determined by the genotype status of CYP2C19. CYP2C19 gene polymorphism challenges the management of drug-drug interactions(DDIs) between voriconazole and tacrolimus. This work aimed to predict the impact of CYP2C19 polymorphism on the DDIs by using physiologically based pharmacokinetics (PBPK) models. The precision of the developed voriconazole and tacrolimus models was reasonable by evaluating the pharmacokinetic parameters fold error, such as AUC0-24, Cmax and tmax. Voriconazole increased tacrolimus concentration immediately in all population. The simulated duration of DDIs disappearance after voriconazole withdrawal were 146h, 90h and 66h in poor metabolizers (PMs), intermediate metabolizers (IMs) and extensive metabolizers(EMs), respectively. The developed and optimized PBPK models in this study can be applied to assit the dose adjustment for tacrolimus with and without voriconazole.
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Tacrolimo/agonistas , Fator de Impacto , Voriconazol/agonistas , Citocromo P-450 CYP2C19/análise , Técnicas In Vitro/métodos , Preparações Farmacêuticas/administração & dosagem , Adaptação Psicológica/classificaçãoRESUMO
The RPW8s (Resistance to Powdery Mildew 8) are atypical broad-spectrum resistance genes that provide resistance to the powdery mildew fungi. Powdery mildew of rubber tree is one of the serious fungal diseases that affect tree growth and latex production. However, the RPW8 homologs in rubber tree and their role of resistance to powdery mildew remain unclear. In this study, four RPW8 genes, HbRPW8-a, b, c, d, were identified in rubber tree, and phylogenetic analysis showed that HbRPW8-a was clustered with AtRPW8.1 and AtRPW8.2 of Arabidopsis. The HbRPW8-a protein was localized on the plasma membrane and its expression in rubber tree was significantly induced upon powdery mildew infection. Transient expression of HbRPW8-a in tobacco leaves induced plant immune responses, including the accumulation of reactive oxygen species and the deposition of callose in plant cells, which was similar to that induced by AtRPW8.2. Consistently, overexpression of HbRPW8-a in Arabidopsis thaliana enhanced plant resistance to Erysiphe cichoracearum UCSC1 and Pseudomonas syringae pv. tomato DC30000 (PstDC3000). Moreover, such HbRPW8-a mediated resistance to powdery mildew was in a salicylic acid (SA) dependent manner. Taken together, we demonstrated a new RPW8 member in rubber tree, HbRPW8-a, which could potentially contribute the resistance to powdery mildew.
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Proteínas de Arabidopsis , Arabidopsis , Ascomicetos , Hevea , Arabidopsis/metabolismo , Hevea/genética , Hevea/metabolismo , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Expressão Ectópica do Gene , Filogenia , Espécies Reativas de Oxigênio/metabolismo , Látex/metabolismo , Doenças das Plantas/microbiologia , Ascomicetos/fisiologia , Erysiphe , Ácido Salicílico/metabolismo , Nicotiana/metabolismo , Resistência à Doença/genéticaRESUMO
BACKGROUND: G protein coupled receptor kinase 2 (GRK2) has been demonstrated to play a crucial role in the development of chronic pain. Acupuncture is an alternative therapy widely used for pain management. In this study, we investigated the role of spinal neuronal GRK2 in electroacupuncture (EA) analgesia. METHODS: The mice model of inflammatory pain was built by subcutaneous injection of Complete Freund's Adjuvant (CFA) into the plantar surface of the hind paws. The mechanical allodynia of mice was examined by von Frey test. The mice were subjected to EA treatment (BL60 and ST36 acupuncture points) for 1 week. Overexpression and downregulation of spinal neuronal GRK2 were achieved by intraspinal injection of adeno associated virus (AAV) containing neuron-specific promoters, and microglial activation and neuroinflammation were evaluated by real-time PCR. RESULTS: Intraplantar injection with CFA in mice induced the decrease of GRK2 and microglial activation along with neuroinflammation in spinal cord. EA treatment increased the spinal GRK2, reduced neuroinflammation, and significantly decreased CFA-induced mechanical allodynia. The effects of EA were markedly weakened by non-cell-specific downregulation of spinal GRK2. Further, intraspinal injection of AAV containing neuron-specific promoters specifically downregulated neuronal GRK2, and weakened the regulatory effect of EA on CFA-induced mechanical allodynia and microglial activation. Meanwhile, overexpression of spinal neuronal GRK2 decreased mechanical allodynia. All these indicated that the neuronal GRK2 mediated microglial activation and neuroinflammation, and subsequently contributed to CFA-induced inflammatory pain. CONCLUSION: The restoration of the spinal GRK2 and subsequent suppression of microglial activation and neuroinflammation might be an important mechanism for EA analgesia. Our findings further suggested that the spinal GRK2, especially neuronal GRK2, might be the potential target for EA analgesia and pain management, and we provided a new experimental basis for the EA treatment of pain.
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Eletroacupuntura , Quinase 2 de Receptor Acoplado a Proteína G/fisiologia , Microglia/fisiologia , Manejo da Dor , Animais , Inflamação/induzido quimicamente , Inflamação/terapia , Camundongos , Neurônios , Dor/induzido quimicamenteRESUMO
INTRODUCTION: The standard approach to thyroidectomy is a collar incision via the anterior neck, and the neck scar has always been a source of worry for patients. Acceptable wound cosmetology has become a focus for thyroid surgeons. OBJECTIVE: To verify the effectiveness and cosmetic results of thyroidectomy through a lateral supraclavicular incision. METHODS: 180 patients were randomly divided into two groups: a lateral supraclavicular approach and a conventional transcervical approach. The main outcomes included incision length, intraoperative blood loss, operative time, total drainage volume, hospitalization expense, early postoperative pain measured by visual analog scale, infection, and perceived cosmetic outcome. RESULTS: There were no statistical significances between the two groups in terms of age, gender, nodule size, intraoperative blood loss, operative time, total drainage volume, hospital expense and postoperative complications, whereas there were significant differences in terms of incision length (5.2±1.04cm vs. 6.9±1.14cm, p<0.05). CONCLUSIONS: The lateral supraclavicular incision is a safe and feasible approach for thyroidectomy. Compared with conventional approach, it provides a better cosmetic result.