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Hepatocellular carcinoma (HCC) is the most common type of liver cancer, characterized by a high morbidity rate. Long non-coding RNAs (lncRNAs) play an important role in regulating various cellular processes and diseases, including cancer. However, their specific roles and mechanisms in HCC are not fully understood. This study used a multi-cohort design to investigate necroptosis-related lncRNAs (NRLs) in patients with HCC. We curated a list of 1095 NRLs and 838 genes showing differential expression between tumor and normal tissues. Among them, we found 105 NRLs closely associated with the prognosis of HCC patients. The 10 lncRNAs (AC100803.3, AC027237.2, AL158166.1, LINC02870, AC026412.3, LINC02159, AC027097.1, AC139887.4, AC007405.1, AL023583.1) generated by LASSO-Cox regression analysis were used to create a prognostic risk model for HCC and group patients into groups based on risk. The KEGG analysis revealed distinct pathway enrichments in high-risk (H-R) and low-risk (L-R) subgroups. According to GO analysis, this study identified 230 differentially expressed genes (DEGs) that were significantly enriched in specific biological processes. Comparison of immune checkpoint-related genes (MCPGs) between H-R and L-R patients revealed significant differences. Moreover, we established a correlation between the risk scores of patients with liver cancer and their sensitivity to 16 chemotherapeutic agents. Employing protein-protein interaction (PPI) analysis, we identified 10 hub genes that potentially regulate the molecular networks involved in HCC development. This study is a pioneering effort to investigate the roles of NRLs in HCC. It opens a new avenue for potential targeted therapies and provides insights into the molecular mechanisms of HCC.
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BACKGROUND: Age-related eye diseases (AREDs) have become increasingly prevalent with the aging population, serving as the leading causes of visual impairment worldwide. Epigenetic clocks are generated based on DNA methylation (DNAm) levels and are considered one of the most promising predictors of biological age. This study aimed to investigate the bidirectional causal association between epigenetic clocks and common AREDs or glaucoma endophenotypes. METHODS: Instrumental variables for epigenetic clocks, AREDs, and glaucoma endophenotypes were obtained from corresponding genome-wide association study data of European descent. Bidirectional two-sample Mendelian randomization (MR) was employed to explore the causal relationship between epigenetic clocks and AREDs or glaucoma endophenotypes. Multivariable MR (MVMR) was used to determine whether glaucoma endophenotypes mediated the association of epigenetic clocks with glaucoma. Multiple sensitivity analyses were conducted to confirm the robustness of MR estimates. RESULTS: The results showed that an increased intrinsic epigenetic age acceleration (HorvathAge) was significantly associated with an increased risk of primary open-angle glaucoma (OR = 1.04, 95% CI 1.02 to 1.06, P = 6.1E-04). The epigenetic age acceleration (EEA) of HannumAge was related to a decreased risk of primary angle-closure glaucoma (OR = 0.92, 95% CI 0.86 to 0.99, P = 0.035). Reverse MR analysis showed that age-related cataract was linked to decreased HannumAge (ß = -0.190 year, 95% CI -0.374 to -0.008, P = 0.041). The EEA of HannumAge (ß = -0.85 µm, 95% CI -1.57 to -0.14, P = 0.019) and HorvathAge (ß = -0.63 µm, 95% CI -1.18 to -0.08, P = 0.024) were associated with decreased central corneal thickness (CCT). PhenoAge was related to an increased retinal nerve fiber layer thickness (ß = 0.06 µm, 95% CI 0.01 to 0.11, P = 0.027). MVMR analysis found no mediation effect of CCT in the association of HannumAge and HorvathAge with glaucoma. DNAm-based granulocyte proportions were significantly associated with presbyopia, rhegmatogenous retinal detachment, and intraocular pressure (P < 0.05). DNAm-based plasminogen activator inhibitor-1 levels were significantly related to age-related macular degeneration and intraocular pressure (P < 0.05). CONCLUSION: The present study revealed a causal association between epigenetic clocks and AREDs. More research is warranted to clarify the potential mechanisms of the biological aging process in AREDs.
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Envelhecimento , Metilação de DNA , Endofenótipos , Epigênese Genética , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Humanos , Análise da Randomização Mendeliana/métodos , Epigênese Genética/genética , Estudo de Associação Genômica Ampla/métodos , Metilação de DNA/genética , Masculino , Envelhecimento/genética , Feminino , Glaucoma/genética , Pessoa de Meia-Idade , Glaucoma de Ângulo Aberto/genética , Idoso , Predisposição Genética para DoençaRESUMO
BACKGROUND: As global aging intensifies, the prevalence of ocular fundus diseases continues to rise. In China, the tense doctor-patient ratio poses numerous challenges for the early diagnosis and treatment of ocular fundus diseases. To reduce the high risk of missed or misdiagnosed cases, avoid irreversible visual impairment for patients, and ensure good visual prognosis for patients with ocular fundus diseases, it is particularly important to enhance the growth and diagnostic capabilities of junior doctors. This study aims to leverage the value of electronic medical record data to developing a diagnostic intelligent decision support platform. This platform aims to assist junior doctors in diagnosing ocular fundus diseases quickly and accurately, expedite their professional growth, and prevent delays in patient treatment. An empirical evaluation will assess the platform's effectiveness in enhancing doctors' diagnostic efficiency and accuracy. METHODS: In this study, eight Chinese Named Entity Recognition (NER) models were compared, and the SoftLexicon-Glove-Word2vec model, achieving a high F1 score of 93.02%, was selected as the optimal recognition tool. This model was then used to extract key information from electronic medical records (EMRs) and generate feature variables based on diagnostic rule templates. Subsequently, an XGBoost algorithm was employed to construct an intelligent decision support platform for diagnosing ocular fundus diseases. The effectiveness of the platform in improving diagnostic efficiency and accuracy was evaluated through a controlled experiment comparing experienced and junior doctors. RESULTS: The use of the diagnostic intelligent decision support platform resulted in significant improvements in both diagnostic efficiency and accuracy for both experienced and junior doctors (P < 0.05). Notably, the gap in diagnostic speed and precision between junior doctors and experienced doctors narrowed considerably when the platform was used. Although the platform also provided some benefits to experienced doctors, the improvement was less pronounced compared to junior doctors. CONCLUSION: The diagnostic intelligent decision support platform established in this study, based on the XGBoost algorithm and NER, effectively enhances the diagnostic efficiency and accuracy of junior doctors in ocular fundus diseases. This has significant implications for optimizing clinical diagnosis and treatment.
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Oftalmologistas , Humanos , Tomada de Decisão Clínica , Registros Eletrônicos de Saúde/normas , Inteligência Artificial , China , Sistemas de Apoio a Decisões ClínicasRESUMO
BACKGROUND AND AIMS: The concept of textbook outcomes (TOs) has gained increased attention as a critical metric to assess the quality and success of outcomes following complex surgery. A simple yet effective scoring system was developed and validated to predict risk of not achieving textbook outcomes (non-TOs) following hepatectomy for hepatocellular carcinoma (HCC). METHODS: Using a multicenter prospectively collected database, risk factors associated with non-TO among patients who underwent hepatectomy for HCC were identified. A predictive scoring system based on factors identified from multivariate regression analysis was used to risk stratify patients relative to non-TO. The score was developed using 70 % of the overall cohort and validated in the remaining 30 %. RESULTS: Among 3681 patients, 1458 (39.6 %) failied to experience a TO. Based on the derivation cohort, obesity, American Society of Anaesthesiologists score(ASA score), Child-Pugh grade, tumor size, and extent of hepatectomy were identified as independent predictors of non-TO. The scoring system ranged from 0 to 10 points. Patients were categorized into low (0-3 points), intermediate (4-6 points), and high risk (7-10 points) of non-TO. In the validation cohort, the predicted risk of developing non-TOs was 39.0 %, which closely matched the observed risk of 39.9 %. There were no differences among the predicted and observed risks within the different risk categories. CONCLUSIONS: A novel scoring system was able to predict risk of non-TO accurately following hepatectomy for HCC. The score may enable early identification of individuals at risk of adverse outcomes and inform surgical decision-making, and quality improvement initiatives.
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(1) Background: A rise in intraocular pressure (IOP) and decreased retinal ganglion cells are frequent indicators of effective modeling of chronic ocular hypertension in mice. In this study, the sensitivity of the mouse model to pharmaceutical therapy to reduce intraocular tension was assessed, the model's safety was confirmed using a cytotoxicity test, and the success rate of the mouse model of ocular hypertension was assessed by assessing alterations in IOP and neurons in the ganglion cell layer. (2) Methods: A mouse model of chronic ocular hypertension was produced in this study by employing photocrosslinkable sericin hydrogel injection and LED lamp irradiation. The eyes of 25 C57BL/6 male mice were subjected to 405 nm UV light from the front for 2 min after being injected with 5 µL of sericin hydrogel in the anterior chamber of the left eye. IOP in the mice was measured daily, and IOP rises greater than 5 mmHg were considered intraocular hypertension. When the IOP was lowered, the intervention was repeated once, but the interval between treatments was at least 2 weeks. The right eyes were not treated with anything as a normal control group. Mice eyeballs were stained with HE, Ni-type, and immunofluorescence to assess the model's efficacy. Two common drugs (tafluprost eye drops and timolol eye drops) were provided for one week after four weeks of stable IOP, and IOP changes were assessed to determine the drug sensitivity of the mouse model of chronic ocular hypertension. Furthermore, CellTiter 96® AQueous One Solution Cell Proliferation Assay (MTS) was utilized to investigate the safety of the ocular hypertension model by evaluating the deleterious effects of photocrosslinkable sericin hydrogel on cells. (3) Results: Before injection, the basal IOP was (9.42 ± 1.28) mmHg (1 kPa = 7.5 mmHg) in the experimental group and (9.08 ± 1.21) in the control group. After injection, cataract occurred in one eye, corneal edema in one eye, endophthalmitis in one eye, iris incarceration in one eye, and eyeball atrophy in one eye. Five mice with complications were excluded from the experiment, and twenty mice were left. Four weeks after injection, the IOP of the experimental group was maintained at (19.7 ± 4.52) mmHg, and that of the control group was maintained at (9.92 ± 1.55) mmHg, and the difference between the two groups was statistically significant (p < 0.05). Before the intervention, the IOP in the experimental group was (21.7 ± 3.31) mmHg in the high IOP control group, (20.33 ± 2.00) mmHg in the tafluprost eye drops group, and (20.67 ± 3.12) mmHg in the timolol maleate eye drops group. The IOP after the intervention was (23.2 ± 1.03) mmHg, (12.7 ± 2.11) mmHg, and (10.4 ± 1.43) mmHg, respectively. Before and after the intervention, there were no significant differences in the high-IOP control group (p > 0.05), there were statistically significant differences in the timolol eye drops group (p < 0.05), and there were statistically significant differences in the tafluprost eye drops group (p < 0.05). One week after drug withdrawal, there was no significant difference in IOP among the three groups (p > 0.05). In the high-IOP group, the protein (sericin hydrogel) showed a short strips or fragmented structure in the anterior chamber, accompanied by a large number of macrophages and a small number of plasma cells. The shape of the chamber angle was normal in the blank control group. The number of retinal ganglion cells decreased significantly 8 weeks after injection of sericin hydrogel into the anterior chamber, and the difference was statistically significant compared with the blank control group (p < 0.05). After the cells were treated with photocrosslinkable sericin hydrogel, there was no significant difference in the data of the CellTiter 96® assay kit of MTS compared with the blank control group (p > 0.05). (4) Conclusions: A mouse model of chronic intraocular hypertension can be established successfully by injecting sericin in the anterior chamber and irradiating with ultraviolet light. The model can simulate the structural and functional changes of glaucoma and can effectively reduce IOP after the action of most antihypertensive drugs, and it is highly sensitive to drugs. Sericin has no obvious toxic effect on cells and has high safety.
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BACKGROUND: Patients with primary hyperparathyroidism (PHPT) are at risk for severe hypocalcemia (SH) following parathyroidectomy (PTX), but limited data exist on the predictors of SH. We aimed to identify risk factors for early postoperative SH after PTX in patients with PHPT and to evaluate the predictive value of clinical parameters. METHODS: A retrospective review of patients with PHPT who underwent PTX between January 2010 and December 2022 was performed. A total of 46 patients were included in the study, with 15 (32.6%) experiencing postoperative SH, 19 (41.3%) having calculi in the ureter or kidney, and 37 (80.4%) having osteoporosis. Patients were divided into SH and non-SH groups based on postoperative serum calcium levels. Preoperative biochemical indicators, bone turnover markers, and renal function parameters were analyzed and correlated with postoperative SH. RESULTS: Statistically significant (P < 0.05) differences were found in preoperative serum calcium (serum Ca), intact parathyroid hormone, serum phosphorus (serum P), serum Ca/P, percentage decrease of serum Ca, total procollagen type 1 intact N-terminal propeptide, osteocalcin (OC), and alkaline phosphatase levels between the two groups. Multivariate analysis showed that serum P (odds ratio [OR] = 0.989; 95% confidence interval [95% CI] = 0.981-0.996; P = 0.003), serum Ca (OR = 0.007; 95% CI = 0.001-0.415; P = 0.017), serum Ca/P (OR = 0.135; 95% CI = 0.019-0.947; P = 0.044) and OC levels (OR = 1.012; 95% CI = 1.001-1.024; P = 0.036) were predictors of early postoperative SH. The receiver operating characteristic curve analysis revealed that serum P (area under the curve [AUC] = 0.859, P < 0.001), serum Ca/P (AUC = 0.735, P = 0.010) and OC (AUC = 0.729, P = 0.013) had high sensitivity and specificity. CONCLUSION: Preoperative serum P, serum Ca/P and osteocalcin levels may identify patients with PHPT at risk for early postoperative SH after PTX.
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Hiperparatireoidismo Primário , Hipocalcemia , Paratireoidectomia , Complicações Pós-Operatórias , Humanos , Hiperparatireoidismo Primário/cirurgia , Hiperparatireoidismo Primário/sangue , Hiperparatireoidismo Primário/complicações , Feminino , Masculino , Paratireoidectomia/efeitos adversos , Pessoa de Meia-Idade , Fatores de Risco , Estudos Retrospectivos , Estudos de Casos e Controles , Hipocalcemia/etiologia , Hipocalcemia/sangue , Hipocalcemia/epidemiologia , Hipocalcemia/diagnóstico , Complicações Pós-Operatórias/sangue , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/diagnóstico , Idoso , Cálcio/sangue , Prognóstico , Biomarcadores/sangue , Adulto , Seguimentos , Hormônio Paratireóideo/sangueRESUMO
BACKGROUND & AIMS: The characterization and prognostic value of body composition parameter/phenotype based on computed tomography (CT) in patients with digestive tract cancers remain incomplete. This study aimed to investigate the relationship between parameter/phenotype and clinical outcomes in patients with digestive tract cancers. METHODS: In this prospective cohort study, 8267 patients with digestive tract cancers were assessed using CT scans to determine body composition. Body composition data, including areas of skeletal muscle (SM), subcutaneous adipose tissue (SAT), and visceral adipose tissue (VAT), were collected at the third lumbar level on CT images obtained within 30 days before surgery. Body composition phenotypes (sarcopenia, cancer cachexia, sarcopenic obesity) were determined based on SM, SAT, and VAT areas. The primary endpoint was overall survival, obtained from electronic medical records and telephone follow-up surveys. Kaplan-Meier and log-rank analyses were employed to compare unadjusted survival, while multivariate survival analyses were conducted using a proportional hazards model adjusted for age, gender, and cancer-node-metastasis (TNM) stages. RESULTS: Adjusted hazard ratios (HRs) for all-cause mortality were calculated for the second (Q2), third (Q3), and fourth (Q4) quantiles relative to the first quantile (Q1) for SM areas, revealing adjusted summary HRs of 0.575 (95% CI, 0.361-0.916), 0.419 (95% CI, 0.241-0.729), and 0.384 (95% CI, 0.203-0.726), respectively. Sarcopenia-adjusted summary HRs were 1.795 (95% CI: 1.012-3.181) for male patients and 1.925 (95% CI: 1.065-3.478) for female patients. Cancer cachexia-adjusted summary HRs were 1.542 (95% CI: 1.023-2.324) for male patients and 1.569 (95% CI: 0.820-3.001) for female patients. Sarcopenic obesity-adjusted summary HRs were 1.122 (95% CI: 0.759-1.657) for male patients and 1.303 (95% CI: 0.623-2.725) for female patients. Subgroup analyses indicated varying prognostic values of body composition parameter/phenotype among different cancer types. CONCLUSIONS: Our findings suggest a large SM area is a favorable prognostic indicator, while cancer cachexia and sarcopenia signify poor prognosis in patients with digestive tract cancers. These findings have important implications for the personalized preoperative assessment of body composition in patients with digestive tract cancers.
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Composição Corporal , Sarcopenia , Humanos , Masculino , Feminino , Estudos Prospectivos , Pessoa de Meia-Idade , Prognóstico , China , Idoso , Músculo Esquelético , Caquexia , Obesidade/complicações , Adulto , Tomografia Computadorizada por Raios X , Gordura Intra-Abdominal/diagnóstico por imagem , Modelos de Riscos Proporcionais , Estimativa de Kaplan-MeierRESUMO
BACKGROUND: The value of serum biomarkers, particularly alpha-fetoprotein (AFP) and protein induced by vitamin K absence or antagonist-II (PIVKA-II), gains increasing attention in prognostic evaluation and recurrence monitoring for patients with hepatocellular carcinoma (HCC). This study investigated the implications of serological incomplete conversion (SIC) of these 2 biomarkers as prognostic indicators for long-term outcomes after HCC resection. METHODS: A multicenter observational study was conducted on a cohort of HCC patients presenting with AFP (>20 ng/mL) or PIVKA-II (>40 mAU/mL) positivity who underwent curative-intent resection. Based on their postoperative AFP and PIVKA-II levels at first postoperative follow-up (4~8 weeks after surgery), these patients were stratified into the serological incomplete conversion (SIC) and serological complete conversion (SCC) groups. The study endpoints were recurrence and overall survival (OS). RESULTS: Among 1755 patients, 379 and 1376 were categorized as having SIC and SCC, respectively. The SIC group exhibited 1- and 5-year OS rates of 67.5% and 26.3%, with the corresponding recurrence rates of 53.2% and 79.0%, respectively; while the SCC group displayed 1- and 5-year OS rates of 95.8% and 62.5%, with the corresponding recurrence rates of 16.8% and 48.8%, respectively (both Pâ <â .001). Multivariate Cox regression analysis demonstrated that postoperative SIC was an independent risk factor for both increased recurrence (HR: 2.40, 95% CI, 2.04-2.81, Pâ <â .001) and decreased OS (HR: 2.69, 95% CI, 2.24-3.24, Pâ <â .001). CONCLUSION: The results emphasize that postoperative incomplete conversion of either AFP or PIVKA-II is a significant prognostic marker, indicating a higher risk for adverse oncologic outcomes following HCC resection. This revelation has crucial implications for refining postoperative adjuvant therapy and surveillance strategies for HCC patients.
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USP1 has emerged as a novel and potential target for drug discovery in single therapeutic agents or combination with chemotherapy and molecular targeted therapy. In this study, based on the disclosed structure of ML323 and KSQ-4279, we designed and synthesized a series of pyrido[2,3-d]pyrimidin-7(8H)-one derivatives as potent USP1 inhibitors by cyclization strategy and the systematic structure-activity relationship exploration was conducted. The representative compounds 1k, 1m and 2d displayed excellent USP1/UAF inhibition and exhibited strong antiproliferation effect in NCI-H1299 cells. Further flow cytometry analysis revealed that they could arrest breast cancer cells MDA-MB-436 in the S phase. Inhibition mechanism study of compound 1m indicated these derivatives acted as reversible and noncompetitive USP1 inhibitors. Of note, the combination of compound 1m with PARP inhibitor olaparib generated enhanced cell killing in olaparib-resistant MDA-MB-436/OP cells, and compound 1m exhibited excellent oral pharmacokinetic properties in mice. Overall, our efforts may provide a reliable basis for the development of novel USP1 inhibitor as a single therapeutic agent and in combination with PARP inhibitors.
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Antineoplásicos , Proliferação de Células , Desenho de Fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Pirimidinonas , Humanos , Relação Estrutura-Atividade , Proliferação de Células/efeitos dos fármacos , Antineoplásicos/farmacologia , Antineoplásicos/síntese química , Antineoplásicos/química , Animais , Pirimidinonas/farmacologia , Pirimidinonas/química , Pirimidinonas/síntese química , Estrutura Molecular , Camundongos , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacologia , Inibidores Enzimáticos/síntese química , Inibidores Enzimáticos/química , Proteases Específicas de Ubiquitina/antagonistas & inibidores , Proteases Específicas de Ubiquitina/metabolismoRESUMO
Background: The association of cognitive function, its changes, and all-cause mortality has not reached a consensus, and the independence of the association between changes in cognitive function and mortality remains unclear. The purpose of this study was to evaluate the longitudinal association between baseline cognitive function and cognitive changes over 1 year with subsequent all-cause mortality among the older adults aged 60 and above. Methods: A prospective cohort study utilizing the Community Older Adults Health Survey data. Initiated in 2018, the study annually assessed all individuals aged 60+ in Dalang Town, Dongguan City. Cognitive function was assessed using the Chinese version of the Mini-Mental State Examination (MMSE). A total of 6,042 older adults individuals were included, and multivariate Cox proportional hazard models were used to examine cognitive function's impact on mortality. Results: Participants' median age was 70 years, with 39% men. Over a median 3.08-year follow-up, 525 died. Mortality risk increased by 6% per MMSE score decrease (adjusted HR = 1.06, 95%CI: 1.05-1.08). Compared to those with normal cognitive function at baseline, participants with mild cognitive impairment and moderate to severe cognitive impairment had significantly higher mortality risks (adjusted HR = 1.40, 95%CI: 1.07-1.82; HR = 2.49, 95%CI: 1.91-3.24, respectively). The risk of death was 5% higher for each one-point per year decrease in cognitive function change rate (HR = 1.05, 95%CI: 1.02-1.08). Compared with participants with stable cognitive function, those with rapid cognitive decline had a 79% increased risk of death (adjusted HR = 1.79, 95% CI: 1.11-2.87), with baseline cognitive function influencing this relationship significantly (P for interaction = 0.002). Conclusion: Baseline cognitive impairment and rapid cognitive decline are associated with higher all-cause mortality risks in Chinese older adults. Baseline function influences the mortality impact of cognitive changes.
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Estrogen-related receptor α (ERRα) is considered a very promising target for treating metabolic diseases such as type 2 diabetes. Development of a prediction model to quickly identify potential ERRα agonists can significantly reduce the time spent on virtual screening. In this study, 298 ERRα agonists and numerous nonagonists were collected from various sources to build a new dataset of ERRα agonists. Then a total of 90 models were built using a combination of different algorithms, molecular characterization methods, and data sampling techniques. The consensus model with optimal performance was also validated on the test set (AUC=0.876, BA=0.816) and external validation set (AUC=0.867, BA=0.777) based on five selected baseline models. Furthermore, the model's applicability domain and privileged substructures were examined, and the feature importance was analyzed using the SHAP method to help interpret the model. Based on the above, it's hoped that our publicly accessible data, models, codes, and analytical techniques will prove valuable in quick screening and rational designing more novel and potent ERRα agonists.
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BACKGROUND: Despite the Barcelona Clinic Liver Cancer system discouraging hepatectomy for intermediate/advanced hepatocellular carcinoma, the procedure is still performed worldwide, particularly in Asia. This study aimed to develop and validate nomograms for predicting survival and recurrence for these patients. METHODS: We analyzed patients who underwent curative-intent hepatectomy for intermediate/advanced hepatocellular carcinoma between 2010 and 2020 across 3 Chinese hospitals. The Eastern Hepatobiliary Surgery Hospital cohort was used as the training cohort for the nomogram construction, and the Jilin First Hospital and Fujian Mengchao Hepatobiliary Hospital cohorts served as the external validation cohorts. Independent preoperative predictors for survival and recurrence were identified through univariable and multivariable Cox regression analyses. Predictive accuracy was measured using the concordance index and calibration curves. The predictive performance between nomograms and conventional hepatocellular carcinoma staging systems was compared. RESULTS: A total of 1,328 patients met the inclusion criteria. The nomograms for predicting survival and recurrence were developed using 10 and 6 independent variables, respectively. Nomograms' concordance indices in the training cohort were 0.777 (95% confidence interval 0.759-0.800) and 0.719 (95% confidence interval 0.697-0.742) for survival and recurrence, outperforming 4 conventional staging systems (P < .001). Nomograms accurately stratified risk into low, intermediate, and high subgroups. These results were validated well by 2 external validation cohorts. CONCLUSION: We developed and validated nomograms predicting survival and recurrence for patients with intermediate/advanced hepatocellular carcinoma, contradicting Barcelona Clinic Liver Cancer surgical guidelines. These nomograms may facilitate clinicians to formulate personalized surgical decisions, estimate long-term prognosis, and strategize neoadjuvant/adjuvant anti-recurrence therapy.
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Carcinoma Hepatocelular , Hepatectomia , Neoplasias Hepáticas , Recidiva Local de Neoplasia , Estadiamento de Neoplasias , Nomogramas , Humanos , Neoplasias Hepáticas/cirurgia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/patologia , Carcinoma Hepatocelular/cirurgia , Carcinoma Hepatocelular/mortalidade , Carcinoma Hepatocelular/patologia , Masculino , Feminino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/epidemiologia , Estudos Retrospectivos , Idoso , AdultoRESUMO
Glucose -sensitive delivery systems hold great promise as a therapeutic approach for high-incidence diabetes owing to their ability to release insulin whenever elevated glycemia is detected. However, they are unstable in a hyperglycemic environment, which leads to short-term sustained insulin release. Herein, we designed dually crosslinked insulin polyionic micelles (DCM@insulin) based on triblock polymers of o-glycol and phenylboronic acid-functionalized poly(ethylene glycol)-poly(dimethylamino carbonate)-poly(dimethylamino-trimethylene carbonate) (mPEG-P(AC-co-MPD)-PDMAC and mPEG-P(AC-co-MAPBA)-PDMATC, respectively) for sustained glucose-responsive insulin release. DCM@insulin with a phenylboronic acid ester structure (first crosslinking structure) enhanced glycemic responsiveness by regulating insulin release in a hyperglycemic environment. Additionally, the UV-crosslinking structure (second crosslinking structure) formed by the residual double bonds in AC units endowed DCM@insulin with the ability to effectively protect the loaded insulin against protease degradation and avoid burst release under multiple insulin release. The in vivo findings demonstrated that DCM@insulin effectively maintained glycemic levels (BGLs) within the normal range for 6 h in comparison to single-crosslinked micelles (SCM@insulin). Therefore, the glucose-responsive and dually crosslinked polyionic micelle system exhibits potential as a viable option for the treatment of diabetes.
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Liberação Controlada de Fármacos , Glucose , Insulina , Micelas , Animais , Camundongos , Glicemia/efeitos dos fármacos , Glicemia/metabolismo , Ácidos Borônicos/química , Ácidos Borônicos/farmacologia , Reagentes de Ligações Cruzadas/química , Preparações de Ação Retardada/química , Portadores de Fármacos/química , Glucose/metabolismo , Glucose/química , Insulina/metabolismo , Insulina/administração & dosagem , Insulina/química , Polietilenoglicóis/química , Masculino , Camundongos Endogâmicos BALB CRESUMO
Hepatocellular carcinoma (HCC), the most prevalent malignancy of the digestive tract, is characterized by a high mortality rate and poor prognosis, primarily due to its initial diagnosis at an advanced stage that precludes any surgical intervention. Recent advancements in systemic therapies have significantly improved oncological outcomes for intermediate and advanced-stage HCC, and the combination of locoregional and systemic therapies further facilitates tumor downstaging and increases the likelihood of surgical resectability for initially unresectable cases following conversion therapies. This shift toward high conversion rates with novel, multimodal treatment approaches has become a principal pathway for prolonged survival in patients with advanced HCC. However, the field of conversion therapy for HCC is marked by controversies, including the selection of potential surgical candidates, formulation of conversion therapy regimens, determination of optimal surgical timing, and application of adjuvant therapy post-surgery. Addressing these challenges and refining clinical protocols and research in HCC conversion therapy is essential for setting the groundwork for future advancements in treatment strategies and clinical research. This narrative review comprehensively summarizes the current strategies and clinical experiences in conversion therapy for advanced-stage HCC, emphasizing the unresolved issues and the path forward in the context of precision medicine. This work not only provides a comprehensive overview of the evolving landscape of treatment modalities for conversion therapy but also paves the way for future studies and innovations in this field.
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Carcinoma Hepatocelular , Neoplasias Hepáticas , Medicina de Precisão , Humanos , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/patologia , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/patologia , Medicina de Precisão/métodos , Terapia Combinada , Estadiamento de Neoplasias , HepatectomiaRESUMO
BACKGROUND: The burgeoning demand for hepatectomy in elderly patients with hepatocellular carcinoma (HCC) necessitates improved perioperative care. Geriatric populations frequently experience functional decline and frailty, predisposing them to adverse postoperative outcomes. The Barthel Index serves as a reliable measure for assessing functional capacity, and this study evaluates its impact on surgical textbook outcomes (TOs) in elderly HCC patients. METHODS: A multicenter retrospective cohort study analyzed elderly patients (≥70 years) following hepatectomy for HCC between 2013 and 2021. Utilizing a Barthel Index cut-off value of 85, patients were divided into two groups: with and without preoperative functional decline and frailty. The primary outcome was the rate of TO, encompassing seven criteria. TO rates were compared between groups, and multivariate logistic regression analyses identified independent risks for achieving TOs. RESULTS: Of 497 elderly patients, 157 (31.6 â%) exhibited preoperative functional decline and frailty (Barthel Index score <85). The overall TO rate was 58.6 â%. Patients with preoperative Barthel Index score <85 had significantly lower TO rates compared to patients with score ≥85 (29.3 â% vs. 72.1 â%, P â< â0.001). Multivariate analysis revealed preoperative Barthel Index score <85 as an independent risk for achieving TO (odds ratio 3.413, 95 â% confidence interval 1.879-6.198, P â< â0.001). Comparable results were observed in the subgroups of patients undergoing open and laparoscopic hepatectomy. CONCLUSION: Preoperative Barthel Index-based assessment of functional decline and frailty significantly predicts TOs following hepatectomy in elderly HCC patients, enabling identification of high-risk patients and informing preoperative management and postoperative care within geriatric oncology.
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Injectable hydrogels based on biopolymers, fabricated utilizing diverse chemical and physical methodologies, exhibit exceptional physical, chemical, and biological properties. They have multifaceted applications encompassing wound healing, tissue regeneration, and across diverse scientific realms. This review critically evaluates their largely uncharted potential in ophthalmology, elucidating their diverse applications across an array of ocular diseases. These conditions include glaucoma, cataracts, corneal disorders (spanning from age-related degeneration to trauma, infections, and underlying chronic illnesses), retina-associated ailments (such as diabetic retinopathy, retinitis pigmentosa, and age-related macular degeneration (AMD)), eyelid abnormalities, and uveal melanoma (UM). This study provides a thorough analysis of applications of injectable hydrogels based on biopolymers across these ocular disorders. Injectable hydrogels based on biopolymers can be customized to have specific physical, chemical, and biological properties that make them suitable as drug delivery vehicles, tissue scaffolds, and sealants in the eye. For example, they can be engineered to have optimum viscosity to be injected intravitreally and sustain drug release to treat retinal diseases. Their porous structure and biocompatibility promote cellular infiltration to regenerate diseased corneal tissue. By accentuating their indispensable role in ocular disease treatment, this review strives to present innovative and targeted approaches in this domain, thereby advancing ocular therapeutics.
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Oftalmopatias , Hidrogéis , Hidrogéis/química , Humanos , Biopolímeros/química , Oftalmopatias/tratamento farmacológico , Animais , Sistemas de Liberação de Medicamentos , Injeções , Materiais Biocompatíveis/químicaRESUMO
Background: Linear associations between circulating insulin-like growth factor-1 (IGF-1) levels and Parkinson's disease (PD) have been evidenced in observational studies. Yet, the causal relationship between IGF-1 levels and PD remains obscure. We conducted Mendelian randomization to examine the correlation between genetically predicted IGF-1 levels and PD. Methods: By reviewing genome-wide association studies (GWAS) that are publicly accessible, we uncovered SNPs linked to both serum concentrations of IGF-1 and PD. A two-sample Mendelian randomization (MR) analysis was carried out to evaluate the individual effect of IGF-1 on PD. Results: In a primary causal effects model in MR analysis, employing the inverse-variance weighted (IVW) method, IGF-1 levels exhibited a notable association with the risk of PD (OR, 1.020, 95% CI, 1.003-1.038, p = 0.0215). Multiple evaluations revealed that horizontal pleiotropy was improbable to distort the main results (MR-Egger: P PD intercept =0.719), and no bias was detected by leave-one-out analysis. Conclusion: This study unearthed evidence indicating that heightened IGF-1 levels might be causally correlated with an increased risk of PD.
RESUMO
To address the problem of poor entity recognition performance caused by the lack of Chinese annotation in clinical electronic medical records, this paper proposes a multi-medical entity recognition method F-MNER using a fusion technique combining BART, Bi-LSTM, and CRF. First, after cleaning, encoding, and segmenting the electronic medical records, the obtained semantic representations are dynamically fused using a bidirectional autoregressive transformer (BART) model. Then, sequential information is captured using a bidirectional long short-term memory (Bi-LSTM) network. Finally, the conditional random field (CRF) is used to decode and output multi-task entity recognition. Experiments are performed on the CCKS2019 dataset, with micro avg Precision, macro avg Recall, weighted avg Precision reaching 0.880, 0.887, and 0.883, and micro avg F1-score, macro avg F1-score, weighted avg F1-score reaching 0.875, 0.876, and 0.876 respectively. Compared with existing models, our method outperforms the existing literature in three evaluation metrics (micro average, macro average, weighted average) under the same dataset conditions. In the case of weighted average, the Precision, Recall, and F1-score are 19.64%, 15.67%, and 17.58% higher than the existing BERT-BiLSTM-CRF model respectively. Experiments are performed on the actual clinical dataset with our MF-MNER, the Precision, Recall, and F1-score are 0.638, 0.825, and 0.719 under the micro-avg evaluation mechanism. The Precision, Recall, and F1-score are 0.685, 0.800, and 0.733 under the macro-avg evaluation mechanism. The Precision, Recall, and F1-score are 0.647, 0.825, and 0.722 under the weighted avg evaluation mechanism. The above results show that our method MF-MNER can integrate the advantages of BART, Bi-LSTM, and CRF layers, significantly improving the performance of downstream named entity recognition tasks with a small amount of annotation, and achieving excellent performance in terms of recall score, which has certain practical significance. Source code and datasets to reproduce the results in this paper are available at https://github.com/xfwang1969/MF-MNER .
Assuntos
Registros Eletrônicos de Saúde , China , Algoritmos , Humanos , Redes Neurais de Computação , Semântica , População do Leste AsiáticoRESUMO
Meisoindigo (Mei) has long been recognized in chronic myeloid leukemia (CML) treatment. To elucidate its molecular target and mechanisms, we embarked on designing and synthesizing a series of Mei-derived PROTACs. Through this endeavor, VHL-type PROTAC 9b was identified to be highly cytotoxic against SW620, SW480, and K562 cells. Employing DiaPASEF-based quantitative proteomic analysis, in combination with extensive validation assays, we unveiled that 9b potently and selectively degraded ATM across SW620 and SW480 cells in a ubiquitin-proteasome-dependent manner. 9b-induced selective ATM degradation prompted DNA damage response cascades, thereby leading to the cell cycle arrest and cell apoptosis. This pioneering discovery renders the advent of ATM degradation for anti-cancer therapy. Notably, 9b-induced ATM degradation synergistically enhanced the efficacy of ATR inhibitor AZD6738 both in vitro and in vivo. This work establishes the synthetic lethality-inducing properties of ATR inhibitors in the ATM-deficient context, thereby providing new avenues to innovative therapies for colorectal cancer.