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As part of the NIH Helping to End Addiction Long-term (HEAL) Initiative, the National Center for Advancing Translational Sciences is dedicated to the development of new pharmacological tools and investigational drugs for managing and treating pain as well as the prevention and treatment of opioid misuse and addiction. In line with these objectives, we created a comprehensive, annotated small molecule library including drugs, probes, and tool compounds that act on published pain- and addiction-relevant targets. Nearly 3000 small molecules associated with approximately 200 known and hypothesized HEAL targets have been assembled, curated, and annotated in one collection. Physical samples of the library compounds have been acquired and plated in 1536-well format, enabling a rapid and efficient high-throughput screen against a wide range of assays. The creation of the HEAL Targets and Compounds Library, coupled with an integrated computational platform for AI-driven machine learning, structural modeling, and virtual screening, provides a valuable source for strategic drug repurposing, innovative profiling, and hypothesis testing of novel targets related to pain and opioid use disorder (OUD). The library is available to investigators for screening pain and OUD-relevant phenotypes.
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Background: The effect of diagnosing Graves' ophthalmopathy (GO) through traditional measurement and observation in medical imaging is not ideal. This study aimed to develop and validate deep learning (DL) models that could be applied to the diagnosis of GO based on magnetic resonance imaging (MRI) and compare them to traditional measurement and judgment of radiologists. Methods: A total of 199 clinically verified consecutive GO patients and 145 normal controls undergoing MRI were retrospectively recruited, of whom 240 were randomly assigned to the training group and 104 to the validation group. Areas of superior, inferior, medial, and lateral rectus muscles and all rectus muscles on coronal planes were calculated respectively. Logistic regression models based on areas of extraocular muscles were built to diagnose GO. The DL models named ResNet101 and Swin Transformer with T1-weighted MRI without contrast as input were used to diagnose GO and the results were compared to the radiologist's diagnosis only relying on MRI T1-weighted scans. Results: Areas on the coronal plane of each muscle in the GO group were significantly greater than those in the normal group. In the validation group, the areas under the curve (AUCs) of logistic regression models by superior, inferior, medial, and lateral rectus muscles and all muscles were 0.897 [95% confidence interval (CI): 0.833-0.949], 0.705 (95% CI: 0.598-0.804), 0.799 (95% CI: 0.712-0.876), 0.681 (95% CI: 0.567-0.776), and 0.905 (95% CI: 0.843-0.955). ResNet101 and Swin Transformer achieved AUCs of 0.986 (95% CI: 0.977-0.994) and 0.936 (95% CI: 0.912-0.957), respectively. The accuracy, sensitivity, and specificity of ResNet101 were 0.933, 0.979, and 0.869, respectively. The accuracy, sensitivity, and specificity of Swin Transformer were 0.851, 0.817, and 0.898, respectively. The ResNet101 model yielded higher AUC than models of all muscles and radiologists (0.986 vs. 0.905, 0.818; P<0.001). Conclusions: The DL models based on MRI T1-weighted scans could accurately diagnose GO, and the application of DL systems in MRI may improve radiologists' performance in diagnosing GO and early detection.
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Cyclin-dependent kinases 4 and 6 (CDK4/6) play a pivotal role in cell cycle and cancer development. Targeting CDK4/6 has demonstrated promising effects against breast cancer. However, resistance to CDK4/6 inhibitors (CDK4/6i), such as palbociclib, remains a substantial challenge in clinical settings. Using high-throughput combinatorial drug screening and genomic sequencing, we find that the microphthalmia-associated transcription factor (MITF) is activated via O-GlcNAcylation by O-GlcNAc transferase (OGT) in palbociclib-resistant breast cancer cells and tumors. Mechanistically, O-GlcNAcylation of MITF at Serine 49 enhances its interaction with importin α/ß, thus promoting its translocation to nuclei, where it suppresses palbociclib-induced senescence. Inhibition of MITF or its O-GlcNAcylation re-sensitizes resistant cells to palbociclib. Moreover, clinical studies confirm the activation of MITF in tumors from patients who are palbociclib-resistant or undergoing palbociclib treatment. Collectively, our studies shed light on the mechanism regulating palbociclib resistance and present clinical evidence for developing therapeutic approaches to treat CDK4/6i-resistant breast cancer patients.
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Neoplasias da Mama , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Resistencia a Medicamentos Antineoplásicos , Fator de Transcrição Associado à Microftalmia , N-Acetilglucosaminiltransferases , Piperazinas , Piridinas , Humanos , Quinase 4 Dependente de Ciclina/metabolismo , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Neoplasias da Mama/metabolismo , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Quinase 6 Dependente de Ciclina/metabolismo , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Fator de Transcrição Associado à Microftalmia/metabolismo , Fator de Transcrição Associado à Microftalmia/genética , Feminino , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Piperazinas/farmacologia , Piridinas/farmacologia , Linhagem Celular Tumoral , N-Acetilglucosaminiltransferases/metabolismo , N-Acetilglucosaminiltransferases/antagonistas & inibidores , N-Acetilglucosaminiltransferases/genética , Animais , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Preparation requires technical research and development, as well as adaptive, proactive governance.
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The eruption of primary teeth is a basic event during physical development of children, which is affected by heredity and environment. This study aimed to analyze the changes in primary teeth eruption among Chinese children with social development. A total of 249,264 healthy children under 2 years were extracted from the 1995, 2005, and 2015 National Survey on the Physical Growth and Development of Children in Nine Cities of China. Their primary teeth were examined and percentiles of primary teeth eruption age were calculated by probit analysis. The median primary teeth eruption age were 6.8 months, 6.7 months, 6.6 months in 1995, 2005 and 2015. Primary teeth eruption age of boys was 0.2 months, 0.3 months, 0.3 months earlier than that of girls in 1995, 2005 and 2015. Primary teeth eruption age was the earliest in children from northern region and was the latest in children from southern region, and this regional difference did not change over time. These findings suggest that primary teeth eruption age slightly advanced with social development, and their gender difference and regional difference have always existed, which supplied some data for understanding the secular trend of primary teeth development in stomatology, pediatrics, anthropology, and other related fields.
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Exantema , Erupção Dentária , Masculino , Lactente , Feminino , Humanos , Criança , Pré-Escolar , Recém-Nascido , Estudos Transversais , China/epidemiologia , Cidades , Dente Decíduo , Fatores EtáriosRESUMO
Objective: This study aimed to analyze the growth patterns of height and foot length (FL) among Chinese children aged 3-18 and examine their associations with puberty development. Methods: A cross-sectional survey was conducted in September 2022 in Beijing. Data were collected through questionnaires and on-site physical examinations. The growth patterns and velocity of height and FL in different age groups were described, and their associations with puberty development were analyzed. Results: From an age perspective, the peak FL growth occurred between 9 and 11 years (boys were 11 years and girls were 9 years), while the peak height growth occurred at 11 ~ 13 years for boys and 9 ~ 11 years for girls. Additionally, boys and girls reached 99.0% of their final FL at the ages of 14 and 13, respectively, while they reached 99.0% of their final height at the ages of 16 and 15, respectively. From the perspective of Tanner stage, the age of peak FL growth in boys coincided with the age of the G2 stage, while in girls it occurred slightly earlier than the mean age of the B2 stage. The peak height growth for both boys and girls occurred between Tanner stages 2 and 3. Conclusion: Boys and girls reach their peak FL growth at 11 and 9 years old, respectively, which were both 2 years earlier than their peak height growth. The peak FL growth occurred around the onset of puberty, while the peak height growth occurred between Tanner stages 2 and 3.
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Estatura , Puberdade , Masculino , Criança , Feminino , Humanos , Estudos Transversais , ChinaRESUMO
Background: Clinical appearance and high-frequency ultrasound (HFUS) are indispensable for diagnosing skin diseases by providing internal and external information. However, their complex combination brings challenges for primary care physicians and dermatologists. Thus, we developed a deep multimodal fusion network (DMFN) model combining analysis of clinical close-up and HFUS images for binary and multiclass classification in skin diseases. Methods: Between Jan 10, 2017, and Dec 31, 2020, the DMFN model was trained and validated using 1269 close-ups and 11,852 HFUS images from 1351 skin lesions. The monomodal convolutional neural network (CNN) model was trained and validated with the same close-up images for comparison. Subsequently, we did a prospective and multicenter study in China. Both CNN models were tested prospectively on 422 cases from 4 hospitals and compared with the results from human raters (general practitioners, general dermatologists, and dermatologists specialized in HFUS). The performance of binary classification (benign vs. malignant) and multiclass classification (the specific diagnoses of 17 types of skin diseases) measured by the area under the receiver operating characteristic curve (AUC) were evaluated. This study is registered with www.chictr.org.cn (ChiCTR2300074765). Findings: The performance of the DMFN model (AUC, 0.876) was superior to that of the monomodal CNN model (AUC, 0.697) in the binary classification (P = 0.0063), which was also better than that of the general practitioner (AUC, 0.651, P = 0.0025) and general dermatologists (AUC, 0.838; P = 0.0038). By integrating close-up and HFUS images, the DMFN model attained an almost identical performance in comparison to dermatologists (AUC, 0.876 vs. AUC, 0.891; P = 0.0080). For the multiclass classification, the DMFN model (AUC, 0.707) exhibited superior prediction performance compared with general dermatologists (AUC, 0.514; P = 0.0043) and dermatologists specialized in HFUS (AUC, 0.640; P = 0.0083), respectively. Compared to dermatologists specialized in HFUS, the DMFN model showed better or comparable performance in diagnosing 9 of the 17 skin diseases. Interpretation: The DMFN model combining analysis of clinical close-up and HFUS images exhibited satisfactory performance in the binary and multiclass classification compared with the dermatologists. It may be a valuable tool for general dermatologists and primary care providers. Funding: This work was supported in part by the National Natural Science Foundation of China and the Clinical research project of Shanghai Skin Disease Hospital.
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OBJECTIVES: To investigate whether the integration of high-frequency ultrasound (HFUS) to routine clinical examinations could improve diagnostic performance and management decision for pigmented skin tumors. METHODS: Three general practitioners trained previously and a dermatologist independently assessed pigmented skin tumors and rendered management decision based on clinical examinations alone or clinical examinations integrating HFUS. RESULTS: After integrating HFUS, the diagnostic area under the curve (AUC) (0.658-0.693 versus 0.848, all P < .05) and specificity (46.6-58.6% versus 89.7%, all P < .05) for pigmented skin malignancies were improved for general practitioners, meanwhile unnecessary biopsy rate reduced (42.9-53.6% versus 10.7%, P < .001). To the dermatologist, the diagnostic AUC (0.822 versus 0.949, P < .001), sensitivity (81.7% versus 96.7%, P = .012) and specificity (0.828 versus 0.931, P = .031) improved significantly, meanwhile both missed biopsy rate (14.5% versus 4.8%, P = .031) and unnecessary biopsy rate (19.6% versus 7.1%, P = .016) decreased. Additionally, the diagnostic performance of the general practitioner with integrating HFUS could be comparable with the dermatologist based on clinical examinations alone (all P > .05). CONCLUSIONS: As a complementary tool of clinical examinations, HFUS could help physicians differentiate pigmented skin malignancies and manage decision.
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Melanoma , Neoplasias Cutâneas , Humanos , Sensibilidade e Especificidade , Neoplasias Cutâneas/diagnóstico por imagem , Neoplasias Cutâneas/patologia , Biópsia , UltrassonografiaRESUMO
PURPOSE: To explore the feasibility of a 5G-based telerobotic ultrasound (US) system for providing qualified abdominal US services on a rural island. METHODS: This prospective study involved two medical centers (the tele-radiologist site's hospital and the patient site's hospital) separated by 72 km. Patients underwent 5G-based telerobotic US by tele-radiologists and conventional US by on-site radiologists from September 2020 to March 2021. The clinical feasibility and diagnostic performance of the 5G-based telerobotic abdominal US examination were assessed based on safety, duration, image quality, diagnostic findings, and questionnaires. RESULTS: A total of 401 patients (217 women and 184 men; mean age, 54.96 ± 15.43 years) were enrolled. A total of 90.1% of patients indicated no discomfort with the telerobotic US examination. For the examination duration, telerobotic US took longer than conventional US (12.54 ± 3.20 min vs. 7.23 ± 2.10 min, p = 0.001). For image quality scores, the results of the two methods were similar (4.54 ± 0.63 vs. 4.57 ± 0.61, p = 0.112). No significant differences were found between the two methods in measurements for the aorta, portal vein, gallbladder, kidney (longitudinal diameter), prostate, and uterus; however, telerobotic US underestimated the transverse diameter of the kidney (p < 0.05). A total of 504 positive results, including 31 different diseases, were detected. Among them, 455 cases were identified by the two methods; 17 cases were identified by telerobotic US only; and 32 cases were identified by conventional US only. There was good consistency in the diagnosis of 29 types of disease between the two methods (κ = 0.773-1.000). Furthermore, more than 90% of patients accepted the telerobotic US examination and agreed to pay additional fees in future. CONCLUSION: The 5G-based telerobotic US system can expand access to abdominal US services for patients in rural areas, thereby reducing health care disparities.
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Robótica , Masculino , Humanos , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Estudos Prospectivos , Robótica/métodos , Ultrassonografia , Abdome/diagnóstico por imagem , RimRESUMO
Cyclin-dependent kinases 4 and 6 (CDK4/6) play a pivotal role in cell cycle and cancer development. Targeting CDK4/6 has demonstrated promising effects against breast cancer. However, resistance to CDK4/6 inhibitors (CDK4/6i), such as palbociclib, remains a substantial challenge in clinical settings. Using high-throughput combinatorial drug screening and genomic sequencing, we found that the microphthalmia-associated transcription factor (MITF) is activated via O-GlcNAcylation by O-GlcNAc transferase (OGT) in palbociclib-resistant breast cancer cells and tumors; O-GlcNAcylation of MITF at Serine 49 enhanced its interaction with importin α/ß, thus promoting its translocation to nuclei, where it suppressed palbociclib-induced senescence; inhibition of MITF or its O-GlcNAcylation re-sensitized resistant cells to palbociclib. Remarkably, clinical studies confirmed the activation of MITF in tumors from patients who are palbociclib-resistant or undergoing palbociclib treatment. Collectively, our studies shed light on a novel mechanism regulating palbociclib-resistance, and present clinical evidence for developing therapeutic approaches to treat CDK4/6i-resistant breast cancer patients.
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Background: Anaplastic thyroid cancer (ATC) is uniformly lethal. BRAFV600E mutation is present in 45% of patients with ATC. Targeted therapy with combined BRAF and MEK inhibition in BRAFV600E-mutant ATC can be effective, but acquired resistance is common because this combination targets the same pathway. Drug matrix screening, in BRAFV600E ATC cells, of highly active compounds in combination with BRAF inhibition showed multitargeting tyrosine kinase inhibitors (MTKIs) had the highest synergistic/additive activity. Thus, we hypothesized that the combination of BRAFV600E inhibition and an MTKI is more effective than a single drug or combined BRAF and MEK inhibition in BRAFV600E-mutant ATC. We evaluated the effect of BRAFV600E inhibitors in combination with the MTKI axitinib and its mechanism(s) of action. Methods: We evaluated the effects of BRAFV600E inhibitors and axitinib alone and in combination in in vitro and in vivo models of BRAFV600E-mutant and wild-type ATC. Results: The combination of axitinib and BRAFV600E inhibitors (dabrafenib and PLX4720) showed an additive effect on inhibiting cell proliferation based on the Chou-Talalay algorithm in BRAFV600E-mutant ATC cell lines. This combination also significantly inhibited cell invasion and migration (p < 0.001) compared with the control. Dabrafenib and PLX4720 arrested ATC cells in the G0/G1 phase. Axitinib arrested ATC cells in the G2/M phase by decreasing phosphorylation of aurora kinase B (Thr232) and histone H3 (Ser10) proteins and by upregulating the c-JUN signaling pathway. The combination of BRAF inhibition and axitinib significantly inhibited tumor growth and was associated with improved survival in an orthotopic ATC model. Conclusions: The novel combination of axitinib and BRAFV600E inhibition enhanced anticancer activity in in vitro and in vivo models of BRAFV600E-mutant ATC. This combination may have clinical utility in BRAFV600E-mutant ATC that is refractory to current standard therapy, namely combined BRAF and MEK inhibition.
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Carcinoma Anaplásico da Tireoide , Neoplasias da Glândula Tireoide , Humanos , Carcinoma Anaplásico da Tireoide/tratamento farmacológico , Carcinoma Anaplásico da Tireoide/genética , Carcinoma Anaplásico da Tireoide/patologia , Axitinibe/farmacologia , Axitinibe/uso terapêutico , Proteínas Proto-Oncogênicas B-raf/genética , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/metabolismo , Inibidores de Proteínas Quinases/farmacologia , Inibidores de Proteínas Quinases/uso terapêutico , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/uso terapêutico , Mutação , Linhagem Celular TumoralRESUMO
BACKGROUND: A more comprehensive assessment of growth and nutrition in children is required in China due to rapid socioeconomic processes. We aimed to investigate height and body mass index (BMI) trajectories from 1975 to 2015 and the prevalence of stunting and obesity in 2016 among children in Chinese cities. METHODS: A total of 904,263 children from birth to 6.9 years were collected from a series of nationally representative surveys in China. Height and BMI trajectories and prevalence of stunting, underweight, overweight and obesity were assessed. RESULTS: The average height level of Chinese urban children under 7 years presented a positive secular trend from 1975 to 2015; however, a slowing tendency occurred in 2005â2015. An apparent increase was observed at the 5th, 50th and 95th percentiles of BMI in urban children aged 3 years and older, with a more prominent increase at the 95th percentile. The total prevalence of stunting and underweight under 7 years was 1.4% and 2.0%, respectively. The total prevalence of overweight and obesity under 7 years was 12.6% and 4.3%, respectively, with 12.7% and 4.9% for boys, 12.6% and 3.6% for girls, 12.1% and 4.0% in urban areas and 13.1% and 4.5% in suburban rural areas. CONCLUSIONS: The average height level of Chinese urban children has reached World Health Organization child growth standards since 2005 and presented a slowing tendency in secular trend in 2005â2015. More attention and efforts and public health interventions should be urgently made to combat overweight and obesity among preschool children. Video Abstract.
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OBJECTIVE: This study aimed to evaluate the diagnostic performance of machine learning (ML)-based ultrasound (US) radiomics models for risk stratification of gallbladder (GB) masses. METHODS: We prospectively examined 640 pathologically confirmed GB masses obtained from 640 patients between August 2019 and October 2022 at four institutions. Radiomics features were extracted from grayscale US images and germane features were selected. Subsequently, 11 ML algorithms were separately used with the selected features to construct optimum US radiomics models for risk stratification of the GB masses. Furthermore, we compared the diagnostic performance of these models with the conventional US and contrast-enhanced US (CEUS) models. RESULTS: The optimal XGBoost-based US radiomics model for discriminating neoplastic from non-neoplastic GB lesions showed higher diagnostic performance in terms of areas under the curves (AUCs) than the conventional US model (0.822-0.853 vs. 0.642-0.706, p < 0.05) and potentially decreased unnecessary cholecystectomy rate in a speculative comparison with performing cholecystectomy for lesions sized over 10 mm (2.7-13.8% vs. 53.6-64.9%, p < 0.05) in the validation and test sets. The AUCs of the XGBoost-based US radiomics model for discriminating carcinomas from benign GB lesions were higher than the conventional US model (0.904-0.979 vs. 0.706-0.766, p < 0.05). The XGBoost-US radiomics model performed better than the CEUS model in discriminating GB carcinomas (AUC: 0.995 vs. 0.902, p = 0.011). CONCLUSIONS: The proposed ML-based US radiomics models possess the potential capacity for risk stratification of GB masses and may reduce the unnecessary cholecystectomy rate and use of CEUS. CLINICAL RELEVANCE STATEMENT: The machine learning-based ultrasound radiomics models have potential for risk stratification of gallbladder masses and may potentially reduce unnecessary cholecystectomies. KEY POINTS: ⢠The XGBoost-based US radiomics models are useful for the risk stratification of GB masses. ⢠The XGBoost-based US radiomics model is superior to the conventional US model for discriminating neoplastic from non-neoplastic GB lesions and may potentially decrease unnecessary cholecystectomy rate for lesions sized over 10 mm in comparison with the current consensus guideline. ⢠The XGBoost-based US radiomics model could overmatch CEUS model in discriminating GB carcinomas from benign GB lesions.
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Carcinoma , Doenças da Vesícula Biliar , Neoplasias da Vesícula Biliar , Humanos , Estudos Prospectivos , Meios de Contraste , Neoplasias da Vesícula Biliar/diagnóstico por imagem , Aprendizado de Máquina , Medição de Risco , Estudos RetrospectivosRESUMO
Recent Alzheimer's research has shown increasing interest in the caspase-2 (Casp2) enzyme. However, the available Casp2 inhibitors, which have been pentapeptides or peptidomimetics, face challenges for use as CNS drugs. In this study, we successfully screened a 1920-compound chloroacetamide-based, electrophilic fragment library from Enamine. Our two-point dose screen identified 64 Casp2 hits, which were further evaluated in a ten-point dose-response study to assess selectivity over Casp3. We discovered compounds with inhibition values in the single-digit micromolar and sub-micromolar range, as well as up to 32-fold selectivity for Casp2 over Casp3. Target engagement analysis confirmed the covalent-irreversible binding of the selected fragments to Cys320 at the active site of Casp2. Overall, our findings lay a strong foundation for the future development of small-molecule Casp2 inhibitors.
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Caspase 2 , Inibidores de Caspase , Caspase 2/metabolismo , Caspase 3/metabolismo , Domínio Catalítico , Inibidores de Caspase/químicaRESUMO
OBJECTIVE: Ultrasound (US) plays an important role in the diagnosis and management of breast diseases; however, effective breast US screening is lacking in rural and remote areas. To alleviate this issue, we prospectively evaluated the clinical availability of 5G-based telerobotic US technology for breast examinations in rural and remote areas. METHODS: Between September 2020 and March 2021, 63 patients underwent conventional and telerobotic US examinations in a rural island (Scenario A), while 20 patients underwent telerobotic US examination in a mobile car located in a remote county (Scenario B) in May 2021. The safety, duration, US image quality, consistency, and acceptability of the 5G-based telerobotic US were assessed. RESULTS: In Scenario A, the average duration of the telerobotic US procedure was longer than that of conventional US (10.3 ± 3.3 min vs. 7.6 ± 3.0 min, p = 0.017), but their average imaging scores were similar (4.86 vs. 4.90, p = 0.159). Two cases of gynecomastia, one of lactation mastitis, and one of postoperative breast effusion were diagnosed and 32 nodules were detected using the two US methods. There was good interobserver agreement between the US features and BI-RADS categories of the identical nodules (ICC = 0.795-1.000). In Scenario B, breast nodules were detected in 65% of the patients using telerobotic US. Its average duration was 10.1 ± 2.3 min, and the average imaging score was 4.85. Overall, 90.4% of the patients were willing to choose telerobotic US in the future, and tele-sonologists were satisfied with 85.5% of the examinations. CONCLUSION: The 5G-based telerobotic US system is feasible for providing effective breast examinations in rural and remote areas.
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BACKGROUND: The similar visual appearance of superficial basal cell carcinoma (sBCC) and Bowen's disease (BD) may cause confusion for diagnosis. OBJECTIVE: The aim of the study was to investigate the value of ultra-high-frequency ultrasound (uHFUS) in differentiating sBCC from BD. MATERIALS AND METHODS: This prospective study included a pilot cohort of 110 patients (73 BDs and 37 sBCCs) from November 2016 to October 2020 and a validation cohort of 42 patients (30 BDs and 12 sBCCs) from July 2021 to December 2021. Clinical and uHFUS features of pathologically confirmed sBCC and BD were assessed. A predictive model was developed based on the uHFUS features of the pilot cohort. Subsequently, the model was validated and compared with clinical diagnosis in the validation cohort. RESULTS: uHFUS features with significant differences between sBCC and BD included lesion surface, skin layer involvement, hyperkeratosis, and hyperechoic spots (all p < 0.05). A prediction model based on the above features was established to identify sBCC and BD in the pilot and validation cohorts with areas under the curve (AUC) of 0.908 and 0.923, sensitivity of 82.3% and 83.3%, specificity of 91.9% and 91.7%, and accuracy of 85.5% and 85.7%, respectively, which were significantly higher than those obtained by clinical diagnosis based on photographic pictures of lesions, with the AUC of 0.692, sensitivity of 63.3%, specificity of 75.3%, and accuracy of 66.7% (all p < 0.05). CONCLUSION: uHFUS provides detailed internal features of sBCC and BD, which facilitates the differentiation between sBCC and BD, and its diagnostic performance is superior to clinical diagnosis.
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Doença de Bowen , Carcinoma Basocelular , Neoplasias Cutâneas , Humanos , Neoplasias Cutâneas/patologia , Estudos Prospectivos , Doença de Bowen/diagnóstico por imagem , Carcinoma Basocelular/patologia , Diferenciação CelularRESUMO
BACKGROUND: INTERGROWTH-21st Newborn Cross-Sectional Study (NCSS) charts were established and recommended for global application. However, whether one international reference is appropriate for all populations is still unclear. We aim to compare the updated Chinese birth size charts by gestational age with INTERGROWTH-21st NCSS charts. METHODS: A cross-sectional survey was carried out, and the birth weight, length and head circumference of 24,375 infants born after uncomplicated pregnancies at gestational age ranging from 24+0 to 42+6 weeks were measured in 13 cities in China from 2015 to 2018. Growth charts were constructed. The measurements of all these infants were evaluated by the methods of calculating their Z scores using the INTERGROWTH-21st standards. The prevalence of small for gestational age (SGA) and large for gestational age (LGA) based on birth weight was analyzed using Chinese charts and INTERGROWTH-21st charts. RESULTS: The mean Z scores were 0.10 for birth weight, 0.35 for length and - 0.02 for head circumference. Compared to the INTERGROWTH-21st charts, the Chinese birth weight percentile curves were higher except for the 90th percentile at 29-37 weeks gestational age, and the length percentile curves were higher after 33 weeks gestational age, while the 10th percentile of the head circumference was lower and the other percentiles were similar. The prevalence of SGA was 10.1% [95% confidence interval (CI) = 9.7%-10.5%] using the Chinese birth weight chart and 6.5% (95% CI = 6.2%-6.8%) using the INTERGROWTH-21st birth weight chart. The prevalence of LGA was 9.9% (95% CI = 9.5%-10.2%) and 8.2% (95% CI = 7.9%-8.6%) using the Chinese and INTERGROWTH-21st birth weight charts, respectively. CONCLUSIONS: Chinese birth size charts based on infants born after uncomplicated pregnancies were different from the INTERGROWTH-21st charts. Differences in the classification of newborns by the two charts should receive attention, and whether the application of INTERGROWTH-21st in Chinese newborns will lead to misclassification needs to be validated in future clinical practice.
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Recém-Nascido Pequeno para a Idade Gestacional , Gravidez , Lactente , Feminino , Recém-Nascido , Humanos , Peso ao Nascer , Idade Gestacional , Estudos Transversais , China/epidemiologiaRESUMO
BACKGROUND: Adrenocortical cancer (ACC) is a rare and aggressive cancer with dismal 5-year survival due to a lack of effective treatments. We aimed to identify a new effective combination of drugs and investigated their synergistic efficacy in ACC preclinical models. METHODS: A quantitative high-throughput drug screening of 4,991 compounds was performed on two ACC cell lines, SW13 and NCI-H295R, based on antiproliferative effect and caspase-3/7 activity. The top candidate drugs were pairwise combined to identify the most potent combinations. The synergistic efficacy of the selected inhibitors was tested on tumorigenic phenotypes, such as cell proliferation, migration, invasion, spheroid formation, and clonogenicity, with appropriate mechanistic validation by cell cycle and apoptotic assays and protein expression of the involved molecules. We tested the efficacy of the drug combination in mice with luciferase-tagged human ACC xenografts. To study the mRNA expression of target molecules in ACC and their clinical correlations, we analyzed the Gene Expression Omnibus and The Cancer Genome Atlas. RESULTS: We chose the maternal embryonic leucine zipper kinase (MELK) inhibitor (OTS167) and cyclin-dependent kinase (CDK) inhibitor (RGB-286638) because of their potent synergy from the pairwise drug combination matrices derived from the top 30 single drugs. Multiple publicly available databases demonstrated overexpression of MELK, CDK1/2, and partnering cyclins mRNA in ACC, which were independently associated with mortality and other adverse clinical features. The drug combination demonstrated a synergistic antiproliferative effect on ACC cells. Compared to the single-agent treatment groups, the combination treatment increased G2/M arrest, caspase-dependent apoptosis, reduced cyclins A2, B1, B2, and E2 expression, and decreased cell migration and invasion with reduced vimentin. Moreover, the combination effectively decreased Foxhead Box M1, Axin2, glycogen synthase kinase 3-beta, and ß-catenin. A reduction in p-stathmin from the combination treatment destabilized microtubule assembly by tubulin depolymerization. The drug combination treatment in mice with human ACC xenografts resulted in a significantly lower tumor burden than those treated with single-agents and vehicle control groups. CONCLUSIONS: Our preclinical study revealed a novel synergistic combination of OTS167 and RGB-286638 in ACC that effectively targets multiple molecules associated with ACC aggressiveness. A phase Ib/II clinical trial in patients with advanced ACC is therefore warranted.
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Neoplasias do Córtex Suprarrenal , Carcinoma Adrenocortical , Neoplasias do Córtex Suprarrenal/tratamento farmacológico , Neoplasias do Córtex Suprarrenal/genética , Neoplasias do Córtex Suprarrenal/metabolismo , Carcinoma Adrenocortical/tratamento farmacológico , Carcinoma Adrenocortical/genética , Carcinoma Adrenocortical/metabolismo , Animais , Apoptose , Caspase 3 , Linhagem Celular Tumoral , Proliferação de Células , Quinases Ciclina-Dependentes , Ciclinas , Pontos de Checagem da Fase G2 do Ciclo Celular , Quinase 3 da Glicogênio Sintase/farmacologia , Quinase 3 da Glicogênio Sintase/uso terapêutico , Humanos , Camundongos , Proteínas Serina-Treonina Quinases , Pirazóis , RNA Mensageiro , Estatmina , Tubulina (Proteína) , Ureia/análogos & derivados , Vimentina , beta CateninaRESUMO
A method is first established for the separation and determination of fenpropathrin enantiomer residues in apple puree, strawberry puree, and tomato puree considered a supplementary food for infants by supercritical fluid chromatography. After the sample was extracted with acetonitrile and cleaned up by a solid-phase extraction column, then it was separated by a CHIRALPAK AD-3 chiral column with gradient elution at a flow rate of 1.5 mL/min using methanol and supercritical carbon dioxide as the mobile phase, detected by ultraviolet detector at 230 nm wavelength and quantified with the external standard method. The limits of quantification of the two fenpropathrin enantiomers were both 0.2 mg/kg, the linear ranges were 1.0-20.0 mg/L with linear correlation coefficients greater than 0.9992, the recoveries in the spiked samples at 0.2, 0.4 and 2.0 mg/kg were from 80.6 to 105%, and the relative standard deviation reached 2.6-7.7%. This method has the advantages of convenient operation, good resolution, and environmental protection, which can satisfy the requirement of determination for fenpropathrin enantiomer residues in fruit and vegetable puree as supplementary food for infants.
Assuntos
Cromatografia com Fluido Supercrítico , Praguicidas , Cromatografia Líquida de Alta Pressão/métodos , Cromatografia com Fluido Supercrítico/métodos , Frutas/química , Humanos , Praguicidas/análise , Piretrinas , Estereoisomerismo , Verduras/químicaRESUMO
BACKGROUND: Nasopharyngeal small cell carcinoma (SmCC) is a rare histological type of nasopharyngeal cancer, and its prognosis remains poor. This study aimed to determine the clinical characteristics and survival prognostic factors of nasopharyngeal SmCC. METHODS: Detailed clinicopathologic and therapeutic characteristics of a patient diagnosed with nasopharyngeal SmCC were determined. Nasopharyngeal SmCC cases reported previously were reviewed and summarized. Furthermore, a retrospective analysis was performed on data from the Surveillance, Epidemiology, and End Results (SEER) Program database. Kaplan-Meier analysis was conducted to compare survival within groups. Univariate and multivariate analyses were performed to investigate prognostic factors. RESULTS: A nasopharyngeal SmCC patient treated with chemoradiotherapy who achieved 46 months long-term survival was reported. In reviewing 16 reported cases with epidemiologic and therapeutic details, we found most of nasopharyngeal SmCC patients were diagnosed with advanced grades and received chemoradiotherapy. In total, 13,993 cases of nasopharyngeal cancer were extracted from the SEER database, from which 57 nasopharyngeal SmCC cases were eventually screened out. The mean age of the patients was 55.70 years, and 64.9% of these cases were either grade III or IV; the median overall survival (OS) was 18 months. Statistically significant differences were observed in the OS values of groups categorized by age (P = .025) or radiotherapy (P = .037). Age (<70 years) and radiotherapy were identified as independent survival and prognostic factors. CONCLUSION: Patients with nasopharyngeal SmCC are usually diagnosed with advanced grades and have poor prognoses; nevertheless, they can benefit from radiotherapy with prolonged overall survival.