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Background: Anxiety-driven clinical interventions have been queried due to the nondeterminacy of pure ground-glass nodules (pGGNs). Although radiomics and radiogenomics aid diagnosis, standardization and reproducibility challenges persist. We aimed to assess a risk score system for invasive adenocarcinoma in pGGNs. Methods: In a retrospective, multi-center study, 772 pGGNs from 707 individuals in The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital were grouped into training (509 patients with 558 observations) and validation (198 patients with 214 observations) sets consecutively from January 2017 to November 2021. An additional test set of 143 observations in Hainan Cancer Hospital was analyzed in the same period. Computed tomography (CT) signs and clinical features were manually collected, and the quantitative parameters were achieved by artificial intelligence (AI). The positive cutoff score was ≥3. Risk scores system 3 combined carcinoma history, chronic obstructive pulmonary disease (COPD), maximum diameters, nodule volume, mean CT values, type II or III vascular supply signs, and other radiographic characteristics. The evaluation included the area under the curves (AUCs), accuracy, sensitivity, specificity, positive predictive values (PPV), and negative predictive values (NPV) for both the risk score systems 1, 2, 3 and the AI model. Results: The risk score system 3 [AUC, 0.840; 95% confidence interval (CI): 0.789-0.890] outperformed the AI model (AUC, 0.553; 95% CI: 0.487-0.619), risk score system 1 (AUC, 0.802; 95% CI: 0.754-0.851), and risk score system 2 (AUC, 0.816; 95% CI: 0.766-0.867), with 88.0% (0.850-0.904) accuracy, 95.6% (0.932-0.972) PPV, 0.620 (0.535-0.702) NPV, 89.6% (0.864-0.920) sensitivity, and 80.6% (0.717-0.872) specificity in the training sets. In the validation and test sets, risk score system 3 performed best with AUCs of 0.769 (0.678-0.860) and 0.801 (0.669-0.933). Conclusions: An AI-based risk scoring system using quantitative image parameters, clinical features, and radiographic characteristics effectively predicts invasive adenocarcinoma in pulmonary pGGNs.
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Broadly neutralizing antibodies (bNAbs) have shown great promise for prevention and treatment of HIV infection. Breadth of bNAb neutralization, measured in vitro across panels of diverse viral isolates, is often used as a predictor of clinical potential. However, recent prevention studies demonstrate that the clinical efficacy of a broad and potent bNAb (VRC01) is undermined by neutralization resistance of circulating strains. Using HIV-infected humanized mice, we find that therapeutic efficacy of bNAbs delivered as Vectored ImmunoTherapy (VIT) is a function of both the fitness cost and resistance benefit of mutations that emerge during viral escape, which we term 'escapability'. Applying this mechanistic framework, we find that the sequence of the envelope V5-loop alters the resistance benefits of mutants that arise during escape, thereby impacting the therapeutic efficacy of VIT-mediated viral suppression. We also find that an emtricitabine-based antiretroviral drug regimen dramatically enhances the efficacy of VIT, by reducing the fitness of mutants along the escape path. Our findings demonstrate that bNAb escapability is a key determinant to consider in the rational design of antibody regimens with maximal efficacy and illustrates a tractable means of minimizing viral escape from existing bNAbs.
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Tobacco is an economically significant industrial crop and model plant for genetic research, yet little is known about its genetic architecture. Quantitative trait loci (QTL) analysis was performed for six agronomic traits on an F_7 population of 341 genotypes, parents, and F1 plants using 1974 SSR markers across two environments. 31 QTLs contributing single-locus additive effects on 13 linkage groups (LGs) and 6 QTL pairs contributing epistatic effects on 6 LGs, were detected by the QTLNetwork 2.0 which was developed for the mixed-linear-model-based composite interval mapping (MCIM). Notably, 5 QTLs and 1 epistatic QTL pair were found to have pleiotropic effects on some genetically related traits. Moreover, the Broad sense heritability of the detected QTLs ranged from 1.05% to 43.33%, while genotype-by-environment interaction heritability spanned from 27.09% to 56.25%. Based on the results of QTL mapping, the potential superior lines for all or specific environments were designed and evaluated. Five major QTLs were finely dissected based on the tobacco reference genome of K326, and 31 candidate genes were predicted. This study offered new insights into the complicated genetic architecture and QTL resources for efficient breeding design for genetic improvement of agronomic traits in tobacco.
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Mapeo Cromosómico , Genotipo , Nicotiana , Sitios de Carácter Cuantitativo , Nicotiana/genética , Mapeo Cromosómico/métodos , Epistasis Genética , Fitomejoramiento/métodos , Ligamiento Genético , FenotipoRESUMEN
BACKGROUND: Alveolar Soft Part Sarcoma (ASPS) is a rare, aggressive cancer whose diagnosis and treatment depend on histological grading. However, tumor variability can lead to underestimation, affecting treatment, and patient survival. OBJECTIVE: To evaluate MRI features associated with Grade III ASPS and to determine the relationship between MRI features and patient prognosis. STUDY TYPE: Retrospective analysis. SUBJECTS: Sixty-seven patients with ASPS were included with 37 males and 30 females (M/F = 1.23) follow-up and survival analysis on 50 patients. FIELD STRENGTH/SEQUENCE: A 3.0 T, T1WI-FSE, T2WI-FSE, DWI-EPI, DCE-MRI (gradient echo). ASSESSMENT: MRI features (margin, peritumoral oedema, peritumoral enhancement, necrosis, vascular flow void signal, heterogeneous signal intensity [SI] at T1WI and T2WI, ADCmean, time-intensity curve [TIC] type, distant metastasis, and bone invasion) and histological grading were independently evaluated by three radiologists and two pathologists, with Grade III considered high-grade. STATISTICAL TESTS: The chi-square or Fisher's exact test was used to assess the correlation between MRI features and histological grading. Multivariable binary logistic regression identified independent factors associated with high-grade tumors. The Kaplan-Meier method and Cox proportional hazards model were used to calculate hazard ratios for MRI features. RESULTS: Tumor necrosis, heterogeneous SI at T2WI ≥50%, and ADCmean were associated with high-grade ASPS. Tumor necrosis was an independent factors associated with local relapse-free survival (odds ratio [OR], 3.88). TIC type was associated with 5-year survival rate (OR, 2.80) and local relapse-free survival (OR, 2.69). Heterogeneous SI at T2WI ≥50% was associated with 5-year survival (OR, 4.00), local relapse-free survival (OR, 5.58), and local relapse-free survival (OR, 4.84). DATA CONCLUSION: MRI features including tumor necrosis, heterogeneity of SI at T2WI, ADCmean, and TIC type aid in assessing ASPS grading and prognosis. EVIDENCE LEVEL: 4 TECHNICAL EFFICACY: Stage 5.
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OBJECTIVE: To investigate the correlation between MRI findings and histological features for preoperative prediction of histological grading and Ki-67 expression level in alveolar soft part sarcoma (ASPS). METHODS: A retrospective analysis was conducted on 63 ASPS patients (Jan 2017-May 2023). All patients underwent 3.0-T MRI examinations, including conventional sequences, dynamic contrast-enhanced scans with time-intensity curve analysis, and diffusion-weighted imaging with apparent diffusion coefficient (ADC) measurements. Patients were divided into low-grade (histological Grade I) and high-grade (histological Grade II/III) groups based on pathology. Immunohistochemistry was used to assess Ki-67 expression levels in ASPS. Statistical analysis included chi-square tests, Wilcoxon rank-sum test, binary logistic regression analysis, Spearman correlation analysis, and receiver operating characteristic curve analysis of various observational data. RESULTS: There were 29 low-grade and 34 high-grade patients (26 males and 37 females) and a wide age range (5-68 years). Distant metastasis, tumor enhancement characteristics, and ADC values were independent predictors of high-grade ASPS. High-grade ASPS had lower ADC values (p = 0.002), with an area under the curve (AUC), sensitivity, and specificity of 0.723, 79.4%, and 58.6%, respectively, for high-grade prediction. There was a negative correlation between ADC values and Ki-67 expression (r = -0.526; p < 0.001). When the cut-off value of ADC was 0.997 × 10-3 mm²/s, the AUC, sensitivity, and specificity for predicting high Ki-67 expression were 0.805, 65.6%, and 83.9%, respectively. CONCLUSION: Qualitative and quantitative MRI parameters are valuable for predicting histological grading and Ki-67 expression levels in ASPS. CRITICAL RELEVANCE STATEMENT: This study will help provide a more nuanced understanding of ASPS and guide personalized treatment strategies. KEY POINTS: There is limited research on assessing ASPS prognosis through MRI. Metastasis, enhancement, and ADC correlated with histological grade; ADC related to Ki-67 expression. MRI provides clinicians with valuable information on ASPS grading and proliferation activity.
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Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a plasma protein that controls cholesterol homeostasis. Here, we design a human PCSK9 mimic, named HIT01, with no consecutive 9-residue stretch in common with any human protein as a potential heart attack vaccine. Murine immunizations with HIT01 reduce low-density lipoprotein (LDL) and cholesterol levels by 40% and 30%, respectively. Immunization of cynomolgus macaques with HIT01-K21Q-R218E, a cleavage-resistant variant, elicits high-titer PCSK9-directed antibody responses and significantly reduces serum levels of cholesterol 2 weeks after each immunization. However, HIT01-K21Q-R218E immunizations also increase serum PCSK9 levels by up to 5-fold, likely due to PCSK9-binding antibodies altering the half-life of PCSK9. While vaccination with a PCSK9 mimic can induce antibodies that block interactions of PCSK9 with the LDL receptor, PCSK9-binding antibodies appear to alter homeostatic levels of PCSK9, thereby confounding its vaccine impact. Our results nevertheless suggest a mechanism for increasing the half-life of soluble regulatory factors by vaccination.
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Colesterol , Inmunización , Macaca fascicularis , Proproteína Convertasa 9 , Proproteína Convertasa 9/inmunología , Proproteína Convertasa 9/metabolismo , Animales , Humanos , Ratones , Colesterol/metabolismo , Colesterol/sangre , Inmunización/métodos , Receptores de LDL/metabolismo , Femenino , Ratones Endogámicos C57BLRESUMEN
Poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitors as maintenance therapy after first-line chemotherapy have improved progression-free survival in women with advanced ovarian cancer; however, not all PARP inhibitors can provide benefit for a biomarker-unselected population. Senaparib is a PARP inhibitor that demonstrated antitumor activity in patients with solid tumors, including ovarian cancer, in phase 1 studies. The multicenter, double-blind, phase 3 trial FLAMES randomized (2:1) 404 females with advanced ovarian cancer (International Federation of Gynecology and Obstetrics stage III-IV) and response to first-line platinum-based chemotherapy to senaparib 100 mg (n = 271) or placebo (n = 133) orally once daily for up to 2 years. The primary endpoint was progression-free survival assessed by blinded independent central review. At the prespecified interim analysis, the median progression-free survival was not reached with senaparib and was 13.6 months with placebo (hazard ratio 0.43, 95% confidence interval 0.32-0.58; P < 0.0001). The benefit with senaparib over placebo was consistent in the subgroups defined by BRCA1 and BRCA2 mutation or homologous recombination status. Grade ≥3 treatment-emergent adverse events occurred in 179 (66%) and 27 (20%) patients, respectively. Senaparib significantly improved progression-free survival versus placebo in patients with advanced ovarian cancer after response to first-line platinum-based chemotherapy, irrespective of BRCA1 and BRCA2 mutation status and with consistent benefits observed between homologous recombination subgroups, and was well tolerated. These results support senaparib as a maintenance treatment for patients with advanced ovarian cancer after a response to first-line chemotherapy. ClinicalTrials.gov identifier: NCT04169997 .
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Neoplasias Ováricas , Inhibidores de Poli(ADP-Ribosa) Polimerasas , Humanos , Femenino , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Neoplasias Ováricas/genética , Persona de Mediana Edad , Inhibidores de Poli(ADP-Ribosa) Polimerasas/uso terapéutico , Inhibidores de Poli(ADP-Ribosa) Polimerasas/efectos adversos , Inhibidores de Poli(ADP-Ribosa) Polimerasas/administración & dosificación , Anciano , Adulto , Quimioterapia de Mantención , Método Doble Ciego , Ftalazinas/uso terapéutico , Ftalazinas/administración & dosificación , Ftalazinas/efectos adversos , Supervivencia sin Progresión , Proteína BRCA2/genética , Anciano de 80 o más Años , Proteína BRCA1/genética , Piperazinas , QuinazolinasRESUMEN
Plant stems constitute the most abundant renewable resource on earth. The function of lysine (K)-2-hydroxyisobutyrylation (Khib), a novel post-translational modification (PTM), has not yet been elucidated in plant stem development. Here, by assessing typical pepper genotypes with straight stem (SS) and prostrate stem (PS), we report the first large-scale proteomics analysis for protein Khib to date. Khib-modifications influenced central metabolic processes involved in stem development, such as glycolysis/gluconeogenesis and protein translation. The high Khib level regulated gene expression and protein accumulation associated with cell wall formation in the pepper stem. Specially, we found that CaMYB61 knockdown lines that exhibited prostrate stem phenotypes had high Khib levels. Most histone deacetylases (HDACs, e.g., switch-independent 3 associated polypeptide function related 1, AFR1) potentially function as the "erasing enzymes" involved in reversing Khib level. CaMYB61 positively regulated CaAFR1 expression to erase Khib and promote cellulose and hemicellulose accumulation in the stem. Therefore, we propose a bidirectional regulation hypothesis of "Khib modifications" and "Khib erasing" in stem development, and reveal a novel epigenetic regulatory network in which the CaMYB61-CaAFR1 molecular module participating in the regulation of Khib levels and biosynthesis of cellulose and hemicellulose for the first time.
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Capsicum , Regulación de la Expresión Génica de las Plantas , Lisina , Proteínas de Plantas , Tallos de la Planta , Proteómica , Tallos de la Planta/genética , Tallos de la Planta/metabolismo , Tallos de la Planta/crecimiento & desarrollo , Proteínas de Plantas/metabolismo , Proteínas de Plantas/genética , Capsicum/genética , Capsicum/crecimiento & desarrollo , Capsicum/metabolismo , Lisina/metabolismo , Procesamiento Proteico-Postraduccional , Pared Celular/metabolismo , Pared Celular/genética , Factores de Transcripción/metabolismo , Factores de Transcripción/genéticaRESUMEN
A protective HIV vaccine will likely need to induce broadly neutralizing antibodies (bnAbs). Vaccination with the germline-targeting immunogen eOD-GT8 60mer adjuvanted with AS01B was found to induce VRC01-class bnAb precursors in 97% of vaccine recipients in the IAVI G001 phase 1 clinical trial; however, heterologous boost immunizations with antigens more similar to the native glycoprotein will be required to induce bnAbs. Therefore, we designed core-g28v2 60mer, a nanoparticle immunogen to be used as a first boost after eOD-GT8 60mer priming. We found, using a humanized mouse model approximating human conditions of VRC01-class precursor B cell diversity, affinity, and frequency, that both protein- and mRNA-based heterologous prime-boost regimens induced VRC01-class antibodies that gained key mutations and bound to near-native HIV envelope trimers lacking the N276 glycan. We further showed that VRC01-class antibodies induced by mRNA-based regimens could neutralize pseudoviruses lacking the N276 glycan. These results demonstrated that heterologous boosting can drive maturation toward VRC01-class bnAb development and supported the initiation of the IAVI G002 phase 1 trial testing mRNA-encoded nanoparticle prime-boost regimens.
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Vacunas contra el SIDA , Anticuerpos Neutralizantes , Anticuerpos Anti-VIH , Animales , Humanos , Vacunas contra el SIDA/inmunología , Anticuerpos Neutralizantes/inmunología , Anticuerpos Anti-VIH/inmunología , Ratones , Vacunación , Inmunización Secundaria , VIH-1/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/prevención & control , Anticuerpos ampliamente neutralizantes/inmunologíaRESUMEN
Background: N-Ethylmaleimide (NEM), an agonist of the potassium chloride cotransporters 2 (KCC2) receptor, has been correlated with neurosuppressive outcomes, including decreased pain perception and the prevention of epileptic seizures. Nevertheless, its relationship with sleep-inducing effects remains unreported. Objective: The present study aimed to investigate the potential enhancement of NEM on the sleep-inducing properties of alprazolam (Alp). Methods: The test of the righting reflex was used to identify the appropriate concentrations of Alp and NEM for inducing sleep-promoting effects in mice. Total sleep duration and sleep quality were evaluated through EEG/EMG analysis. The neural mechanism underlying the sleep-promoting effect was examined through c-fos immunoreactivity in the brain using immunofluorescence. Furthermore, potential CNS-side effects of the combination Alp and NEM were assessed using LABORAS automated home-cage behavioral phenotyping. Results: Combination administration of Alp (1.84 mg/kg) and NEM (1.0 mg/kg) significantly decreased sleep latency and increased sleep duration in comparison to administering 1.84 mg/kg Alp alone. This effect was characterized by a notable increase in REM duration. The findings from c-fos immunoreactivity indicated that NEM significantly suppressed neuron activation in brain regions associated with wakefulness. Additionally, combination administration of Alp and NEM showed no effects on mouse neural behaviors during automated home cage monitoring. Conclusions: This study is the first to propose and demonstrate a combination therapy involving Alp and NEM that not only enhances the hypnotic effect but also mitigates potential CNS side effects, suggesting its potential application in treating insomnia.
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Alprazolam , Sinergismo Farmacológico , Sueño , Animales , Alprazolam/farmacología , Alprazolam/administración & dosificación , Ratones , Masculino , Sueño/efectos de los fármacos , Electroencefalografía/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Reflejo de Enderezamiento/efectos de los fármacos , Hipnóticos y Sedantes/farmacología , Hipnóticos y Sedantes/administración & dosificaciónRESUMEN
Tobacco (Nicotiana tabacum L.) use is the leading cause of preventable death, due to deleterious chemical components and smoke from tobacco products, and therefore reducing harmful chemical components in tobacco is one of the crucial tobacco breeding targets. However, due to complexity of tobacco smoke and unavailability of high-density genetic maps, the genetic architecture of representative hazardous smoke has not been fully dissected. The present study aimed to explore the genetic architecture of nine hazardous component traits of mainstream smoke through QTL mapping using 271 recombinant inbred lines (RILs) derived from K326 and Y3 in multiple environments. The analysis of genotype and genotype by environment interaction (GE) revealed substantially greater heritability over 95% contributed mostly by GE interaction effects. We also observed strong genetic correlations among most studied hazardous smoke traits, with the highest correlation coefficient of 0.84 between carbon monoxide and crotonaldehyde. Based on a published high-density genetic map, a total of 19 novel QTLs were detected for eight traits using a full QTL model, of which 17 QTLs showed significant additive effects, six showed significant additive-by-environment interaction effects, and one pair showed significant epistasis-by-environment interaction effect. Bioinformatics analysis of sequence in QTL region predicted six genes as candidates for four traits, of which Nt21g04598.1, Nt21g04600.1, and Nt21g04601.1 had pleiotropic effects on PHE and TAR.
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OBJECTIVE: To retrospectively evaluate the diagnostic performance of contrast-enhanced ultrasound (CEUS) LI-RADS in liver nodules < 20 mm at high risk of hepatocellular carcinoma (HCC) and their correlation with clinic-pathological features. METHODS: A total of 432 pathologically proved liver nodules < 20 mm were included from January 2019 to June 2022. Each nodule was categorized as LI-RADS grade (LR)-1 to LR-5 through LR-M according to CEUS LI-RADS. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and area under the curve (AUC) of CEUS LI-RADS were evaluated using pathological reference standard. Correlations between clinic-pathological features and CEUS LI-RADS categorization, together with major CEUS features, were further explored. RESULTS: With LR-5 to diagnose HCC, the sensitivity, specificity, PPV, NPV, and AUC were 50.3%, 70.0%, 91.2%, 18.5%, and 0.601, respectively. The proportion of LR-5 in primary HCCs was significantly higher than that in recurrent ones (p = 0.014). HCC 10-19 mm showed significantly more frequent arterial phase hyper-enhancement (APHE) and late washout (p < 0.05) and less no-washout (p = 0.003) compared with those in HCC < 10 mm. Well-differentiated HCCs showed more frequent non-APHE and no-washout than moderate- and poor-differentiated HCCs (p < 0.05). Upgrading "APHE without washout" LR-4 nodules 10-19 mm with HCC history and "APHE with late mild washout" LR-4 nodules < 10 mm to LR-5 could improve the diagnostic performance of LR-5. The corresponding sensitivity, specificity, PPV, NPV, and AUC are 60.2%, 70.0%, 92.6%, 22.1%, and 0.651, respectively. CONCLUSIONS: CEUS LI-RADS is valuable in the diagnosis of HCC < 20 mm and performance can be improved with the combination of clinic-pathological features. CRITICAL RELEVANCE STATEMENT: CEUS LI-RADS was valuable in the diagnosis of HCC < 20 mm and its diagnostic performance can be improved by combining clinic-pathological features. Further research is needed to define its value in this set of lesions. KEY POINTS: Contrast-enhanced ultrasound can detect small liver lesions where LI-RADS accuracy is uncertain. Many LI-RADS Grade-4 nodules were upgraded to Grade-5 by combining imaging with clinic-pathological factors. The reclassification of LI-RADS Grade-5 can improve sensitivity without decreasing positive predictive value.
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Potassium ion (K+) is one of the most essential nutrients for the growth and development of tobacco (Nicotiana tabacum L.), however, the molecular regulation of K+ concentration in tobacco remains unclear. In this study, a two-pore K (TPK) channel gene NtTPKa was cloned from tobacco, and NtTPKa protein contains the unique K+ selection motif GYGD and its transmembrane region primarily locates in the tonoplast membrane. The expression of NtTPKa gene was significantly increased under low-potassium stress conditions. The concentrations of K+ in tobacco were significantly increased in the NtTPKa RNA interference lines and CRISPR/Cas9 knockout mutants. In addition, the transport of K+ by NtTPKa was validated using patch clamp technique, and the results showed that NtTPKa channel protein exclusively transported K+ in a concentration-dependent manner. Together, our results strongly suggested that NtTPKa is a key gene in maintaining K+ homeostasis in tobacco, and it could provide a new genetic resource for increasing the concentration of K+ in tobacco.
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Regulación de la Expresión Génica de las Plantas , Nicotiana , Proteínas de Plantas , Potasio , Nicotiana/genética , Nicotiana/metabolismo , Potasio/metabolismo , Proteínas de Plantas/genética , Proteínas de Plantas/metabolismo , Canales de Potasio de Dominio Poro en Tándem/metabolismo , Canales de Potasio de Dominio Poro en Tándem/genética , Sistemas CRISPR-Cas , Canales de Potasio/metabolismo , Canales de Potasio/genéticaRESUMEN
Broadly neutralizing antibodies are proposed as therapeutic and prophylactic agents against HIV-1, but their potency and breadth are less than optimal. This study describes the immunization of a llama with the prefusion-stabilized HIV-1 envelope (Env) trimer, BG505 DS-SOSIP, and the identification and improvement of potent neutralizing nanobodies recognizing the CD4-binding site (CD4bs) of vulnerability. Two of the vaccine-elicited CD4bs-targeting nanobodies, G36 and R27, when engineered into a triple tandem format with llama IgG2a-hinge region and human IgG1-constant region (G36×3-IgG2a and R27×3-IgG2a), neutralized 96% of a multiclade 208-strain panel at geometric mean IC80s of 0.314 and 0.033 µg mL-1, respectively. Cryo-EM structures of these nanobodies in complex with Env trimer revealed the two nanobodies to neutralize HIV-1 by mimicking the recognition of the CD4 receptor. To enhance their neutralizing potency and breadth, nanobodies are linked to the light chain of the V2-apex-targeting broadly neutralizing antibody, CAP256V2LS. The resultant human-llama bispecific antibody CAP256L-R27×3LS exhibited ultrapotent neutralization and breadth exceeding other published HIV-1 broadly neutralizing antibodies, with pharmacokinetics determined in FcRn-Fc mice similar to the parent CAP256V2LS. Vaccine-elicited llama nanobodies, when combined with V2-apex broadly neutralizing antibodies, may therefore be able to fulfill anti-HIV-1 therapeutic and prophylactic clinical goals.
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Anticuerpos Biespecíficos , Anticuerpos Neutralizantes , Camélidos del Nuevo Mundo , VIH-1 , Animales , VIH-1/inmunología , Humanos , Anticuerpos Biespecíficos/inmunología , Camélidos del Nuevo Mundo/inmunología , Anticuerpos Neutralizantes/inmunología , Anticuerpos Anti-VIH/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/prevención & control , RatonesRESUMEN
BACKGROUND: Retifanlimab is a humanized monoclonal antibody targeting programmed death protein-1, and INCB001158 is an oral arginase inhibitor. This phase Ib study investigated retifanlimab, INCB001158, and their combination in Japanese patients with advanced solid tumors. METHODS: Patients received retifanlimab (500 mg every 4 weeks [Q4W] i.v.) or escalating doses of INCB001158 (75 or 100 mg twice daily [BID]) monotherapy in Part 1 and combination of retifanlimab (500 mg Q4W) and INCB001158 (100 mg BID) in Part 2. Primary endpoints were safety, tolerability, dose-limiting toxicities (DLTs), and determination of recommended phase II doses in Japanese patients. RESULTS: Eighteen patients (retifanlimab or INCB001158 monotherapy and combination; n = 6 each) were enrolled at 2 sites in Japan. There were no DLTs, fatal adverse events (AEs), or discontinuations due to AEs. Rash (all grade 1) was the most common treatment-emergent AE with retifanlimab (n = 6). Treatment-related AEs were reported with retifanlimab (n = 4) or INCB001158 (n = 2) monotherapy and with combination (n = 4); an immune-related AE (thyroid disorder, grade 2) was reported with combination. Two responses were observed with retifanlimab monotherapy (1 complete, 1 partial) and 1 stable disease (SD), for an overall response rate of 33.3% (95% confidence interval [CI], 4.3-77.7) and disease control rate (DCR) of 50% (95% CI, 11.8-88.2). Three patients had SD with INCB001158 monotherapy (DCR 50%; 95% CI, 11.8-88.2). No responses or SD were observed with combination therapy. CONCLUSION: Retifanlimab, INCB001158, and their combination had acceptable safety profiles. Promising retifanlimab antitumor activity warrants further investigation in Japanese patients.
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Arginasa , Neoplasias , Humanos , Femenino , Masculino , Neoplasias/tratamiento farmacológico , Persona de Mediana Edad , Anciano , Arginasa/antagonistas & inhibidores , Adulto , Japón , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Anticuerpos Monoclonales Humanizados/uso terapéutico , Anticuerpos Monoclonales Humanizados/efectos adversos , Anticuerpos Monoclonales Humanizados/administración & dosificación , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/efectos adversos , Pueblos del Este de AsiaRESUMEN
In vitro biotransformation (ivBT) facilitated by in vitro synthetic enzymatic biosystems (ivSEBs) has emerged as a highly promising biosynthetic platform. Several ivSEBs have been constructed to produce poly-3-hydroxybutyrate (PHB) via acetyl-coenzyme A (acetyl-CoA). However, some systems are hindered by their reliance on costly ATP, limiting their practicality. This study presents the design of an ATP-free ivSEB for one-pot PHB biosynthesis via acetyl-CoA utilizing starch-derived maltodextrin as the sole substrate. Stoichiometric analysis indicates this ivSEB can self-maintain NADP+/NADPH balance and achieve a theoretical molar yield of 133.3%. Leveraging simple one-pot reactions, our ivSEBs achieved a near-theoretical molar yield of 125.5%, the highest PHB titer (208.3 mM, approximately 17.9 g/L) and the fastest PHB production rate (9.4 mM/h, approximately 0.8 g/L/h) among all the reported ivSEBs to date, and demonstrated easy scalability. This study unveils the promising potential of ivBT for the industrial-scale production of PHB and other acetyl-CoA-derived chemicals from starch.
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Hidroxibutiratos , Polihidroxibutiratos , Polisacáridos , Almidón , Acetilcoenzima A/metabolismo , Almidón/metabolismo , Hidroxibutiratos/metabolismo , Poliésteres/metabolismo , NADP/metabolismo , BiotransformaciónRESUMEN
Ionic liquids (ILs) have been proven to be an effective technology for enhancing drug transdermal absorption. However, due to the unique structural components of ILs, the design of efficient ILs and elucidation of action mechanisms remain to be explored. In this review, basic design principles of ideal ILs for transdermal drug delivery system (TDDS) are discussed considering melting point, skin permeability, and toxicity, which depend on the molar ratios, types, functional groups of ions and inter-ionic interactions. Secondly, the contributions of ILs to the development of TDDS through different roles are described: as novel skin penetration enhancers for enhancing transdermal absorption of drugs; as novel solvents for improving the solubility of drugs in carriers; as novel active pharmaceutical ingredients (API-ILs) for regulating skin permeability, solubility, release, and pharmacokinetic behaviors of drugs; and as novel polymers for the development of smart medical materials. Moreover, diverse action mechanisms, mainly including the interactions among ILs, drugs, polymers, and skin components, are summarized. Finally, future challenges related to ILs are discussed, including underlying quantitative structure-activity relationships, complex interaction forces between anions, drugs, polymers and skin microenvironment, long-term stability, and in vivo safety issues. In summary, this article will promote the development of TDDS based on ILs.
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OBJECTIVE: To explore the correlation between skewed X chromosome inactivation (XCI) and clinical phenotype of a Chinese pedigree with loss of heterozygosity at Xq22.1q22.3. METHODS: A pedigree diagnosed at Taizhou Hospital on November 10, 2021 was selected as the study subject. G-banded chromosomal karyotyping and copy number variation sequencing (CNV-seq) were carried out to analyze the amniotic fluid and peripheral blood samples from the couple. XCI was detected by PCR amplification of CAG repeats in exon 1 of androgen receptor gene before and after the digestion with methylation-sensitive restriction enzyme Hpa II. Correlation between the genotype and clinical phenotype was analyzed. RESULTS: The karyotypes of the pregnant woman and the fetus were both determined as 46,X,del(X)(q22), and the result of CNV-seq was seq[hg19]del(X)(q22.1q22.3) chrX: g.10046000_105740000del, suggesting that both had harbored a 5.28 Mb deletion on the X chromosome. No obvious abnormality was found in the husband. XCI analysis showed that the activity ratio of the two X chromosomes of the pregnant woman and her fetus was 0 : 100. The X chromosome harboring the q22.1q22.3 deletion was completely inactivated, and the inactivated X chromosome of the fetus was derived from its mother. CONCLUSION: The fetus has harbored a maternally derived inactivated X chromosome del(X)(q22) , and its phenotype is closely associated with the activity of the abnormal X chromosome. Pedigree XCI analysis combined with the clinical phenotype has facilitated recognition of the maternal phenotype and prognosis of female fetus with loss of heterozygosity at Xq22.1q22.3.
Asunto(s)
Variaciones en el Número de Copia de ADN , Inactivación del Cromosoma X , Femenino , Humanos , Embarazo , Linaje , Diagnóstico Prenatal , Líquido Amniótico , Aberraciones Cromosómicas , Pérdida de Heterocigocidad , ChinaRESUMEN
RATIONALE AND OBJECTIVES: To evaluate the potential of Synthetic Magnetic Resonance Imaging (SynMRI) in identifying muscular invasion in bladder cancer (BCa), and explore whether there is additional value in combination with the Vesical Imaging-Reporting and Data System (VI-RADS). METHODS: In this prospective single-center study, pathologically-confirmed BCa were enrolled between May 2023 and November 2023. All participants underwent preoperative multiparametric MRI, including T1/T2 weighted, SynMRI and diffusion-weighted imaging. T1/T2/PD values and apparent diffusion coefficient (ADC) values were compared between muscle invasive (MIBC) and non-invasive (NMIBC) groups. Receiver operating characteristic (ROC) analysis with the variables and their combination was performed to explore the performance of distinguishing the MIBC from NMIBC, and the ROC curves were compared using DeLong's test. RESULTS: A total of 54 BCa patients were enrolled (38 males; NMIBC/MIBC=37/19) and all assessed with VI-RADS without dynamic enhanced imaging (DCE). Compared to NMIBC group, MIBC group had significantly larger diameter, higher VI-RADS score, lower T2 and ADC values (P < 0.05). VI-RADS score and T2 showed independent predictive value in differentiating NMIBC and MIBC. The combined model (T2 + VI-RADS+Diameter) resulted in significantly improved specificity (0.842), sensitivity (0.914), and AUC (0.943), in comparison to VI-RADS or ADC alone (P < 0.05). CONCLUSION: T2 relaxation time can be easily obtained from SynMRI in routine clinical protocol and assist VI-RADS score system without DCE to improve differentiation performance in identifying NMIBC and MIBC.