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A visible-light-induced radical cascade regioselective acylation/cyclization of 1,7-dienes with acyl oxime esters for the preparation of acylation polycyclic compounds via NCR-mediated C-C σ-bond cleavage is established. The transformation involves the cleavage of the C-C σ-bond in acyl oxime esters and selective addition of the electron neutral CâC bonds in 1,7-dienes for the synthesis of acyl polycyclic quinolinone derivatives, not the traditional seven-membered ring products. The strategy offers several advantages, including broad substrate tolerance, no need for bases, hyperstoichiometric radical initiators, and other auxiliaries.
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A novel strategy for the difunctionalization of electron-deficient alkenes with aryl sulfonium salts to access remote sulfur-containing oxindole derivatives by using in situ-formed copper(I)-based complexes as a photoredox catalyst is presented. This method enables the generation of the C(sp3)-centered radicals through site selective cleavage of the C-S bond of aryl sulfonium salts under mild conditions. Moreover, the oxidation reactions of desired products provide a new strategy for the preparation of sulfoxide or sulfone-containing compounds. Importantly, this approach can be easily applied to late-stage modification of pharmaceuticals molecules.
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A convenient method for oxidant-promoted radical cascade acylation or decarbonylative alkylation of 1,7-dienes with aldehydes has been established. This method allows for the rapid construction of N-containing polycyclic skeletons in a highly regio- and stereoselective manner. This transformation provides a simple and efficient method for the preparation of a range of tetrahydro-6H-indeno[2,1-c]quinolinone derivatives by sequential formation of three new carbon-carbon bonds. Additionally, this radical cascade cyclization can selectively convert aldehydes into aroyl/primary aliphatic acyl radicals and secondary or tertiary alkyl radicals.
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2-Aminobenzothiazoles are commonly encountered in various functional compounds. Herein, we disclose an electro-oxidative three-component reaction for the effective synthesis of 2-aminobenzothiazoles under mild conditions, utilizing non-toxic and abundant elemental sulfur as the sulfur source. Both aliphatic amines and aryl amines demonstrate good compatibility at room temperature, highlighting the broad functional group tolerance of this approach. Additionally, elemental selenium demonstrated reactivities comparable to those of elemental sulfur.
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An oxidant-assisted tandem sulfonylation/cyclization of electron-deficient alkenes with 4-alkyl-substituted Hantzsch esters and Na2S2O5 for the preparation of 3-alkylsulfonylated oxindoles under mild conditions in the absence of a photocatalyst and transition metal catalyst is established. The mechanism studies show that the alkyl radicals, which come from the cleavage of the C-C bond in 4-substituted Hantzsch esters under oxidant conditions, subsequently undergo the in situ insertion of sulfur dioxide to generate the crucial alkylsulfonyl radical intermediates. This three-component reaction provides an efficient and facile route for the construction of alkylsulfonylated oxindoles and avoids the use of highly toxic alkylsulfonyl chlorides or alkylsulfonyl hydrazines as alkylsulfonyl sources.
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The extracellular superoxide dismutases (ecSODs) secreted by Microplitis bicoloratus reduce the reactive oxygen species (ROS) stimulated by the Microplitis bicoloratus bracovirus. Here, we demonstrate that the bacterial transferase hexapeptide (hexapep) motif and bacterial-immunoglobulin-like (BIg-like) domain of ecSODs bind to the cell membrane and transiently open hemichannels, facilitating ROS reductions. RNAi-mediated ecSOD silencing in vivo elevated ROS in host hemocytes, impairing parasitoid larva development. In vitro, the ecSOD-monopolymer needed to be membrane bound to open hemichannels. Furthermore, the hexapep motif in the beta-sandwich of ecSOD49 and ecSOD58, and BIg-like domain in the signal peptides of ecSOD67 were required for cell membrane binding. Hexapep motif and BIg-like domain deletions induced ecSODs loss of adhesion and ROS reduction failure. The hexapep motif and BIg-like domain mediated ecSOD binding via upregulating innexins and stabilizing the opened hemichannels. Our findings reveal a mechanism through which ecSOD reduces ROS, which may aid in developing anti-redox therapy.
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Prostate cancer pathology plays a crucial role in clinical management but is time-consuming. Artificial intelligence (AI) shows promise in detecting prostate cancer and grading patterns. We tested an AI-based digital twin of a pathologist, vPatho, on 2603 histological images of prostate tissue stained with hematoxylin and eosin. We analyzed various factors influencing tumor grade discordance between the vPatho system and six human pathologists. Our results demonstrated that vPatho achieved comparable performance in prostate cancer detection and tumor volume estimation, as reported in the literature. The concordance levels between vPatho and human pathologists were examined. Notably, moderate to substantial agreement was observed in identifying complementary histological features such as ductal, cribriform, nerve, blood vessel, and lymphocyte infiltration. However, concordance in tumor grading decreased when applied to prostatectomy specimens (κ = 0.44) compared to biopsy cores (κ = 0.70). Adjusting the decision threshold for the secondary Gleason pattern from 5 to 10% improved the concordance level between pathologists and vPatho for tumor grading on prostatectomy specimens (κ from 0.44 to 0.64). Potential causes of grade discordance included the vertical extent of tumors toward the prostate boundary and the proportions of slides with prostate cancer. Gleason pattern 4 was particularly associated with this population. Notably, the grade according to vPatho was not specific to any of the six pathologists involved in routine clinical grading. In conclusion, our study highlights the potential utility of AI in developing a digital twin for a pathologist. This approach can help uncover limitations in AI adoption and the practical application of the current grading system for prostate cancer pathology.
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Artificial Intelligence , Prostatic Neoplasms , Humans , Male , Pathologists , Prostate , BiopsyABSTRACT
A visible-light-induced radical alkylarylation of N-aryl bicyclobutyl amides with α-carbonyl alkyl bromides for the synthesis of functionalized 3-spirocyclobutyl oxindoles is described in which ß-selective radical addition of the alkyl radical to N-aryl bicyclobutyl amides forms a key radical intermediate followed by interception with intrinsic arene functional group. This approach can be applicable to a wide range of α-carbonyl alkyl bromides, including primary, secondary, and tertiary α-bromoalkyl esters, ketones, nitriles, and nitro compounds.
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OBJECTIVE: To analyze the immune reconstitution after BTKi treatment in patients with chronic lymphocytic leukemia (CLL). METHODS: The clinical and laboratorial data of 59 CLL patients admitted from January 2017 to March 2022 in Fujian Medical University Union Hospital were collected and analyzed retrospectively. RESULTS: The median age of 59 CLL patients was 60.5(36-78). After one year of BTKi treatment, the CLL clones (CD5 +/CD19 +) of 51 cases (86.4%) were significantly reduced, in which the number of cloned-B cells decreased significantly from (46±6.1)×109/L to (2.3±0.4)×109/L (P =0.0013). But there was no significant change in the number of non-cloned B cells (CD19 + minus CD5 +/CD19 +). After BTKi treatment, IgA increased significantly from (0.75±0.09)g/L to (1.31±0.1)g/L (P <0.001), while IgG and IgM decreased from (8.1±0.2)g/L and (0.52±0.6)g/L to (7.1±0.1)g/L and (0.47±0.1)g/L, respectively (P <0.001, P =0.002). BTKi treatment resulted in a significant change in T cell subpopulation of CLL patients, which manifested as both a decrease in total number of T cells from (2.1±0.1)×109/L to (1.6±0.4)×109/L and NK/T cells from (0.11±0.1)×109/L to (0.07±0.01)×109/L (P =0.042, P =0.038), both an increase in number of CD4 + cells from (0.15±6.1)×109/L to (0.19±0.4)×109/L and CD8 + cells from (0.27±0.01)×109/L to (0.41±0.08)×109/L (both P <0.001). BTKi treatment also up-regulated the expression of interleukin (IL)-2 while down-regulated IL-4 and interferon (IFN)-γ. However, the expression of IL-6, IL-10, and tumor necrosis factor (TNF)-α did not change significantly. BTKi treatment could also restored the diversity of TCR and BCR in CLL patients, especially obviously in those patients with complete remission (CR) than those with partial remission (PR). Before and after BTKi treatment, Shannon index of TCR in patients with CR was 0.02±0.008 and 0.14±0.001 (P <0.001), while in patients with PR was 0.01±0.03 and 0.05±0.02 (P >0.05), respectively. Shannon index of BCR in patients with CR was 0.19±0.003 and 0.33±0.15 (P <0.001), while in patients with PR was 0.15±0.009 and 0.23±0.18 (P <0.05), respectively. CONCLUSIONS: BTKi treatment can shrink the clone size in CLL patients, promote the expression of IgA, increase the number of functional T cells, and regulate the secretion of cytokines such as IL-2, IL-4, and IFN-γ. BTKi also promote the recovery of diversity of TCR and BCR. BTKi treatment contributes to the reconstitution of immune function in CLL patients.
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Immune Reconstitution , Leukemia, Lymphocytic, Chronic, B-Cell , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy , Retrospective Studies , Interleukin-4 , Tumor Necrosis Factor-alpha , Immunoglobulin A , Receptors, Antigen, T-CellABSTRACT
Rationale & Objective: Intradialytic hypotension (IDH) is associated with mortality in adults with kidney failure requiring hemodialysis (HD); however, large-scale pediatric studies are lacking. Moreover, there is no evidence-based consensus definition of IDH in pediatric literature. We aimed to examine the association of commonly used definitions of IDH with mortality in adolescents and young adults. Study Design: This was a retrospective observational cohort study. Setting & Participants: In total, 1,199 adolescents and young adults (N = 320, aged 10-18 years and N = 879, aged 19-21 years) who initiated HD in a large dialysis organization were included. Exposures: This study used different definitions of IDH. Outcome: The study outcome was 2-year all-cause mortality. Analytical Approach: Several definitions of IDH were selected a priori based on a literature review. Patients were classified as having IDH if it was present in at least 30% of HD treatments during the first 90 days after dialysis initiation. Cox proportional hazards regression was used to test whether IDH associated with 2-year all-cause mortality. Results: Over a 2-year follow-up period, 54 (4.5%) patients died. Dependent on its definition, IDH was present in 2.9%-61.1% of patients. After the multivariable adjustment for sociodemographic and clinical characteristics, we found no association of IDH with mortality. Results were consistent across subgroups stratified by age (aged <18 and 19-21 years) and predialysis systolic blood pressure (<120, 120-150, and >150 mm Hg). We also examined IDH as occurring in <5%, 5%-29%, 30%-50%, and >50% of baseline treatments, and did not find a dose-response association with mortality (P > 0.05). Limitations: Owing to low event rates, our current sample size may have been too small to detect a difference in mortality. Conclusions: Our study found that IDH was not associated with mortality in adolescents and young adults.
Intradialytic hypotension (IDH), or hypotension experienced during dialysis, is common among children and young adults with kidney failure requiring hemodialysis. We examined the association of commonly used definitions of IDH with death in adolescents and young adults with kidney failure receiving hemodialysis. Intradialytic hypotension was present in 2.9%-61.1% of patients, depending on the definition, and over a 2-year follow-up period, 4.5% of the patients died. We found no association of IDH with mortality.
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BACKGROUND. Sarcopenia is commonly assessed on CT by use of the skeletal muscle index (SMI), which is calculated as the skeletal muscle area (SMA) at L3 divided by patient height squared (i.e., a height scaling power of 2). OBJECTIVE. The purpose of this study was to determine the optimal height scaling power for SMA measurements on CT and to test the influence of the derived optimal scaling power on the utility of SMI in predicting all-cause mortality. METHODS. This retrospective study included 16,575 patients (6985 men, 9590 women; mean age, 56.4 years) who underwent abdominal CT from December 2012 through October 2018. The SMA at L3 was determined using automated software. The sample was stratified into two groups: 5459 patients without major medical conditions (based on ICD-9 and ICD-10 codes) who were included in the analysis for determining the optimal height scaling power and 11,116 patients with major medical conditions who were included for the purpose of testing this power. The optimal scaling power was determined by allometric analysis (whereby regression coefficients were fitted to log-linear sex-specific models relating height to SMA) and by analysis of statistical independence of SMI from height across scaling powers. Cox proportional hazards models were used to test the influence of the derived optimal scaling power on the utility of SMI in predicting all-cause mortality. RESULTS. In allometric analysis, the regression coefficient of log(height) in patients 40 years old and younger was 1.02 in men and 1.08 in women, and in patients older than 40 years old, it was 1.07 in men and 1.10 in women (all p < .05 vs regression coefficient of 2). In analyses for statistical independence of SMI from height, the optimal height scaling power (i.e., those yielding correlations closest to 0) was, in patients 40 years old and younger, 0.97 in men and 1.08 in women, whereas in patients older than 40 years old, it was 1.03 in men and 1.09 in women. In the Cox model used for testing, SMI predicted all-cause mortality with a higher concordance index using of a height scaling power of 1 rather than 2 in men (0.675 vs 0.663, p < .001) and in women (0.664 vs 0.653, p < .001). CONCLUSION. The findings support a height scaling power of 1, rather than a conventional power of 2, for SMI computation. CLINICAL IMPACT. A revised height scaling power for SMI could impact the utility of CT-based sarcopenia diagnoses in risk assessment.
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Sarcopenia , Male , Humans , Female , Middle Aged , Adult , Sarcopenia/etiology , Retrospective Studies , Muscle, Skeletal/pathology , Proportional Hazards Models , Tomography, X-Ray Computed/methodsABSTRACT
Objective To investigate the protective effects of melatonin(MT)on early embryo in vitro development of mice after exposure to benzophenone-3(BP-3).Methods Fertilized mouse oocytes at the synge-neic stage were cultured in KSOM culture medium,0.8 μmol/L BP-3 culture medium,and 1×10-7 mol/L MT + 0.8 μmol/L BP-3 mixed culture medium,respectively.The rescue effect of MT on the early embryos developmental potential of BP-3-exposed mice in vitro was explored by detecting the blastocyst rate,gene transcription level,protein expression level,and the degree of DNA damage in the three groups of embryos.Results MT improved the developmental potential of mouse embryos exposed to BP-3 in vitro.Compared with the control group,MT treatment significantly increased the protein expression of ATP5A and ATP5B and decreased the DNA damage(P<0.05).Furthermore,the transcription levels of antioxidant gene Gpx1 and pluripotency related genes Pou5f1 and Cdx2 were significantly up-regulated in MT-treated blastocysts,and the expression of pro-apoptotic gene Bax was decreased.Compared with the control group,BP-3 treatment enhanced the signal intensity of γ-H2AX in blastocysts(P<0.05),while adding MT could effectively alleviate DSBs(P<0.05).Conclusion The physiological concentration of BP-3 exposure has reproductive toxicity,but the addition of appropriate con-centration of MT could significantly improve the in vitro developmental potential and quality of BP-3-exposed early embryos.
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Importance: The lack of data quality frameworks to guide the development of artificial intelligence (AI)-ready data sets limits their usefulness for machine learning (ML) research in health care and hinders the diagnostic excellence of developed clinical AI applications for patient care. Objective: To discern what constitutes high-quality and useful data sets for health and biomedical ML research purposes according to subject matter experts. Design, Setting, and Participants: This qualitative study interviewed data set experts, particularly those who are creators and ML researchers. Semistructured interviews were conducted in English and remotely through a secure video conferencing platform between August 23, 2022, and January 5, 2023. A total of 93 experts were invited to participate. Twenty experts were enrolled and interviewed. Using purposive sampling, experts were affiliated with a diverse representation of 16 health data sets/databases across organizational sectors. Content analysis was used to evaluate survey information and thematic analysis was used to analyze interview data. Main Outcomes and Measures: Data set experts' perceptions on what makes data sets AI ready. Results: Participants included 20 data set experts (11 [55%] men; mean [SD] age, 42 [11] years), of whom all were health data set creators, and 18 of the 20 were also ML researchers. Themes (3 main and 11 subthemes) were identified and integrated into an AI-readiness framework to show their association within the health data ecosystem. Participants partially determined the AI readiness of data sets using priority appraisal elements of accuracy, completeness, consistency, and fitness. Ethical acquisition and societal impact emerged as appraisal considerations in that participant samples have not been described to date in prior data quality frameworks. Factors that drive creation of high-quality health data sets and mitigate risks associated with data reuse in ML research were also relevant to AI readiness. The state of data availability, data quality standards, documentation, team science, and incentivization were associated with elements of AI readiness and the overall perception of data set usefulness. Conclusions and Relevance: In this qualitative study of data set experts, participants contributed to the development of a grounded framework for AI data set quality. Data set AI readiness required the concerted appraisal of many elements and the balancing of transparency and ethical reflection against pragmatic constraints. The movement toward more reliable, relevant, and ethical AI and ML applications for patient care will inevitably require strategic updates to data set creation practices.
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Artificial Intelligence , Adult , Female , Humans , Male , Delivery of Health Care , Machine Learning , Qualitative ResearchABSTRACT
Parasitoid wasps control pests via a precise attack leading to the death of the pest. However, parasitoid larvae exhibit self-protection strategies against bracovirus-induced reactive oxygen species impairment. This has a detrimental effect on pest control. Here, we report a strategy for simulating Microplitis bicoloratus bracovirus using Mix-T dsRNA targeting 14 genes associated with transcription, translation, cell-cell communication, and humoral signaling pathways in the host, and from wasp extracellular superoxide dismutases. We implemented either one-time feeding to the younger instar larvae or spraying once on the corn leaves, to effectively control the invading pest Spodoptera frugiperda. This highlights the conserved principle of "biological pest control," as elucidated by the triple interaction of parasitoid-bracovirus-host in a cooperation strategy of bracovirus against its pest host.
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Polydnaviridae , Wasps , Animals , Spodoptera , Polydnaviridae/genetics , Host-Parasite Interactions , LarvaABSTRACT
Importance: Limited sharing of data sets that accurately represent disease and patient diversity limits the generalizability of artificial intelligence (AI) algorithms in health care. Objective: To explore the factors associated with organizational motivation to share health data for AI development. Design, Setting, and Participants: This qualitative study investigated organizational readiness for sharing health data across the academic, governmental, nonprofit, and private sectors. Using a multiple case studies approach, 27 semistructured interviews were conducted with leaders in data-sharing roles from August 29, 2022, to January 9, 2023. The interviews were conducted in the English language using a video conferencing platform. Using a purposive and nonprobabilistic sampling strategy, 78 individuals across 52 unique organizations were identified. Of these, 35 participants were enrolled. Participant recruitment concluded after 27 interviews, as theoretical saturation was reached and no additional themes emerged. Main Outcome and Measure: Concepts defining organizational readiness for data sharing and the association between data-sharing factors and organizational behavior were mapped through iterative qualitative analysis to establish a framework defining organizational readiness for sharing clinical data for AI development. Results: Interviews included 27 leaders from 18 organizations (academia: 10, government: 7, nonprofit: 8, and private: 2). Organizational readiness for data sharing centered around 2 main constructs: motivation and capabilities. Motivation related to the alignment of an organization's values with data-sharing priorities and was associated with its engagement in data-sharing efforts. However, organizational motivation could be modulated by extrinsic incentives for financial or reputational gains. Organizational capabilities comprised infrastructure, people, expertise, and access to data. Cross-sector collaboration was a key strategy to mitigate barriers to access health data. Conclusions and Relevance: This qualitative study identified sector-specific factors that may affect the data-sharing behaviors of health organizations. External incentives may bolster cross-sector collaborations by helping overcome barriers to accessing health data for AI development. The findings suggest that tailored incentives may boost organizational motivation and facilitate sustainable flow of health data for AI development.
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Artificial Intelligence , Delivery of Health Care , Humans , Private Sector , Information Dissemination , MotivationABSTRACT
Cyclobutanone oximes and their derivatives are pivotal core structural motifs in organic chemistry. Iminyl-radical-triggered C-C bond cleavage of cyclobutanone oximes delivers an efficient strategy to produce stable distal cyano-substituted alkyl radicals, which can capture SO2, CO or O2 to form cyanoalkylsulfonyl radicals, cyanoalkylcarbonyl radicals or cyanoalkoxyl radicals under mild conditions. In the past several years, cyanoalkylsulfonylation/cyanoalkylcarbonyaltion/cyanoalkoxylation has attracted a lot of interest. In this updated report, the strategies for trapping SO2, CO or O2via iminyl-radical-triggered ring-opening of cyclobutanone oximes are summarized.
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Introduction: Vaccination rates may be improved through culturally tailored messages, but little is known about them among disaggregated Asian American subgroups. We assessed the vaccination rates for key vaccines among these subgroups. Methods: Using the National Health Interview Survey, we analyzed recent vaccination rates (2015-2018, n=188,250) and trends (2006-2018) among Asians (Chinese [n=3,165], Asian Indian [n=3,525], Filipino [n=3,656], other Asian [n=5,819]) and non-Hispanic White adults (n=172,085) for 6 vaccines (the human papillomavirus, hepatitis B, pneumococcal, influenza, tetanus-diphtheria [tetanus], and shingles vaccines). We controlled demographic, socioeconomic, and health-related variables in multivariable logistic regression and predicted marginal modeling analyses. We also computed vaccination rates among Asian American subgroups on the 2015-2018 National Health Interview Survey data stratified by foreign-born and U.S.-born status. We used Joinpoint regression to analyze trends in vaccination rates. All analyses were conducted in 2021 and 2022. Results: Among Asians, shingles (29.2%; 95% CI=26.6, 32.0), tetanus (53.7%; 95% CI=51.8, 55.6), and pneumococcal (53.8%; 95% CI=50.1, 57.4) vaccination rates were lower than among non-Hispanic Whites. Influenza (47.9%; 95% CI=46.2, 49.6) and hepatitis B (40.5%; 95% CI=39.0, 42.7) vaccination rates were similar or higher than among non-Hispanic Whites (48.4%; 95% CI=47.9, 48.9 and 30.7%; 95% CI=30.1, 31.3, respectively). Among Asians, we found substantial variations in vaccination rates and trends. For example, Asian Indian women had lower human papillomavirus vaccination rates (12.9%; 95% CI=9.1, 18.0) than all other Asian subgroups (Chinese: 37.9%; 95% CI=31.1, 45.2; Filipinos: 38.7%; 95% CI=29.9, 48.3; other Asians: 30.4%; 95% CI=24.8, 36.7) and non-Hispanic Whites (36.1%; 95% CI=34.8, 37.5). Being male, having lower educational attainment and income, having no health insurance or covered by public health insurance only, and lower frequency of doctor visits were generally associated with lower vaccine uptakes. Foreign-born Asian aggregate had lower vaccination rates than U.S.-born Asian aggregate for all vaccines except for influenza. We also found subgroup-level differences in vaccination rates between foreign-born and U.S.-born Asians. We found that (1) foreign-born Chinese, Asian Indians, and other Asians had lower human papillomavirus and hepatitis B vaccination rates; (2) foreign-born Chinese and Filipinos had lower pneumococcal vaccination rates; (3) foreign-born Chinese and Asian Indians had lower influenza vaccination rates; and (4) all foreign-born Asian subgroups had lower tetanus vaccination rates. Conclusions: Vaccination rates and trends differed among Asian American subgroups. Culturally tailored messaging and interventions may improve vaccine uptakes.
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Pancreatic cancer is characterized by its high malignancy, insidious onset and poor prognosis. Most patients with pancreatic cancer are usually diagnosed at advanced stage or with the distant metastasis due to the lack of an effective early screening method. Liquid biopsy technology is promising in studying the occurrence, progression, and early metastasis of pancreatic cancer. In particular, exosomes are pivotal biomarkers in lipid metabolism and liquid biopsy of blood exosomes is valuable for the evaluation of pancreatic cancer. Lipid metabolism is crucial for the formation and activity of exosomes in the extracellular environment. Exosomes and lipids have a complex relationship of mutual influence. Furthermore, spatial metabolomics can quantify the levels and spatial locations of individual metabolites in cancer tissue, cancer stroma, and para-cancerous tissue in pancreatic cancer. However, the relationship among exosomes, lipid metabolism, and pancreatic cancer is also worth considering. This study mainly updates the research progress of metabolomics in pancreatic cancer, their relationship with exosomes, an important part of liquid biopsy, and their lipometabolic roles in pancreatic cancer. We also discuss the mechanisms by which possible metabolites, especially lipid metabolites through exosome transport and other processes, contribute to the recurrence and metastasis of pancreatic cancer.