Phosphorus‐substituted heterocycles represent an important class of organophosphorus compounds, which not only widely exist in biologically active pharmaceuticals, agrochemicals, but also have ...widespread applications in material science and organic synthesis as ligands for transition metal complexes. The synthesis of such compounds integrates the development of new synthetic methods and exploration of efficient catalytic systems, reflects the latest achievements in organic, transition metal, photo and even electrochemical catalysis, and facilitates the synthesis of sufficient quantities of related compounds as potential medicinal agents and biological probes in this area. Over the past few decades, two major synthetic strategies have been established toward phosphorus‐substituted heterocycles. This review summarizes the recent progress in this field and discusses the reaction mechanisms in detail. The advantages and limitations of each subdivisional tactic are presented, and the synthetic opportunities still open are outlined.
To develop and validate a radiomics model for evaluating pathologic complete response (pCR) to neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer (LARC).
We enrolled 222 ...patients (152 in the primary cohort and 70 in the validation cohort) with clinicopathologically confirmed LARC who received chemoradiotherapy before surgery. All patients underwent T2-weighted and diffusion-weighted imaging before and after chemoradiotherapy; 2,252 radiomic features were extracted from each patient before and after treatment imaging. The two-sample
test and the least absolute shrinkage and selection operator regression were used for feature selection, whereupon a radiomics signature was built with support vector machines. Multivariable logistic regression analysis was then used to develop a radiomics model incorporating the radiomics signature and independent clinicopathologic risk factors. The performance of the radiomics model was assessed by its calibration, discrimination, and clinical usefulness with independent validation.
The radiomics signature comprised 30 selected features and showed good discrimination performance in both the primary and validation cohorts. The individualized radiomics model, which incorporated the radiomics signature and tumor length, also showed good discrimination, with an area under the receiver operating characteristic curve of 0.9756 (95% confidence interval, 0.9185-0.9711) in the validation cohort, and good calibration. Decision curve analysis confirmed the clinical utility of the radiomics model.
Using pre- and posttreatment MRI data, we developed a radiomics model with excellent performance for individualized, noninvasive prediction of pCR. This model may be used to identify LARC patients who can omit surgery after chemoradiotherapy.
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Since December 2019, a novel coronavirus SARS-CoV-2 has emerged and rapidly spread throughout the world, resulting in a global public health emergency. The lack of vaccine and antivirals has brought ...an urgent need for an animal model. Human angiotensin-converting enzyme II (ACE2) has been identified as a functional receptor for SARS-CoV-2. In this study, we generated a mouse model expressing human ACE2 (hACE2) by using CRISPR/Cas9 knockin technology. In comparison with wild-type C57BL/6 mice, both young and aged hACE2 mice sustained high viral loads in lung, trachea, and brain upon intranasal infection. Although fatalities were not observed, interstitial pneumonia and elevated cytokines were seen in SARS-CoV-2 infected-aged hACE2 mice. Interestingly, intragastric inoculation of SARS-CoV-2 was seen to cause productive infection and lead to pulmonary pathological changes in hACE2 mice. Overall, this animal model described here provides a useful tool for studying SARS-CoV-2 transmission and pathogenesis and evaluating COVID-19 vaccines and therapeutics.
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•Human ACE2 knockin mice were generated by using CRISPR/Cas9 technology•SARS-CoV-2 leads to robust replication in lung, trachea, and brain•SARS-CoV-2 causes interstitial pneumonia and elevated cytokine in aged hACE2 mice•High dose of SARS-CoV-2 can establish infection via intragastric route in hACE2 mice
The COVID-19 pandemic has brought an urgent need for small animal models. Here, Sun et al. established an ACE2 humanized mouse by CRISPR/Cas9 knockin technology. These hACE2 mice are susceptible to SARS-CoV-2 infection upon intranasal inoculation, and the resulting pulmonary infection and pathological changes resemble those observed in COVID-19 patients.
Statins are lipid-lowering therapeutics with favorable anti-inflammatory profiles and have been proposed as an adjunct therapy for COVID-19. However, statins may increase the risk of SARS-CoV-2 viral ...entry by inducing ACE2 expression. Here, we performed a retrospective study on 13,981 patients with COVID-19 in Hubei Province, China, among which 1,219 received statins. Based on a mixed-effect Cox model after propensity score-matching, we found that the risk for 28-day all-cause mortality was 5.2% and 9.4% in the matched statin and non-statin groups, respectively, with an adjusted hazard ratio of 0.58. The statin use-associated lower risk of mortality was also observed in the Cox time-varying model and marginal structural model analysis. These results give support for the completion of ongoing prospective studies and randomized controlled trials involving statin treatment for COVID-19, which are needed to further validate the utility of this class of drugs to combat the mortality of this pandemic.
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•Statin treatment among 13,981 patients with COVID-19 was retrospectively studied•Statin use in this cohort was associated with a lower risk of all-cause mortality•Adding an ACE inhibitor or an ARB did not affect statin-associated outcome in the cohort•The benefit of statins among this cohort may be due to immunomodulatory benefits
Statins have anti-inflammatory benefits and were suggested as an adjunct therapy for COVID-19. But statins may increase the expression of ACE2, the receptor for SARS-CoV-2. Here, Zhang et al. retrospectively analyzed 13,981 COVID-19 cases and found that in-hospital statin use is associated with a lower risk of all-cause mortality.
Effective reversal of tumor immunosuppression is of critical importance in cancer therapy. A multifunctional delivery vector that can effectively deliver CRISPR‐Cas9 plasmid for β‐catenin knockout to ...reverse tumor immunosuppression is constructed. The multi‐functionalized delivery vector is decorated with aptamer‐conjugated hyaluronic acid and peptide‐conjugated hyaluronic acid to combine the tumor cell/nuclear targeting function of AS1411 with the cell penetrating/nuclear translocation function of TAT‐NLS. Due to the significantly enhanced plasmid enrichment in malignant cell nuclei, the genome editing system can induce effective β‐catenin knockout and suppress Wnt/β‐catenin pathway, resulting in notably downregulated proteins involved in tumor progression and immunosuppression. Programmed death‐ligand 1 (PD‐L1) downregulation in edited tumor cells not only releases the PD‐1/PD‐L1 brake to improve the cancer killing capability of CD8+ T cells, but also enhances antitumor immune responses of immune cells. This provides a facile strategy to reverse tumor immunosuppression and to restore immunosurveillance and activate anti‐tumor immunity.
An aptamer/peptide‐functionalized delivery vector is constructed to effectively deliver CRISPR‐Cas9 plasmid to tumor cells for β‐catenin knockout to eliminate tumor immunosuppression. The significantly decreased programmed death‐ligand 1 (PD‐L1) in edited tumor cells not only releases the PD‐1/PD‐L1 brake to improve the cancer‐killing capability of T cells, but also enhances the antitumor immune responses of the immune cells co‐cultured with edited tumor cells.
Perfluoroalkyl substances (PFAS) are widely used in various manufacturing processes. Accumulation of these chemicals has adverse effects on human health, including inflammation in multiple organs, ...yet how PFAS are sensed by host cells, and how tissue inflammation eventually incurs, is still unclear. Here, we show that the double-stranded DNA receptor AIM2 is able to recognize perfluorooctane sulfonate (PFOS), a common form of PFAS, to trigger IL-1β secretion and pyroptosis. Mechanistically, PFOS activates the AIM2 inflammasome in a process involving mitochondrial DNA release through the Ca
-PKC-NF-κB/JNK-BAX/BAK axis. Accordingly, Aim2
mice have reduced PFOS-induced inflammation, as well as tissue damage in the lungs, livers, and kidneys in both their basic condition and in an asthmatic exacerbation model. Our results thus suggest a function of AIM2 in PFOS-mediated tissue inflammation, and identify AIM2 as a major pattern recognition receptor in response to the environmental organic pollutants.
Indole derivatives are important heterocycles in organic synthesis for serving as privileged building blocks for functional material and as key components in a lot of bioactive compounds. Propargylic ...alcohols, bearing alkynyl and hydroxyl functional groups, have emerged as promising feedstock materials for the construction of carbo‐ and heterocycles. Especially, in the last decade, the Lewis or Brønsted acid catalysed tandem annulations of propargylic alcohols to build structurally diverse indole derivatives have been well‐investigated. In this review, we summarize two main synthetic strategies toward indole derivatives via the cascade reactions of propargylic alcohols: indole‐ring formation involved tandem reactions and the direct function‐alization of indole skeletons. We hope this review would help to develop new and more efficient protocols for the synthesis of indole‐included N‐heterocycles.
Copper and zinc are essential micronutrients, whose imbalance may be involved in the development and progression of cancer. However, the role of copper and/or zinc imbalance in the prognosis of ...hepatocellular carcinoma (HCC) is currently unclear. Our objective was to investigate the association between serum levels of copper, zinc and their ratio (copper/zinc) at diagnosis with HCC survival. We included 989 patients with incident HCC in this prospective cohort study, who were enrolled in the Guangdong Liver Cancer Cohort (GLCC) study within 30 days of diagnosis between September 2013 and February 2017. Serum copper and zinc were measured using inductively coupled plasma mass spectrometry. Primary outcomes were liver cancer‐specific survival (LCSS) and overall survival (OS). Cox proportional hazards models were used to calculate the multivariable hazard ratios (HRs) and 95% confidence interval (CI). Higher serum copper levels were strongly associated with worse LCSS (Q4 vs. Q1: HR = 1.87, 95% CI: 1.22–2.86; p < 0.01 for trend) and OS (Q4 vs. Q1: HR = 2.06, 95% CI: 1.36–3.11; p < 0.01 for trend). The calculated copper/zinc ratio was positively associated with LCSS (Q4 vs. Q1: HR = 1.31, 95% CI: 0.89–1.92; P = 0.04 for trend) and OS (Q4 vs. Q1: HR = 1.43, 95% CI: 0.99–2.08; P = 0.01 for trend). No overall associations were observed between serum zinc levels and LCSS or OS in the entire cohort. The results suggest that higher serum copper and copper in relation to zinc levels (i.e., higher copper/zinc ratio) may be associated with worse HCC survival, but serum zinc levels may be not associated with HCC survival.
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Copper and zinc are essential micronutrients whose imbalance may be involved in development and progression of cancer. Currently, the role of copper and/or zinc imbalance in the prognosis of hepatocellular carcinoma (HCC) however remains unclear. The authors examine for the first time whether serum levels of copper, zinc, and their ratios are associated with survival in a large prospective cohort of newly diagnosed patients. The findings suggest that higher copper levels and copper/zinc ratios are associated with worse survival, but serum zinc levels are not associated with HCC survival. The results may have important implications for the prognosis of HCC.
The SARS-CoV-2-infected disease (COVID-19) outbreak is a major threat to human beings. Previous studies mainly focused on Wuhan and typical symptoms. We analysed 74 confirmed COVID-19 cases with GI ...symptoms in the Zhejiang province to determine epidemiological, clinical and virological characteristics.
COVID-19 hospital patients were admitted in the Zhejiang province from 17 January 2020 to 8 February 2020. Epidemiological, demographic, clinical, laboratory, management and outcome data of patients with GI symptoms were analysed using multivariate analysis for risk of severe/critical type. Bioinformatics were used to analyse features of SARS-CoV-2 from Zhejiang province.
Among enrolled 651 patients, 74 (11.4%) presented with at least one GI symptom (nausea, vomiting or diarrhoea), average age of 46.14 years, 4-day incubation period and 10.8% had pre-existing liver disease. Of patients with COVID-19 with GI symptoms, 17 (22.97%) and 23 (31.08%) had severe/critical types and family clustering, respectively, significantly higher than those without GI symptoms, 47 (8.14%) and 118 (20.45%). Of patients with COVID-19 with GI symptoms, 29 (39.19%), 23 (31.08%), 8 (10.81%) and 16 (21.62%) had significantly higher rates of fever >38.5°C, fatigue, shortness of breath and headache, respectively. Low-dose glucocorticoids and antibiotics were administered to 14.86% and 41.89% of patients, respectively. Sputum production and increased lactate dehydrogenase/glucose levels were risk factors for severe/critical type. Bioinformatics showed sequence mutation of SARS-CoV-2 with m
A methylation and changed binding capacity with ACE2.
We report COVID-19 cases with GI symptoms with novel features outside Wuhan. Attention to patients with COVID-19 with non-classic symptoms should increase to protect health providers.
Use of ACEIs (angiotensin-converting enzyme inhibitors) and ARBs (angiotensin II receptor blockers) is a major concern for clinicians treating coronavirus disease 2019 (COVID-19) in patients with ...hypertension.
To determine the association between in-hospital use of ACEI/ARB and all-cause mortality in patients with hypertension and hospitalized due to COVID-19.
This retrospective, multi-center study included 1128 adult patients with hypertension diagnosed with COVID-19, including 188 taking ACEI/ARB (ACEI/ARB group; median age 64 interquartile range, 55-68 years; 53.2% men) and 940 without using ACEI/ARB (non-ACEI/ARB group; median age 64 interquartile range 57-69; 53.5% men), who were admitted to 9 hospitals in Hubei Province, China from December 31, 2019 to February 20, 2020. In mixed-effect Cox model treating site as a random effect, after adjusting for age, gender, comorbidities, and in-hospital medications, the detected risk for all-cause mortality was lower in the ACEI/ARB group versus the non-ACEI/ARB group (adjusted hazard ratio, 0.42 95% CI, 0.19-0.92;
=0.03). In a propensity score-matched analysis followed by adjusting imbalanced variables in mixed-effect Cox model, the results consistently demonstrated lower risk of COVID-19 mortality in patients who received ACEI/ARB versus those who did not receive ACEI/ARB (adjusted hazard ratio, 0.37 95% CI, 0.15-0.89;
=0.03). Further subgroup propensity score-matched analysis indicated that, compared with use of other antihypertensive drugs, ACEI/ARB was also associated with decreased mortality (adjusted hazard ratio, 0.30 95% CI, 0.12-0.70;
=0.01) in patients with COVID-19 and coexisting hypertension.
Among hospitalized patients with COVID-19 and coexisting hypertension, inpatient use of ACEI/ARB was associated with lower risk of all-cause mortality compared with ACEI/ARB nonusers. While study interpretation needs to consider the potential for residual confounders, it is unlikely that in-hospital use of ACEI/ARB was associated with an increased mortality risk.
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