In recent decades, iodine-catalyzed oxidative coupling reactions utilizing C - H and X - H as nucleophiles have received considerable attention because they represent more efficient, greener, more ...atom-economical, and milder bond-formation strategies over transition-metal-catalyzed oxidative coupling reactions. This Focus Review gives a brief summary of recent development on iodine-catalyzed oxidative coupling reactions utilizing C - H and X - H as nucleophiles.
The efficacy of checkpoint immunotherapy to non-small cell lung cancer (NSCLC) largely depends on the tumor microenvironment (TME). Here, we demonstrate that CCL7 facilitates anti-PD-1 therapy for ...the Kras
Tp53
(KP) and the Kras
Lkb1
(KL) NSCLC mouse models by recruiting conventional DC 1 (cDC1) into the TME to promote T cell expansion. CCL7 exhibits high expression in NSCLC tumor tissues and is positively correlated with the infiltration of cDC1 in the TME and the overall survival of NSCLC patients. CCL7 deficiency impairs the infiltration of cDC1 in the TME and the subsequent expansion of CD8
and CD4
T cells in bronchial draining lymph nodes and TME, thereby promoting tumor development in the KP mouse model. Administration of CCL7 into lungs alone or in combination with anti-PD-1 significantly inhibits tumor development and prolongs the survival of KP and KL mice. These findings suggest that CCL7 potentially serves as a biomarker and adjuvant for checkpoint immunotherapy of NSCLC.
Abstract
Background
Understanding the long-term effects of coronavirus disease 2019 (COVID-19) on cognitive function is essential for monitoring the cognitive decline in the elderly population. This ...study aims to assess the current cognitive status and the longitudinal cognitive decline in elderly patients recovered from COVID-19.
Methods
This cross-sectional study recruited 1539 COVID-19 inpatients aged over 60 years who were discharged from three COVID-19-designated hospitals in Wuhan, China, from February 10 to April 10, 2020. In total, 466 uninfected spouses of COVID-19 patients were selected as controls. The current cognitive status was assessed using a Chinese version of the Telephone Interview of Cognitive Status-40 (TICS-40) and the longitudinal cognitive decline was assessed using an Informant Questionnaire on Cognitive Decline in the Elderly (IQCODE). Cognitive assessments were performed 6 months after patient discharge.
Results
Compared with controls, COVID-19 patients had lower TICS-40 scores and higher IQCODE scores TICS-40 median (IQR): 29 (25 to 32) vs. 30 (26 to 33),
p
< 0.001; IQCODE median (IQR): 3.19 (3.00 to 3.63) vs. 3.06 (3.00 to 3.38),
p
< 0.001. Severe COVID-19 patients had lower TICS-40 scores and higher IQCODE scores than non-severe COVID-19 patients TICS-40 median (IQR): 24 (18 to 28) vs. 30 (26 to 33),
p
< 0.001; IQCODE median (IQR): 3.63 (3.13 to 4.31) vs. 3.13 (3.00 to 3.56),
p
< 0.001 and controls TICS-40 median (IQR): 24 (18 to 28) vs. 30 (26 to 33),
p
< 0.001; IQCODE median (IQR) 3.63 (3.13 to 4.31) vs. 3.06 (3.00 to 3.38),
p
< 0.001. Severe COVID-19 patients had a higher proportion of cases with current cognitive impairment and longitudinal cognitive decline than non-severe COVID-19 patients dementia: 25 (10.50 %) vs. 9 (0.69 %),
p
< 0.001; Mild cognitive impairment (MCI): 60 (25.21 %) vs. 63 (4.84 %),
p
< 0.001 and controls dementia: 25 (10.50 %) vs. 0 (0 %),
p
< 0.001; MCI: 60 (25.21 %) vs. 20 (4.29 %),
p
< 0.001). COVID-19 severity, delirium and COPD were risk factors of current cognitive impairment. Low education level, severe COVID-19, delirium, hypertension and COPD were risk factors of longitudinal cognitive decline.
Conclusions
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with an increased risk of long-term cognitive decline in elderly population. COVID-19 patients, especially severe patients, should be intensively monitored for post-infection cognitive decline.
Cisplatin-based adjuvant chemotherapy is the standard of care for patients with resected stage II–IIIA non-small-cell lung cancer (NSCLC). RADIANT and SELECT trial data suggest patients with ...EGFR-mutant stage IB–IIIA resected NSCLC could benefit from adjuvant EGFR tyrosine kinase inhibitor treatment. We aimed to compare the efficacy of adjuvant gefitinib versus vinorelbine plus cisplatin in patients with completely resected EGFR-mutant stage II–IIIA (N1–N2) NSCLC.
We did a randomised, open-label, phase 3 trial at 27 centres in China. We enrolled patients aged 18–75 years with completely resected (R0), stage II–IIIA (N1–N2), EGFR-mutant (exon 19 deletion or exon 21 Leu858Arg) NSCLC. Patients were stratified by N stage and EGFR mutation status and randomised (1:1) by Pocock and Simon minimisation with a random element to either gefitinib (250 mg once daily) for 24 months or intravenous vinorelbine (25 mg/m2 on days 1 and 8) plus intravenous cisplatin (75 mg/m2 on day 1) every 3 weeks for four cycles. The primary endpoint was disease-free survival in the intention-to-treat population, which comprised all randomised patients; the safety population included all randomised patients who received at least one dose of study medication. Enrolment to the study is closed but survival follow-up is ongoing. The study is registered with ClinicalTrials.gov, number NCT01405079.
Between Sept 19, 2011, and April 24, 2014, 483 patients were screened and 222 patients were randomised, 111 to gefitinib and 111 to vinorelbine plus cisplatin. Median follow-up was 36·5 months (IQR 23·8–44·8). Median disease-free survival was significantly longer with gefitinib (28·7 months 95% CI 24·9–32·5) than with vinorelbine plus cisplatin (18·0 months 13·6–22·3; hazard ratio HR 0·60, 95% CI 0·42–0·87; p=0·0054). In the safety population, the most commonly reported grade 3 or worse adverse events in the gefitinib group (n=106) were raised alanine aminotransferase and asparate aminotransferase (two 2% patients with each event vs none with vinorelbine plus cisplatin). In the vinorelbine plus cisplatin group (n=87), the most frequently reported grade 3 or worse adverse events were neutropenia (30 34% patients vs none with gefitinib), leucopenia (14 16% vs none), and vomiting (eight 9% vs none). Serious adverse events were reported for seven (7%) patients who received gefitinib and 20 (23%) patients who received vinorelbine plus cisplatin. No interstitial lung disease was noted with gefitinib. No deaths were treatment related.
Adjuvant gefitinib led to significantly longer disease-free survival compared with that for vinorelbine plus cisplatin in patients with completely resected stage II–IIIA (N1–N2) EGFR-mutant NSCLC. Based on the superior disease-free survival, reduced toxicity, and improved quality of life, adjuvant gefitinib could be a potential treatment option compared with adjuvant chemotherapy in these patients. However, the duration of benefit with gefitinib after 24 months might be limited and overall survival data are not yet mature.
Guangdong Provincial Key Laboratory of Lung Cancer Translational Medicine; National Health and Family Planning Commission of People's Republic of China; Guangzhou Science and Technology Bureau; AstraZeneca China.
Efficient brain drug delivery has been a challenge in the treatment of Alzheimer's disease (AD) and other brain disorders as blood‐brain barrier (BBB) impedes most drugs to reach brain. To overcome ...this obstacle, a novel poly(lactic‐co‐glycolic acid) (PLGA) nanoparticle conjugated with CD47 extracellular domain via reactive oxygen species (ROS)‐responsive phenylborate ester bond exhibiting “do not eat me” signal and BBB penetrating peptide CRTIGPSVC (CRT) and microglia modulation agent Nec‐1s encapsulated in it is developed. The experimental results show that the designed nanoparticle efficiently increases its half‐life in blood circulation by preventing engulfment via phagocytes, and enhances its brain distribution by synergistic effect of CD47 and CRT. The high level of ROS in mouse brain releases CD47 from the nanoparticles and the resultant particles are effectively phagocytized by resident microglia. The engulfed Nec‐1s modulates pathological microglia to a beneficial state, which reduces Aβ burden, microgliosis and astrocytosis, decreases cytokine production and oxidative stress in the brains of AD mice, and finally attenuates cognition deficits and synapse loss. The results first demonstrate that the conditionally releasable “do not eat me” CD47 signal remarkably facilitates microglia‐targeted drug delivery and warrants further study to develop therapeutic agent for AD treatment.
A poly(lactic‐co‐glycolic acid) (PLGA) nanoparticle conjugated with the “do not eat me” CD47 signal via reactive oxygen species‐responsive bond and blood‐brain barrier penetrating peptide CRTIGPSVC is developed for microglia‐targeted Nec‐1s delivery. This nanoparticle shows increased brain distribution and microglial delivery of drug via conditionally releasable CD47 and can modulate pathological microglia to a beneficial state in Alzheimer's disease treatment.
With the unprecedented progresses of biomedical nanotechnology during the past few decades, conventional drug delivery systems (DDSs) have been involved into smart DDSs with stimuli-responsive ...characteristics. Benefiting from the response to specific internal or external triggers, those well-defined nanoplatforms can increase the drug targeting efficacy, in the meantime, reduce side effects/toxicities of payloads, which are key factors for improving patient compliance. In academic field, variety of smart DDSs have been abundantly demonstrated for various intriguing systems, such as stimuli-responsive polymeric nanoparticles, liposomes, metals/metal oxides, and exosomes. However, these nanoplatforms are lack of standardized manufacturing method, toxicity assessment experience, and clear relevance between the pre-clinical and clinical studies, resulting in the huge difficulties to obtain regulatory and ethics approval. Therefore, such relatively complex stimulus-sensitive nano-DDSs are not currently approved for clinical use. In this review, we highlight the recent advances of smart nanoplatforms for targeting drug delivery. Furthermore, the clinical translation obstacles faced by these smart nanoplatforms have been reviewed and discussed. We also present the future directions and perspectives of stimuli-sensitive DDS in clinical applications.
AIM To analyze the diagnostic value of a circular RNA(circR NA), circ-LDLRAD3, in pancreatic cancer.METHODS Expression levels of circ-LDLRAD3 were tested in both cells and clinical samples; the ...latter included 30 paired pancreatic cancer tissues and adjacent non-tumorous tissues, 31 plasma samples from patients with pancreatic cancer, and 31 plasma samples from healthy volunteers. Real-time quantitative reverse transcriptionpolymerase chain reaction(q RT-PCR) was performed to measure expression levels of circ-LDLRAD3 in cells and clinical samples; then, the relationship between clinicopathological factors of patient samples and expression of circ-LDLRAD3 in pancreatic cancer was analyzed. The diagnostic value of circ-LDLRAD3 was verified by receiver operating characteristic(ROC) curve analysis.RESULTS Circ-LDLRAD3 was up-regulated in pancreatic cancer cell lines(P < 0.01), pancreatic cancer tissues(P < 0.01), and plasma samples from patients with pancreatic cancer(P < 0.01). High expression of circLDLRAD3 was significantly associated with venous invasion, lymphatic invasion, and metastasis. The area under the ROC curve of circ-LDLRAD3 alone or combination with CA19-9 was 0.67 and 0.87, respectively, with a sensitivity and specificity of 0.5738(alone) and 0.7049(alone), and 0.8033(combination) and 0.9355(combination), respectively.CONCLUSION These data suggest that circ-LDLRAD3 may be a biomarker in the diagnosis of pancreatic cancer.
Direct energy deposition (DED) is a promising additive manufacturing technology for large-scale fabrications of high-value components. Grain structure control is challenging but meaningful for ...achieving desirable mechanical properties. A multi-scale three-dimensional (3D) Finite Volume Method-Cellular Automaton (CA-FVM) model is developed. The grain structure evolution in the transition-mode melting is investigated, and the simulated grain structures show fairly good qualitative and quantitative agreement with the experimental results. The influences of laser power and scanning speed on the formed grain structure are examined. A progressive columnar-to-equiaxed transition (CET) is found. The elongated grain is the primary grain morphology, even with the CET. The effects of high temperature gradient on the development of columnar structure are difficult to overcome. Moreover, nanoparticle reinforcement is numerically investigated as a promising technique to realize the site-specific grain structure control by interfering with the columnar growth. We expect this study to provide a deeper understanding of the DED-produced grain structure and improve confidence in the site-specific structure control.
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•A multi-scale three-dimensional Finite Volume Method-Cellular Automaton model is developed.•Columnar-to-equiaxed transition in transition-mode melting is simulated.•Elongated grain is primary grain morphology even with equiaxed nucleation.•Nanoparticle refinement is an efficient way to promote massive nucleation of equiaxed grains.
CHoose nickel: The nickel‐catalyzed oxidative arylation of C(sp3)H bonds has been achieved. Several substituted arylboronic acids and various C(sp3)H bonds were found to be suitable substrates for ...this novel transformation, which is likely to proceed through a radical pathway. This method allows the introduction of simple ether derivatives to construct α‐arylated ethers. FG=functional group.
How to understand the order of Floquet stationary states in the presence of external bath coupling and their statistical mechanics is challenging; the answers are important for preparation and ...control of those Floquet states. Here, we propose a scheme to classify the statistical distribution of Floquet states for time-periodic systems which couple to an external heat bath. If an effective Hamiltonian and a system-bath coupling operator, which are all time independent, can be simultaneously obtained via a time-periodic unitary transformation, the statistical mechanics of the Floquet states is equivalent to the equilibrium statistical mechanics of the effective Hamiltonian. In the large driving frequency cases, we also show that the conditions of this theorem can be weakened to the following: The time-period part in the system Hamiltonian commutes with the system-bath coupling operator. A Floquet-Markov approach is applied to numerically compute the Floquet state occupation distribution of a bosonic chain, and the results agree with the theoretical predictions.
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