AXL antibody and AXL-ADC mediate antitumor efficacy via targeting AXL in tumor-intrinsic epithelial-mesenchymal transition and tumor-associated M2-like macrophage.

The receptor tyrosine kinase AXL is an emerging driver of cancer recurrence, while its molecular mechanism remains unclear. In this study we investigated how AXL regulated the disease progression and poor prognosis in non-small cell lung cancer (NSCLC) and triple negative breast cancer (TNBC). We performed AXL transcriptome analysis from TCGA datasets, and found that AXL expression was significantly elevated in NSCLC and TNBC correlating with poor prognosis, epithelial-mesenchymal transition (EMT) and immune-tolerant tumor microenvironment (TME). Knockdown of AXL or treatment with two independent AXL antibodies (named anti-AXL and AXL02) all diminished cell migration and EMT in AXL-high expressing NSCLC and TNBC cell lines. In a mouse model of 4T1 TNBC, administration of anti-AXL antibody substantially inhibited lung metastases formation and growth, accompanied by reduced downstream signaling activation, EMT and proliferation index, as well as an increased apoptosis and activated anti-tumor immunity. We found that AXL was abundantly activated in tumor nodule-infiltrated M2-macrophages. A specific anti-AXL antibody blocked bone marrow-derived macrophage (BMDM) M2-polarization in vitro. Targeting of AXL in M2-macrophage in addition to tumor cell substantially suppressed CSF-1 production and eliminated M2-macrophage in TME, leading to a coordinated enhancement in both the innate and adaptive immunity reflecting M1-like macrophages, mature dendritic cells, cytotoxic T cells and B cells. We generated a novel and humanized AXL-ADC (AXL02-MMAE) employing a site-specific conjugation platform. AXL02-MMAE exerted potent cytotoxicity against a panel of AXL-high expressing tumor cell lines (IC50 < 0.1 nmol/L) and suppressed in vivo growth of multiple NSCLC and glioma tumors (a minimum efficacy dose<1 mg/kg). Compared to chemotherapy, AXL02-MMAE achieved a superior efficacy in regressing large sized tumors, eliminated AXL-H tumor cell-dependent M2-macrophage infiltration with a robust accumulation of inflammatory macrophages and mature dendritic cells. Our results support AXL-targeted therapy for treatment of advanced NSCLC and TNBC.

Quantum Interference between Photons and Single Quanta of Stored Atomic Coherence.

Essential for building quantum networks over remote independent nodes, the indistinguishability of photons has been extensively studied by observing the coincidence dip in the Hong-Ou-Mandel interferometer. However, indistinguishability is not limited to the same type of bosons. For the first time, we hereby observe quantum interference between flying photons and a single quantum of stored atomic coherence (magnon) in an atom-light beam splitter interface. We demonstrate that the Hermiticity of this interface determines the type of quantum interference between photons and magnons. Consequently, not only the bunching behavior that characterizes bosons is observed, but counterintuitively, fermionlike antibunching as well. The hybrid nature of the demonstrated magnon-photon quantum interface can be applied to versatile quantum memory platforms, and can lead to fundamentally different photon distributions from those occurring in boson sampling.

Resveratrol improves estrus disorder induced by bisphenol A through attenuating oxidative stress, autophagy, and apoptosis.

Bisphenol A (BPA), as a widely used plasticizer, is easily absorbed by animals and humans. It has certain toxic effects on various tissues, including liver, heart, kidney, testis, and ovary. The toxic effects of BPA on animal reproduction have aroused widespread concern, but its regulatory mechanism and antidote in female animals estrus cycle remain unclear. In this study, the results displayed that BPA destroyed the normal estrus cycle of mice through decreasing the levels of progesterone and estradiol. Furthermore, BPA significantly increased the levels of oxidative stress, autophagy, and apoptosis in ovaries and granulosa cells. Interestingly, we found that the natural antioxidant resveratrol rescued estrus disorder and impaired estradiol secretion, reduced the abnormal reactive oxygen species accumulation, autophagy, and apoptosis in BPA exposed ovarian tissues. Moreover, transmission electron microscopy showed that resveratrol reduced BPA-induced autophagic vesicles formation and flow cytometry showed that resveratrol inhibited the increase of apoptotic cells induced by BPA on granulosa cells. Therefore, the supplement of resveratrol could restore BPA-induced estrus disorder by protecting ovarian granulosa cells. Overall, resveratrol is a potential drug to alleviate BPA-induced estrous cycle disorders and ovarian damage.

Therapeutic efficacy and mechanism of CD73-TGFß dual-blockade in a mouse model of triple-negative breast cancer.

Although chemotherapy and recently approved immunotherapies have improved treatment of triple-negative breast cancer (TNBC), the clinical outcome for this deadly disease remains unsatisfactory. We found that both cluster of differentiation 73 (CD73) and transforming growth factor (TGF)ß were elevated in TNBC and correlated with the epithelial-mesenchymal transition (EMT), fibrotic stroma, an immune-tolerant tumor environment, and poor prognosis. To explore the efficacy of CD73-TGFß dual-blockade, we generated a bifunctional anti-CD73-TGFß construct consisting of the CD73 antibody MEDI9447 fused with the TGFßRII extracellular-domain (termed MEDI-TGFßR). MEDI-TGFßR retained full and simultaneous blocking efficiency for CD73 and TGFß. Compared with MEDI9447 activity alone, MEDI-TGFßR demonstrated superior inhibitory activity against CD73-dependent cell migration and the EMT in CD73-high TNBC cells and effectively reduced lung metastasis in a syngeneic mouse model of TNBC. Mechanistically, the CD73-TGFß dual-blockade reverted the EMT and stromal fibrosis and induced tumor cell death, which was accompanied by the accumulation of M1-macrophages and production of tumor necrosis factor α (TNFα). The CD73-TGFß dual-blockade promoted a multifaceted inflammatory tumor microenvironment, as shown by the diminished levels of myeloid-derived suppressor cells (MDSCs) and M2-macrophages, and substantially increased levels of activated dendritic cells, cytotoxic T cells, and B cells. Collectively, our results have highlighted a novel strategy for TNBC treatment.

CircRNA pappalysin 1 facilitates prostate cancer development through miR-515-5p/FKBP1A axis.

The role of circular RNA (circRNA) pappalysin 1 (circ-PAPPA; hsa_circ_0088233) in prostate cancer (PCa) cells was explored in the current study. Circ-PAPPA abundance was markedly enhanced in PCa. Circ-PAPPA interference restrained cell viability, proliferation, motility and glycolysis while elevated the apoptosis rate of PCa cells. Circ-PAPPA negatively regulated microRNA-515-5p (miR-515-5p) abundance. MiR-515-5p silencing largely diminished circ-PAPPA knockdown-mediated effects in PCa cells. MiR-515-5p directly bound to FKBP prolyl isomerase 1A (FKBP1A). MiR-515-5p overexpression-mediated impacts were partly counteracted by FKBP1A overexpression. Circ-PAPPA silencing reduced FKBP1A protein level partly by elevating miR-515-5p expression. Circ-PAPPA knockdown significantly restrained the tumour growth in vivo. Circ-PAPPA elevated the malignant phenotypes of PCa cells by sequestering miR-515-5p to induce the expression of FKBP1A.

Total Synthesis of (+)-3-Deoxyfortalpinoid†F, (+)-Fortalpinoid†A, and (+)-Cephinoid†H.

3-Deoxyfortalpinoid F, fortalpinoid A, and cephinoid H are members of the Cephalotaxus diterpenoids class of natural products, which feature diverse chemical structures and valuable biological activities. We report herein the development of a diastereoselective Pauson-Khand reaction as an effective pathway to access the core tetracyclic skeleton, which is found widely in Cephalotaxus diterpenoids. Furthermore, we enabled the construction of the tropone moiety through a ring-closing metathesis/elimination protocol. Based on the developed strategy, asymmetric synthesis of the title compounds has been achieved for the first time.

Rapid asymmetric reduction of ethyl 4-chloro-3-oxobutanoate using a thermostabilized mutant of ketoreductase ChKRED20.

Ethyl (S)-4-chloro-3-hydroxybutanoate ((S)-CHBE) is an important chiral intermediate for the synthesis of "blockbuster" drug statins. The carbonyl reductase ChKRED20 from Chryseobacterium sp. CA49 was found to catalyze the bio-reductive production of (S)-CHBE with excellent stereoselectivity (>99.5 % ee). Perceiving a capacity for improvement, we sought to increase the thermostability of ChKRED20 to allow a higher reaction temperature. After one round of error-prone PCR (epPCR) library screening followed by the combination of beneficial mutations, a triple-mutant MC135 was successfully achieved with substantially enhanced thermostablity. The activity of MC135 at 50 °C was similar to the wild type. However, at its temperature optima of 65 °C, the mutant displayed 63 % increase of activity compared to the wild type and remained >95 % activity after being incubated for 15 days, while the wild type had a half-life of 11.9 min at 65 °C. At a substrate/catalyst ratio of 100 (w/w), the mutant catalyzed the complete conversion of 300 g/l substrate within 1 h to yield enantiopure (S)-CHBE with an isolated yield of 95 %, corresponding to a space-time yield of 1824 mM/h.

Influence of the potential well on the breakage rate of colloidal aggregates in simple shear and uniaxial extensional flows.

In this work we build on our previous paper (Harshe, Y. M.; Lattuada, M. Langmuir 2012, 28, 283-292) and compute the breakage rate of colloidal aggregates under the effect of shear forces by means of Stokesian dynamics simulations. A library of clusters made of identical spherical particles covering a broad range of masses and fractal dimension values (from 1.8 to 3.0) was generated by means of a combination of several Monte Carlo methods. DLVO theory has been used to describe the interparticle interactions, and contact forces have been introduced by means of the discrete element method. The aggregate breakage process was investigated by exposing them to well-defined shear forces, generated under both simple shear and uniaxial extensional flow conditions, and by recording the time required to reach the first breakage event. It has been found that the breakage rate of clusters was controlled by the potential well between particles as described by DLVO theory. A semiempirical Arrhenius-type exponential equation that relates the potential well to the breakage rate has been used to fit the simulation results. The dependence of the breakage process on the radius of gyration, on the external shear strength, and on the fractal dimension has been obtained, providing a very general relationship for the breakage rate of clusters. It was also found that the fragment mass distribution is insensitive to the presence of electrostatic repulsive interactions. We also clarify the physical reason for the large difference in the breakage rate of clusters between simple shear and the uniaxial extensional flow using a criterion based on the energy dissipation rate. Finally, in order to answer the question of the minimum cluster size that can break under simple shear conditions, a critical rotation number has been introduced, expressing the maximum number of rotations that a cluster exposed to simple shear could sustain before breakage.

Short-Chain Carboxylates Facilitate the Counting of Yeasts in Sub-High Temperature Daqu.

Sub-high temperature Daqu, a traditional solid fermenting agent used in Chinese strong-aroma Baijiu production, is abundant in diverse microorganisms, including bacteria, yeasts, molds, and actinomycetes. Among these, yeasts are pivotal for ethanol production and flavor formation. However, counting yeasts in Daqu is challenging due to interference from molds and bacteria. Antibiotics are employed to inhibit bacterial growth, but there is no practical way to suppress molds without affecting the growth of yeasts. In this study, short-chain carboxylates (C1-C6) were added to the culture medium at various pH conditions to investigate their effects on the growth of molds and yeasts. The results demonstrated distinct inhibitory effects of the short-chain carboxylates, depending on both pH and concentration. Several tested short-chain carboxylates effectively suppressed mold growth on agar plates while leaving yeast growth unaffected. This suggests a simple and feasible method for enhancing the efficiency of yeast isolation and counting in Daqu. Such an approach is valuable for studying yeasts in diverse and complex habitats.

Tissue factor overexpression promotes resistance to KRAS-G12C inhibition in non-small cell lung cancer.

The recently approved KRASG12C mutation-specific inhibitors sotorasib and adagrasib (KRASG12C-I) represent a promising therapy for KRASG12C-driven non-small cell lung cancer (NSCLC). However, many eligible patients do not benefit due to intrinsic or acquired drug resistance. Tissue factor (TF) is overexpressed in KRAS-mutated (KRASmut) NSCLC and is the target of the FDA-approved ADC Tivdak. Here, we employed HuSC1-39, the parent antibody of a clinical stage TF-ADC (NCT04843709), to investigate the role of TF in KRASmut NSCLC. We found that patients with TF-overexpression had poor survival, elevated P-ERK/P-AKT activity levels and low immune effector cell infiltration in the tumor. In a panel of KRASG12C cell lines, KRASG12C-I response correlated with suppression of TF mRNA, which was not observed in resistant cells. In the drug resistant cells, TF-overexpression relied on an mTORC2-mediated and proteasome-dependent pathway. Combination treatment of HuSC1-39 or mTORC1/2 inhibitor MTI-31 with KRASG12C-I each produced synergistic antitumor efficacy in cell culture and in an orthotopic lung tumor model. TF-depletion in the resistant cells diminished epithelial mesenchymal transition, reduced tumor growth and greatly sensitized KRASG12C-I response. Moreover, employing immunohistochemistry and coculture studies, we demonstrated that HuSC1-39 or MTI-31 reset the tumor microenvironment and restore KRASG12C-I sensitivity by reshaping an M1-like macrophage profile with greatly enhanced phagocytic capacity toward tumor cell killing. Thus, we have identified the TF/mTORC2 axis as a critical new mechanism for triggering immunosuppression and KRASG12C-I resistance. We propose that targeting this axis with HuSC1-39 or MTI-31 will improve KRASG12C-I response in KRAS-driven NSCLC.

Highly robust supramolecular polymer networks crosslinked by a tiny amount of metallacycles.

Supramolecular polymeric materials have exhibited attractive features such as self-healing, reversibility, and stimuli-responsiveness. However, on account of the weak bonding nature of most noncovalent interactions, it remains a great challenge to construct supramolecular polymeric materials with high robustness. Moreover, high usage of supramolecular units is usually necessary to promote the formation of robust supramolecular polymeric materials, which restrains their applications. Herein, we describe the construction of highly robust supramolecular polymer networks by using only a tiny amount of metallacycles as the supramolecular crosslinkers. A norbornene ring-opening metathesis copolymer with a 120° dipyridine ligand is prepared and self-assembled with a 60° or 120° Pt(II) acceptor to fabricate the metallacycle-crosslinked polymer networks. With only 0.28 mol% or less pendant dipyridine units to form the metallacycle crosslinkers, the mechanical properties of the polymers are significantly enhanced. The tensile strengths, Young's moduli, and toughness of the reinforced polymers reach up to more than 20 MPa, 600 MPa, and 150 MJ/m3, respectively. Controllable destruction and reconstruction of the metallacycle-crosslinked polymer networks are further demonstrated by the sequential addition of tetrabutylammonium bromide and silver triflate, indicative of good stimuli-responsiveness of the networks. These remarkable performances are attributed to the thermodynamically stable, but dynamic metallacycle-based supramolecular coordination complexes that offer strong linkages with good adaptive characteristics.

Beneficial Effects of Low-Dose Intravenous Dexmedetomidine Premedication in Patient Undergoing Laparoscopic Cholecystectomy Under General Anesthesia: A Prospective, Double-Blind, Randomized Controlled Trial.

Purpose: Dexmedetomidine (Dex) is a potent and highly selective α2-adrenergic receptor agonist. Within an appropriate dose range, Dex can effectively attenuate the surgical stress response, provide intraoperative hemodynamic stability, and improve the patient recovery quality. High-dose Dex can delay patient awakening from anesthesia and increase the incidence of bradycardia. This randomized controlled trial aimed to investigate the effects of low-dose intravenous Dex premedication in patients undergoing laparoscopic cholecystectomy (LC). Material and Methods: In total, 100 patients undergoing LC were equally randomized into Group C (premedication with saline) and Group D (premedication with 0.5 µg/kg Dex). The patients were premedicated with saline or Dex, depending on the group, before anesthesia induction. Following this, anesthesia induction and endotracheal intubation was performed, and anesthesia was maintained during surgery. Following the completion of the surgery, the patients were transferred the post-anesthesia care unit (PACU) and stayed there until they met the PACU discharge criteria. The hemodynamic parameters, consumption of anesthetics, surgical duration, postoperative awakening time, extubation time, postoperative pain, and complications were recorded. Results: No significant differences were observed in the heart rate (HR) and mean arterial pressure (MAP) between the two groups before premedication (P>0.05). The MAP and HR immediately after endotracheal intubation and immediately after extubation were significantly lower in Group D than in Group C (P<0.05 for both). The incidence of bradycardia was significantly higher in Group D than in Group C (P<0.05), while atropine was used in neither group. Propofol and remifentanil consumption was significantly lower in Group D than in Group C (P<0.05). The postoperative awakening and extubation times were significantly shorter in Group D than in Group C (P<0.05). The postoperative visual analog scale scores for pain and incidence of nausea, vomiting, and cough were significantly lower in Group D than in Group C (P<0.05 for all). Conclusion: Our data suggest that premedication with dexmedetomidine (0.5 µg/kg) before general anesthesia induction can effectively attenuate intraoperative stress response and postoperative pain, maintain perioperative hemodynamic stability, and decrease the incidence of adverse events, which might be an effective and safe anesthetic protocol during LC worthy of further clinical application.

Bioinformatics and system biology approach to identify potential common pathogenesis for COVID-19 infection and sarcopenia.

Sarcopenia is a condition characterized by age-related loss of muscle mass and strength. Increasing evidence suggests that patients with sarcopenia have higher rates of coronavirus 2019 (COVID-19) infection and poorer post-infection outcomes. However, the exact mechanism and connections between the two is unknown. In this study, we used high-throughput data from the GEO database for sarcopenia (GSE111016) and COVID-19 (GSE171110) to identify common differentially expressed genes (DEGs). We conducted GO and KEGG pathway analyses, as well as PPI network analysis on these DEGs. Using seven algorithms from the Cytoscape plug-in cytoHubba, we identified 15 common hub genes. Further analyses included enrichment, PPI interaction, TF-gene and miRNA-gene regulatory networks, gene-disease associations, and drug prediction. Additionally, we evaluated immune cell infiltration with CIBERSORT and assessed the diagnostic accuracy of hub genes for sarcopenia and COVID-19 using ROC curves. In total, we identified 66 DEGs (34 up-regulated and 32 down-regulated) and 15 hub genes associated with sarcopenia and COVID-19. GO and KEGG analyses revealed functions and pathways between the two diseases. TF-genes and TF-miRNA regulatory network suggest that FOXOC1 and hsa-mir-155-5p may be identified as key regulators, while gene-disease analysis showed strong correlations with hub genes in schizophrenia and bipolar disorder. Immune infiltration showed a correlation between the degree of immune infiltration and the level of infiltration of different immune cell subpopulations of hub genes in different datasets. The ROC curves for ALDH1L2 and KLF5 genes demonstrated their potential as diagnostic markers for both sarcopenia and COVID-19. This study suggests that sarcopenia and COVID-19 may share pathogenic pathways, and these pathways and hub genes offer new targets and strategies for early diagnosis, effective treatment, and tailored therapies for sarcopenia patients with COVID-19.

[Feasibility of enlarging the ventral space by using a drill under spinal endoscopy in the treatment of severe free lumbar disc herniation].

OBJECTIVE: To evaluate the clinical efficacy of spinal endoscopy in the treatment of severe free lumbar disc herniation and explore the feasibility and application of microscopic drills to expand ventral space. METHODS: Thirty patients with severe free lumbar intervertebral disc herniation treated by spinal endoscopic technique from April 2019 to March 2021 were collected, including 19 males and 11 females;aged from 19 to 76 years with an average of (44.03±16.92) years old. All patients had a single segmental lesion with prolapse of the nucleus pulposus. Among them, there were 3 cases on L2,3, 3 cases on L3,4, 15 cases on L4,5, and 9 cases on L5S1. During operation, posterior bone of vertebral body and pedicle notch were removed by a drill under the endoscope to enlarge the ventral space. And the free nucleus pulposus was exposed and completely removed. The intraoperative blood loss, operation time, hospital stay and postoperative neurological complications were recorded, and Japanese Orthopaedic Association (JOA) score, Oswestry Disability Index (ODI) and visual analogue scale (VAS) were compared before operation, 2 days, 3 months and 1 year after operation, and Macnab standard was used to evaluate clinical efficacy. RESULTS: All operations were successful and the free nucleus pulposus was completely removed. Pain in the lower back and legs was significantly relieved on the day after operation. Two patients experienced transient pain and numbness in lower limbs after operation, and no serious nerve injury complications occurred. ODI and VAS at each time point after surgery were significantly lower than those before surgery (P<0.01), and JOA score was significantly higher than before surgery (P<0.01). The excellent and good rates of Macnab were 66.67% (20/30), 83.33% (25/30) and 90.00% (27/30) on 2 days, 3 months and 1 year after operation, respectively. CONCLUSION: For severe free lumbar intervertebral disc herniation, using of a drill under endoscope to expand the ventral space can smoothly remove the free nucleus pulposus and avoid nerve damage.

Tissue factor overexpression in triple-negative breast cancer promotes immune evasion by impeding T-cell infiltration and effector function.

Triple-negative breast cancer (TNBC) remains a most deadly human malignancy with limited response to chemotherapy, targeted therapy and immunotherapy. Tumor immunoenvironment plays an increasingly important role in therapy outcome. Tissue factor (TF) is the target of the FDA-approved ADC Tivdak. HuSC1-39 is the parent antibody of MRG004A, a clinical stage TF-ADC (NCT04843709). Here, we employed HuSC1-39 (termed "anti-TF") to investigate the role of TF in regulating immune-tolerance in TNBC. We found that patients with aberrant TF expression had a poor prognosis and low immune effector cell infiltration, characterizing as "cold tumor". In the 4T1 TNBC syngeneic mouse model, knockout of tumor cell TF inhibited tumor growth and increased tumor infiltration of effector T cell, which was not dependent on the clotting inhibition. In an immune-reconstituted M-NSG mouse model of TNBC, anti-TF inhibited tumor growth, which was further enhanced by a dual-targeting anti-TF&TGFßR fusion protein. There were diminished P-AKT and P-ERK signaling and profound tumor cell death in treated tumors. Transcriptome analyses and immunohistochemistry revealed a dramatically improved tumor immunoenvironment including the increase of effector T cells, decrease of Treg cells and the transformation of tumor into "hot tumor". Moreover, employing qPCR analysis and T cell culture, we further demonstrated that TF expression in tumor cells is sufficient to block the synthesis and secretion of T cell-recruiting chemokine CXCL9/10/11. Treatment of TF-high TNBC cells with anti-TF or TF-knockout all stimulated CXCL9/10/11 production, promoted T cell migration and effector function. Thus, we have identified a new mechanism of TF in TNBC tumor progression and therapy resistance.

Application of multimodal analgesia combined with opioid-free anesthetics in a non-intubated video-assisted thoracoscopic surgery bullectomy: A case report.

Background: Non-intubated video-assisted thoracoscopic surgery (NIVATS) has been increasingly applied worldwide owing to its benefits of enhanced recovery after surgery (ERAS). Anesthetic management for patients with asthma should focus on minimizing airway stimulation. Case description: A 23-year-old male patient with a history of asthma was diagnosed with left-sided spontaneous pneumothorax. The patient then underwent left-sided NIVATS bullectomy under general anesthesia with preserved spontaneous breathing. Left thoracic paravertebral nerve block (TPVB) with an injection of 0.375% ropivacaine (30 ml) was performed in the 6th paravertebral space under ultrasound guidance. Anesthesia induction commenced until the cold sensation in the surgical area had disappeared. General anesthesia was induced by midazolam, penehyclidine hydrochloride, esketamine, and propofol and then maintained using propofol and esketamine. Surgery commenced after the patient was positioned in the right lateral recumbency. The collapse of the left lung was satisfactory, and the operative field was ensured after artificial pneumothorax. The surgical procedure was uneventful, intraoperative arterial blood gases were within normal ranges, and vital signs were stable. The patient awakened rapidly without any adverse reactions at the end of the surgery and was then transferred to the ward. During the postoperative follow-up, the patient experienced mild pain 48 h after surgery. The patient was discharged from the hospital 2 days postoperatively and developed no nausea, vomiting, or any other complications. Conclusion: The present case suggests the feasibility of TPVB in combination with non-opioid anesthetics to provide high-quality anesthesia in patients undergoing NIVATS bullectomy.

Investigation of the Relationship between Aptamers' Targeting Functions and Human Plasma Proteins.

Aptamers are single-stranded DNA or RNA molecules capable of recognizing targets via specific three-dimensional structures. Taking advantage of this unique targeting function, aptamers have been extensively applied to bioanalysis and disease theranostics. However, the targeting functionality of aptamers in the physiological milieu is greatly impeded compared with their in vitro applications. To investigate the physiological factors that adversely affect the in vivo targeting ability of aptamers, we herein systematically studied the interactions between human plasma proteins and aptamers and the specific effects of plasma proteins on aptamer targeting. Microscale thermophoresis and flow cytometry analysis showed that plasma interacted with aptamers, restricting their affinity toward targeted tumor cells. Further pull-down assay and proteomic identification verified that the interactions between aptamers and plasma proteins were mainly involved in complement activation and immune response as well as showed structure-selective and sequence-specific features. Particularly, the fibronectin 1 (FN1) protein showed dramatically specific interactions with nucleolin (NCL) targeting aptamer AS1411. The competitive binding between FN1 and NCL almost deprived the AS1411 aptamer's targeting ability in vivo. In order to maintain the targeting function in the physiological milieu, a series of optimizations were performed via the chemical modifications of AS1411 aptamer, and 3'-terminal pegylation was demonstrated to be resistant to the interaction with FN1, leading to improved tumor-targeting effects. This work emphasizes the physiological environment influences on aptamers targeting functionality and suggests that rational design and modification of aptamers to minimize the nonspecific interaction with plasma proteins might be effective to maintain aptamer functionality in future clinical uses.

The relationship between physical activity and subjective cognitive decline: Evidence from the behavioral risk factor surveillance system (BRFSS).

BACKGROUND: Studies have shown that subjective cognitive decline (SCD) is a major risk factor for mild cognitive impairment or even dementia, but the relationship between physical activity (PA) and SCD is still unclear. The goal of current study is to address how various physical activities relate to SCD. METHODS: 216,593 adults from the Behavioral Risk Factor Surveillance System (BRFSS) were included in this study. We measured SCD and PA with participants' self-report. With the unconditional logistic regression model, the association between PA and SCD was investigated. We used a four-way decomposition method to explore the mediation roles of depression between PA and SCD. The nearest matching method of propensity score and multinomial propensity score were used to reduce the effects of confounding factors. RESULTS: Compared with those inactive, the weighted adjusted odds ratios (AORs) of SCD among those who were physically active were <1 (p < 0.005), regardless of the type of PA. The top three PA in weighted AORs were: running (AOR: 0.51, 95 % CI: 0.50-0.52), aerobics exercise (AOR: 0.55, 95 % CI: 0.53-0.56), and weightlifting (AOR: 0.60, 95 % CI: 0.59-0.62). The dose-response relationship between PA and SCD was found. Participants who engaged in PA for 241-300 min per week (AOR: 0.61, 95 % CI: 0.59-0.62) or exercised metabolic equivalent of 801-1000 per week (AOR: 0.62, 95 % CI: 0.62-0.65) had the lowest risk of SCD. CONCLUSIONS: Regardless of the specific PA types, engaging in PA is associated with a reduced risk of having SCD, and people who engage in running had the lowest risk of SCD. There was a dose-response relationship between PA and SCD, and PA-based interventions should be developed accordingly to prevent cognitive deterioration in older age.

Compositional isotemporal substitution analysis of physical activity, sedentary behaviour and cardiometabolic biomarkers in US adults: A nationally representative study.

Substantial evidence links physical activity and sedentary behaviour (SB) with cardiovascular health. However, studies usually examine time-use behaviours independently, rather than considering daily activities as a 24-hour time-use composition. This study aimed to use compositional data models to investigate how time reallocations from SB to moderate-to-vigorous physical activity (MVPA)/ light physical activity (LPA) were associated with changes in cardiometabolic biomarkers. Compositional isotemporal substitution analysis was conducted using data from a representative cross-sectional sample of adults aged 20 years or older (n = 5213 full sample; n = 2221 fasting subsample) from the 2003-2004 and 2005-2006 cycles of the National Health and Nutrition Examination Survey. Overall as well as gender- and age-specific estimates were obtained for reallocating time between the behaviours associated with cardiometabolic outcomes. Replacing SB with MVPA was associated with decreased levels of C-reactive protein (CRP), white blood cells (WBCs), red blood cell distribution width (RDW), insulin, insulin resistance homeostasis model assessment (HOMA-IR) and 2-hour glucose, and increased high-density lipoprotein cholesterol (HDL-C), except for WBCs in older adults, insulin and HOMA-IR in females and older adults, 2-hour glucose in young and older adults, and HDL-C in older adults. Substituting LPA for SB resulted in lower CRP in older adults, lower RDW in males and older adults, lower insulin in young and middle-aged adults, lower HOMA-IR in females and middle-aged adults, and higher HDL-C in males and young adults. Our findings provide new evidence for the potential benefits of LPA and MVPA in cardiovascular health and help make population-specific recommendations for physical activity.HighlightsShorter sedentary behaviour (SB) time and longer active behaviours time are associated with a lower cardiovascular disease risk profile.Although replacing SB with MVPA has stronger positive health effects, LPA, as a simpler and more feasible activity, may has greater potential in promoting cardiovascular health.The expected changes in cardiometabolic biomarkers caused by time reallocations from SB to MVPA/LPA vary with gender and age, and physical activity guidelines with specific recommendations should be tailed to the subpopulations.

Efficacy and Safety of a Subanesthetic Dose of Esketamine Combined with Propofol in Patients with Obesity Undergoing Painless Gastroscopy: A Prospective, Double-Blind, Randomized Controlled Trial.

Purpose: Patients with obesity are more susceptible to hypoxemia. Anesthetic management for patients with obesity undergoing painless gastroscopy presents a severe challenge for anesthesiologists. Esketamine is a NMDA antagonist that has been proven to be beneficial for ameliorating respiratory depression owing to its sympathomimetic effect; however, there are no relevant reports on its use in patients with obesity. We designed a randomized controlled trial to evaluate whether esketamine can be the ideal adjuvant to propofol sedation in patients with obesity undergoing painless gastroscopy. Patients and Methods: A total of 104 patients with obesity undergoing painless gastroscopy were randomly divided into group C (propofol+saline) and group S (propofol+esketamine 0.25 mg/kg). Anesthesia was induced by 2 mg/kg propofol with saline or esketamine. The consumption of propofol, hemodynamic parameters, duration of procedure, induction time, postoperative awakening time, and orientation recovery time were recorded. Adverse events and satisfaction scores were also recorded. Results: Propofol consumption was 274.4±22.6 mg and 201.3±16.6 mg in groups C and S, respectively. The induction time of groups C and S were 25.4±2.3 s and 17.8±1.9 s, respectively. The postoperative awakening times of groups C and S were 6.2±1.1 min and 4.8±1.3 min, respectively. Hemodynamic parameters were more stable in group S than in group C. The incidence of adverse events such as injection pain, hypoxemia, hypotension, bradycardia, choking, and body movement were significantly lower in group S. The satisfaction scores of the endoscopist and anesthesiologist were (4.58±0.49 vs 3.71±0.83) and (4.75±0.44 vs 3.33±0.92), respectively. Conclusion: The combination of propofol and esketamine (0.25 mg/kg) improves the safety and reduces the incidence of adverse events in patients with obesity during painless gastroscopy. Thus, this method is worthy of clinical application. Clinical Trials Registration: ChiCTR 2200062547.