Some syphilis patients remain in a serologically active state after the recommended therapy. We currently know too little about the characteristics of this serological response.
We conducted a cohort ...study using the clinical database from Zhongshan Hospital, Medical College of Xiamen. In total, 1,327 HIV-negative patients with primary, secondary, latent, and tertiary syphilis were enrolled. Bivariate and multivariate analyses were utilised to identify factors associated with a serological cure and serofast state in syphilis patients one year after therapy. Chi-square tests were used to determine the differences in the serological cure rate across different therapy time points.
One year after the recommended therapy, 870 patients achieved a serological cure, and 457 patients (34.4%) remained in the serofast state. The serological cure rate increased only within the first 6 months. The bivariate analysis indicated that male or younger patients had a higher likelihood of a serological cure than female or older patients. Having a baseline titre ≤ 1∶2 or ≥ 1∶64 was associated with an increased likelihood of a serological cure. The serological cure rate decreased for the different disease stages in the order of primary, secondary, latent, and tertiary syphilis. A distinction should be drawn between early and late syphilis. The multivariate analysis indicated that a serological cure was significantly associated with the disease phase, gender, age, and baseline rapid plasma reagin (RPR) titre.
The serofast state is common in clinical work. After one year of the recommended therapy, quite a few syphilis patients remained RPR positive. The primary endpoint of the study indicated that disease phase, gender, age and baseline RPR titre were crucial factors associated with a serological cure.
Two-dimensional materials provide extraordinary opportunities for exploring phenomena arising in atomically thin crystals. Beginning with the first isolation of graphene, mechanical exfoliation has ...been a key to provide high-quality two-dimensional materials, but despite improvements it is still limited in yield, lateral size and contamination. Here we introduce a contamination-free, one-step and universal Au-assisted mechanical exfoliation method and demonstrate its effectiveness by isolating 40 types of single-crystalline monolayers, including elemental two-dimensional crystals, metal-dichalcogenides, magnets and superconductors. Most of them are of millimeter-size and high-quality, as shown by transfer-free measurements of electron microscopy, photo spectroscopies and electrical transport. Large suspended two-dimensional crystals and heterojunctions were also prepared with high-yield. Enhanced adhesion between the crystals and the substrates enables such efficient exfoliation, for which we identify a gold-assisted exfoliation method that underpins a universal route for producing large-area monolayers and thus supports studies of fundamental properties and potential application of two-dimensional materials.
Abnormal activation of the extrasynaptic N‐methyl‐d‐aspartate receptor (NMDAR) contributes to the pathogenesis of Alzheimer's disease (AD). Ceftriaxone (Cef) can improve cognitive impairment by ...upregulating glutamate transporter‐1 and promoting the glutamate–glutamine cycle in an AD mouse model. This study aimed to investigate the effects of Cef on synaptic plasticity and cognitive‐behavioral impairment and to unravel the associated underlying mechanisms. We used an APPswe/PS1dE9 (APP/PS1) mouse model of AD in this study. Extrasynaptic components from hippocampal tissue homogenates were isolated using density gradient centrifugation. Western blot was performed to evaluate the expressions of extrasynaptic NMDAR and its downstream elements. Intracerebroventricular injections of adeno‐associated virus (AAV)‐striatal enriched tyrosine phosphatase 61 (STEP61) and AAV‐STEP61‐shRNA were used to modulate the expressions of STEP61 and extrasynaptic NMDAR. Long‐term potentiation (LTP) and Morris water maze (MWM) tests were performed to evaluate the synaptic plasticity and cognitive function. The results showed that the expressions of GluN2B and GluN2BTyr1472 in the extrasynaptic fraction were upregulated in AD mice. Cef treatment effectively prevented the upregulation of GluN2B and GluN2BTyr1472 expressions. It also prevented changes in the downstream signals of extrasynaptic NMDAR, including increased expressions of m‐calpain and phosphorylated p38 MAPK in AD mice. Furthermore, STEP61 upregulation enhanced, whereas STEP61 downregulation reduced the Cef‐induced inhibition of the expressions of GluN2B, GluN2BTyr1472, and p38 MAPK in the AD mice. Similarly, STEP61 modulation affected Cef‐induced improvements in induction of LTP and performance in MWM tests. In conclusion, Cef improved synaptic plasticity and cognitive behavioral impairment in APP/PS1 AD mice by inhibiting the overactivation of extrasynaptic NMDAR and STEP61 cleavage due to extrasynaptic NMDAR activation.
Glutamate receptor GLT‐1 damage leads to increased perisynaptic glutamate concentration in Alzheimer's disease (AD), which activates extrasynaptic N‐methyl‐d‐aspartate receptor (eNMDAR) and its downstream signaling and causes impairment of synaptic plasticity and cognition. The results showed that ceftriaxone downregulated eNMDAR expression, inhibited eNMDAR‐STEP61 and p38 MAPK signaling, and improved impairments of long‐term potentiation (LTP) and Morris water maze in AD mice. The STEP61‐mediated modulation of eNMDAR confirmed the hypothesis that ceftriaxone exerts anti‐AD effects by improving GLT‐1 impairment and inhibiting the activation of eNMDAR and its downstream signals.
Lung cancer is often diagnosed at an advanced stage and has a poor prognosis. Conventional treatments are not effective for metastatic lung cancer therapy. Although some of molecular targets have ...been identified with favorable response, those targets cannot be exploited due to the lack of suitable drug carriers. Lung cancer cell-derived exosomes (LCCDEs) receive recent interest in its role in carcinogenesis, diagnosis, therapy, and prognosis of lung cancer due to its biological functions and natural ability to carry donor cell biomolecules. LCCDEs can promote cell proliferation and metastasis, affect angiogenesis, modulate antitumor immune responses during lung cancer carcinogenesis, regulate drug resistance in lung cancer therapy, and be now considered an important component in liquid biopsy assessments for detecting lung cancer. Therapeutic deliverable exosomes are emerging as promising drug delivery agents specifically to tumor high precision medicine because of their natural intercellular communication role, excellent biocompatibility, low immunogenicity, low toxicity, long blood circulation ability, biodegradable characteristics, and their ability to cross various biological barriers. Several studies are currently underway to develop novel diagnostic and prognostic modalities using LCCDEs, and to develop methods of exploiting exosomes for use as efficient drug delivery vehicles. Current status of lung cancer and extensive applicability of LCCDEs are illustrated in this review. The promising data and technologies indicate that the approach on LCCDEs implies the potential application of LCCDEs to clinical management of lung cancer patients.
We analyzed the number of circulating tumor cells (CTCs) and Epstein–Barr virus DNA (EBV DNA) for diagnosis, monitoring and prognosis of patients with metastatic nasopharyngeal carcinoma (mNPC). The ...levels of CTCs and EBV DNA were measured at baseline and after first‐line chemotherapy in 148 mNPC patients prospectively enrolled between December 2014 and August 2016. We also collected 122 non‐mNPC cases within the same time frame for examining CTCs and EBV DNA at baseline. In 270 NPC patients, we observed improved specificity (86.0% vs. 41.0%) and inferior sensitivity (42.3% vs. 81.3%) of CTCs as compared to EBV DNA for diagnosis of distant metastasis. mNPC patients were stratified into unfavorable and favorable prognostic groups, respectively, based on CTC of 12 at baseline and 1 after first‐line chemotherapy and EBV DNA of 10,000 at baseline and 4,000 after first‐line chemotherapy. Conversion of baseline unfavorable CTCs and EBV DNA to favorable after first‐line chemotherapy was associated with significantly longer progression‐free survival (PFS) and overall survival (OS) compared to patients with unfavorable CTCs and EBV DNA at both time points. Among patients with a complete/partial response as per imaging evaluation, favorable CTCs and EBV DNA levels after first‐line chemotherapy were associated with significantly longer PFS and OS. In conclusion, our data demonstrated the number of CTCs and EBV DNA before, after and during first‐line chemotherapy were strong predictive markers for mNPC patients. When utilized in conjunction with imaging studies, CTCs and EBV DNA could provide additional prognostic information.
What's new?
Endemic nasopharyngeal carcinoma (NPC) is associated with latent infection of the oncogenic Epstein‐Barr virus (EBV) and frequently metastasizes to distant lymph nodes and organs. Metastatic NPC is treated by serial administration of cytotoxic or targeted therapies and treatment response is generally assessed with serial imaging, which often fails to detect changes in tumor burden. Here, the authors show that the number of circulating tumor cells (CTCs) and EBV DNA levels before, after, and during first‐line chemotherapy are strong predictive markers for mNPC patients. When utilized in conjunction with imaging studies, CTCs and EBV DNA could provide additional prognostic information.
Medicines for the treatment of 2019-novel coronavirus (2019-nCoV) infections are urgently needed. However, drug screening using live 2019-nCoV requires high-level biosafety facilities, which imposes ...an obstacle for those institutions without such facilities or 2019-nCoV. This study aims to repurpose the clinically approved drugs for the treatment of coronavirus disease 2019 (COVID-19) in a 2019-nCoV-related coronavirus model.
A 2019-nCoV-related pangolin coronavirus GX_P2V/pangolin/2017/Guangxi was described. Whether GX_P2V uses angiotensin-converting enzyme 2 (ACE2) as the cell receptor was investigated by using small interfering RNA (siRNA)-mediated silencing of ACE2. The pangolin coronavirus model was used to identify drug candidates for treating 2019-nCoV infection. Two libraries of 2406 clinically approved drugs were screened for their ability to inhibit cytopathic effects on Vero E6 cells by GX_P2V infection. The anti-viral activities and anti-viral mechanisms of potential drugs were further investigated. Viral yields of RNAs and infectious particles were quantified by quantitative real-time polymerase chain reaction (qRT-PCR) and plaque assay, respectively.
The spike protein of coronavirus GX_P2V shares 92.2% amino acid identity with that of 2019-nCoV isolate Wuhan-hu-1, and uses ACE2 as the receptor for infection just like 2019-nCoV. Three drugs, including cepharanthine (CEP), selamectin, and mefloquine hydrochloride, exhibited complete inhibition of cytopathic effects in cell culture at 10 μmol/L. CEP demonstrated the most potent inhibition of GX_P2V infection, with a concentration for 50% of maximal effect EC50 of 0.98 μmol/L. The viral RNA yield in cells treated with 10 μmol/L CEP was 15,393-fold lower than in cells without CEP treatment (6.48 ± 0.02 × 10vs. 1.00 ± 0.12, t = 150.38, P < 0.001) at 72 h post-infection (p.i.). Plaque assays found no production of live viruses in media containing 10 μmol/L CEP at 48 h p.i. Furthermore, we found CEP had potent anti-viral activities against both viral entry (0.46 ± 0.12, vs.1.00 ± 0.37, t = 2.42, P < 0.05) and viral replication (6.18 ± 0.95 × 10vs. 1.00 ± 0.43, t = 3.98, P < 0.05).
Our pangolin coronavirus GX_P2V is a workable model for 2019-nCoV research. CEP, selamectin, and mefloquine hydrochloride are potential drugs for treating 2019-nCoV infection. Our results strongly suggest that CEP is a wide-spectrum inhibitor of pan-betacoronavirus, and further study of CEP for treatment of 2019-nCoV infection is warranted.
The preparation of chiral monohydrosilanes remains a rarely achieved goal. To this end a Rh‐catalyzed desymmetrization of dihydrosilanes by way of intramolecular C(sp2)−H functionalization under ...simple and mild conditions has now been developed. This method provides easy access to a broad range of chiral monohydrosilanes in good yields with excellent enantioselectivities (up to >99 % ee). The resulting monohydrosilanes constitute a good platform to access stereogenic silicon compounds, as well as useful compounds to probe silicon stereochemistry.
A Rh‐chiral diphosphine complex was found to catalyze desymmetrization of dihydrosilanes by formal intramolecular Si−H/C−H dehydrogenative coupling reactions. This simple, mild, and practical method results in unprecedently high enantioselectivity and a broad substrate scope. The chiral monohydrosilanes could be further elaborated into various stereogenic silicon compounds in a stereospecific manner.
Single atom catalysts exhibit particularly high catalytic activities in contrast to regular nanomaterial-based catalysts. Until recently, research has been mostly focused on single atom catalysts, ...and it remains a great challenge to synthesize bimetallic dimer structures. Herein, we successfully prepare high-quality one-to-one A-B bimetallic dimer structures (Pt-Ru dimers) through an atomic layer deposition (ALD) process. The Pt-Ru dimers show much higher hydrogen evolution activity (more than 50 times) and excellent stability compared to commercial Pt/C catalysts. X-ray absorption spectroscopy indicates that the Pt-Ru dimers structure model contains one Pt-Ru bonding configuration. First principle calculations reveal that the Pt-Ru dimer generates a synergy effect by modulating the electronic structure, which results in the enhanced hydrogen evolution activity. This work paves the way for the rational design of bimetallic dimers with good activity and stability, which have a great potential to be applied in various catalytic reactions.
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