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1.
J Cell Sci ; 135(5)2022 Mar 01.
Artigo em Inglês | MEDLINE | ID: mdl-34080635

RESUMO

Despite the recognized significance of reversible protein lipidation (S-acylation) for T cell receptor signal transduction, the enzymatic control of this post-translational modification in T cells remains poorly understood. Here, we demonstrate that DHHC21 (also known as ZDHHC21), a member of the DHHC family of mammalian protein acyltransferases, mediates T cell receptor-induced S-acylation of proximal T cell signaling proteins. Using Zdhhc21dep mice, which express a functionally deficient version of DHHC21, we show that DHHC21 is a Ca2+/calmodulin-dependent enzyme critical for activation of naïve CD4+ T cells in response to T cell receptor stimulation. We find that disruption of the Ca2+/calmodulin-binding domain of DHHC21 does not affect thymic T cell development but prevents differentiation of peripheral CD4+ T cells into Th1, Th2 and Th17 effector T helper lineages. Our findings identify DHHC21 as an essential component of the T cell receptor signaling machinery and define a new role for protein acyltransferases in regulation of T cell-mediated immunity.

2.
J Oral Rehabil ; 2021 Jun 02.
Artigo em Inglês | MEDLINE | ID: mdl-34075611

RESUMO

BACKGROUND: Orofacial pain is more prevalent in women than in men, and estrogen may underlie this sex difference. Genistein reversed the potentiation of 17ß-estradiol (E2) on glutamate-induced acute masseter nociceptive behavior, but its role in dental experimental occlusal interference (EOI)-induced chronic masseter hyperalgesia remains unclear. OBJECTIVE: This study aimed to investigate sex differences, and to explore the role and underlying mechanisms of genistein in E2-potentiated EOI-induced chronic masseter hyperalgesia in rats. METHODS: Female and male rats were prepared to compare the sex differences of masseter hyperalgesia induced by EOI using a 0.4-mm-thick metal crown. Female rats were ovariectomized (OVX) and treated with E2 and genistein, followed by EOI. The head withdrawal threshold (HWT) was examined to assess masseter sensitivity. The protein expression of transient receptor potential vanilloid-1 (TRPV1) in the trigeminal ganglion (TG) was detected using western blotting. Immunofluorescence staining was used to reveal the colocalization of estrogen receptors (ERs) with TRPV1 and the percentage of TRPV1-positive neurons in the TG. RESULTS: To some extent, female rats displayed enhanced sensitivity to EOI-induced chronic masseter hyperalgesia compared with males. Female rats showed the lowest HWT in the proestrus phase. Pretreatment with genistein antagonized E2 potentiation in EOI-induced masseter hyperalgesia, and blocked the effect of E2 by downregulating TRPV1 protein expression and the percentage of TRPV1-positive neurons in the TG. CONCLUSION: Female rats showed greater masseter hyperalgesia than males under EOI. Genistein antagonized the facilitation of EOI-induced chronic masseter hyperalgesia by E2 probably through inhibiting TRPV1 in the TG.

3.
Ann Palliat Med ; 2021 May 31.
Artigo em Inglês | MEDLINE | ID: mdl-34118831

RESUMO

Leptomeningeal metastasis (LM) is associated with poor prognosis and represents a terminal event of non-small cell lung cancers (NSCLC). In previous studies, most of LM-patients have detected epidermal growth factor receptor (EGFR) mutation and responded to the third generation of EGFR-tyrosine kinase inhibitor (TKI). This study aimed to report a case of ERBB2 (HER2) exon 20 insertion mutations in the cerebrospinal fluid (CSF) of LM-patient which response to poziotinib. At the beginning, postoperative pathology showed a primary invasive adenocarcinoma with no mutations in EGFR and ROS-1. Pemetrexed plus carboplatin combined with bevacizumab was administered as the first-line followed by bevacizumab alone for continuation maintenance therapy. Targeted therapy and immunotherapy were given after the disease progressed in two months. Subsequently, the patient developed mental symptoms and adenocarcinoma cells were found in the CSF. Next-generation sequencing (NGS) results showed HER2 exon 20 insertion mutations in the primary tissue, CSF and plasma samples. Then, poziotinib was administered and the symptoms improved significantly after 3 days and the progress free survival was nearly 2 months. Therefore, we speculate that the CSF concentration and penetration rate of poziotinib may significantly higher than of other TKIs so that it achieves a higher CSF concentration than standard dosing, and successfully controlled LM. It may provide a new therapeutic option for LM-patient and may be especially who are lung adenocarcinoma with HER2 exon 20 insertion.

4.
Acta Neuropathol ; 2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34125248

RESUMO

Heterozygous gain-of-kinase function variants in LRRK2 (leucine-rich repeat kinase 2) cause 1-2% of all cases of Parkinson's disease (PD) albeit with incomplete and age-dependent penetrance. All pathogenic LRRK2 mutations reside within the two catalytic domains of LRRK2-either in its kinase domain (e.g. G2019S) with modest effect or its ROC-COR GTPase domain (e.g. R1441G/H) with large effect on LRRK2 kinase activity. We have previously reported assays to interrogate LRRK2 kinase pathway activity in human bio-samples measuring phosphorylation of its endogenous substrate Rab10, that mirrors LRRK2 kinase activation status. Here, we isolated neutrophils from fresh peripheral blood from 101 participants including 42 LRRK2 mutation carriers (21 with the G2019S and 21 with the R1441G mutations), 27 patients with idiopathic PD, and 32 controls. Using a dual approach, LRRK2 dependent Rab10 phosphorylation at Threonine 73 (pRab10Thr73) was measured by quantitative multiplexed immunoblotting for pRab10Thr73/total Rab10 as well as targeted mass-spectrometry for absolute pRab10Thr73 occupancy. We found a significant over fourfold increase in pRab10Thr73 phosphorylation in carriers of the LRRK2 R1441G mutation irrespective of clinical disease status. The effect of the LRRK2 G2019S mutation did not reach statistical significance. Furthermore, we show that LRRK2 phosphorylation at Serine 935 is not a marker for LRRK2 kinase activity in human neutrophils. When analysing pRab10Thr73 phosphorylation in post-mortem brain samples, we observed overall high variability irrespective of clinical and LRRK2 mutation status and attributed this mainly to the adverse effect of the peri- and post-mortem period on the stability of posttranslational modifications such as protein phosphorylation. Overall, in vivo LRRK2 dependent pRab10Thr73 phosphorylation in human peripheral blood neutrophils is a specific, robust and promising biomarker for significant LRRK2 kinase hyperactivation, as with the LRRK2 R1441G mutation. Additional readouts and/or assays may be needed to increase sensitivity to detect modest LRRK2 kinase activation, as with the LRRK2 G2019S mutation. Our assays could be useful for patient stratification and target engagement studies for LRRK2 kinase inhibitors.

5.
J Bone Miner Res ; 2021 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-34131944

RESUMO

Adiponectin (AdipoQ), a hormone abundantly secreted by adipose tissues, has multiple beneficial functions, including insulin sensitization as well as lipid and glucose metabolism. It has been reported that bone controls energy metabolism through an endocrine-based mechanism. In this study, we observed that bone also acts as an important endocrine source for AdipoQ, and its capacity in osteoblasts is controlled by the FOXP1 transcriptional factor. Deletion of the Foxp1 gene in osteoblasts led to augmentation of AdipoQ levels accompanied by fueled energy expenditure in adipose tissues. In contrast, overexpression of Foxp1 in bones impaired AdipoQ secretion and restrained energy consumption. ChIP-seq analysis revealed that AdipoQ expression, which increases as a function of bone age, is directly controlled by FOXP1. Our results indicate that bones, especially aged bones, provide an important source of a set of endocrine factors, including AdipoQ, that control body metabolism.

6.
Anal Chem ; 2021 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-34125523

RESUMO

Uniform two-dimensional plasmonic nanoparticle (NP)-semiconductor composite films could retard the attenuation of electromagnetic evanescent wave and show intensive Raman activity for the multiplex monitoring of hazards in a practical food matrix. Here, an efficient Raman platform is developed by employing a plasmonic nanoparticle (NP)-persistent luminescence material (PLM) composite film. PLM show upconversion photoluminescence (UCPL) properties. The emitted photons are absorbed by plasmonic NPs, which further boost the surface plasmon resonance for the generation of high polarizability and induce strong electromagnetic strength for surface-enhanced Raman scattering (SERS) enhancement. A UCPL-assisted SERS-enhanced mechanism is proposed and verified. A plasmonic NP-PLM film with superior SERS activity and detection capability becomes an alternative candidate for the sensitive and multiple detection of illegal addition of dyes in a food matrix. The proposed UCPL-assisted SERS-enhanced mechanism provides promising future directions to this end to design a next-generation SERS-active plasmonic NP-PLM composite film for the specific detection in complex samples.

7.
J Neurosci ; 2021 Jun 03.
Artigo em Inglês | MEDLINE | ID: mdl-34088795

RESUMO

Two forms of information - frequency (content) and ordinal position (structure) - have to be stored when retaining a sequence of auditory tones in working memory (WM). However, the neural representations and coding characteristics of content and structure, particularly during WM maintenance, remain elusive. Here, in two electroencephalography (EEG) studies in human participants (both sexes), by transiently perturbing the 'activity-silent' WM retention state and decoding the reactivated WM information, we demonstrate that content and structure are stored in a dissociative manner with distinct characteristics throughout WM process. First, each tone in the sequence is associated with two codes in parallel, characterizing its frequency and ordinal position, respectively. Second, during retention, a structural retrocue successfully reactivates structure but not content, whereas a following white noise triggers content but not structure. Third, structure representation remains stable whereas content code undergoes a dynamic transformation through memory progress. Finally, the noise-triggered content reactivations during retention correlate with subsequent WM behavior. Overall, our results support distinct content and structure representations in auditory WM and provide an efficient approach to access the silently stored WM information in the human brain. The dissociation of content and structure could facilitate efficient memory formation via generalizing stable structure to new auditory contents.SIGNIFICANCE STATEMENTIn memory experiences, contents do not exist independently but are linked with each other via ordinal structure. For instance, recalling a piece of favorite music relies on correct ordering (sequence structure) of musical tones (content). How are the structure and content for an auditory temporally structured experience maintained in working memory? Here, by employing impulse-response approach and time-resolved representational dissimilarity analysis on human EEG recordings in an auditory working memory task, we reveal that content and structure are stored in a dissociated way, which would facilitate efficient and rapid memory formation through generalizing stable structure knowledge to new auditory inputs.

8.
PLoS One ; 16(5): e0251182, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33983987

RESUMO

BACKGROUND: Lactation mastitis (LM) affects approximately 3% to 33% of postpartum women and the risk factors of LM have been extensively studied. However, some results in the literature reports are still not conclusive due to the complexity of LM etiology and variation in the populations. To provide nationally representative evidence of the well-accepted risk factors for LM in China, this study was aimed to systematically summary the risk factors for LM among Chinese women and to determine the effect size of individual risk factor. MATERIAL AND METHODS: Six major Chinses and English electronic literature databases (PubMed, Web of Science, Chinese Biomedical Literature Database, China National Knowledge Infrastructure, Wan fang Database and China Science Technology Journal Database) were searched from their inception to December 5st, 2020. Two authors extracted data and assessed the quality of included trials, independently. The strength of the association was summarized using the odds ratio (OR) with 95% confidence intervals (CI). The population attributable risk (PAR) percent was calculated for significant risk factors. RESULTS: Fourteen studies involving 8032 participants were included. A total of 18 potential risk factors were eventually evaluated. Significant risk factors for LM included improper milking method (OR 6.79, 95%CI 3.45-13.34; PAR 59.14%), repeated milk stasis (OR 6.23, 95%CI 4.17-9.30; PAR 49.75%), the first six months postpartum (OR 5.11, 95%CI 2.66-9.82; PAR 65.93%), postpartum rest time less than 3 months (OR 4.71, 95%CI 3.92-5.65; PAR 56.95%), abnormal nipple or crater nipple (OR 3.94, 95%CI 2.34-6.63; PAR 42.05%), breast trauma (OR 3.07, 95%CI 2.17-4.33; PAR 15.98%), improper breastfeeding posture (OR 2.47, 95%CI 2.09-2.92; PAR 26.52%), postpartum prone sleeping position (OR 2.46, 95%CI 1.58-3.84; PAR 17.42%), little or no nipple cleaning (OR 2.05, 95%CI 1.58-2.65; PAR 24.73%), primipara (OR 1.73, 95%CI 1.25-2.41; PAR 32.62%), low education level (OR 1.63, 95%CI 1.09-2.43; PAR 23.29%), cesarean section (OR 1.51, 95%CI 1.26-1.81; PAR 18.61%), breast massage experience of non-medical staff (OR 1.51, 95%CI 1.25-1.82; PAR 15.31%) and postpartum mood disorders (OR 1.47, 95%CI 1.06-2.02; PAR 21.27%). CONCLUSIONS: This review specified several important risk factors for LM in China. In particular, the incidence of LM can be reduced by controlling some of the modifiable risk factors such as improper breastfeeding posture, improper milking method, repeated milk stasis, nipple cleaning, breast massage experience of non-medical staff and postpartum sleeping posture.

9.
Front Cell Infect Microbiol ; 11: 625589, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33996618

RESUMO

Background: The pathogenesis of choledocholithiasis is closely related to the role of bacteria. However, little is known about the predictive role of bile bacteria in clinical conditions of patients and the compositional and functional characteristics of biliary microbiota in choledocholithiasis. Methods: To investigate the predictive value of biliary bacteria, clinical data of 488 patients with choledocholithiasis were collected. The predictive value of common bile bacteria to patients' clinical conditions was analyzed by logistic regression. Samples of bile and corresponding duodenal juice from 10 selected patients with choledocholithiasis were obtained, and the composition and function of microbial communities were analyzed based on 16S rRNA sequencing and Tax4Fun. Results: The clinical conditions of patients with choledocholithiasis, such as recurrence, the severity of acute cholangitis, and duration of hospital stay were closely related to different species of bile bacteria as well as antimicrobial-resistant bacteria. Employing 16S rRNA sequencing, the dominant phyla of biliary and duodenal microbiota were Proteobacteria and Firmicutes. The top three core microbiota at the genus level were Escherichia-Shigella, Fusobacterium, and Enterococcus. Escherichia coli accounted for the most abundant annotated species in both. Differences in composition between biliary and duodenal microbiota were not significant according to the alpha and beta diversities. Differential abundant features were not found in biliary microbiota indicated by A linear discriminant analysis effective size algorithm. The major pathways identified in biliary and duodenal microbiota were related to membrane transport, translation, replication and repair, carbohydrate and amino acid metabolism. However, no significant difference in those major pathways, as well as antimicrobial-resistance patterns, was observed between biliary and duodenal microbiota. Conclusion: Our study first demonstrates the predictive contribution of biliary bacteria to the clinical conditions of patients with choledocholithiasis, and then it offers new insights into the compositional and functional features of biliary and duodenal microbiota. Similarities between biliary and duodenal microbiota support the theory of bacterial duodenal-biliary reflux in patients with choledocholithiasis. Meanwhile, when it is impracticable to obtain a bile sample, duodenal juice may be used as an alternative for bacterial culture and susceptibility tests.

10.
Transl Oncol ; 14(8): 101123, 2021 May 14.
Artigo em Inglês | MEDLINE | ID: mdl-34000642

RESUMO

Pulmonary enteric adenocarcinoma (PEAC) is an exceptionally rare subtype of non-small cell lung cancer (NSCLC). It is characterized by pathological features similar to those of colorectal adenocarcinoma. Most patients with PEAC have almost no special clinical manifestations, and it is often difficult to differentiate from metastatic colorectal adenocarcinoma (MCRC). As a special type of lung adenocarcinoma, PEAC has unique mutation expression and immune characteristics; its mutation profile shows higher Kirsten rat sarcoma viral oncogene (KRAS), human epidermal growth factor receptor-2 (HER2) , DNA mismatch repair(MMR) mutation rates, and much lower epidermal growth factor receptor (EGFR) rate. So in the future, targeted therapy may tend to be a new light in the treatment of PEAC. As for immunohistochemistry (IHC), CDX-2, villin, and CK7 are significantly positive in PEAC. This review focuses on the pathologic features, immunohistochemical examination, mutation analysis, diagnosis, treatment, and prognosis of PEAC.

11.
J Environ Manage ; 290: 112659, 2021 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-33894485

RESUMO

Low-carbon power generation has been proposed as the key to address climate change. However, the sustainability and ecological efficiency of the generating plants have not been fully understood. This study applies emergy analysis and systems accounting to a pilot solar power tower plant in China for the first time to elaborate its sustainable and ecological performances. Emergy analysis covers virtually all aspects of sustainability and ecological efficiency by considering different forms of materials inputs, environmental support and human labor on the same unit of "solar joule". The input-output analysis based systems accounting is applied to trace the complete emergy embodied in the supply chain for all product materials of the given plant against the back ground of complex economic network, which improved the accuracy of accounting. This analysis illustrated unexpectedly low sustainability and ecological efficiency of this particular plant compared with the emergy analysis based on the primary materials (steel, iron, cement, etc.). Purchased emergy responses more than 95% of the total and emergy input in the construction phase is more than twice as much as that in the operation phase. Comparisons with other kinds of clean energy technologies indicate previous studies may have overestimated the sustainability and ecological benefits of low-carbon power plants. Thus, it is necessary to establish this kind of unified accounting framework. In addition, sensitivity analysis suggests that strictly controlling monetary costs of purchased inputs, extending service lifetime and improving power generation efficiency can promote higher sustainability and ecological efficiency for solar power tower plants. This study provides a more comprehensive framework for quantitative emergy-based evaluation of the sustainability and ecological efficiency for low-carbon power systems.


Assuntos
Conservação dos Recursos Naturais , Energia Solar , Carbono , China , Ecossistema , Humanos , Centrais Elétricas
12.
J Transl Med ; 19(1): 167, 2021 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-33902640

RESUMO

BACKGROUND: Myopic maculopathy (MM) is the most serious and irreversible complication of pathologic myopia, which is a major cause of visual impairment and blindness. Clinic proposed limited number of factors related to MM. To explore additional features strongly related with MM from optic disc region, we employ a machine learning based radiomics analysis method, which could explore and quantify more hidden or imperceptible MM-related features to the naked eyes and contribute to a more comprehensive understanding of MM and therefore may assist to distinguish the high-risk population in an early stage. METHODS: A total of 457 eyes (313 patients) were enrolled and were divided into severe MM group and without severe MM group. Radiomics analysis was applied to depict features significantly correlated with severe MM from optic disc region. Receiver Operating Characteristic were used to evaluate these features' performance of classifying severe MM. RESULTS: Eight new MM-related image features were discovered from the optic disc region, which described the shapes, textural patterns and intensity distributions of optic disc region. Compared with clinically reported MM-related features, these newly discovered features exhibited better abilities on severe MM classification. And the mean values of most features were markedly changed between patients with peripapillary diffuse chorioretinal atrophy (PDCA) and macular diffuse chorioretinal atrophy (MDCA). CONCLUSIONS: Machine learning and radiomics method are useful tools for mining more MM-related features from the optic disc region, by which complex or even hidden MM-related features can be discovered and decoded. In this paper, eight new MM-related image features were found, which would be useful for further quantitative study of MM-progression. As a nontrivial byproduct, marked changes between PDCA and MDCA was discovered by both new image features and clinic features.


Assuntos
Degeneração Macular , Miopia Degenerativa , Disco Óptico , Doenças Retinianas , Humanos , Aprendizado de Máquina , Disco Óptico/diagnóstico por imagem
13.
Acta Pharmacol Sin ; 2021 Apr 06.
Artigo em Inglês | MEDLINE | ID: mdl-33824458

RESUMO

Heat shock protein 90 (Hsp90) is the most common molecular chaperone that controls the maturation of many oncoproteins critical in tumor development. Hsp90 has been considered as a promising target for cancer treatment, but the clinical significance of Hsp90 and the mechanisms of Hsp90 regulating the tumor-promoting effects in hepatocellular carcinoma (HCC) remain obscure. Previous studies have shown that curcumin, a polyphenol derived from the plant turmeric (Curcuma longa), inhibits tumor growth, which may provide an effective alternative therapy for HCC. Compared to curcumin, a novel derivative of curcumin, 3,5-(E)-Bis(3-methoxy-4-hydroxybenzal)-4-piperidinone hydrochloride (C0818) that is more potent in Hsp90 inhibition and antitumor activity. In this study, we investigated the effect of C0818 on HCC cells in vitro and its relation to Hsp90 inhibition. We showed that C0818 concentration-dependently inhibited the proliferation, the colony formation and induced apoptosis in HepG2 and Sk-Hep-1 cells. C0818 concentration-dependently inhibited DNA synthesis and induced G2/M phase arrest in HepG2 and Sk-Hep-1 cells. We further demonstrated that C0818 induced ROS- and caspase-dependent apoptosis in HCC cells through the mitochondrial-mediated pathway. C0818 induced the degradation of Hsp90 client proteins as RAS, C-Raf, P-C-Raf, Erk, P-ERK, MEK, P-MEK, Akt and P-Akt, which led to subsequent inhibition of the RAS/RAF/MEK/ERK and PI3K/AKT pathways. We revealed that C0818 could inhibit the binding of Hsp90 with its clients without affecting their transcription, which subsequently induced the degradation of Hsp90 clients by the proteasome rather than the lysosome. These results are of potential importance for elucidating a novel Hsp90 inhibitor targeting HCC.

14.
J Biol Chem ; : 100655, 2021 Apr 23.
Artigo em Inglês | MEDLINE | ID: mdl-33901491

RESUMO

Highly conserved amino acids are generally anticipated to have similar functions across a protein superfamily, including that of the P2X ion channels, which are gated by extracellular ATP. However, whether and how these functions are conserved becomes less clear when neighboring amino acids are not conserved. Here, we investigate one such case, focused on the highly conserved residue from P2X4, E118 (rat P2X4 numbering, rP2X4), a P2X subtype associated with human neuropathic pain. When we compared the crystal structures of P2X4 with those of other P2X subtypes, including P2X3, P2X7 and AmP2X, we observed a slightly altered side-chain orientation of E118. We used protein chimeras, double mutant cycle analysis and molecular modeling to reveal that E118 forms specific contacts with amino acids in the "beak" region, which facilitates ATP binding to rP2X4. These contacts are not present in other subtypes due to sequence variance in the beak region, resulting in decoupling of this conserved residue from ATP recognition and/or channel gating of P2X receptors. Our study provides an example of a conserved residue with a specific role in functional proteins enabled by adjacent non-conserved residues. The unique role established by the E118-beak region contact provides a blueprint for the development of subtype-specific inhibitors of P2X4.

15.
Artigo em Inglês | MEDLINE | ID: mdl-33895900

RESUMO

PURPOSE: We conducted a single-arm prospective phase II trial to evaluate the efficacy and safety of oral metronomic vinorelbine combined with trastuzumab (mNH) in human epidermal growth factor receptor 2-positive (HER2-positive) metastatic breast cancer (MBC) patients. METHODS: HER2-positive MBC patients received oral vinorelbine 40 mg thrice a week and trastuzumab (loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks) until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoints were objective response rate (ORR), clinical benefit rate (CBR; CR + PR + SD for ≥ 24 weeks). The secondary endpoints were progression-free survival (PFS), tolerability, and overall survival (OS). RESULTS: Twenty patients with HER2-positive MBC were enrolled, with a median of 1 prior chemotherapy regimens for MBC. Median age was 61.5 years (95% Confidence Interval (CI) 48.6-63.1). Visceral involvements presented in 14 patients (70.0%). ORR was 20.0%, and CBR was 75% with 4 PR (20.0%) and 11 SD (55.0%). The median PFS (mPFS) and median OS (mOS) were 7.4 months (95% CI 3.2-11.5) and 45.8 months (95%CI: not reached), respectively. The mPFS was 17.7 months (95%CI not reached) and 5.8 months (95%CI 5.6-5.9) in mNH as first-line and ≥ second-line therapy (log rank p = 0.03), respectively. The most common grade 1 adverse events (AEs) included nausea (15%), leukopenia (15%), ALT/AST elevation (15%), diarrhea (10%), and peripheral neuropathy (10%). Grade 2 adverse events included leukopenia (5%) and neutropenia (10%). No grade 3/4 AEs were observed. CONCLUSIONS: Oral metronomic vinorelbine combined with trastuzumab is a well-tolerated and effective anti-tumor regimen for HER2-positive MBC.

16.
Biochem Biophys Res Commun ; 557: 166-173, 2021 Jun 11.
Artigo em Inglês | MEDLINE | ID: mdl-33865225

RESUMO

BACKGROUND: Renal ischemia reperfusion injury (IRI) has become a growing concern in clinical practice with high morbidity and mortality rates. There is currently no effective prophylactic regimen available to prevent its occurrence and to improve its clinical prognosis. Dl-3-n-butylphthalide (NBP) has been used for stroke treatment in China for years. Little is known about its role in preventing kidney injury. METHODS: The kidneys of male C57BL/6J mice were subjected to 33 min of ischemia followed by 24 h of reperfusion. NBP was administered by gavage prior to surgery. The reno-protective effect of NBP was evaluated by serum creatinine, kidney injury markers and renal pathological changes. Furthermore, the inflammation, oxidative stress, and apoptosis markers in kidney tissue were examined. In vitro, HK2 cells were treated prophylactically with NBP and then exposed to hypoxia/reoxygenation (H/R). Cell viability and apoptosis related protein were quantified to verify the protective effect of NBP. Pro-inflammation genes expression as well as ROS generation were further investigated also. RESULTS: NBP pretreatment significantly improved renal dysfunction and alleviated pathological injury, renal inflammation response, oxidative stress and cell apoptosis. Consistently, NBP attenuated H/R induced increases in ROS, pro-inflammatory genes expression, apoptosis and cleaved caspase-3 levels in HK2 cells. CONCLUSION: Our promising results validated for the first time that NBP could ameliorate renal IRI via attenuating inflammation, oxidative stress, and apoptosis, which indicated that NBP might be a good candidate against AKI.

17.
Med Sci Monit ; 27: e929170, 2021 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-33875631

RESUMO

BACKGROUND Postmenopausal osteoporosis, a common disease among elderly women, is linked to estrogen deficiency, mechanical loading, and genotype. Circular RNAs (circRNAs) are formed through reverse splicing of the splice donor at the 3' end and the splice accepter at the 5' end in pre-mRNA and have been shown to be involved in the development of multiple diseases. Based on their high sequence conservation and stability, circRNAs may be useful biomarkers in different diseases. However, the roles of circRNAs in postmenopausal osteoporosis remain incompletely understood. MATERIAL AND METHODS Fifty-three postmenopausal women were assigned to either the postmenopausal osteoporosis group (n=28) or the control group (n=25). Reverse-transcriptase quantitative polymerase chain reaction (RT-qPCR) analysis was performed to determine the differential expression of circRNAs between the 2 groups. Receiver-operating characteristic (ROC) curve analysis was conducted to evaluate the clinical diagnostic value of circRNA. Prediction of the binding sites between circRNA and miRNAs was conducted using miRanda and RNAhybrid. The function of the circRNA in osteoclastogenesis was determined by circRNA overexpression followed by tartrate-resistant acid phosphatase staining and RT-qPCR analysis. RESULTS Among 4 circRNAs previously identified by RNA-sequencing analysis as differentially expressed in patients with postmenopausal osteoporosis, only hsa_circ_0021739 showed a significant difference in expression between the groups and was downregulated in patients with postmenopausal osteoporosis. The hsa_circ_0021739 expression level was determined to be correlated with the lumbar vertebra, femur, and forearm T-scores. Overexpression of hsa_circ_0021739 decreased the level of hsa-miR-502-5p and inhibited the differentiation of osteoclasts. CONCLUSIONS The circRNA hsa_circ_0021739 is a potential blood biomarker for postmenopausal osteoporosis. In addition, hsa-miR-502-5p is a likely target of hsa_circ_0021739, which acts to regulate the differentiation of osteoclasts.


Assuntos
Leucócitos Mononucleares/imunologia , MicroRNAs/genética , Osteoclastos/fisiologia , Osteoporose Pós-Menopausa/genética , RNA Circular/genética , Idoso , Biomarcadores , Diferenciação Celular , Células Cultivadas , Regulação para Baixo , Feminino , Humanos , Osteoporose Pós-Menopausa/imunologia , Curva ROC , Transcriptoma
18.
Nat Hum Behav ; 2021 Apr 05.
Artigo em Inglês | MEDLINE | ID: mdl-33820976

RESUMO

Teamwork is one of the most prominent features in modern science. It is now well understood that team size is an important factor that affects the creativity of the team. However, the crucial question of how the character of research studies is related to the freshness of a team remains unclear. Here, we quantify the team freshness according to the absence of prior collaboration among team members. Our results suggest that papers produced by fresher teams are associated with greater originality and a greater multidisciplinary impact. These effects are even stronger in larger teams. Furthermore, we find that freshness defined by new team members in a paper is a more effective indicator of research originality and multidisciplinarity compared with freshness defined by new collaboration relationships among team members. Finally, we show that the career freshness of team members is also positively correlated with the originality and multidisciplinarity of produced papers.

19.
Nature ; 591(7850): 391-395, 2021 03.
Artigo em Inglês | MEDLINE | ID: mdl-33731949

RESUMO

Most rivers exchange water with surrounding aquifers1,2. Where groundwater levels lie below nearby streams, streamwater can infiltrate through the streambed, reducing streamflow and recharging the aquifer3. These 'losing' streams have important implications for water availability, riparian ecosystems and environmental flows4-10, but the prevalence of losing streams remains poorly constrained by continent-wide in situ observations. Here we analyse water levels in 4.2 million wells across the contiguous USA and show that nearly two-thirds (64 per cent) of them lie below nearby stream surfaces, implying that these streamwaters will seep into the subsurface if it is sufficiently permeable. A lack of adequate permeability data prevents us from quantifying the magnitudes of these subsurface flows, but our analysis nonetheless demonstrates widespread potential for streamwater losses into underlying aquifers. These potentially losing rivers are more common in drier climates, flatter landscapes and regions with extensive groundwater pumping. Our results thus imply that climatic factors, geological conditions and historic groundwater pumping jointly contribute to the widespread risk of streams losing flow into surrounding aquifers instead of gaining flow from them. Recent modelling studies10 have suggested that losing streams could become common in future decades, but our direct observations show that many rivers across the USA are already potentially losing flow, highlighting the importance of coordinating groundwater and surface water policy.


Assuntos
Água Subterrânea/análise , Rios , Clima , Secas , Ecossistema , Umidade , Estados Unidos , Abastecimento de Água
20.
Sci Total Environ ; 770: 144841, 2021 May 20.
Artigo em Inglês | MEDLINE | ID: mdl-33736406

RESUMO

Compared with centralized wastewater treatment systems, constructed wetlands are generally regarded as not suitable for wide deployment due to the comparatively larger direct land area. Much of the traditional thinking is based on an onsite perspective, while the offsite information is left out. By a comparative case study with systems accounting of both onsite and offsite land use, this study questioned the traditional picture and found that constructed wetlands can be more land use efficient than centralized wastewater treatment systems. On a unit of wastewater treated basis, the land use induced by a typical constructed wetland in China is revealed to be less than half of that by the case of a centralized wastewater treatment plant or a hybrid system. On a unit removal basis for biological oxygen demand (BOD5), chemical oxygen demand (COD), total suspended solid (TSS) and ammonia­nitrogen (NH3-N), the land use induced by a constructed wetland is only around 61%, 67%, 73% and 64% of that by a centralized wastewater treatment system, respectively. Meanwhile, the indirect effect is demonstrated to be significant for these three systems: this magnitude amounts to three times the direct land occupation for a constructed wetland, and one order of magnitude higher of that for the a centralized wastewater treatment system. By a scenario analysis for China in 2017, it is preliminarily estimated that over two billion square meters of land use could be reduced if all the centralized wastewater treatment systems are replaced by constructed wetlands. The outcome may serve a benchmark and offers a new way of thinking for management of wastewater treatment systems.

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