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1.
Eur J Haematol ; 2020 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-32421883

RESUMO

BACKGROUND: In multiple myeloma (MM), impact of specific chromosomal translocations involving IgH (14q21 locus, including t(4;14), t(11;14), and t(14;16) etc.) has been explored extensively. However, over 15% MM patients harboring IgH translocation with undefined partners have long been ignored. METHODS: A prospective non-randomized cohort study with a total of 715 newly-diagnosed MM cases was conducted, 13.6% of whom were t(14;undefined) positive. The whole cohort was divided into four groups: no IgH split (47.7%); t(14;undefined) (13.6%); t(11;14) (17.6%); and t(4;14) or t(14;16) group (21.1%). RESULTS: Median OS for the four groups were 84.2, not reached (NR), 58.7, and 44.2 months respectively, with p values for t(14;undefined) vs. no IgH split, t(11;14), and t(4;14)/t(14;16) groups of 0.197, 0.022 and 0.001, respectively. In bortezomib-based group, the survival advantage gained by t(14;undefined) group was much more significant compared to t(11;14) and t(4;14)/t(14;16) groups. Importantly, t(14;undefined) turned out to be an independent predictive factor for longer OS of MM patients in multivariate analysis, especially in the context of bortezomib-treatment. Similar results were also observed in the PUMCH external validation cohort. CONCLUSION: Collectively, our data confirmed and externally validated the favorable prognosis of the t(14;undefined) groups, especially in the era of novel agents.

2.
Nat Commun ; 11(1): 2498, 2020 May 19.
Artigo em Inglês | MEDLINE | ID: mdl-32427827

RESUMO

Plasticity of neoplasia, whereby cancer cells attain stem-cell-like properties, is required for disease progression and represents a major therapeutic challenge. We report that in breast cancer cells NANOG, SNAIL and NODAL transcripts manifest multiple isoforms characterized by different 5' Untranslated Regions (5'UTRs), whereby translation of a subset of these isoforms is stimulated under hypoxia. The accumulation of the corresponding proteins induces plasticity and "fate-switching" toward stem cell-like phenotypes. Mechanistically, we observe that mTOR inhibitors and chemotherapeutics induce translational activation of a subset of NANOG, SNAIL and NODAL mRNA isoforms akin to hypoxia, engendering stem-cell-like phenotypes. These effects are overcome with drugs that antagonize translational reprogramming caused by eIF2α phosphorylation (e.g. ISRIB), suggesting that the Integrated Stress Response drives breast cancer plasticity. Collectively, our findings reveal a mechanism of induction of plasticity of breast cancer cells and provide a molecular basis for therapeutic strategies aimed at overcoming drug resistance and abrogating metastasis.

3.
Zhongguo Zhong Yao Za Zhi ; 45(1): 163-168, 2020 Jan.
Artigo em Chinês | MEDLINE | ID: mdl-32237426

RESUMO

This study aimed to explore the main active ingredients and potential targets of Solanum nigrum(SN), so as to reveal the potential molecular mechanism of SN in the treatment of hepatocellular carcinoma(HCC) based on network pharmacology and molecular docking. First,the main active ingredients and predictive targets of SN were collected in the traditional Chinese medicine systems pharmacology database and analysis platform(TCMSP). Then,the targets relating to HCC were collected through retrieval of integrated bio-pharmacological network database for traditional Korean medicine(PharmDB-K), oncogenomic database of hepatocellular carcinoma(OncoDB.hcc). The common targets of disease-drug component were selected through intersection between predictive targets and disease targets. Next, based on the String platform, protein-protein interaction network(PPI) model of the potential anti-HCC targets was constructed using the software Cytoscape 3.7.1. ClueGO and CluePedia APP in Cytoscape were used to analyze the gene function of SN in the treatment of HCC, and construct the main active ingredients-potential targets-signal pathways topology network of SN. Finally,DISCOVERY STUDIO software was applied in verifying the molecular docking between the key active ingredient and potential protein target. The results showed that there were 4 main active ingredients of SN, involving 22 potential targets relating to HCC and 7 signal pathways relating to potential anti-HCC targets of SN. Network analysis showed that SN may play a therapeutic role in HCC by acting on key targets, such as EGFR, TP53, MYC, CCND1 and CTNNB1. Molecular docking results showed that quercetin and EGFR could bind stably and interact through amino acid residues LEU718, LYS745 and GLN791. This study revealed the potential active ingredients and the possible molecular mechanism of SN for treatment of HCC, providing scientific basis for follow-up exploration of the molecular mechanism of SN against HCC.

4.
Spectrochim Acta A Mol Biomol Spectrosc ; 233: 118195, 2020 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-32135500

RESUMO

Ficin has been reported to possess peroxidase activity, but its applications in some respects have been limited because of its relatively low activity. Herein, a mesoporous metal-organic framework, PCN-333(Fe), was synthesized, which was selected to encapsulate ficin to form ficin@PCN-333(Fe). Compared with ficin, the peroxidase-like activity of ficin@PCN-333(Fe) toward 3,3',5,5'-tetramethylbenzidine (TMB) oxidation was about 3 times increase in the presence of H2O2, and followed classical Michaelis-Menten model. The kinetic parameters showed that stronger affinity and higher catalytic constant (Kcat) of ficin@PCN-333(Fe) to both TMB and H2O2 compared with ficin, and Kcat of ficin@PCN-333(Fe) was increased by 3.65 folds and 3.59 folds for TMB and H2O2, respectively. Taking advantages of higher catalytic property of ficin@PCN-333(Fe), we developed a colorimetric method with high sensitivity and selectivity to detect glucose, which displayed a good linear response toward glucose in the range of 0.5-180 µM with a limit of detection of 97 nM. Furthermore, ficin@PCN-333(Fe) has been proven to successfully detect glucose in human serum, implying its great potentialities and wide applications as peroxidase mimics.

5.
J Pharm Pharmacol ; 72(4): 561-574, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32034768

RESUMO

OBJECTIVES: Meriolins, a kind of chemical hybrid between meridianins and variolins, have lately been determined as kinase inhibitors and reportedly have antitumour activity. However, there is currently no in-depth study for the action mechanism. This study aimed to elucidate the potentially antitumour action mechanism of Meriolin1 on human neuroblastoma (SH-SY5Y) cells. METHODS: Firstly, cell viability was detected by MTT assay. Secondly, cell cycle, cell apoptosis, cell autophagy, reactive oxygen species and mitochondrial membrane potential (ΔΨm) were measured by flow cytometry. Then, cell cycle-associated proteins, Bcl-2 family proteins, Akt/MAPK proteins and autophagy-associated proteins expressions were evaluated by Western blot. Bcl-2 and Bax mRNA expressions were also evaluated by qRT-PCR. Furthermore, cell adhesion assay and Hoechst 33258 fluorescent staining were carried out to detect the effect of Meriolin1 on cell adhesion and morphology. Finally, to gain further insight into mechanism of action of Meriolin1 to CDK protein, the molecular docking study was performed by using the CDOCKER module of DS software. KEY FINDINGS: Meriolin1 could exert the antitumour activity on SH-SY5Y cells by inducing cell cycle arrest, cell autophagy, the mitochondrion-dependent cell apoptosis and targeting the Akt/MAPKs signalling pathway. CONCLUSIONS: Meriolin1 might be a promising therapeutic candidate for neuroblastoma.

6.
Medicine (Baltimore) ; 99(8): e19213, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-32080112

RESUMO

This study described the prevalence of adverse pregnancy outcomes (APOs) in Chinese HIV-infected pregnant women, and examined the relationship between maternal HIV infection /HIV-related factors and APOs.This prospective cohort study was carried out among 483 HIV-infected pregnant women and 966 HIV-uninfected pregnant women. The HIV-infected and HIV-uninfected women were enrolled from midwifery hospitals in Hunan province between October 2014 and September 2017. All data were extracted in a standard structured form, including maternal characteristics, HIV infection status, HIV-related factors and their pregnancy outcomes. APOs were assessed by maternal HIV infection status and HIV-related factors using logistic regression analysis.The incidences of stillbirth (3.9% vs 1.1%), preterm birth (PTB) (8.9% vs 3.7%), low birth weight (LBW) (12.2% vs 3.1%) and small for gestational age (SGA) (21.3% vs 7.0%) were higher in HIV-infected women than HIV-uninfected women, with adjusted ORs of 2.77 (95%CI: 1.24-6.17), 2.37 (95%CI: 1.44-3.89), 4.20 (95%CI: 2.59-6.82) and 3.26 (95%CI: 3.26-4.64), respectively. No differences were found in neonatal asphyxia or birth defects between HIV-infected and HIV-uninfected groups, with adjusted ORs of 1.12 (95%CI: 0.37-3.43) and 1.10 (95%CI: 0.51-2.39), respectively. Among HIV-infected pregnant women, different antiretroviral (ARV) regimens were significantly associated with stillbirths, but not PTB, LBW or SGA. Compared with untreated HIV infection (10.1%), both mono/dual therapy and HAART were associated with a reduced risk of stillbirths (2.0% and 3.2%, respectively), with an AOR of 0.19 (95%CI: 0.04-0.92) and 0.31 (95%CI: 0.11-0.85), respectively. Initial time of ARV drugs use and HIV infection status of the sexual partner were not associated with maternal APOs.The findings of this study indicated that maternal HIV infection was associated with significantly increased risks of stillbirth, PTB, LBW and SGA, but not neonatal asphyxia or birth defects. On the condition that most HIV-infected pregnant women started ARV therapy in or after the second trimester, both mono/dual therapy and HAART had a protective effect on stillbirth compared with untreated HIV infection. As some important confounders were not effectively controlled and the specific regimens of HAART were not analyzed, the above findings may have certain bias.


Assuntos
Antirretrovirais/uso terapêutico , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Complicações Infecciosas na Gravidez/epidemiologia , Resultado da Gravidez/epidemiologia , Adulto , Fatores Etários , Antirretrovirais/administração & dosagem , Antirretrovirais/efeitos adversos , China/epidemiologia , Feminino , Humanos , Recém-Nascido de Baixo Peso , Gravidez , Nascimento Prematuro , Estudos Prospectivos , Características de Residência , Fatores Socioeconômicos , Natimorto/epidemiologia , Adulto Jovem
7.
Adv Mater ; 32(14): e1908324, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32091153

RESUMO

Controlling the structures and functions of gels is important for both fundamental research and technological applications. Introducing photoresponsive units into gels enables remote control of their properties with light. However, existing gels show photoresponsiveness only at room temperature or elevated temperatures. The development of photoresponsive gels that work below 0 °C can expand their usage in cold environments. Here, photoresponsive metallopolymer organohydrogels that function even at -20 °C are reported. The organohydrogels are prepared using photoresponsive Ru-thioether coordination bonds as reversible crosslinks to form polymer networks. A water/glycerol mixture is used as an anti-freezing solvent. At -20 °C, the Ru-thioether coordination bonds are dissociated under light irradiation and reformed reversibly in the dark, which result in alternating crosslinking densities in the polymer networks. This process enables inducing reversible gel-to-sol transitions, healing damaged gels, controlling the mechanical properties and volumes of the gels, and rewriting microstructures on the gels below 0 °C.

8.
Sci Total Environ ; 714: 136689, 2020 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-31978772

RESUMO

Residual chemicals discharged from wastewater treatment plants (WWTPs) and subsequent ecological risk are important in production safety when reuse of the effluent water occurs. Thus, this work provides an investigation of the occurrence and removal of dissolved Endocrine-disrupting chemicals (EDCs) in 38 WWTPs in Guangdong Province, China. The results indicate that EDCs are widely distributed in the investigated WWTPs, while nonylphenols (NPs) are the predominant chemical among the target EDCs, accounting for >98% of the concentration in the influent and >97% of the concentration in the effluent. Moreover, 4 main types of wastewater treatment processes (oxidation ditch, A2/O, conventional activated sludge and microaeration oxidation ditch followed by A2/O) were found to be inefficient for removing dissolved EDCs, with a mean removal rate of approximately 25%. The potential environmental risk was predicted for residual EDCs. Specifically, 17α-ethynylestradiol (EE2) was considered to be the most hazardous chemical among the target EDCs, with a median risk quotient (RQ) of 8.94. In addition, ß-estradiol (E2) and estrone (E1) have median RQs of 1.14 and 0.27, and NPs have median RQs of 0.61 (algae), 0.37 (inverberate) and 0.25 (fish), respectively.


Assuntos
Águas Residuárias/química , China , Disruptores Endócrinos , Monitoramento Ambiental , Medição de Risco , Eliminação de Resíduos Líquidos , Poluentes Químicos da Água
9.
Phytother Res ; 34(5): 1142-1153, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31985119

RESUMO

Cisplatin (DDP) is one of the first-line chemotherapeutic agents for non-small cell lung cancer (NSCLC). However, repeated use of cisplatin in clinical practice often induces chemoresistance. The aims of this study were to investigate whether rosmarinic acid (RA) could reverse multidrug resistance (MDR) in NSCLC and to explore the underlying mechanisms. Our data demonstrated that RA significantly inhibited NSCLC cell proliferation and cell colony formation in a dose-dependent manner, induced G1 phase cell cycle arrest and apoptosis, and increased the sensitivity of cell lines resistant to DDP. Mechanistically, RA inhibited NSCLC cell growth, arrested cell cycle, and induced apoptosis by activating MAPK and inhibiting the expression of P-gp and MDR1, which correspondingly enhanced p21 and p53 expression. We observed that the growth of xenograft tumors derived from NSCLC cell lines in nude mice was significantly inhibited by combination therapy. We demonstrate that RA is a potentially effective MDR reversal agent for NSCLC, based on downregulation of MDR1 mRNA expression and P-gp. Together, these results emphasize the putative role of RA as a resistance reversal agent in NSCLC.

10.
J Virol ; 94(8)2020 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-31969439

RESUMO

P3N-PIPO, the only dedicated movement protein (MP) of potyviruses, directs cylindrical inclusion (CI) protein from the cytoplasm to the plasmodesma (PD), where CI forms conical structures for intercellular movement. To better understand potyviral cell-to-cell movement, we further characterized P3N-PIPO using Turnip mosaic virus (TuMV) as a model virus. We found that P3N-PIPO interacts with P3 via the shared P3N domain and that TuMV mutants lacking the P3N domain of either P3N-PIPO or P3 are defective in cell-to-cell movement. Moreover, we found that the PIPO domain of P3N-PIPO is sufficient to direct CI to the PD, whereas the P3N domain is necessary for localization of P3N-PIPO to 6K2-labeled vesicles or aggregates. Finally, we discovered that the interaction between P3 and P3N-PIPO is essential for the recruitment of CI to cytoplasmic 6K2-containing structures and the association of 6K2-containing structures with PD-located CI inclusions. These data suggest that both P3N and PIPO domains are indispensable for potyviral cell-to-cell movement and that the 6K2 vesicles in proximity to PDs resulting from multipartite interactions among 6K2, P3, P3N-PIPO, and CI may also play an essential role in this process.IMPORTANCE Potyviruses include numerous economically important viruses that represent approximately 30% of known plant viruses. However, there is still limited information about the mechanism of potyviral cell-to-cell movement. Here, we show that P3N-PIPO interacts with and recruits CI to the PD via the PIPO domain and interacts with P3 via the shared P3N domain. We further report that the interaction of P3N-PIPO and P3 is associated with 6K2 vesicles and brings the 6K2 vesicles into proximity with PD-located CI structures. These results support the notion that the replication and cell-to-cell movement of potyviruses are processes coupled by anchoring viral replication complexes at the entrance of PDs, which greatly increase our knowledge of the intercellular movement of potyviruses.

11.
Vet Microbiol ; 240: 108509, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31902506

RESUMO

We evaluated the phenotype and genotype of a fatal influenza/canine distemper virus coinfection found in farmed mink in China. We identified a novel subtype H1N1 influenza virus strain from the lungs of infected mink designated A/Mink/Shandong/1121/2017 (H1N1). The results of phylogenetic analysis of 8 gene fragments of the H1N1 strain showed the virus was a swine origin triple-reassortant H1N1 influenza virus: with the 2009 pandemic H1N1 segments (PB2, PB1, PA, NP and M), Eurasian avian-like H1N1 swine segments (HA and NA) and classical swine (NS) lineages. The EID50/0.2 mL of this strain was 10-6.2 and pathogenicity tests were 100 % lethal in a mouse model of infection. We found that while not lethal and lacking any overt signs of infection in mink, the virus could proliferate in the upper respiratory tracts and the animals were converted to seropositive for the HA protein.

12.
Leukemia ; 34(2): 578-588, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31591469

RESUMO

Recent attempts have focused on identifying fewer magnitude of minimal residual disease (MRD) rather than exploring the biological and genetic features of the residual plasma cells (PCs). Here, a cohort of 193 patients with at least one cytogenetic abnormalities (CA) at diagnosis were analyzed, and interphase fluorescence in situ hybridization (iFISH) analyses were performed in patient-paired diagnostic and posttherapy samples. Persistent CA in residual PCs were observed for the majority of patients (63%), even detectable in 28/63 (44%) patients with MRD negativity (<10-4). The absence of CA in residual PCs was associated with prolonged survival regardless of MRD status. According to the change of the clonal size of specific CA, patients were clustered into five groups, reflecting different patterns of clone selection under therapy pressure. Therapy-induced clonal selection exerted a significant impact on survival (HR = 4.0; P < 0.001). According to the longitudinal cytogenetic studies at relapse, sequential cytogenetic dynamics were observed in most patients, and cytogenetic architecture of residual PCs could to some extent predict the evolutional pattern at relapse. Collectively, the repeat cytogenetic evaluation in residual PCs could not only serves as a good complementary tool for MRD detection, but also provides a better understanding of clinical response and clonal evolution.

13.
Leuk Lymphoma ; 61(5): 1201-1210, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31842644

RESUMO

Chromosome 1q21 aberrations in multiple myeloma have attracted much attention for a long time, however, the prognostic value is still under investigation. We confirmed the independent prognostic impact of 1q21 aberrations in this non-randomized clinical study. Our study noted that additional copies and larger clonal size of 1q21 gain did not worsen the outcome. We discovered that 1q21 gain was associated with the acquisition of new chromosome abnormalities and genomic instability, evidenced by the strong correlation between 1q21 gain and complex karyotypes or the acquisition of more than two cytogenetic aberrations. Moreover, 1q21 gain and/or del(17p) were powerful enough to discriminate high-risk patients. Furthermore, 1q21 gain retained unfavorable even when stratified by concurrent presence of t(4;14), especially in the bortezomib arm. Finally, although bortezomib might benefit patients with 1q21 gain, it could not completely overcome its adverse effects, suggesting the necessity of more effective therapies for these patients.

14.
Artigo em Inglês | MEDLINE | ID: mdl-31817595

RESUMO

Urban green space is believed as a beneficial landscape for mental restoration in the urban settings. This study aims to examine the restorative quality of the urban green space from a multi-sensory perspective, focusing on both direct and indirect connections between visual, auditory, and tactile sensations and mental restoration. Two hundred and fifty park users of Tianhe Park in Guangzhou, China, were surveyed. Data were collected regarding their three types of sensations, i.e., the perceived mental restoration, health-related behavioral activities and emotional responses in the urban park. As a result, visual and auditory sensation were found to be linked with mental restoration directly and indirectly, while the tactile sensation was only associated with mental restoration indirectly; and health-related behaviors and emotional response mediated the relations between the three sensations and mental restoration significantly. It is concluded that the greater effects of auditory sensation and the under-studied potential effects of tactile sensation on mental restoration should be more emphasized in the future design of urban park. This is expected to contribute to the high restorative quality of the urban green space and promote public health.

15.
Invest New Drugs ; 2019 Nov 23.
Artigo em Inglês | MEDLINE | ID: mdl-31758360

RESUMO

Chemotherapy has always been the first therapeutic option for patients with advanced non-small cell lung cancer (NSCLC) with untreatable oncogenic mutations. However, chemotherapy has demonstrated limited success and is associated with severe side effects. This research aimed to investigate the antitumor efficacy and cytotoxic safety of the conjugate ZHER2:V2-pemetrexed, a novel targeted chemotherapeutic drug. In this context, human epidermal growth factor receptor 2 (HER2) + A549 lung xenografts were treated using ZHER2:V2-pemetrexed, pemetrexed or physiological saline. Therapeutic efficacy was monitored by single photon emission computed tomography (SPECT) imaging using the 99mTc-labeled ZHER2:V2-pemetrexed conjugate and further confirmed by performing apoptosis assays using flow cytometry analysis and hematoxylin-eosin (H&E) staining. To evaluate the expression of HER2 in tumor tissues, immunohistochemistry was performed, accompanied by quantitative analysis using flow cytometry. A toxicological evaluation was also conducted. Imaging with 99mTc-ZHER2:V2-pemetrexed demonstrated that in HER2+ A549 models, ZHER2:V2-pemetrexed showed better antineoplastic effects than pemetrexed. Compared with pemetrexed, the results from the pathological and flow cytometry analyses also revealed that ZHER2:V2-pemetrexed exhibits high antitumor activity against A549 tumors, inducing necrosis, apoptosis and cell cycle arrest. In addition, the clinical signs of toxicity in the ZHER2:V2-pemetrexed treated group were reduced compared with those in the pemetrexed treated group. These data revealed that the ZHER2:V2-pemetrexed conjugate encompasses promising targeted antitumor activity against HER2-positive lung adenocarcinoma, with reduced side effects compared with pemetrexed. Thus, the ZHER2:V2-pemetrexed conjugate may serve as a novel molecular agent with tremendous clinical breakthrough potential in the diagnosis and treatment of HER2-positive lung adenocarcinoma.

16.
Blood Adv ; 3(19): 2895-2904, 2019 Oct 08.
Artigo em Inglês | MEDLINE | ID: mdl-31594763

RESUMO

Rapid remission by induction therapy has long been recognized as an important predictor for long-time survival in acute leukemia. However, the impact of response kinetics on multiple myeloma (MM) seems to be different and remains unexplored. The relationship between response kinetics and outcome were assessed in 626 patients with newly diagnosed MM who were included in a prospective, nonrandomized clinical trial (BDH 2008/02). Patients were assigned to either immunomodulatory drug- or proteasome inhibitor-based therapy. The response depth, time to best response (TBR) and duration of best response (DBR) were collected. Depth of response was associated with superior outcomes, consistent with findings from other studies. However, the early responders (defined as TBR ≤3 months) showed significantly worse survival compared with late responders. We found that patients with rapid complete remission experienced inferior survivals comparable to those attaining a gradual partial remission. Moreover, 4 distinct response kinetics patterns were identified. Patients with gradual and sustained remission ("U-valley" pattern) experienced superior outcomes, whereas poor outcomes were observed in rapid and transient responders ("roller coaster" pattern) (median overall survival, 126 vs 30 months). The effects of response patterns on survival were confirmed in patients at different stages of disease and cytogenetic risk, including transplant-eligible patients and those attaining different extents of response depth. Collectively, our data indicated that slow and gradual response is a favorable prognostic factor in MM. In addition to response depth, the kinetic pattern of response is a simple and powerful predictor for survival even in the era of novel agents.

17.
Environ Int ; 133(Pt B): 105162, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31648155

RESUMO

Cities play a significant role in climate change mitigation and adaptation. Urban land planning shapes the urban form and is considered to be an effective approach for climate change mitigation and adaptation. Yet, there is little knowledge about what urban forms can reduce both greenhouse gas (GHG) emissions and climate stresses while considering trade-offs between them. Here, we investigate the role of urban land use in both climate change mitigation and adaptation. In particular, we assess quantitatively the competition between strategies for mitigation and adaptation and identify potential win-win solutions in land use responses. Using a coastal city as a case study, we find that the land use strategies for unilateral mitigation or adaptation can cause contradicting consequences with respect to the reductions in GHG emissions and climate stresses, i.e. reductions in GHGs could increase climate stresses or vice versa. Poorly integrated strategies potentially may compromise international efforts to meet the Climate Action in the Sustainable Development Goals. Properly integrated mitigation and adaptation strategies, or climate-sensitive land use planning, however, can lead to win-win outcomes and eventually achieve co-benefits. Yet, any co-benefits will gradually diminish if there is a delay in climate-sensitive land use planning, implying growing GHGs and intensified climate stresses. Our analysis indicates that integrating climate change mitigation and adaptation in urban land use needs to be enacted as soon as possible: any delays in implementation reduce the window to act to maximize the co-benefits.


Assuntos
Planejamento de Cidades , Mudança Climática , Aclimatação , Cidades , Humanos , Oceanos e Mares
18.
Theranostics ; 9(16): 4764-4778, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31367256

RESUMO

The currently used anti-cancer therapies work by killing cancer cells but result in adverse effects and resistance to treatment, which accelerates aging and causes damage to normal somatic cells. On one hand, chicken and zebrafish embryos can reprogram cancer cells towards a non-tumorigenic phenotype; however, they cannot be used in the clinical practice. On the other hand, embryonic stem cells (ESCs) mimic the early embryonic microenvironment and are easily available. We investigated the therapeutic efficacy of the ESC microenvironment (ESCMe) in human uveal melanoma in vitro and in vivo. Methods: Human uveal melanoma C918 cells co-cultured with ESCs were used to measure the levels of mRNA and protein of the phosphoinositide 3-kinase (PI3K) pathway. Cell proliferation, invasiveness, and tumorigenicity of C918 cells were also analyzed. To mimic the tumor microenvironment in vivo, we co-cultured C918 cells and normal somatic cells with ESCs in a co-culture system and evaluated the therapeutic potential of ESCMe in both cell types. For an in vivo study, a mouse tumor model was used to test the safety and efficacy of the transplanted ESC. Elimination of the transplanted ESCs in mice was carried out by using the ESC-transfected with a thymidine kinase suicidal gene followed by administration of ganciclovir to prevent the formation of teratomas by ESCs. Results: In vitro studies confirmed that ESCMe inhibits the proliferation, invasiveness, and tumorigenicity of C918 cells, and the PI3K agonist abolished these effects. ESCMe suppressed the various malignant behaviors of uveal melanoma cells but enhanced the proliferation of normal somatic cells both in vitro and in vivo. Further, we demonstrated that ESCMe suppressed the PI3K pathway in tumor cells but activated in somatic cells. Conclusions: The ESCMe can effectively suppress the malignant phenotype of uveal melanoma cells and modulate the tumor-promoting aging environment by preventing the senescence of normal cells through the bidirectional regulation of the PI3K signaling. Our results suggest that ESC transplantation can serve as an effective and safe approach for treating cancer without killing cells.

19.
iScience ; 19: 388-401, 2019 Sep 27.
Artigo em Inglês | MEDLINE | ID: mdl-31419632

RESUMO

Breast cancer-induced activated fibroblasts support tumor progression. However, the role of normal fibroblasts in tumor progression remains controversial. In this study, we used modified patient-derived organoid cultures and demonstrate that constitutively secreted cytokines from normal breast fibroblasts initiate a paracrine signaling mechanism with estrogen receptor-positive (ER+) breast cancer cells, which results in the creation of an interleukin (IL)-1ß-enriched microenvironment. We found that this paracrine signaling mechanism is shared between normal and activated fibroblasts. Interestingly, we observed that in reconstructed tumor microenvironment containing autologous ER+ breast cancer cells, activated fibroblasts, and immune cells, tamoxifen is more effective in reducing tumor cell proliferation when this paracrine signaling is blocked. Our findings then suggest that ER+ tumor cells could create a growth-promoting environment without activating stromal fibroblasts and that in breast-conserving surgeries, normal fibroblasts could be a significant modulator of tumor recurrence by enhancing the proliferation of residual breast cancer cells in the tumor-adjacent breast tissue.

20.
Phytother Res ; 33(9): 2298-2309, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31268205

RESUMO

Cisplatin represents one of the first-line drugs used for non-small-cell lung cancer treatment. However, considerable side effects and the emergence of drug resistance are becoming critical limitations to its application. Combinatorial strategies may be able to extend the use of cisplatin. Both Tanshinone IIA and cisplatin inhibit non-small-cell lung cancer cell growth in a time- and dose-dependent manner. When Tanshinone IIA was combined with cisplatin at a ratio of 20:1, they were observed to exert a synergistic inhibitory effect on non-small-cell lung cancer cells. The combination treatment was shown to impair cell migration and invasion, arrest the cell cycle in the S phases, and induce apoptosis in A549 and PC9 cells in a synergistic manner. KEGG pathway analysis and molecular docking indicated that Tanshinone IIA might mainly influence the phosphatidylinositol 3-kinase-Akt signalling pathway. In all treated groups, the expression levels of Bax and cleaved Caspase-3 were up-regulated, whereas the expression levels of Bcl-2, Caspase-3, p-Akt, and p-PI3K proteins were down-regulated. Among these, the combination of Tan IIA and cisplatin exhibited the most significant difference. Tanshinone IIA may function as a novel option for combination therapy for non-small-cell lung cancer treatment.


Assuntos
/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Cisplatino/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Fosfatidilinositol 3-Quinase/metabolismo , Proteínas Proto-Oncogênicas c-akt/metabolismo , /farmacologia , Animais , Linhagem Celular Tumoral , Cisplatino/farmacologia , Regulação para Baixo , Sinergismo Farmacológico , Humanos , Camundongos , Camundongos Nus , Transdução de Sinais
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