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B cell activation during normal immune responses and oncogenic transformation impose increased metabolic demands on B cells and their ability to retain redox homeostasis. While the serine/threonine-protein phosphatase 2A (PP2A) was identified as a tumor suppressor in multiple types of cancer, our genetic studies revealed an essential role of PP2A in B cell tumors. Thereby, PP2A redirects glucose carbon utilization from glycolysis to the pentose phosphate pathway (PPP) to salvage oxidative stress. This unique vulnerability reflects constitutively low PPP activity in B cells and transcriptional repression of G6PD and other key PPP enzymes by the B cell transcription factors PAX5 and IKZF1. Reflecting B-cell-specific transcriptional PPP-repression, glucose carbon utilization in B cells is heavily skewed in favor of glycolysis resulting in lack of PPP-dependent antioxidant protection. These findings reveal a gatekeeper function of the PPP in a broad range of B cell malignancies that can be efficiently targeted by small molecule inhibition of PP2A and G6PD.
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Carbono/metabolismo , Glucose/metabolismo , Leucemia-Linfoma Linfoblástico de Células Precursoras/patologia , Animais , Linfócitos B/citologia , Linfócitos B/metabolismo , Linhagem Celular Tumoral , Sobrevivência Celular , Glucosefosfato Desidrogenase/genética , Glucosefosfato Desidrogenase/metabolismo , Glicólise , Humanos , Fator de Transcrição Ikaros/genética , Fator de Transcrição Ikaros/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Estresse Oxidativo , Fator de Transcrição PAX5/genética , Fator de Transcrição PAX5/metabolismo , Via de Pentose Fosfato , Leucemia-Linfoma Linfoblástico de Células Precursoras/metabolismo , Proteína Fosfatase 2/deficiência , Proteína Fosfatase 2/genética , Proteína Fosfatase 2/metabolismo , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transcrição GênicaRESUMO
PURPOSE: A substantial need for effective and safe treatment options is still unmet for patients with heavily pre-treated human epidermal growth factor receptor 2 (HER2)-positive metastatic breast cancer (MBC). Herein, we assessed the efficacy and safety of pyrotinib plus trastuzumab and chemotherapy in patients with heavily treated HER2-positive MBC. METHODS: In this single-arm exploratory phase II trial, patients with HER2-positive MBC previously treated with trastuzumab plus lapatinib or pertuzumab, received pyrotinib plus trastuzumab and chemotherapy. The primary end point was progression-free survival (PFS) in the total population (TP). Secondary end points included PFS in the subgroup with brain metastases (Sub-BrM), confirmed objective response rate (ORR), clinical benefit rate (CBR), disease control rate (DCR), exploration of predictive factors of PFS, and safety. RESULTS: Between November 1, 2018, and March 31, 2021, 40 patients were eligible for this study. The median PFS reached 7.5 months (95% confidence interval [CI] 4.7 to 9.9 months) and 9.4 months (95% CI 6.6 to 12.1 months) in the TP and Sub-BrM, respectively. ORR was 50.5% (20/40). CBR was 75.5% (30/40) and DCR reached 97.5% (39/40). Cox univariate and multivariate analyses demonstrated that liver or/and lung metastases was the significant adverse prognostic factor for PFS (p = 0.018; p = 0.026; respectively). The most frequent grade 3 or 4 treatment-related adverse events were diarrhea, neutropenia and leukopenia. No new safety signals were observed. CONCLUSION: Pyrotinib plus trastuzumab and chemotherapy offered a promising option with manageable safety profile for heavily pre-treated HER2-positive MBC, especially for those without liver or/and lung metastases.
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Neoplasias da Mama , Humanos , Feminino , Trastuzumab , Neoplasias da Mama/patologia , Receptor ErbB-2/metabolismo , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
As a kind of plant-specific transcription factor (TF), DNA-Binding One Zinc Finger (Dof) is widely involved in the response to environmental change, and as an evolutionarily important perennial plant species, Akebia trifoliata is ideal for studying environmental adaptation. In this study, a total of 41 AktDofs were identified in the A. trifoliata genome. First, the characteristics, including the length, exon number, and chromosomal distribution of the AktDofs and the isoelectric point (PI), amino acid number, molecular weight (MW), and conserved motifs of their putative proteins, were reported. Second, we found that all AktDofs evolutionarily underwent strong purifying selection, and many (33, 80.5%) of them were generated by whole-genome duplication (WGD). Third, we outlined their expression profiles by the use of available transcriptomic data and RT-qPCR analysis. Finally, we identified four candidate genes (AktDof21, AktDof20, AktDof36, and AktDof17) and three other candidate genes (AktDof26, AktDof16, and AktDof12) that respond to long day (LD) and darkness, respectively, and that are closely associated with phytohormone-regulating pathways. Overall, this research is the first to identify and characterize the AktDofs family and is very helpful for further research on A. trifoliata adaptation to environmental factors, especially photoperiod changes.
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Reguladores de Crescimento de Plantas , Fatores de Transcrição , Fatores de Transcrição/metabolismo , Fotoperíodo , Filogenia , Dedos de Zinco , Plantas/metabolismo , DNA , Proteínas de Plantas/genéticaRESUMO
Polygalacturonase (PG) is one of the largest families of hydrolytic enzymes in plants. It is involved in the breakdown of pectin in the plant cell wall and even contributes to peel cracks. Here, we characterize PGs and outline their expression profiles using the available reference genome and transcriptome of Akebia trifoliata. The average length and exon number of the 47 identified AktPGs, unevenly assigned on 14 chromosomes and two unassembled contigs, were 5399 bp and 7, respectively. The phylogenetic tree of 191 PGs, including 47, 57, 51, and 36 from A. trifoliata, Durio zibethinus, Actinidia chinensis, and Vitis vinifera, respectively, showed that AktPGs were distributed in all groups except group G and that 10 AktPGs in group E were older, while the remaining 37 AktPGs were younger. Evolutionarily, all AktPGs generally experienced whole-genome duplication (WGD)/segmental repeats and purifying selection. Additionally, the origin of conserved domain III was possibly associated with a histidine residue (H) substitute in motif 8. The results of both the phylogenetic tree and expression profiling indicated that five AktPGs, especially AktPG25, could be associated with the cracking process. Detailed information and data on the PG family are beneficial for further study of the postharvest biology of A. trifoliata.
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Genes de Plantas , Poligalacturonase , Filogenia , Poligalacturonase/metabolismo , Transcriptoma , Plantas/metabolismoRESUMO
Molecular ferroelectrics (MFs) have been proven to demonstrate excellent properties even comparable to those of inorganic counterparts usually with heavy metals. However, the validation of their device applications is still at the infant stage. The polycrystalline feature of conventionally obtained MF films, the patterning challenges for microelectronics and the brittleness of crystalline films significantly hinder their development for organic integrated circuits, as well as emerging flexible electronics. Here, a large-area flexible memory array is demonstrated of oriented molecular ferroelectric single crystals (MFSCs) with nearly saturated polarization. Highly-uniform MFSC arrays are prepared on large-scale substrates including Si wafers and flexible substrates using an asymmetric-wetting and microgroove-assisted coating (AWMAC) strategy. Resultant flexible memory arrays exhibit excellent nonvolatile memory properties with a low-operating voltage of <5 V, i.e., nearly saturated ferroelectric polarization (6.5 µC cm-2 ), and long bending endurance (>103 ) under various bending radii. These results may open an avenue for scalable flexible MF electronics with high performance.
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BACKGROUND: Trace elements may affect neurodevelopment. There is a lack of data on breast-milk rubidium (Rb) in relation to neurodevelopment in infants. The associations of copper (Cu), zinc (Zn) and strontium (Sr) with neurodevelopment in infants remain uncertain. OBJECTIVES: We sought to evaluate the associations of breast-milk Rb (primary exposure), Cu, Zn, and Sr with neurodevelopment in infants at age 8 months. METHODS: The study cohort included 117 breastfed infants. Breast-milk samples were collected at 42 days and 8 months postpartum. Breast-milk Rb, Zn, Cu, and Sr were measured by inductively coupled plasma mass spectrometer. Neurodevelopment was assessed at age 8 months. The primary outcomes were attention and working memory scores, as evaluated by the A-not-B task. Other outcomes included the Mental Development Index (MDI) and Psychomotor Development Index (PDI) as evaluated by the Bayley Scale of Infant Development III. Generalized linear models and restricted cubic spline regression were used to assess the associations between trace elements and neurodevelopment indices. Bonferroni correction was conducted on all data presented. RESULTS: A nonlinear association was observed between breast-milk Rb at 42 days and infant's attention at age 8 months (nonlinearity P = 0.037). Positive associations were observed with infant MDI scores and breast-milk Rb at 42 days (ß = 4.46; P = 0.06) and 8 months (ß = 3.79; P = 0.009) postpartum. Breast-milk Zn at 42 days was positively associated with infant's attention (ß = 0.31; P = 0.039). Sr at 42 days was positively correlated with attention (ß = 0.18; P = 0.043) and MDI scores (ß = 2.18; P = 0.015) at 8 months. Inverted U-shape associations were observed for breast-milk Cu at 42 days with infant attention and PDI scores. All associations were not significant after correction for multiple tests. CONCLUSIONS: Our data suggest that Rb, Zn, Cu, and Sr in breast milk at certain concentrations are associated with neurodevelopment in breastfed infants. Further studies are warranted to validate the findings.
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Leite Humano , Oligoelementos , Aleitamento Materno , Criança , Desenvolvimento Infantil , Feminino , Humanos , Lactente , Leite Humano/química , Rubídio , Oligoelementos/análise , ZincoRESUMO
Vitamin E is effective for preventing the risk of cancer. However, few studies have elucidated the mechanism of vitamin E in cancer occurrence. Herein, we aimed to identify the genetic variants in vitamin E-related pathway genes associated with colorectal cancer risk. We applied logistic regression models to assess the association between single-nucleotide polymorphisms (SNPs) in vitamin E-related pathway genes and colorectal cancer risk in the Chinese and European population. The false discovery rate (FDR) method was used to correct multiple comparisons. The mRNA and protein expression analysis were evaluated in public database and in-house RNA-Seq data. SCARB1 rs73227586 was identified significantly increased risk of colorectal cancer in the Chinese population (odd ratio (OR) = 1.46, 95% confidence interval (CI) = 1.22-1.75, P = 2.99 × 10-5). This finding was further validated in the European population (OR = 1.11, 95% CI = 1.02-1.20, P = 1.44 × 10-2). Additionally, the mRNA and protein expression of SCARB1 were markedly up-regulated in colorectal tumor tissues. Moreover, rs73227586 T allele could increase the minimum free energy (MFE) and weaken binding ability to transcription factor ELL2. Our findings indicated that SCARB1 may play a carcinogenic role in colorectal cancer. Genetic variants in vitamin E-related pathway genes may concern to be predictors of colorectal cancer risk.
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Neoplasias Colorretais , Predisposição Genética para Doença , Estudos de Casos e Controles , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Humanos , Polimorfismo de Nucleotídeo Único , Fatores de Elongação da Transcrição/genética , Vitamina ERESUMO
Increased lifespans and population growth have resulted in an older U.S. society that must reckon with the complex oral health needs that arise as adults age. Understanding accessibility to screening and treatment facilities for older adults is necessary in order to provide them with preventive and restorative services. This study uses an agent-based model to examine the accessibility of screening and treatment facilities via transportation networks for older adults living in the neighborhoods of northern Manhattan, New York City. Older adults are simulated as socioeconomically distinct agents who move along a GIS-based transportation network using transportation modes that mediate their access to screening and treatment facilities. This simulation model includes four types of mobile agents as a simplifying assumption: walk, by car, by bus, or by van (i.e., a form of transportation assistance for older adults). These mobile agents follow particular routes: older adults who travel by car, bus, and van follow street roads, whereas pedestrians follow walkways. The model enables the user to focus on one neighborhood at a time for analysis. The spatial dimension of an older adult's accessibility to screening and treatment facilities is simulated through the travel costs (indicated by travel time or distance) incurred in the GIS-based model environment, where lower travel costs to screening and treatment facilities imply better access. This model provides a framework for representing health-seeking behavior that is contextualized by a transportation network in a GIS environment.
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BACKGROUND: Supraclavicular lymph node (SCLN) biopsies play an important role in diagnosing and staging lung cancer. However, not all patients with SCLN metastasis can have a complete resection. It is still unknown whether SCLN incisional biopsies affect the prognosis of non-small cell lung cancer (NSCLC) patients. METHODS: Patients who were histologically confirmed to have NSCLC with SCLN metastasis were enrolled in the study from January 2007 to December 2012 at Guangdong Lung Cancer Institute. The primary endpoint was OS, and the secondary endpoints were complications and local recurrence/progression. RESULTS: Two hundred two consecutive patients who had histologically confirmed NSCLC with SCLN metastasis were identified, 163 with excisional and 39 with incisional biopsies. The median OS was not significantly different between the excisional (10.9 months, 95% CI 8.7-13.2) and incisional biopsy groups (10.1 months, 95% CI 6.3-13.9), P = 0.569. Multivariable analysis showed that an Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥2 (HR = 2.75, 95% CI 1.71-4.38, P < 0.001) indicated a worse prognosis. Having an epidermal growth factor receptor (EGFR) mutation (HR = 0.58, 95% CI 0.40-0.84, P = 0.004) and receiving systemic treatment (HR = 0.36, 95% CI 0.25-0.53, P < 0.001) were associated with a favorable OS. Neither the number (multiple vs. single) nor site (bilateral vs. unilateral) of SCLNs was associated with an unfavorable OS, and SCLN size or fixed SCLNs did not affect OS. CONCLUSIONS: SCLN incisional biopsies did not negatively influence the prognosis of NSCLC patients. It was safe and feasible to partly remove a metastatic SCLN as a last resort in advanced NSCLC.
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Adenocarcinoma/secundário , Carcinoma de Células Grandes/secundário , Carcinoma Pulmonar de Células não Pequenas/secundário , Carcinoma de Células Escamosas/secundário , Neoplasias Pulmonares/patologia , Linfonodos/cirurgia , Recidiva Local de Neoplasia/patologia , Adenocarcinoma/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Grandes/cirurgia , Carcinoma Pulmonar de Células não Pequenas/cirurgia , Carcinoma de Células Escamosas/cirurgia , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/cirurgia , Excisão de Linfonodo , Linfonodos/patologia , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/cirurgia , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Taxa de SobrevidaRESUMO
BACKGROUND: According to the literature and our experience, the most common sites of non-small cell lung cancer (NSCLC) metastases include the brain, bone, liver, adrenal glands, contralateral lung and distant lymph nodes. Metastases to other organs are relatively rare. There have been numerous case reports and a few small case series of uncommon metastases derived from NSCLC. METHODS: We defined all organs except the common metastatic sites mentioned above as uncommon sites of metastasis. Patients with uncommon metastases among 2,872 consecutive NSCLC patients with stage IV disease at the Guangdong Lung Cancer Institute (GLCI) from 2006 to 2012 were included in this study. The diagnosis of uncommon metastases was based on pathology or imaging studies. RESULTS: Uncommon metastases were diagnosed in 193 cases at anatomical sites such as the soft tissue, kidney, pancreas, spleen, peritoneum, intestine, bone marrow, eye, ovary, thyroid, heart, breast, tonsil and nasal cavity. Uncommon metastases were identified as independent poor prognostic factors through a multivariate analysis with a HR (hazard ratio) of 1.29 [95% confidence interval (CI) 1.09-1.52, P < 0.01]. Those patients who received systemic therapy plus local treatment had a better survival rate than did those who received systemic therapy only (P < 0.01); all patients received best supportive care. CONCLUSIONS: Metastases to the above mentioned sites are infrequent. The presentation of uncommon metastases tends to indicate a poor outcome, and selected patients may benefit from local treatment.
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Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Pulmonares/patologia , Metástase Neoplásica/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Modelos de Riscos Proporcionais , Taxa de Sobrevida , Adulto JovemRESUMO
It is widespread of endemic fluorosis in China, and the exposure of excessive fluoride will cause nervous system disease and activate microglia. However, the mechanism of the damage is not clear. It is well-known that NLRP3/Caspase-1/GSDMD pathway, a classic pyroptosis pathway, is widely involved in the occurrence and development of nervous system-related diseases, infectious diseases, and atherosclerotic diseases. This research aimed to explore the molecular mechanism of sodium fluoride on inflammation and pyroptosis in BV2 microglia based on the NLRP3/Caspase-1/GSDMD signaling pathway. BV2 microglia was treated with sodium fluoride at the dose of 0.25, 1, and 2 mmol/L for 24, 48, and 72 h, respectively. Cell viability, cell morphology, lactate dehydrogenase content, and related proteins and genes were examined to investigate if sodium fluoride caused damage to BV2 microglia through the pyroptosis pathway. Dithiolam (5 µmol/L), a pyroptosis inhibitor, was added for further verification. NaF could induced BV2 cells injury in a dose-dependent fashion through disrupting the integrity of cell membranes and increasing IL-1ß via upregulating NLRP3, Caspase-1, and its downstream protein GSDMD. Disulfiram could improve these changes caused by NaF. In conclusion, our results suggested that NLRP3/Caspase-1/GSDMD-mediated classical pyroptosis pathway was involved in fluoride-induced BV2 microglia damage.
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Fluoretos , Microglia , Fluoreto de Sódio , Caspase 1/efeitos dos fármacos , Caspase 1/metabolismo , Fluoretos/toxicidade , Microglia/efeitos dos fármacos , Microglia/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/efeitos dos fármacos , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Fluoreto de Sódio/toxicidade , Gasderminas/efeitos dos fármacos , Gasderminas/metabolismo , Animais , CamundongosRESUMO
BACKGROUND: Several studies have focused on the impact of frailty on the health outcomes of individuals with diabetes mellitus (DM). This meta-analysis aims to systematically synthesize the existing evidence on frailty and its association with mortality, hospitalizations, cardiovascular diseases, and diabetic complications in DM. METHODS: A comprehensive search in PubMed, Embase, and SCOPUS was carried out to identify relevant studies assessing the impact of frailty on mortality, hospitalizations, complications, and cardiovascular events in individuals with DM. The quality of the included studies was evaluated using the New Castle Ottawa Scale. RESULTS: From the 22 studies included, our meta-analysis revealed significant associations between frailty and adverse outcomes in individuals with DM. The pooled hazard ratios for mortality and frailty showed a substantial effect size of 1.84 (95% CI 1.46-2.31). Similarly, the odds ratio for hospitalization and frailty demonstrated a significant risk with an effect size of 1.63 (95% CI 1.50-1.78). In addition, frailty was associated with an increased risk of developing diabetic nephropathy (HR, 3.17; 95% CI 1.16-8.68) and diabetic retinopathy (HR, 1.94; 95% CI 0.80-4.71). CONCLUSION: Our results show a consistent link between frailty and increased mortality, heightened hospitalization rates, and higher risks of cardiovascular disease, diabetic nephropathy, and diabetic retinopathy for patients with DM. PROSPERO Registration Number: CRD42023485166.
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This is a systematic review of the literature on the Belt and Road Initiative (BRI) and its impact on tourism and heritage in participating countries along the Silk Roads. China launched the BRI in 2013 with the aim of promoting global trade and stimulating economic growth through the development of infrastructure and cultural cooperation. This review examines studies for the period from 2013 to 2023, focusing on key themes such as tourist flows, destination development, urban renewal, heritage preservation, and cultural route revival. The systematic review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, incorporating 56 relevant documents that cover both tourism and heritage domains. The findings highlight substantial potential for the development of new tourism products and destinations, improved urban renewal, and the preservation of cultural heritage, provided that integrated policies, public-private collaboration, and equitable community participation frameworks are implemented with attention to ecological limits. However, the review also identifies significant challenges, including financial imbalances, uneven access to benefits, social disruption, cultural commodification, and environmental degradation. Addressing these issues requires careful, context-specific planning. The study concludes with a proposal for a future research agenda that includes exploring underrepresented regions, developing sustainable tourism models, and fostering interdisciplinary research to ensure a balanced approach to economic development and heritage preservation. This review's findings provide valuable insight for policymakers, tourism officials, and cultural heritage managers, guiding the development of policies that balance economic growth with the preservation of cultural and natural heritage sites. This research contributes to the academic discourse by elucidating the complex interplay between the BRI and the Silk Roads' tourism and heritage, offering a pathway for sustainable and inclusive growth.
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Turismo , Humanos , China , Comércio , Desenvolvimento EconômicoRESUMO
Background: The correlation between acute ischemic stroke (AIS) and gut microbiota has opened a promising avenue for improving stroke prognosis through the utilization of specific gut bacterial species. This study aimed to identify gut bacterial species in AIS patients and their correlation with stroke severity, 3-month prognosis, and inflammatory markers. Methods: We enrolled 59 AIS patients (from June 2021 to July 2022) and 31 age-matched controls with similar cerebrovascular risk profiles but no stroke history. Fecal samples were analyzed using 16 S rDNA V3-V4 sequencing to assess α and ß diversity and identify significant microbiota differences. AIS cases were categorized based on the National Institute of Health Stroke Scale (NIHSS) scores and 3-month modified Rankin Scale (mRS) scores. Subgroup analyses were performed, and correlation analysis was used to examine associations between flora abundance, inflammatory markers and stroke outcome. Results: Significant differences in ß-diversity were observed between case and control groups (P < 0.01). Bacteroides dominated AIS samples, while Clostridia, Lachnospirales, Lachnospiraceae, Ruminococcaceae, Faecalibacterium, and Faecalibacterium prausnitzii were prominent in controls. Faecalibacterium and Faecalibacterium prausnitzii were significantly reduced in non-minor stroke and 3-month poor prognosis groups compared to controls, while this difference was less pronounced in patients with minor stroke and 3-month good prognosis. Both Faecalibacterium and Faecalibacterium prausnitzii were negatively correlated with the NIHSS score on admission (r = -0.48, -0.48, P < 0.01) and 3-month mRS score (r = -0.48, -0.44, P < 0.01). Additionally, they showed negative correlations with pro-inflammatory factors and positive correlations with anti-inflammatory factors (both P < 0.01). Conclusions: Faecalibacterium prausnitzii is negatively associated with stroke severity, impaired prognosis, and pro-inflammatory markers, highlighting its potential application in AIS treatments.
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BACKGROUND: The eastern edge of the QinghaiâTibet Plateau (QTP) and subtropical China have various regions where plant species originate and thrive, but these regions have been the focus of very few integrative studies. Here, we elucidated the phylogeographic structure of a continuous and widespread Akebia trifoliata population across these two regions. RESULTS: Sixty-one populations consisting of 391 genotypes were examined to assess population diversity and structure via network distribution analysis, maximum likelihood phylogenetic tree reconstruction, divergence time estimation, demographic history inference, and ancestral area reconstruction of both conserved internal transcribed spacer (ITS) and chloroplast (rps16) DNA sequences. The results showed that the ITS region was more variable than the rps16 region and could be suitable for studying intraspecific phylogeography. The A. trifoliata population displayed high genetic diversity, genetic differentiation and obvious phylogeographical structure, possibly originating on the eastern QTP, expanding during the last glacial-interglacial cycle, diverging in the early Pleistocene and middle Pleistocene, and extensively migrating thereafter. The migration route from west to east along rivers could be largely responsible for the long-distance dispersal of this species, while three main refuges (Qinba Mountains, Nanling Mountains and Yunnan-Guizhou Plateau) with multiple ice shelters facilitated its wide distribution. CONCLUSIONS: Our results suggested that the from west to east long migration accompanying with the minor short reciprocal migration in the south-north direction, and the three main refuges (the Qinba Mountains, Nanling Mountains and Yunnan-Guizhou Plateau) contributed to the extant geographical distribution of A. trifoliata. In addition, this finding also strongly reduced the discrepancy between glacial contraction and postglacial expansion and the in situ survival hypothesis by simultaneously considering the existence of many similar climate-related ecological niches and migration influences.
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Filogeografia , China , DNA de Cloroplastos/genética , Análise de Sequência de DNA , Variação Genética/genética , Filogenia , Tibet , Evolução Molecular , DNA de Plantas/genéticaRESUMO
OBJECTIVE: This real-world study aimed to investigate the efficacy and safety of palbociclib plus endocrine therapy in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer in the real world in a Chinese population. METHODS: The clinical data of consecutively enrolled patients from the Cancer Hospital Chinese Academy of Medical Sciences, Shenzhen Center, and the University of Hong Kong - Shenzhen Hospital were collected. Progression-free survival curves were generated using log-rank tests with the Kaplan-Meier method. Univariate and multivariate logistic regression analyses were performed to identify the factors affecting progression-free survival. RESULTS: In total, 118 patients were enrolled, including 6 patients with brain metastases. At the last follow-up date, the median progression-free survival was 16.8 months (95% confidence interval, 11.1-22.5), with the 6-month and 12-month progression-free survival rates of 77.1% and 57.6%, respectively. The disease control rate and the intracranial disease control rate were 82.2% and 50%, respectively. A longer progression-free survival was observed for patients with the following characteristics: treatment-naive; without hepatic metastasis; sensitive to previous endocrine therapy and harboring fewer metastatic sites. The multivariate logistic regression analysis demonstrated that treatment lines and exposure to palliative chemotherapy were independent influencing factors of progression-free survival. CONCLUSIONS: Palbociclib plus endocrine therapy in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative metastatic breast cancer was effective and well-tolerated, even in patients with brain metastases. More benefits were observed in frontline therapy, chemotherapy-naive, and endocrine therapy-sensitive patients with fewer metastatic sites.
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Neoplasias Encefálicas , Neoplasias da Mama , Piperazinas , Piridinas , Humanos , Feminino , Neoplasias da Mama/patologia , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Receptor ErbB-2/metabolismo , Neoplasias Encefálicas/tratamento farmacológicoRESUMO
AIMS: To investigate the performance of a combined biomarker approach using the methylation status of the short stature homeobox 2 (SHOX2) and prostaglandin E2 receptor EP4 (PTGER4) genes, along with the serum levels of CYFRA21-1, for differential diganosis of malignant pleural mesothelioma (MPM) from benign reactive mesothelial hyperplasia (RMH). METHODS: We analysed 48 MPM tissue or pleural effusion cell block specimens and 42 cases with RMH. Real-time quantitative methylation-specific PCR was used to examine the methylation status of SHOX2, PTGER4, ras association domain family 1 isoform A, septin 9 gene and homeobox gene A9 genes. Additionally, we employed electrochemiluminescence immunoassay to measure nine serum tumour markers commonly used in pan-cancer screening tests. RESULTS: The receiver operating curve indicated that SHOX2, PTGER4 gene methylation and serum biomarker CYFRA21-1 exhibited good diagnostic performance in identifying MPM, with area under curves (AUCs) of 0.761, 0.904 and 0.847, respectively. The combination of SHOX2, PTGER4 methylation and CYFRA21-1 yielded an AUC value of 0.972. The diagnostic sensitivity and specificity of this panel in differentiating MPM from RMH were 91.3% (42/46) and 97.6% (41/42), respectively. Both tissue and cell block specimens can be used in the diagnostic process. Furthermore, elevated CYFRA21-1 levels were associated with poor prognosis (p<0.05). Hypermethylation level of PTGER4 may indicate an unfavourable prognosis of MPM, but the difference was not statistically significant. CONCLUSIONS: The combined detection of SHOX2 and PTGER4 methylation alongside serum CYFRA21-1 level significantly enhances the diagnosis of MPM. Additionally, CYFRA21-1 can serve as a prognostic indicator for MPM.
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Akebia trifoliata is a newly domesticated perennial fruit tree, and the lack of molecular research on stress resistance seriously affects its genetic improvement and commercial value development. Superoxide dismutase (SOD) can effectively eliminate the accumulation of reactive oxygen species (ROS) during the rapid growth of plant organs under biotic and abiotic stresses, maintaining a steady state of physiological metabolism. In this study, 13 SODs consisting of two FeSODs (FSDs), four MnSODs (MSDs) and seven Cu/ZnSODs (CSDs) were identified in the A. trifoliata genome. Structurally, the phylogeny, intron-exon pattern and motif sequences within these three subfamilies show high conservation. Evolutionarily, segmental/wide genome duplication (WGD) and dispersed duplication form the current SOD profile of A. trifoliata. Weighted gene coexpression network analysis (WGCNA) revealed the metabolic pathways of nine (69.2%) SODs involved in fruit development, among which AktMSD4 regulates fruit development and AktCSD4 participates in the stress response. In addition, under the stress of multiple pathogens, six (46.6%) SODs were continuously upregulated in the rinds of resistant lines; of these, three SODs (AktMSD1, AktMSD2 and AktMSD3) were weakly or not expressed in susceptible lines. The results pave the way for theoretical research on SODs and afford the opportunity for genetic improvement of A. trifoliata.
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BACKGROUND: More than half of the metastatic breast cancer patients with brain metastases (BCBM) are HER-2 negative, and the prognosis of HER2-negative BCBM is dismal. But few clinical trials have investigated systemic therapies for this subgroup of patients. METHODS: This real-world study included 58 HER2-negative BCBMs who received low-dose apatinib (250 mg daily) in combination with chemotherapy between 18 March 2017 and 31 December 2021. The objective response rate (ORR) of the central nervous system, clinical benefit rate (CBR), progression-free survival of central nervous system (CNS-PFS) and overall survival (OS) were analyzed. Univariate and multivariate Cox regression model was used to estimate the prognostic factors for CNS-PFS and OS. RESULTS: At the cut-off date, the median follow-up time was 28.2 months. Of the 58 patients, 36 patients were HR+/HER2-, and 22 patients were TNBC. The CNS-ORR was 17.2% (95%CI 9.6% to 28.9%) and the CBR was 53.4% (95%CI 40.8% to 65.7%). The median duration of CNS-PFS for the entire cohort was 6.4 months, and the median OS was 10.7 months. The median CNS-PFS and OS were not affected by hormone receptor status, disease-free survival, the number of prior lines of therapy and local treatment. The most common grade 2-3 adverse events associated with low-dose apatinib were hypertension (20.6%), elevated bilirubin (10.4%), hypothyroidism (10.3%), and hand-foot skin reaction (10.3%). CONCLUSION: Apatinib-based chemotherapy demonstrates potential feasibility with acceptable tolerance for HER2-negative BCBM. Its clinical application in BCBM still needs further verification.
HER2-negative breast cancer patients with brain metastases (BCBM) face an extremely poor prognosis, and a lack of effective treatment options. Apatinib, as a small molecule anti-angiogenic TKI, might have special central nervous system activity. Apatinib-based chemotherapy exhibits good tolerance and gains a favorable survival for HER2-negative BCBM.
Assuntos
Neoplasias Encefálicas , Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Resultado do Tratamento , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias Encefálicas/tratamento farmacológicoRESUMO
The most common sites of metastasis for breast cancer are the soft tissues, bones, lungs, liver and brain; however, metastases to the gastrointestinal tract and thyroid gland from breast cancer rarely occur. The present study describes the case of a 30-year-old woman who developed gastric and thyroid metastases 5 years after her initial diagnosis of invasive ductal breast carcinoma. The initial pathological diagnosis when receiving modified radical mastectomy was invasive ductal carcinoma, and further immunohistochemical examination revealed the cancer to be estrogen receptor (-), progesterone receptor (-), human epidermal growth factor receptor 2 (HER2; ++) and Ki-67 (70%). Genetic testing indicated the HER2 amplification mutation, whereas BRCA1/2 testing was negative. A total of 21 months after surgery, during regular follow-up, the patient was revealed to have developed an enlarged lymph node in the left side of the neck and the first recurrence was confirmed. Approximately 5 years after surgery, the patient gradually developed multi-site metastasis, and developed metastases to the thyroid gland and stomach confirmed by pathology and imaging. Combined chemotherapy and targeted therapy were administered and exhibited good efficacy; however, the patient subsequently died due to heart failure. This case report describes the occurrence of gastric and thyroid metastases from breast cancer, and highlights the importance of distinguishing between metastatic and primary tumors. Distinguishing between a metastatic and primary tumor is crucial as treatment protocols vary significantly for these two types of tumors. For patients with a history of breast cancer it should first be considered whether they have metastasis of the primary disease or discomfort caused by treatment; however, the possibility of a second primary tumor cannot be ignored. If the patient has symptoms such as loss of appetite, nausea, vomiting, stomach pain and stomach discomfort, a gastroscopy should be performed in a timely manner.