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1.
Cell Metab ; 2020 Nov 06.
Artigo em Inglês | MEDLINE | ID: mdl-33181091

RESUMO

Triple-negative breast cancer (TNBC) remains an unmet medical challenge. We investigated metabolic dysregulation in TNBCs by using our multi-omics database (n = 465, the largest to date). TNBC samples were classified into three heterogeneous metabolic-pathway-based subtypes (MPSs) with distinct metabolic features: MPS1, the lipogenic subtype with upregulated lipid metabolism; MPS2, the glycolytic subtype with upregulated carbohydrate and nucleotide metabolism; and MPS3, the mixed subtype with partial pathway dysregulation. These subtypes were validated by metabolomic profiling of 72 samples. These three subtypes had distinct prognoses, molecular subtype distributions, and genomic alterations. Moreover, MPS1 TNBCs were more sensitive to metabolic inhibitors targeting fatty acid synthesis, whereas MPS2 TNBCs showed higher sensitivity to inhibitors targeting glycolysis. Importantly, inhibition of lactate dehydrogenase could enhance tumor response to anti-PD-1 immunotherapy in MPS2 TNBCs. Collectively, our analysis demonstrated the metabolic heterogeneity of TNBCs and enabled the development of personalized therapies targeting unique tumor metabolic profiles.

2.
Nat Commun ; 11(1): 5679, 2020 11 10.
Artigo em Inglês | MEDLINE | ID: mdl-33173047

RESUMO

The remarkable advances in next-generation sequencing technology have enabled the wide usage of sequencing as a clinical tool. To promote the advance of precision oncology for breast cancer in China, here we report a large-scale prospective clinical sequencing program using the Fudan-BC panel, and comprehensively analyze the clinical and genomic characteristics of Chinese breast cancer. The mutational landscape of 1,134 breast cancers reveals that the most significant differences between Chinese and Western patients occurred in the hormone receptor positive, human epidermal growth factor receptor 2 negative breast cancer subtype. Mutations in p53 and Hippo signaling pathways are more prevalent, and 2 mutually exclusive and 9 co-occurring patterns exist among 9 oncogenic pathways in our cohort. Further preclinical investigation partially suggests that NF2 loss-of-function mutations can be sensitive to a Hippo-targeted strategy. We establish a public database (Fudan Portal) and a precision medicine knowledge base for data exchange and interpretation. Collectively, our study presents a leading approach to Chinese precision oncology treatment and reveals potentially actionable mutations in breast cancer.

3.
Nat Commun ; 11(1): 5767, 2020 Nov 13.
Artigo em Inglês | MEDLINE | ID: mdl-33188189

RESUMO

Enhancing the intrinsic activity and space time yield of Cu based heterogeneous methanol synthesis catalysts through CO2 hydrogenation is one of the major topics in CO2 conversion into value-added liquid fuels and chemicals. Here we report inverse ZrO2/Cu catalysts with a tunable Zr/Cu ratio have been prepared via an oxalate co-precipitation method, showing excellent performance for CO2 hydrogenation to methanol. Under optimal condition, the catalyst composed by 10% of ZrO2 supported over 90% of Cu exhibits the highest mass-specific methanol formation rate of 524 gMeOHkgcat-1h-1 at 220 °C, 3.3 times higher than the activity of traditional Cu/ZrO2 catalysts (159 gMeOHkgcat-1h-1). In situ XRD-PDF, XAFS and AP-XPS structural studies reveal that the inverse ZrO2/Cu catalysts are composed of islands of partially reduced 1-2 nm amorphous ZrO2 supported over metallic Cu particles. The ZrO2 islands are highly active for the CO2 activation. Meanwhile, an intermediate of formate adsorbed on the Cu at 1350 cm-1 is discovered by the in situ DRIFTS. This formate intermediate exhibits fast hydrogenation conversion to methoxy. The activation of CO2 and hydrogenation of all the surface oxygenate intermediates are significantly accelerated over the inverse ZrO2/Cu configuration, accounting for the excellent methanol formation activity observed.

4.
Org Lett ; 2020 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-33170727

RESUMO

A rhodium-catalyzed C-H amidation/cyclization sequence provides benzothiadiazine-1-oxides from sulfoximines and 1,4,2-dioxazol-5-ones in good yields. The reaction is characterized by a high functional group tolerance and, in contrast to most previous transformations of this type, is well-suited for S-alkyl-S-aryl-substituted sulfoximines.

5.
J Natl Cancer Inst ; 2020 Nov 05.
Artigo em Inglês | MEDLINE | ID: mdl-33151324

RESUMO

BACKGROUND: The germline variant spectrum of triple-negative breast cancer (TNBC) is different from that of other subtypes and has demonstrated ethnic differences. However, the germline variants of TNBC among Chinese patients and its clinical significance remain unclear. METHODS: Using our multi-omics TNBC cohort (n = 325), we determined the spectrum of germline variants in TNBC and aimed to illustrate their biological and clinical implications. RESULTS: Overall, 16.0% (52 of 325) of TNBC patients harbored at least one pathogenic or likely pathogenic germline variant. These germline variants were associated with early-onset of TNBC, the occurrence of contralateral breast cancer, the basal-like immune-suppressed mRNA subtype, and the homologous recombination deficiency (HRD) mutation subtype. Somatic allele-specific imbalance was observed in 54.1% of these germline variants, which was correlated with early-onset of breast cancer and elevated HRD. BRCA1 (7.4%), RAD51D (2.8%) and BRCA2 (2.2%) were the genes most frequently mutated. RAD51D germline variants, especially K91fs, were enriched in Chinese patients with TNBC compared to Caucasian and African American patients. The Chinese-specific RAD51D germline variants were functionally associated with the instability of the RAD51D protein, HRD and sensitivity to PARP inhibitors. CONCLUSIONS: Chinese TNBC patients have a distinct spectrum of germline variants, with a remarkable impact on the clinical and molecular characteristics of the tumor. Integrative germline-somatic analysis may help in identifying TNBC patients who are most likely to be affected by their germline variants and in performing clinical interventions more precisely. The RAD51D variants enriched in our cohort may serve as therapeutic targets and guide precision treatment of TNBC.

6.
Org Lett ; 2020 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-33124424

RESUMO

In visible light, sulfoximidoyl-containing hypervalent iodine reagents react with aryl alkynes to give N-α-ketoacylated sulfoximines in good to high yields. The process is metal- and base-free, providing the diketonic products without the use of highly oxygenated reagents such as peroxides. Results from mechanistic investigations suggest the intermediacy of radicals and reveal the importance of molecular oxygen.

7.
J Reprod Immunol ; 142: 103208, 2020 Sep 21.
Artigo em Inglês | MEDLINE | ID: mdl-33002799

RESUMO

Immune checkpoint molecules may play a crucial role in safeguarding pregnancy by regulating immune responses at the maternal-fetal interface. In this study, we aim to investigate the expression of PD-1, GITR, HLA-G, and CTLA-4 on T cell subsets in peripheral blood (PB), retroplacental blood (RPB), and cord blood (CB) in normal pregnancy (NP), preeclampsia (PE) and gestational diabetes mellitus (GDM). PB, RPB, and CB were collected immediately after delivery, and the expression of PD-1, GITR, HLA-G, and CTLA-4 on T cell subsets were measured by flow cytometric analysis. The proportions of Tregs in PB, RPB, and CB from NP were significantly higher than those of PE and GDM (P < 0.01, respectively). PD-1+ and GITR+ T cell subsets (CD3+, CD4+, and CD8+ T cells, and Tregs) in PB, as well as PD-1+ T cell subsets in RPB from NP, were significantly higher than those of PE and GDM (P < 0.01, respectively). In NP, PE, and GDM, the proportion of PD-1+ Tregs was significantly decreased in CB as compared to those of PB and RPB (P < 0.05, respectively) and the proportion of GITR+ Tregs was significantly higher in PB as compared to those of CB and RPB (P < 0.01, respectively). The proportion of HLA-G+ Tregs in PB was significantly lower than those of CB and RPB (P < 0.01, respectively). In conclusion, decreased PD-1+ and GITR+ T cell subsets and decreased proportion of Tregs in PB and RPB may play a role in chronic inflammatory immune activation of effector T cells in PE and GDM.

8.
Theranostics ; 10(24): 10940-10956, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33042263

RESUMO

Background: Taxanes are frontline chemotherapeutic drugs for patients with triple-negative breast cancer (TNBC); however, chemoresistance reduces their effectiveness. We hypothesized that the molecular profiling of tumor samples before and after neoadjuvant chemotherapy (NAC) would help identify genes associated with drug resistance. Methods: We sequenced 10 samples by RNA-seq from 8 NAC patients with TNBC: 3 patients with a pathologic complete response (pCR) and the other 5 with non-pCR. Differentially expressed genes that predicted chemotherapy response were selected for in vitro functional screening via a small-scale siRNAs pool. The clinical and functional significance of the gene of interest in TNBC was further investigated in vitro and in vivo, and biochemical assays and imaging analysis were applied to study the mechanisms. Results: Synaptotagmin-like 4 (SYTL4), a Rab effector in vesicle transport, was identified as a leading functional candidate. High SYTL4 expression indicated a poor prognosis in multiple TNBC cohorts, specifically in taxane-treated TNBCs. SYTL4 was identified as a novel chemoresistant gene as validated in TNBC cells, a mouse model and patient-derived organoids. Mechanistically, downregulating SYTL4 stabilized the microtubule network and slowed down microtubule growth rate. Furthermore, SYTL4 colocalized with microtubules and interacted with microtubules through its middle region containing the linker and C2A domain. Finally, we found that SYTL4 was able to bind microtubules and inhibit the in vitro microtubule polymerization. Conclusion: SYTL4 is a novel chemoresistant gene in TNBC and its upregulation indicates poor prognosis in taxane-treated TNBC. Further, SYTL4 directly binds microtubules and decreases microtubule stability.

9.
Psychon Bull Rev ; 2020 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-33006121

RESUMO

Although most category-learning studies use feedback for training, little attention has been paid to how individuals use feedback value and framing of feedback as gains or losses to support learning. We compared learning of rule-based (RB) and information-integration (II) categories with point-valued feedback in which participants gained or lost higher point values for more difficult category members (those closer to the decision bound). We implemented point-valued feedback in four different conditions: Gain (earn points for correct answers), Loss (lose points for incorrect answers), Gain+Loss (earn points for correct answers and lose points for incorrect answers), and Control (accuracy feedback only without point gain or loss). Participants were trained until they reached criterion. Overall, point-valued feedback led to better learning than control conditions. However, the patterns differed across category-learning tasks. In the II task participants reached learning criterion fastest when they received both Gains and Losses. This is consistent with the reliance of II learning on reinforcement-based mechanisms and research showing common coding of gains and losses in neural regions underlying II learning. In contrast, in the RB task, participants reached criterion most rapidly when they received either Gains or Losses, but not both Gains and Losses together. The relative impairment in the Gain+Loss condition in RB learning may be due to conflicting executive function demands for interpreting and using the separate Gain and Loss information, and is consistent with reliance of RB learning on explicit hypothesis-testing mechanisms.

10.
Ther Drug Monit ; 2020 Jul 28.
Artigo em Inglês | MEDLINE | ID: mdl-33009291

RESUMO

PURPOSE: With the development of industrialization in human society, ambient pollutants are becoming more harmful to human health. Epidemiological and toxicological studies indicate that a close relationship exists between particulate matter with a diameter ≤ 2.5 µm (PM2.5) and neurodegenerative diseases such as Alzheimer's disease (AD) and Parkinson's disease (PD). To further confirm the relationship, we focus on possible relevant mechanisms of oxidative stress and neuroinflammation underlying the association between PM2.5 and neurodegenerative diseases in the review. METHODS: A literature search was performed on the studies about PM2.5 and neurodegenerative diseases via Pubmed. A total of 113 articles published were selected, and 31 studies were included. RESULTS: PM2.5 can enter the CNS through two main pathways, the BBB and olfactory neurons. The inflammatory response and oxidative stress are two primary mechanisms via which PM2.5 leads to toxicity in the brain. PM2.5 abnormally activates microglia, inducing the neuroinflammatory process. Inflammatory markers such as IL-1ß play an essential role in neurodegenerative diseases such as AD and PD. Moreover, the association between lipid mechanism disorders related to PM2.5 and neurodegenerative diseases has been gaining momentum. CONCLUSION: In conclusion, PM2.5 could significantly increase the risk of neurological disorders, such as AD and PD. Furthermore, any policy aimed at reducing air-polluting emissions and increasing air quality would be protective in human beings.

11.
Nat Commun ; 11(1): 5033, 2020 10 06.
Artigo em Inglês | MEDLINE | ID: mdl-33024092

RESUMO

Soaring cases of coronavirus disease (COVID-19) are pummeling the global health system. Overwhelmed health facilities have endeavored to mitigate the pandemic, but mortality of COVID-19 continues to increase. Here, we present a mortality risk prediction model for COVID-19 (MRPMC) that uses patients' clinical data on admission to stratify patients by mortality risk, which enables prediction of physiological deterioration and death up to 20 days in advance. This ensemble model is built using four machine learning methods including Logistic Regression, Support Vector Machine, Gradient Boosted Decision Tree, and Neural Network. We validate MRPMC in an internal validation cohort and two external validation cohorts, where it achieves an AUC of 0.9621 (95% CI: 0.9464-0.9778), 0.9760 (0.9613-0.9906), and 0.9246 (0.8763-0.9729), respectively. This model enables expeditious and accurate mortality risk stratification of patients with COVID-19, and potentially facilitates more responsive health systems that are conducive to high risk COVID-19 patients.


Assuntos
Infecções por Coronavirus/mortalidade , Aprendizado de Máquina , Pandemias , Pneumonia Viral/mortalidade , Idoso , Betacoronavirus , China/epidemiologia , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Redes Neurais de Computação , Medição de Risco , Máquina de Vetores de Suporte
12.
Oncol Rep ; 44(5): 1917-1928, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-33000247

RESUMO

Paclitaxel (PXL) is a chemotherapeutic agent widely used in solid tumors. However, whether PXL causes premature ovarian insufficiency in women of reproductive age remains controversial. The aim of the present study was to answer how and for how long PXL affects fertility, and to identify the protective effect of gonadotropin­releasing hormone agonist (GnRHa) in mice. A single dose of PXL was administered to 7­week­old female ICR mice. Mice were treated with GnRHa for 1 estrous cycle prior to chemotherapy, and for another following chemotherapy. On the days 1, 6, 11 and 16 following the administration of PXL, mice were assessed by ovarian histology, ovarian stimulation and mating experiment. Multiple doses of PXL were also administered to verify the duration of the gonadotoxicity of PXL. It was determined that PXL only destroyed antral follicles on day 1 following chemotherapy without reducing primordial follicles. In vitro experiments revealed that PXL impaired oocytes in metaphase, excluding those at the germinal vesicle stage. The number and quality of retrieved metaphaseⅡ(MⅡ) oocytes in PXL­exposed mice were reduced on day 1 following chemotherapy, which was recovered on day 11. MⅡ oocytes from mice pretreated with GnRHa recovered on day 6 following chemotherapy. Following 3 estrous cycles in mice after the last dose of the 3­dose paclitaxel administration, follicles in all stages and retrieved MII oocytes were recovered. It was concluded that the impairment caused by PXL on follicles and oocytes in mice lasted for <3 estrous cycles, which was shortened by pretreatment of GnRHa.

13.
Mol Diagn Ther ; 24(6): 715-721, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32970304

RESUMO

International guidelines recommend BRCA testing for patients with breast and ovarian cancer. Little is known about the genetic testing practices of BRCA1/2 mutations in laboratories across China. This study was designed to assess the discrepancies in genetic testing procedures of BRCA1/2 mutations across China. An online survey was developed for depicting the BRCA1/2 testing landscape in China. Our results show that there were several variations among the laboratories in technologies adopted, large genomic rearrangement detection, probe design, quality control, variant of uncertain significance interpretation, and disposition of variants in public databases. The discrepancies observed in our study would affect the authenticity of results, thus necessitating the formulation of proper national and international guidelines for optimal BRCA1/2 testing clinical practice for efficient management and patient care of this population.

14.
BMC Pregnancy Childbirth ; 20(1): 542, 2020 Sep 17.
Artigo em Inglês | MEDLINE | ID: mdl-32943000

RESUMO

BACKGROUND: Heterotopic pregnancy occurred after frozen embryo transfer with two D3 embryos, and the case had a history of bilateral salpingectomy due to salpingocyesis. An ectopic heterotopic pregnancy was implanted in the left psoas major muscle, which has not been previously reported. CASE PRESENTATION: A 33-year-old woman presented with left back pain after curettage due to foetal arrest in the uterus without vaginal bleeding and spotting, and painkillers relieved the pain initially. When the painkillers ceased to work, the patient returned to the hospital. The ß-human chorionic gonadotropin (ß-hCG) level remained increased compared with the time of curettage, and a diagnosis of retroperitoneal abdominal pregnancy was suggested by ultrasonography and computerized tomography (CT) with the gestational sac implanted in the left psoas major muscle at the left hilum level. Laparotomy was performed to remove the ectopic pregnancy. During the operation, we carefully separated the adipose tissue between the space of the left kidney door and left psoas major muscle, peeled away the gestational sac that was approximately 50 mm × 40 mm with a 25-mm-long foetal bud, and gave a local injection of 10 mg of methotrexate in the psoas major muscle. Fifty days later, ß-hCG decreased to normal levels. CONCLUSION: It is necessary to pay more attention to the main complaints to exclude rare types of ectopic pregnancies of the pelvis and abdomen after embryo transfer.

15.
Adv Sci (Weinh) ; 7(16): 1903323, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32832347

RESUMO

The combined treatment with nanoparticles and autophagy inhibitors, such as chloroquine (CQ) and hydroxychloroquine (HCQ), is extensively explored for cancer therapy. However, the toxicity of autophagy inhibitors and their unselective for tumoricidal autophagy have seriously hindered the application of the combined treatment. In this study, a carboxy-functional iron oxide nanoparticle (Fe2O3@DMSA) is designed and identified to significantly exert an antitumor effect without adding CQ or HCQ. Further investigation indicates that the effective inhibition effect of Fe2O3@DMSA alone on hepatoma growth is triggered by inhibiting the fusion of autophagosomes and lysosomes to enhance tumoricidal autophagy, which is induced by intracellular iron-retention-induced sustained reactive oxygen species (ROS) production. Furthermore, in two hepatoma-bearing mouse models, Fe2O3@DMSA alone effectively suppresses the growth of tumors without obvious toxic side effects. These studies offer a promising strategy for cancer therapy.

16.
Artigo em Inglês | MEDLINE | ID: mdl-32809247

RESUMO

Mn and Na additives have been widely studied to improve the efficiency of CO2 hydrogenation to valuable olefins on Fe catalysts, but their effects on the catalytic properties and mechanism are still under vigorous debate. This study shows that Fe-based catalysts with moderate Mn and Na contents are highly selective for CO2 hydrogenation to olefins, together with low selectivities for both CO and CH4 and much improved space-time olefin yields compared to state-of-the-art catalysts. Combined kinetic assessment and quasi in situ characterizations further unveil that the sole presence of Mn suppresses the activity of Fe catalysts because of the close contact between Fe and Mn, whereas the introduction of Na mediates the Fe-Mn interaction and provides strong basic sites. This subtle synergy between Na and Mn sheds light on the importance of the interplay of multiple additives that could bring an enabling strategy to improve catalytic activity and selectivity.

17.
JAMA Oncol ; 6(9): 1390-1396, 2020 Sep 01.
Artigo em Inglês | MEDLINE | ID: mdl-32789480

RESUMO

Importance: The value of platinum-based adjuvant chemotherapy in patients with triple-negative breast cancer (TNBC) remains controversial, as does whether BRCA1 and BRCA2 (BRCA1/2) germline variants are associated with platinum treatment sensitivity. Objective: To compare 6 cycles of paclitaxel plus carboplatin (PCb) with a standard-dose regimen of 3 cycles of cyclophosphamide, epirubicin, and fluorouracil followed by 3 cycles of docetaxel (CEF-T). Design, Setting, and Participants: This phase 3 randomized clinical trial was conducted at 9 cancer centers and hospitals in China. Between July 1, 2011, and April 30, 2016, women aged 18 to 70 years with operable TNBC after definitive surgery (having pathologically confirmed regional node-positive disease or node-negative disease with tumor diameter >10 mm) were screened and enrolled. Exclusion criteria included having metastatic or locally advanced disease, having non-TNBC, or receiving preoperative anticancer therapy. Data were analyzed from December 1, 2019, to January 31, 2020, from the intent-to-treat population as prespecified in the protocol. Interventions: Participants were randomized to receive PCb (paclitaxel 80 mg/m2 and carboplatin [area under the curve = 2] on days 1, 8, and 15 every 28 days for 6 cycles) or CEF-T (cyclophosphamide 500 mg/m2, epirubicin 100 mg/m2, and fluorouracil 500 mg/m2 every 3 weeks for 3 cycles followed by docetaxel 100 mg/m2 every 3 weeks for 3 cycles). Main Outcomes and Measures: The primary end point was disease-free survival (DFS). Secondary end points included overall survival, distant DFS, relapse-free survival, DFS in patients with germline variants in BRCA1/2 or homologous recombination repair (HRR)-related genes, and toxicity. Results: A total of 647 patients (mean [SD] age, 51 [44-57] years) with operable TNBC were randomized to receive CEF-T (n = 322) or PCb (n = 325). At a median follow-up of 62 months, DFS time was longer in those assigned to PCb compared with CEF-T (5-year DFS, 86.5% vs 80.3%, hazard ratio [HR] = 0.65; 95% CI, 0.44-0.96; P = .03). Similar outcomes were observed for distant DFS and relapse-free survival. There was no statistically significant difference in overall survival between the groups (HR = 0.71; 95% CI, 0.42-1.22, P = .22). In the exploratory and hypothesis-generating subgroup analyses of PCb vs CEF-T, the HR for DFS was 0.44 (95% CI, 0.15-1.31; P = .14) in patients with the BRCA1/2 variant and 0.39 (95% CI, 0.15-0.99; P = .04) in those with the HRR variant. Safety data were consistent with the known safety profiles of relevant drugs. Conclusions and Relevance: These findings suggest that a paclitaxel-plus-carboplatin regimen is an effective alternative adjuvant chemotherapy choice for patients with operable TNBC. In the era of molecular classification, subsets of TNBC sensitive to PCb should be further investigated. Trial Registration: ClinicalTrials.gov Identifier: NCT01216111.

18.
Nat Commun ; 11(1): 4269, 2020 08 28.
Artigo em Inglês | MEDLINE | ID: mdl-32859890

RESUMO

Mitochondria generate most cellular energy via oxidative phosphorylation. Twenty-two species of mitochondrial (mt-)tRNAs encoded in mtDNA translate essential subunits of the respiratory chain complexes. mt-tRNAs contain post-transcriptional modifications introduced by nuclear-encoded tRNA-modifying enzymes. They are required for deciphering genetic code accurately, as well as stabilizing tRNA. Loss of tRNA modifications frequently results in severe pathological consequences. Here, we perform a comprehensive analysis of post-transcriptional modifications of all human mt-tRNAs, including 14 previously-uncharacterized species. In total, we find 18 kinds of RNA modifications at 137 positions (8.7% in 1575 nucleobases) in 22 species of human mt-tRNAs. An up-to-date list of 34 genes responsible for mt-tRNA modifications are provided. We identify two genes required for queuosine (Q) formation in mt-tRNAs. Our results provide insight into the molecular mechanisms underlying the decoding system and could help to elucidate the molecular pathogenesis of human mitochondrial diseases caused by aberrant tRNA modifications.


Assuntos
Processamento Pós-Transcricional do RNA , RNA Mitocondrial/química , RNA de Transferência/química , Feminino , Código Genético , Células HEK293 , Células HeLa , Humanos , Espectrometria de Massas , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Doenças Mitocondriais/genética , Doenças Mitocondriais/patologia , Estrutura Molecular , Nucleosídeo Q/biossíntese , Nucleosídeo Q/química , Fosforilação Oxidativa , Placenta , Gravidez , RNA Mitocondrial/isolamento & purificação , RNA Mitocondrial/metabolismo , RNA de Transferência/isolamento & purificação , RNA de Transferência/metabolismo , RNA-Seq
19.
Cell Res ; 2020 Jul 27.
Artigo em Inglês | MEDLINE | ID: mdl-32719455

RESUMO

Triple-negative breast cancer (TNBC) is a highly heterogeneous disease, and molecular subtyping may result in improved diagnostic precision and targeted therapies. Our previous study classified TNBCs into four subtypes with putative therapeutic targets. Here, we conducted the FUTURE trial (ClinicalTrials.gov identifier: NCT03805399), a phase Ib/II subtyping-based and genomic biomarker-guided umbrella trial, to evaluate the efficacy of these targets. Patients with refractory metastatic TNBC were enrolled and stratified by TNBC subtypes and genomic biomarkers, and assigned to one of these seven arms: (A) pyrotinib with capecitabine, (B) androgen receptor inhibitor with CDK4/6 inhibitor, (C) anti PD-1 with nab-paclitaxel, (D) PARP inhibitor included, (E) and (F) anti-VEGFR included, or (G) mTOR inhibitor with nab-paclitaxel. The primary end point was the objective response rate (ORR). We enrolled 69 refractory metastatic TNBC patients with a median of three previous lines of therapy (range, 1-8). Objective response was achieved in 20 (29.0%, 95% confidence interval (CI): 18.7%-41.2%) of the 69 intention-to-treat (ITT) patients. Our results showed that immunotherapy (arm C), in particular, achieved the highest ORR (52.6%, 95% CI: 28.9%-75.6%) in the ITT population. Arm E demonstrated favorable ORR (26.1%, 95% CI: 10.2%-48.4% in the ITT population) but with more high grade (≥ 3) adverse events. Somatic mutations of TOP2A and CD8 immunohistochemical score may have the potential to predict immunotherapy response in the immunomodulatory subtype of TNBC. In conclusion, the phase Ib/II FUTURE trial suggested a new concept for TNBC treatment, demonstrating the clinical benefit of subtyping-based targeted therapy for refractory metastatic TNBC.

20.
Nat Commun ; 11(1): 3319, 2020 07 03.
Artigo em Inglês | MEDLINE | ID: mdl-32620772

RESUMO

The movement of tropical cyclones (TCs), particularly around the time of landfall, can substantially affect the resulting damage. Recently, trends in TC translation speed and the likelihood of stalled TCs such as Harvey have received significant attention, but findings have remained inconclusive. Here, we examine how the June-September steering wind and translation speed of landfalling Texas TCs change in the future under anthropogenic climate change. Using several large-ensemble/multi-model datasets, we find pronounced regional variations in the meridional steering wind response over North America, but-consistently across models-stronger June-September-averaged northward steering winds over Texas. A cluster analysis of daily wind patterns shows more frequent circulation regimes that steer landfalling TCs northward in the future. Downscaling experiments show a 10-percentage-point shift from the slow-moving to the fast-moving end of the translation-speed distribution in the future. Together, these analyses indicate increases in the likelihood of faster-moving landfalling Texas TCs in the late 21st century.

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