Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 42
Filtrar
1.
JCI Insight ; 9(17)2024 Sep 10.
Artigo em Inglês | MEDLINE | ID: mdl-39253977

RESUMO

Bladder cancer (BLCA) mortality is higher in African American (AA) patients compared with European American (EA) patients, but the molecular mechanism underlying race-specific differences are unknown. To address this gap, we conducted comprehensive RNA-Seq, proteomics, and metabolomics analysis of BLCA tumors from AA and EA. Our findings reveal a distinct metabolic phenotype in AA BLCA characterized by elevated mitochondrial oxidative phosphorylation (OXPHOS), particularly through the activation of complex I. The results provide insight into the complex I activation-driven higher OXPHOS activity resulting in glutamine-mediated metabolic rewiring and increased disease progression, which was also confirmed by [U]13C-glutamine tracing. Mechanistic studies further demonstrate that knockdown of NDUFB8, one of the components of complex I in AA BLCA cells, resulted in reduced basal respiration, ATP production, GLS1 expression, and proliferation. Moreover, preclinical studies demonstrate the therapeutic potential of targeting complex I, as evidenced by decreased tumor growth in NDUFB8-depleted AA BLCA tumors. Additionally, genetic and pharmacological inhibition of GLS1 attenuated mitochondrial respiration rates and tumor growth potential in AA BLCA. Taken together, these findings provide insight into BLCA disparity for targeting GLS1-Complex I for future therapy.


Assuntos
Negro ou Afro-Americano , Glutaminase , Glutamina , Mitocôndrias , Fosforilação Oxidativa , Neoplasias da Bexiga Urinária , Animais , Feminino , Humanos , Masculino , Camundongos , Pessoa de Meia-Idade , Negro ou Afro-Americano/genética , Linhagem Celular Tumoral , Proliferação de Células , Complexo I de Transporte de Elétrons/metabolismo , Complexo I de Transporte de Elétrons/genética , Glutaminase/metabolismo , Glutaminase/genética , Glutamina/metabolismo , Metabolômica/métodos , Mitocôndrias/metabolismo , Neoplasias da Bexiga Urinária/metabolismo , Neoplasias da Bexiga Urinária/patologia , Neoplasias da Bexiga Urinária/genética
2.
J Biomed Sci ; 31(1): 81, 2024 Aug 20.
Artigo em Inglês | MEDLINE | ID: mdl-39164686

RESUMO

BACKGROUND: Betulinic acid (BA) has been well investigated for its antiproliferative and mitochondrial pathway-mediated apoptosis-inducing effects on various cancers. However, its poor solubility and off-target activity have limited its utility in clinical trials. Additionally, the immune modulatory role of betulinic acid analogue in the tumor microenvironment (TME) is largely unknown. Here, we designed a potential nanotherapy for colorectal cancer (CRC) with a lead betulinic acid analogue, named as 2c, carrying a 1,2,3-triazole-moiety attached to BA through a linker, found more effective than BA for inhibiting CRC cell lines, and was chosen here for this investigation. Epithelial cell adhesion molecule (EpCAM) is highly overexpressed on the CRC cell membrane. A single-stranded short oligonucleotide sequence, aptamer (Apt), that folds into a 3D-defined architecture can be used as a targeting ligand for its specific binding to a target protein. EpCAM targeting aptamer was designed for site-specific homing of aptamer-conjugated-2c-loaded nanoparticles (Apt-2cNP) at the CRC tumor site to enhance therapeutic potential and reduce off-target toxicity in normal cells. We investigated the in vitro and in vivo therapeutic efficacy and anti-tumorigenic immune response of aptamer conjugated nanotherapy in CRC-TME. METHODS: After the characterization of nanoengineered aptamer conjugated betulinic acid nanotherapy, we evaluated therapeutic efficacy, tumor targeting efficiency, and anti-tumorigenic immune response using cell-based assays and mouse and rat models. RESULTS: We found that Apt-2cNP improved drug bioavailability, enhanced its biological half-life, improved antiproliferative activity, and minimized off-target cytotoxicity. Importantly, in an in vivo TME, Apt-2cNP showed promising signs of anti-tumorigenic immune response (increased mDC/pDC ratio, enhanced M1 macrophage population, and CD8 T-cells). Furthermore, in vivo upregulation of pro-apoptotic while downregulation of anti-apoptotic genes and significant healing efficacy on cancer tissue histopathology suggest that Apt-2cNP had predominantly greater therapeutic potential than the non-aptamer-conjugated nanoparticles and free drug. Moreover, we observed greater tumor accumulation of the radiolabeled Apt-2cNP by live imaging in the CRC rat model. CONCLUSIONS: Enhanced therapeutic efficacy and robust anti-tumorigenic immune response of Apt-2cNP in the CRC-TME are promising indicators of its potential as a prospective therapeutic agent for managing CRC. However, further studies are warranted.


Assuntos
Ácido Betulínico , Neoplasias Colorretais , Molécula de Adesão da Célula Epitelial , Triterpenos Pentacíclicos , Microambiente Tumoral , Neoplasias Colorretais/tratamento farmacológico , Animais , Microambiente Tumoral/efeitos dos fármacos , Camundongos , Triterpenos Pentacíclicos/farmacologia , Molécula de Adesão da Célula Epitelial/metabolismo , Humanos , Nanopartículas/química , Linhagem Celular Tumoral , Ratos
3.
iScience ; 27(6): 109995, 2024 Jun 21.
Artigo em Inglês | MEDLINE | ID: mdl-38868185

RESUMO

The canonical mechanism behind tamoxifen's therapeutic effect on estrogen receptor α/ESR1+ breast cancers is inhibition of ESR1-dependent estrogen signaling. Although ESR1+ tumors expressing wild-type p53 were reported to be more responsive to tamoxifen (Tam) therapy, p53 has not been factored into choice of this therapy and the mechanism underlying the role of p53 in Tam response remains unclear. In a window-of-opportunity trial on patients with newly diagnosed stage I-III ESR1+/HER2/wild-type p53 breast cancer who were randomized to arms with or without Tam prior to surgery, we reveal that the ESR1-p53 interaction in tumors was inhibited by Tam. This resulted in functional reactivation of p53 leading to transcriptional reprogramming that favors tumor-suppressive signaling, as well as downregulation of oncogenic pathways. These findings illustrating the convergence of ESR1 and p53 signaling during Tam therapy enrich mechanistic understanding of the impact of p53 on the response to Tam therapy.

4.
Cancer Lett ; 587: 216724, 2024 Apr 10.
Artigo em Inglês | MEDLINE | ID: mdl-38373689

RESUMO

CD24 is a well-characterized breast cancer (BC) stem cell (BCSC) marker. Primary breast tumor cells having CD24-negativity together with CD44-positivity is known to maintain high metastatic potential. However, the functional role of CD24 gene in triple-negative BC (TNBC), an aggressive subtype of BC, is not well understood. While the significance of CD24 in regulating immune pathways is well recognized in previous studies, the significance of CD24 low expression in onco-signaling and metabolic rewiring is largely unknown. Using CD24 knock-down and over-expression TNBC models, our in vitro and in vivo analysis suggest that CD24 is a tumor suppressor in metastatic TNBC. Comprehensive in silico gene expression analysis of breast tumors followed by lipidomic and metabolomic analyses of CD24-modulated cells revealed that CD24 negativity induces mitochondrial oxidative phosphorylation and reprograms TNBC metabolism toward the fatty acid beta-oxidation (FAO) pathway. CD24 silencing activates PPARα-mediated regulation of FAO in TNBC cells. Further analysis using reverse-phase protein array and its validation using CD24-modulated TNBC cells and xenograft models nominated CD24-NF-κB-CPT1A signaling pathway as the central regulatory mechanism of CD24-mediated FAO activity. Overall, our study proposes a novel role of CD24 in metabolic reprogramming that can open new avenues for the treatment strategies for patients with metastatic TNBC.


Assuntos
NF-kappa B , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/patologia , PPAR alfa/genética , Linhagem Celular Tumoral , Ácidos Graxos/metabolismo , Antígeno CD24/genética , Antígeno CD24/metabolismo
5.
Cancer Res ; 84(2): 291-304, 2024 01 16.
Artigo em Inglês | MEDLINE | ID: mdl-37906431

RESUMO

Approximately one-third of endocrine-treated women with estrogen receptor alpha-positive (ER+) breast cancers are at risk of recurrence due to intrinsic or acquired resistance. Thus, it is vital to understand the mechanisms underlying endocrine therapy resistance in ER+ breast cancer to improve patient treatment. Mitochondrial fatty acid ß-oxidation (FAO) has been shown to be a major metabolic pathway in triple-negative breast cancer (TNBC) that can activate Src signaling. Here, we found metabolic reprogramming that increases FAO in ER+ breast cancer as a mechanism of resistance to endocrine therapy. A metabolically relevant, integrated gene signature was derived from transcriptomic, metabolomic, and lipidomic analyses in TNBC cells following inhibition of the FAO rate-limiting enzyme carnitine palmitoyl transferase 1 (CPT1), and this TNBC-derived signature was significantly associated with endocrine resistance in patients with ER+ breast cancer. Molecular, genetic, and metabolomic experiments identified activation of AMPK-FAO-oxidative phosphorylation (OXPHOS) signaling in endocrine-resistant ER+ breast cancer. CPT1 knockdown or treatment with FAO inhibitors in vitro and in vivo significantly enhanced the response of ER+ breast cancer cells to endocrine therapy. Consistent with the previous findings in TNBC, endocrine therapy-induced FAO activated the Src pathway in ER+ breast cancer. Src inhibitors suppressed the growth of endocrine-resistant tumors, and the efficacy could be further enhanced by metabolic priming with CPT1 inhibition. Collectively, this study developed and applied a TNBC-derived signature to reveal that metabolic reprogramming to FAO activates the Src pathway to drive endocrine resistance in ER+ breast cancer. SIGNIFICANCE: Increased fatty acid oxidation induced by endocrine therapy activates Src signaling to promote endocrine resistance in breast cancer, which can be overcome using clinically approved therapies targeting FAO and Src.


Assuntos
Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/metabolismo , Linhagem Celular Tumoral , Fosforilação , Transdução de Sinais , Ácidos Graxos/metabolismo , Resistencia a Medicamentos Antineoplásicos/genética
6.
Nat Metab ; 5(9): 1595-1614, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37653044

RESUMO

In most eukaryotic cells, fatty acid synthesis (FAS) occurs in the cytoplasm and in mitochondria. However, the relative contribution of mitochondrial FAS (mtFAS) to the cellular lipidome is not well defined. Here we show that loss of function of Drosophila mitochondrial enoyl coenzyme A reductase (Mecr), which is the enzyme required for the last step of mtFAS, causes lethality, while neuronal loss of Mecr leads to progressive neurodegeneration. We observe a defect in Fe-S cluster biogenesis and increased iron levels in flies lacking mecr, leading to elevated ceramide levels. Reducing the levels of either iron or ceramide suppresses the neurodegenerative phenotypes, indicating an interplay between ceramide and iron metabolism. Mutations in human MECR cause pediatric-onset neurodegeneration, and we show that human-derived fibroblasts display similar elevated ceramide levels and impaired iron homeostasis. In summary, this study identifies a role of mecr/MECR in ceramide and iron metabolism, providing a mechanistic link between mtFAS and neurodegeneration.


Assuntos
Adipogenia , Mitocôndrias , Criança , Animais , Humanos , Ceramidas , Drosophila , Ferro , Ácidos Graxos
7.
Elife ; 122023 Jul 07.
Artigo em Inglês | MEDLINE | ID: mdl-37417957

RESUMO

Flavin adenine dinucleotide (FAD) interacts with flavoproteins to mediate oxidation-reduction reactions required for cellular energy demands. Not surprisingly, mutations that alter FAD binding to flavoproteins cause rare inborn errors of metabolism (IEMs) that disrupt liver function and render fasting intolerance, hepatic steatosis, and lipodystrophy. In our study, depleting FAD pools in mice with a vitamin B2-deficient diet (B2D) caused phenotypes associated with organic acidemias and other IEMs, including reduced body weight, hypoglycemia, and fatty liver disease. Integrated discovery approaches revealed B2D tempered fasting activation of target genes for the nuclear receptor PPARα, including those required for gluconeogenesis. We also found PPARα knockdown in the liver recapitulated B2D effects on glucose excursion and fatty liver disease in mice. Finally, treatment with the PPARα agonist fenofibrate activated the integrated stress response and refilled amino acid substrates to rescue fasting glucose availability and overcome B2D phenotypes. These findings identify metabolic responses to FAD availability and nominate strategies for the management of organic acidemias and other rare IEMs.


Assuntos
Glucose , Hepatopatia Gordurosa não Alcoólica , Camundongos , Animais , Glucose/metabolismo , PPAR alfa/genética , PPAR alfa/metabolismo , Flavina-Adenina Dinucleotídeo/metabolismo , Ácidos Graxos/metabolismo , Fígado/metabolismo , Jejum/metabolismo , Hepatopatia Gordurosa não Alcoólica/metabolismo , Oxirredução , Flavoproteínas/metabolismo
8.
Orthop J Sports Med ; 11(3): 23259671221143996, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-36970316

RESUMO

Background: The remnant preservation of a primary vertical graft in revision anterior cruciate ligament reconstruction (ACLR) can benefit anteroposterior stability. However, studies that address this concept are rare. Purpose: To evaluate clinical outcomes of remnant preservation of primary vertical graft in revision ACLR. Study Design: Cohort study; Level of evidence, 3. Methods: A total of 74 patients with revision ACLR were included in this retrospective study. Remnant preservation revision ACLR was performed only in patients with primary vertical grafts. The patients were divided into 2 groups according to whether the primary remnant vertical graft was preserved (remnant group; n = 48) or absent or sacrificed (no-remnant group; n = 26). The remnant group was further divided according to the degree of remnant tissue: sufficiently preserved subgroup (graft coverage, ≥50%; n = 25) and insufficiently preserved subgroup (graft coverage, <50%; n = 23). Clinical outcomes were evaluated using the International Knee Documentation Committee (IKDC) subjective form, Lysholm score, Tegner activity scale, manual laxity tests, and side-to-side difference in anterior tibial translation on Telos stress radiographs. Results: The mean time to final follow-up was 40.7 ± 16.8 months. The remnant group showed more improved results in the postoperative Lachman test and Telos side-to-side difference than did the no-remnant group (P = .017 and .016, respectively). The post hoc test revealed that the side-to-side difference in laxity in the sufficiently preserved subgroup significantly outperformed that in the no-remnant group (P = .001), although no significant difference existed between the insufficiently preserved and no-remnant subgroups (P = .850). The postoperative IKDC subjective form, Lysholm score, and Tegner activity scale did not show significant differences between the 2 groups (P = .480, .277, and .883, respectively). Conclusion: The remnant preservation of the primary vertical graft in revision ACLR may result in better anteroposterior stability. However, subjective outcomes in the remnant group did not exceed that of the no-remnant group. The subgroup analysis revealed that only sufficiently preserved remnants demonstrated better anteroposterior stability.

9.
Health Informatics J ; 29(1): 14604582231169297, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-36995242

RESUMO

Objectives: This study aimed to evaluate the quality and readability of web pages providing information about hand osteoarthritis using several authorized methods.Methods: A web page exploration was performed using the Google internet search engine. The three search terms, "hand osteoarthritis," "finger osteoarthritis," and "hand OA," were used and the top 100 ranked websites were selected and divided into six categories. The Health on the Net Foundation (HON) grade scale, an instrument for judging the quality of written consumer health information on treatment choice (DISCERN instrument), and the Ensuring Quality Information for Patients (EQIP) score were used to evaluate the quality of each website. The Flesch-Kincaid reading ease (FRE) score, Flesch-Kincaid grade (FKG) level, Gunning-Fog index, and Simple Measure of Gobbledygook grade level were used to evaluate website readability.Results: Among 300 websites, 57 websites were selected following exclusion criteria. News portal websites, including the online version of newspapers and periodicals, showed the highest score in all three quality evaluation tools. Only four websites were regarded as high-quality websites based on the HON grade scale (n = 3) and the EQIP score (n = 1). Each type of website showed an average FKG level higher than 7th grade and obtained an average FRE score of less than 80 points, indicating an inappropriate level for a layperson to read.Conclusions: The online information about hand osteoarthritis is low quality and difficult to read for the general public. There is a need to enhance the quality and readability of web-based information related to hand osteoarthritis for patients to obtain credible information and receive proper treatment for the disease.


Assuntos
Compreensão , Informação de Saúde ao Consumidor , Humanos , Leitura , Ferramenta de Busca , Internet
10.
Front Pharmacol ; 13: 1049640, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-36561339

RESUMO

Drug repurposing can overcome both substantial costs and the lengthy process of new drug discovery and development in cancer treatment. Some Food and Drug Administration (FDA)-approved drugs have been found to have the potential to be repurposed as anti-cancer drugs. However, the progress is slow due to only a handful of strategies employed to identify drugs with repurposing potential. In this study, we evaluated GPCR-targeting drugs by high throughput screening (HTS) for their repurposing potential in triple-negative breast cancer (TNBC) and drug-resistant human epidermal growth factor receptor-2-positive (HER2+) breast cancer (BC), due to the dire need to discover novel targets and drugs in these subtypes. We assessed the efficacy and potency of drugs/compounds targeting different GPCRs for the growth rate inhibition in the following models: two TNBC cell lines (MDA-MB-231 and MDA-MB-468) and two HER2+ BC cell lines (BT474 and SKBR3), sensitive or resistant to lapatinib + trastuzumab, an effective combination of HER2-targeting therapies. We identified six drugs/compounds as potential hits, of which 4 were FDA-approved drugs. We focused on ß-adrenergic receptor-targeting nebivolol as a candidate, primarily because of the potential role of these receptors in BC and its excellent long-term safety profile. The effects of nebivolol were validated in an independent assay in all the cell line models. The effects of nebivolol were independent of its activation of ß3 receptors and nitric oxide production. Nebivolol reduced invasion and migration potentials which also suggests its inhibitory role in metastasis. Analysis of the Surveillance, Epidemiology and End Results (SEER)-Medicare dataset found numerically but not statistically significant reduced risk of all-cause mortality in the nebivolol group. In-depth future analyses, including detailed in vivo studies and real-world data analysis with more patients, are needed to further investigate the potential of nebivolol as a repurposed therapy for BC.

12.
Knee ; 39: 253-260, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36283283

RESUMO

BACKGROUND: Implant design and surgical techniques affect postoperative knee kinematics in total knee arthroplasty (TKA). This study aimed to compare femoral roll-back between cruciate-retaining (CR) and posterior-stabilized (PS) TKA in the same knee by objectively quantifying the contact point kinematics of the tibiofemoral joint using a sensor. METHODS: In the present prospective study, we used an intraoperative sensor to compare medial and lateral roll-back during 0-120° knee flexion in 33 knees that underwent CR and PS TKA. We also examined the relationship between mediolateral balance and the lateral-to-medial roll-back ratio. We defined the contact percentage position as the vertical length to the contact point divided by the anteroposterior length of the tibial plate. RESULTS: The roll-back percentage following PS TKA (19.8 ± 5.1%) was significantly higher than that after CR TKA in both the medial (19.8 ± 5.1% versus 7.1 ± 2.5%, P < 0.001) and lateral (26.8% ± 3.8% versus 18.7 ± 3.8%, P < 0.001) compartments. The medial contact pressure at 90° was significantly correlated with the increased lateral-to-medial roll-back ratio in both CR and PS TKA (both P < 0.001). CONCLUSION: PS TKA resulted in a higher percentage of femoral roll-back in the medial and lateral compartments than CR TKA. CR TKA caused a higher lateral-to-medial roll-back ratio compared to PS TKA. To reproduce medial pivot knee motion similar to that of a normal knee, the medial soft tissue needed to be balanced more tightly than the lateral soft tissue during TKA. These findings provide some clinical evidence of TKA design selection and proper mediolateral balancing for successful TKA.


Assuntos
Artroplastia do Joelho , Prótese do Joelho , Osteoartrite do Joelho , Humanos , Artroplastia do Joelho/métodos , Estudos Prospectivos , Osteoartrite do Joelho/cirurgia , Amplitude de Movimento Articular , Articulação do Joelho/cirurgia , Fenômenos Biomecânicos
13.
Commun Biol ; 5(1): 493, 2022 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-35610507

RESUMO

The major limitations of DNA-targeting chemotherapy drugs include life-threatening toxicity, acquired resistance and occurrence of secondary cancers. Here, we report a small molecule, Carbazole Blue (CB), that binds to DNA and inhibits cancer growth and metastasis by targeting DNA-related processes that tumor cells use but not the normal cells. We show that CB inhibits the expression of pro-tumorigenic genes that promote unchecked replication and aberrant DNA repair that cancer cells get addicted to survive. In contrast to chemotherapy drugs, systemic delivery of CB suppressed breast cancer growth and metastasis with no toxicity in pre-clinical mouse models. Using PDX and ex vivo explants from estrogen receptor (ER) positive, ER mutant and TNBC patients, we further demonstrated that CB effectively blocks therapy-sensitive and therapy-resistant breast cancer growth without affecting normal breast tissue. Our data provide a strong rationale to develop CB as a viable therapeutic for treating breast cancers.


Assuntos
Neoplasias da Mama , Animais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , DNA , Reparo do DNA , Feminino , Humanos , Camundongos , Receptores de Estrogênio/metabolismo
14.
PLoS Comput Biol ; 18(2): e1009841, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-35148308

RESUMO

While aerobic glycolysis, or the Warburg effect, has for a long time been considered a hallmark of tumor metabolism, recent studies have revealed a far more complex picture. Tumor cells exhibit widespread metabolic heterogeneity, not only in their presentation of the Warburg effect but also in the nutrients and the metabolic pathways they are dependent on. Moreover, tumor cells can switch between different metabolic phenotypes in response to environmental cues and therapeutic interventions. A framework to analyze the observed metabolic heterogeneity and plasticity is, however, lacking. Using a mechanistic model that includes the key metabolic pathways active in tumor cells, we show that the inhibition of phosphofructokinase by excess ATP in the cytoplasm can drive a preference for aerobic glycolysis in fast-proliferating tumor cells. The differing rates of ATP utilization by tumor cells can therefore drive heterogeneity with respect to the presentation of the Warburg effect. Building upon this idea, we couple the metabolic phenotype of tumor cells to their migratory phenotype, and show that our model predictions are in agreement with previous experiments. Next, we report that the reliance of proliferating cells on different anaplerotic pathways depends on the relative availability of glucose and glutamine, and can further drive metabolic heterogeneity. Finally, using treatment of melanoma cells with a BRAF inhibitor as an example, we show that our model can be used to predict the metabolic and gene expression changes in cancer cells in response to drug treatment. By making predictions that are far more generalizable and interpretable as compared to previous tumor metabolism modeling approaches, our framework identifies key principles that govern tumor cell metabolism, and the reported heterogeneity and plasticity. These principles could be key to targeting the metabolic vulnerabilities of cancer.


Assuntos
Glicólise , Neoplasias , Trifosfato de Adenosina/metabolismo , Ciclo do Ácido Cítrico , Humanos , Neoplasias/metabolismo , Fosfofrutoquinase-1/metabolismo
15.
Small ; 18(2): e2104944, 2022 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-34802184

RESUMO

The charging process of secondary batteries is always associated with a large volume expansion of the alloying anodes, which in many cases, develops high compressive residual stresses near the propagating interface. This phenomenon causes a significant reduction in the rate performance of the anodes and is detrimental to the development of fast-charging batteries. However, for the Na-Sn battery system, the residual stresses that develop near the interface are not stored, but are relieved by the generation of high-density dislocations in crystalline Sn. Direct-contact diffusion experiments show that these dislocations facilitate the preferential transport of Na and accelerate the Na diffusion into crystalline Sn at ultrafast rates via "dislocation-pipe diffusion". Advanced analyses are performed to observe the evolution of atomic-scale structures while measuring the distribution and magnitude of residual stresses near the interface. In addition, multi-scale simulations that combined classical molecular dynamics and first-principles calculations are performed to explain the structural origins of the ultrafast diffusion rates observed in the Na-Sn system. These findings not only address the knowledge gaps regarding the relationship between pipe diffusion and the diffusivity of carrier ions but also provide guidelines for the appropriate selection of anode materials for use in fast-charging batteries.

16.
PLoS Genet ; 17(12): e1009971, 2021 12.
Artigo em Inglês | MEDLINE | ID: mdl-34965247

RESUMO

Rothmund-Thomson syndrome (RTS) is an autosomal recessive genetic disorder characterized by poikiloderma, small stature, skeletal anomalies, sparse brows/lashes, cataracts, and predisposition to cancer. Type 2 RTS patients with biallelic RECQL4 pathogenic variants have multiple skeletal anomalies and a significantly increased incidence of osteosarcoma. Here, we generated RTS patient-derived induced pluripotent stem cells (iPSCs) to dissect the pathological signaling leading to RTS patient-associated osteosarcoma. RTS iPSC-derived osteoblasts showed defective osteogenic differentiation and gain of in vitro tumorigenic ability. Transcriptome analysis of RTS osteoblasts validated decreased bone morphogenesis while revealing aberrantly upregulated mitochondrial respiratory complex I gene expression. RTS osteoblast metabolic assays demonstrated elevated mitochondrial respiratory complex I function, increased oxidative phosphorylation (OXPHOS), and increased ATP production. Inhibition of mitochondrial respiratory complex I activity by IACS-010759 selectively suppressed cellular respiration and cell proliferation of RTS osteoblasts. Furthermore, systems analysis of IACS-010759-induced changes in RTS osteoblasts revealed that chemical inhibition of mitochondrial respiratory complex I impaired cell proliferation, induced senescence, and decreased MAPK signaling and cell cycle associated genes, but increased H19 and ribosomal protein genes. In summary, our study suggests that mitochondrial respiratory complex I is a potential therapeutic target for RTS-associated osteosarcoma and provides future insights for clinical treatment strategies.


Assuntos
Complexo I de Transporte de Elétrons/genética , Osteossarcoma/genética , RNA Longo não Codificante/genética , RecQ Helicases/genética , Síndrome de Rothmund-Thomson/genética , Trifosfato de Adenosina/biossíntese , Proliferação de Células/efeitos dos fármacos , Respiração Celular/efeitos dos fármacos , Senescência Celular/genética , Complexo I de Transporte de Elétrons/antagonistas & inibidores , Regulação da Expressão Gênica no Desenvolvimento/genética , Humanos , Células-Tronco Pluripotentes Induzidas/efeitos dos fármacos , Células-Tronco Pluripotentes Induzidas/metabolismo , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Mutação/genética , Osteoblastos/efeitos dos fármacos , Osteogênese/genética , Osteossarcoma/complicações , Osteossarcoma/patologia , Oxidiazóis/farmacologia , Fosforilação Oxidativa/efeitos dos fármacos , Piperidinas/farmacologia , Síndrome de Rothmund-Thomson/complicações , Síndrome de Rothmund-Thomson/patologia
17.
Nano Lett ; 21(21): 9044-9051, 2021 Nov 10.
Artigo em Inglês | MEDLINE | ID: mdl-34714657

RESUMO

The fabrication of battery anodes simultaneously exhibiting large capacity, fast charging capability, and high cyclic stability is challenging because these properties are mutually contrasting in nature. Here, we report a rational strategy to design anodes outperforming the current anodes by simultaneous provision of the above characteristics without utilizing nanomaterials and surface modifications. This is achieved by promoting spontaneous structural evolution of coarse Sn particles to 3D-networked nanostructures during battery cycling in an appropriate electrolyte. The anode steadily exhibits large capacity (∼480 mAhg-1) and energy retention capability (99.9%) during >1500 cycles even at an ultrafast charging rate of 12 690 mAg-1 (15C). The structural and chemical origins of the measured properties are explained using multiscale simulations combining molecular dynamics and density functional theory calculations. The developed method is simple, scalable, and expandable to other systems and provides an alternative robust route to obtain nanostructured anode materials in large quantities.

18.
Hip Pelvis ; 33(2): 102-107, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-34141697

RESUMO

We report a case of bilateral femur fracture which may have resulted in part from long-term administration of antipsychotic agents. A 43-year-old female patient with pain in both thighs visited our clinic. We conducted X-ray and magnetic resonance imaging (MRI) examinations which revealed bilateral femur fractures. The right proximal femur had a complete fracture, and the left proximal femur had an incomplete fracture, both of which were in the subtrochanteric area. The patient was treated by intramedullary nailing in the right femur. Laboratory analysis showed hyperprolactinemia and hypogonadism. Bone mineral density analysis showed osteoporosis. Antipsychotic drug-induced hyperprolactinemia is a well-known phenomenon. Despite concerns about hyperprolactinemia induced osteoporotic fracture in patients treated with only prolactin-elevating medications, the issue has not been extensively studied. If hyperprolactinemia patients suffer from uncontrolled pain, we recommend MRI examination as surgeons should be aware of the possibility of osteoporotic fracture induced by hyperprolactinemia.

19.
Br J Cancer ; 124(12): 1902-1911, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33859341

RESUMO

Cancer cells have the plasticity to adjust their metabolic phenotypes for survival and metastasis. A developmental programme known as epithelial-to-mesenchymal transition (EMT) plays a critical role during metastasis, promoting the loss of polarity and cell-cell adhesion and the acquisition of motile, stem-cell characteristics. Cells undergoing EMT or the reverse mesenchymal-to-epithelial transition (MET) are often associated with metabolic changes, as the change in phenotype often correlates with a different balance of proliferation versus energy-intensive migration. Extensive crosstalk occurs between metabolism and EMT, but how this crosstalk leads to coordinated physiological changes is still uncertain. The elusive connection between metabolism and EMT compromises the efficacy of metabolic therapies targeting metastasis. In this review, we aim to clarify the causation between metabolism and EMT on the basis of experimental studies, and propose integrated theoretical-experimental efforts to better understand the coupled decision-making of metabolism and EMT.


Assuntos
Metabolismo Energético/fisiologia , Transição Epitelial-Mesenquimal/fisiologia , Neoplasias/patologia , Animais , Diferenciação Celular , Transição Epitelial-Mesenquimal/genética , Humanos , Metástase Neoplásica , Neoplasias/metabolismo , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/fisiologia
20.
J Back Musculoskelet Rehabil ; 34(4): 649-656, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33720874

RESUMO

BACKGROUND: The number of patients with an osteoporotic vertebral compression fracture, which is often accompanied by lower back pain and restrained activities, is growing. Balloon kyphoplasty involves the inflation of a balloon to restore height and reduce kyphotic deformity before stabilization with polymethylmethacrylate. However, there is a great deal of debate about whether balloon kyphoplasty also increases fracture morbidity by either inducing or facilitating subsequent adjacent vertebral fractures. OBJECTIVE: To evaluate the relationship between the rate of vertebral body height loss before balloon kyphoplasty and the etiology of early adjacent vertebral fracture after augmentation. METHODS: A total of 59 patients with osteoporotic vertebral compression fractures who underwent kyphoplasty were enrolled. This study defined early adjacent segmental fractures as new fractures occurring within three months after surgery. This study included the rate of vertebral body height loss. RESULTS: Early adjacent vertebral fractures were diagnosed in nine (15%) of the 59 patients. The patients were divided into two groups, with and without adjacent vertebral fractures. There was no significant difference in terms of age, body mass index, bone mineral density, local kyphotic angle, Cobb's angle, cement volume, cement leakage, and percent height restored between the groups with fractures and without fractures. There was a statistically significant difference between the two groups in the rate of vertebral body height loss. The rate of vertebral body height loss was significantly higher in the fracture group than in the without fracture group. CONCLUSIONS: A high rate of vertebral body height loss increased the risk of early adjacent vertebral fractures after balloon kyphoplasty.


Assuntos
Fraturas por Compressão/cirurgia , Cifoplastia/métodos , Fraturas por Osteoporose/cirurgia , Fraturas da Coluna Vertebral/cirurgia , Idoso , Idoso de 80 Anos ou mais , Cimentos Ósseos , Densidade Óssea , Feminino , Fraturas por Compressão/diagnóstico por imagem , Humanos , Masculino , Fraturas por Osteoporose/diagnóstico por imagem , Estudos Retrospectivos , Fraturas da Coluna Vertebral/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Resultado do Tratamento
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA