Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 44.853
Filtrar
1.
Nat Commun ; 12(1): 737, 2021 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-33531491

RESUMO

The human neuropeptide Y (NPY) Y2 receptor (Y2R) plays essential roles in food intake, bone formation and mood regulation, and has been considered an important drug target for obesity and anxiety. However, development of drugs targeting Y2R remains challenging with no success in clinical application yet. Here, we report the crystal structure of Y2R bound to a selective antagonist JNJ-31020028 at 2.8 Å resolution. The structure reveals molecular details of the ligand-binding mode of Y2R. Combined with mutagenesis studies, the Y2R structure provides insights into key factors that define antagonistic activity of diverse antagonists. Comparison with the previously determined antagonist-bound Y1R structures identified receptor-ligand interactions that play different roles in modulating receptor activation and mediating ligand selectivity. These findings deepen our understanding about molecular mechanisms of ligand recognition and subtype specificity of NPY receptors, and would enable structure-based drug design.


Assuntos
Receptores de Neuropeptídeo Y/metabolismo , Benzamidas/farmacologia , Cristalografia por Raios X , Células HEK293 , Humanos , Mutagênese/genética , Mutagênese/fisiologia , Hormônios Peptídicos/farmacologia , Piperazinas/farmacologia , Estrutura Secundária de Proteína , Piridinas/farmacologia , Receptores de Neuropeptídeo Y/genética , Difração de Raios X
2.
Nat Commun ; 12(1): 736, 2021 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-33531508

RESUMO

Poly-(ADP-ribose) polymerase 1 and 2 (PARP1 and PARP2) are key enzymes in the DNA damage response. Four different inhibitors (PARPi) are currently in the clinic for treatment of ovarian and breast cancer. Recently, histone PARylation Factor 1 (HPF1) has been shown to play an essential role in the PARP1- and PARP2-dependent poly-(ADP-ribosylation) (PARylation) of histones, by forming a complex with both enzymes and altering their catalytic properties. Given the proximity of HPF1 to the inhibitor binding site both PARPs, we hypothesized that HPF1 may modulate the affinity of inhibitors toward PARP1 and/or PARP2. Here we demonstrate that HPF1 significantly increases the affinity for a PARP1 - DNA complex of some PARPi (i.e., olaparib), but not others (i.e., veliparib). This effect of HPF1 on the binding affinity of Olaparib also holds true for the more physiologically relevant PARP1 - nucleosome complex but does not extend to PARP2. Our results have important implications for the interpretation of PARP inhibition by current PARPi as well as for the design and analysis of the next generation of clinically relevant PARP inhibitors.


Assuntos
Antineoplásicos/farmacologia , Proteínas de Transporte/metabolismo , Enzimas Reparadoras do DNA/metabolismo , Proteínas Nucleares/metabolismo , Poli(ADP-Ribose) Polimerase-1/metabolismo , Benzamidas/farmacologia , Benzimidazóis/farmacologia , Sítios de Ligação , Proteínas de Transporte/genética , Catálise/efeitos dos fármacos , Domínio Catalítico , Enzimas Reparadoras do DNA/genética , Humanos , Indazóis/farmacologia , Indóis/farmacologia , Proteínas Nucleares/genética , Ftalazinas/farmacologia , Piperazinas/farmacologia , Piperidinas/farmacologia , Ligação Proteica/efeitos dos fármacos
3.
J Assoc Physicians India ; 69(2): 25-29, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33527807

RESUMO

Achieving adequate glycemic control in type 2 diabetes mellitus (T2DM) remains a difficult but achievable goal. Oral agents (OADs) are important option for management of T2DM. Most T2DM patients require more than one medication for adequate glycemic control. Metformin based combination therapy is recommended when monotherapy is insufficient. Evogliptin is a recently developed dipeptidyl peptidase-4 (DPP-4) inhibitor, which can to be combined with metformin for treating T2DM. Combination therapy of Evogliptin and Metformin lowers blood glucose via augmentation of insulin secretion, suppression of glucagon secretion, and insulin sensitization. Co-administration of Evogliptin and Metformin showed no clinically relevant pharmacokinetic differences compared to the administration of each drug alone. Combination therapy of Evogliptin and Metformin also provides significantly better glycemic control compared to the respective monotherapies. Efficacy and safety of Evogliptin and Metformin had been demonstrated in several multicentre randomized clinical trials conducted in various countries like South Korea, Russia and India. Consequently, fixed dose combination (FDC) of Evogliptin and Metformin is approved in South Korea and India. Complexity of the treatment regimen and polypharmacy are well-known factors of poor medication adherence and FDCs have the potential to improve adherence by reducing the pill burden. Adoption of this combination therapy in clinical practice for management of T2DMs will provide a greater degree of HbA1c reduction than that observed with the use of either drug as monotherapy, and is unlikely to cause significant hypoglycemia. Combination therapy of Evogliptin and Metformin is a promising strategy in the treatment of T2DM.


Assuntos
Diabetes Mellitus Tipo 2 , Inibidores da Dipeptidil Peptidase IV , Metformina , Glicemia , Diabetes Mellitus Tipo 2/tratamento farmacológico , Inibidores da Dipeptidil Peptidase IV/uso terapêutico , Quimioterapia Combinada , Hemoglobina A Glicada , Humanos , Hipoglicemiantes/uso terapêutico , Índia , Metformina/uso terapêutico , Piperazinas , Federação Russa
4.
Lancet Oncol ; 22(2): 212-222, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33460574

RESUMO

BACKGROUND: Palbociclib added to endocrine therapy improves progression-free survival in hormone-receptor-positive, HER2-negative, metastatic breast cancer. The PALLAS trial aimed to investigate whether the addition of 2 years of palbociclib to adjuvant endocrine therapy improves invasive disease-free survival over endocrine therapy alone in patients with hormone-receptor-positive, HER2-negative, early-stage breast cancer. METHODS: PALLAS is an ongoing multicentre, open-label, randomised, phase 3 study that enrolled patients at 406 cancer centres in 21 countries worldwide with stage II-III histologically confirmed hormone-receptor-positive, HER2-negative breast cancer, within 12 months of initial diagnosis. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance score of 0 or 1. Patients were randomly assigned (1:1) in permuted blocks of random size (4 or 6), stratified by anatomic stage, previous chemotherapy, age, and geographical region, by use of central telephone-based and web-based interactive response technology, to receive either 2 years of palbociclib (125 mg orally once daily on days 1-21 of a 28-day cycle) with ongoing standard provider or patient-choice adjuvant endocrine therapy (tamoxifen or aromatase inhibitor, with or without concurrent luteinising hormone-releasing hormone agonist), or endocrine therapy alone, without masking. The primary endpoint of the study was invasive disease-free survival in the intention-to-treat population. Safety was assessed in all randomly assigned patients who started palbociclib or endocrine therapy. This report presents results from the second pre-planned interim analysis triggered on Jan 9, 2020, when 67% of the total number of expected invasive disease-free survival events had been observed. The trial is registered with ClinicalTrials.gov (NCT02513394) and EudraCT (2014-005181-30). FINDINGS: Between Sept 1, 2015, and Nov 30, 2018, 5760 patients were randomly assigned to receive palbociclib plus endocrine therapy (n=2883) or endocrine therapy alone (n=2877). At the time of the planned second interim analysis, at a median follow-up of 23·7 months (IQR 16·9-29·2), 170 of 2883 patients assigned to palbociclib plus endocrine therapy and 181 of 2877 assigned to endocrine therapy alone had invasive disease-free survival events. 3-year invasive disease-free survival was 88·2% (95% CI 85·2-90·6) for palbociclib plus endocrine therapy and 88·5% (85·8-90·7) for endocrine therapy alone (hazard ratio 0·93 [95% CI 0·76-1·15]; log-rank p=0·51). As the test statistic comparing invasive disease-free survival between groups crossed the prespecified futility boundary, the independent data monitoring committee recommended discontinuation of palbociclib in patients still receiving palbociclib and endocrine therapy. The most common grade 3-4 adverse events were neutropenia (1742 [61·3%] of 2840 patients on palbociclib and endocrine therapy vs 11 [0·3%] of 2903 on endocrine therapy alone), leucopenia (857 [30·2%] vs three [0·1%]), and fatigue (60 [2·1%] vs ten [0·3%]). Serious adverse events occurred in 351 (12·4%) of 2840 patients on palbociclib plus endocrine therapy versus 220 (7·6%) of 2903 patients on endocrine therapy alone. There were no treatment-related deaths. INTERPRETATION: At the planned second interim analysis, addition of 2 years of adjuvant palbociclib to adjuvant endocrine therapy did not improve invasive disease-free survival compared with adjuvant endocrine therapy alone. On the basis of these findings, this regimen cannot be recommended in the adjuvant setting. Long-term follow-up of the PALLAS population and correlative studies are ongoing. FUNDING: Pfizer.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Inibidores da Aromatase/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Piperazinas/administração & dosagem , Piridinas/administração & dosagem , Adolescente , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Inibidores da Aromatase/efeitos adversos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Pré-Escolar , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Piperazinas/efeitos adversos , Modelos de Riscos Proporcionais , Piridinas/efeitos adversos , Receptor ErbB-2/genética , Receptores Estrogênicos/genética , Tamoxifeno/administração & dosagem
5.
Nat Commun ; 12(1): 647, 2021 01 28.
Artigo em Inglês | MEDLINE | ID: mdl-33510144

RESUMO

Ferroptosis is a type of iron-dependent regulated cell death, representing an emerging disease-modulatory mechanism. Transcription factors play multiple roles in ferroptosis, although the key regulator for ferroptosis in iron metabolism remains elusive. Using NanoString technology, we identify NUPR1, a stress-inducible transcription factor, as a driver of ferroptosis resistance. Mechanistically, NUPR1-mediated LCN2 expression blocks ferroptotic cell death through diminishing iron accumulation and subsequent oxidative damage. Consequently, LCN2 depletion mimics NUPR1 deficiency with respect to ferroptosis induction, whereas transfection-enforced re-expression of LCN2 restores resistance to ferroptosis in NUPR1-deficient cells. Pharmacological or genetic blockade of the NUPR1-LCN2 pathway (using NUPR1 shRNA, LCN2 shRNA, pancreas-specific Lcn2 conditional knockout mice, or the small molecule ZZW-115) increases the activity of the ferroptosis inducer erastin and worsens pancreatitis, in suitable mouse models. These findings suggest a link between NUPR1-regulated iron metabolism and ferroptosis susceptibility.


Assuntos
Proteínas de Ligação a DNA/genética , Ferroptose/genética , Regulação Neoplásica da Expressão Gênica , Ferro/metabolismo , Lipocalina-2/genética , Proteínas de Neoplasias/genética , Neoplasias Pancreáticas/genética , Animais , Linhagem Celular Tumoral , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/metabolismo , Humanos , Estimativa de Kaplan-Meier , Lipocalina-2/metabolismo , Camundongos Knockout , Camundongos Nus , Camundongos Transgênicos , Proteínas de Neoplasias/antagonistas & inibidores , Proteínas de Neoplasias/metabolismo , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/terapia , Piperazinas/farmacologia , Terapêutica com RNAi/métodos , Transdução de Sinais/genética , Tiazinas/farmacologia , Ensaios Antitumorais Modelo de Xenoenxerto/métodos
7.
Gan To Kagaku Ryoho ; 48(1): 53-56, 2021 Jan.
Artigo em Japonês | MEDLINE | ID: mdl-33468723

RESUMO

In 2018, olaparib, a PARP inhibitor, was approved for the treatment of BRCA1/2 gene-mutation positive and HER2-negative inoperable and recurrent breast cancer; BRCA1/2 gene testing was also listed as a companion diagnostics. Here, we identified microRNAs(miRNAs) expressed after treatment with olaparib, which differed in the presence or absence of BRCA1 mutations in triple negative breast cancer(TNBC), and examined the changes in miRNAs after exposure to the combination of the PARP-1 inhibitor and a chemotherapeutic agent. After exposure to the PARP-1 inhibitor, the expression of miR-141, miR-155, miR-205, and miR-223 decreased in MDA-MB-231, HCC1143, and BT549 cells and increased more than 10 times in MDA-MB-436 cells. Moreover, the expression of miR-141 in MDA-MB-436 cells treated with the PARP-1 inhibitor together with gemcitabine increased more than 10 times; additionally, the expression of miR-205 increased more in the context of combination therapy versus single exposure to olaparib. The miR-200 family(including miR-141)and miR- 205 are known to function as ZEB1/2 targets and to act as epithelial-to-mesenchymal transition(EMT)-suppressors. Overall, these results suggest that it may be possible to recover the sensitivity of TNBC cells to chemotherapy via the suppressing EMT through the use of a PARP-1 inhibitor in the context of BRCA1 mutation.


Assuntos
MicroRNAs , Neoplasias de Mama Triplo Negativas , Proteína BRCA1/genética , Linhagem Celular Tumoral , Humanos , MicroRNAs/genética , Mutação , Recidiva Local de Neoplasia , Ftalazinas , Piperazinas , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/genética
9.
Anticancer Res ; 41(2): 551-556, 2021 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-33517260

RESUMO

Treatment of metastatic prostate cancer has evolved significantly over the past decade. Palliative therapy has, historically, consisted of androgen deprivation, chemotherapy and different radiation therapy approaches. More recently, breakthrough therapy with the use of poly-ADP-ribose polymerase (PARP) inhibitors has led to significant improvement in the outcome of patients with metastatic prostate cancer who harbor certain genetic mutations. This concise review focuses on the 3 PARP inhibitors that have shown activity in metastatic prostate cancer.


Assuntos
Indazóis/uso terapêutico , Indóis/uso terapêutico , Ftalazinas/uso terapêutico , Piperazinas/uso terapêutico , Piperidinas/uso terapêutico , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Neoplasias da Próstata/tratamento farmacológico , Animais , Proteína BRCA1/genética , Proteína BRCA2/genética , Predisposição Genética para Doença , Humanos , Indazóis/efeitos adversos , Indóis/efeitos adversos , Masculino , Mutação , Metástase Neoplásica , PTEN Fosfo-Hidrolase/genética , Fenótipo , Ftalazinas/efeitos adversos , Piperazinas/efeitos adversos , Piperidinas/efeitos adversos , Inibidores de Poli(ADP-Ribose) Polimerases/efeitos adversos , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/genética , Neoplasias da Próstata/patologia , Resultado do Tratamento
10.
Lancet HIV ; 8(1): e33-e41, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33387477

RESUMO

BACKGROUND: Dolutegravir has been widely available in Brazil since 2017. Following the signal that infants born to women with dolutegravir exposure at conception in Botswana had a higher risk of neural tube defects (NTDs), public health leaders initiated a national investigation to evaluate periconception dolutegravir exposure among all pregnant Brazilian women with HIV and its potential association with risk of NTDs, stillbirth, or miscarriage before 22 weeks (also called spontaneous abortion). METHODS: In this retrospective, observational, national, cohort study, we identified all women with pregnancies and possible dolutegravir exposure within 8 weeks of estimated date of conception between Jan 1, 2017, and May 31, 2018, and approximately 3:1 matched pregnant women exposed to efavirenz between Jan 1, 2015, and May 31, 2018, using the Brazilian antiretroviral therapy database. We did detailed chart reviews for identified women. The primary outcomes were NTD and a composite measure of NTD, stillbirth, or miscarriage. NTD incidences were calculated with 95% CI. The composite outcome was examined with logistic regression using propensity score matching weights to balance confounders. FINDINGS: Of 1427 included women, 382 were exposed to dolutegravir within 8 weeks of estimated date of conception. During pregnancy, 183 (48%) of 382 dolutegravir-exposed and 465 (44%) of 1045 efavirenz-exposed women received folic acid supplementation. There were 1452 birth outcomes. There were no NTDs in either dolutegravir-exposed (0, 95% CI 0-0·0010) or efavirenz-exposed groups (0, 95% CI 0-0·0036). There were 23 (6%) stillbirths or miscarriages in 384 dolutegravir-exposed fetuses and 28 (3%) in the 1068 efavirenz-exposed fetuses (p=0·0037). Logistic regression models did not consistently indicate an association between dolutegravir exposure and risk of stillbirths or miscarriages. After study closure, two confirmed NTD outcomes in fetuses with periconception dolutegravir exposure were reported to public health officials. An updated estimate of NTD incidence incorporating these cases and the estimated number of additional dolutegravir-exposed pregnancies between Jan 1, 2015 and Feb 28, 2019, is 0·0018 (95% CI 0·0005-0·0067). INTERPRETATION: Neither dolutegravir nor efavirenz exposure was associated with NTDs in our national cohort; incidence of NTDs is probably well under 1% in dolutegravir-exposed HIV-positive women but still slightly above HIV-uninfected women (0·06%) in Brazil. FUNDING: The Brazilian Ministry of Health and the United States' National Institutes of Health.


Assuntos
Infecções por HIV/complicações , Inibidores de Integrase de HIV/efeitos adversos , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Defeitos do Tubo Neural/etiologia , Oxazinas/efeitos adversos , Piperazinas/efeitos adversos , Piridonas/efeitos adversos , Aborto Espontâneo/epidemiologia , Aborto Espontâneo/etiologia , Adulto , Terapia Antirretroviral de Alta Atividade/efeitos adversos , Brasil/epidemiologia , Comorbidade , Feminino , Infecções por HIV/tratamento farmacológico , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , Inibidores de Integrase de HIV/administração & dosagem , Inibidores de Integrase de HIV/uso terapêutico , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Humanos , Defeitos do Tubo Neural/diagnóstico , Defeitos do Tubo Neural/epidemiologia , Oxazinas/administração & dosagem , Oxazinas/uso terapêutico , Piperazinas/administração & dosagem , Piperazinas/uso terapêutico , Gravidez , Resultado da Gravidez , Piridonas/administração & dosagem , Piridonas/uso terapêutico , Estudos Retrospectivos , Natimorto , Adulto Jovem
14.
BMC Infect Dis ; 21(1): 5, 2021 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-33446115

RESUMO

BACKGROUND: Dolutegravir (DTG)-based antiretroviral therapy (ART) is highly effective and well-tolerated in adults and is rapidly being adopted globally. We describe the design of the ODYSSEY trial which evaluates the efficacy and safety of DTG-based ART compared with standard-of-care in children and adolescents. The ODYSSEY trial includes nested pharmacokinetic (PK) sub-studies which evaluated pragmatic World Health Organization (WHO) weight-band-based DTG dosing and opened recruitment to children < 14 kg while dosing was in development. METHODS: ODYSSEY (Once-daily DTG based ART in Young people vS. Standard thErapY) is an open-label, randomised, non-inferiority, basket trial comparing the efficacy and safety of DTG + 2 nucleos(t) ides (NRTIs) versus standard-of-care (SOC) in HIV-infected children < 18 years starting first-line ART (ODYSSEY A) or switching to second-line ART (ODYSSEY B). The primary endpoint is clinical or virological failure by 96 weeks. RESULTS: Between September 2016 and June 2018, 707 children weighing ≥14 kg were enrolled; including 311 ART-naïve children and 396 children starting second-line. 47% of children were enrolled in Uganda, 21% Zimbabwe, 20% South Africa, 9% Thailand, 4% Europe. 362 (51%) participants were male; median age [range] at enrolment was 12.2 years [2.9-18.0]. 82 (12%) children weighed 14 to < 20 kg, 135 (19%) 20 to < 25 kg, 206 (29%) 25 to < 35 kg, 284 (40%) ≥35 kg. 128 (18%) had WHO stage 3 and 60 (8%) WHO stage 4 disease. Challenges encountered include: (i) running the trial across high- to low-income countries with differing frequencies of standard-of-care viral load monitoring; (ii) evaluating pragmatic DTG dosing in PK sub-studies alongside FDA- and EMA-approved dosing and subsequently transitioning participants to new recommended doses; (iii) delays in dosing information for children weighing 3 to < 14 kg and rapid recruitment of ART-naïve older/heavier children, which led to capping recruitment of participants weighing ≥35 kg in ODYSSEY A and extending recruitment (above 700) to allow for ≥60 additional children weighing between 3 to < 14 kg with associated PK; (iv) a safety alert associated with DTG use during pregnancy, which required a review of the safety plan for adolescent girls. CONCLUSIONS: By employing a basket design, to include ART-naïve and -experienced children, and nested PK sub-studies, the ODYSSEY trial efficiently evaluates multiple scientific questions regarding dosing and effectiveness of DTG-based ART in children. TRIAL REGISTRATION: NCT, NCT02259127 , registered 7th October 2014; EUDRACT, 2014-002632-14, registered 18th June 2014 ( https://www.clinicaltrialsregister.eu/ctr-search/trial/2014-002632-14/ES ); ISRCTN, ISRCTN91737921 , registered 4th October 2014.


Assuntos
Infecções por HIV/tratamento farmacológico , Inibidores de Integrase de HIV/administração & dosagem , Inibidores de Integrase de HIV/efeitos adversos , HIV-1/genética , Compostos Heterocíclicos com 3 Anéis/administração & dosagem , Compostos Heterocíclicos com 3 Anéis/efeitos adversos , Oxazinas/administração & dosagem , Oxazinas/efeitos adversos , Piperazinas/administração & dosagem , Piperazinas/efeitos adversos , Piridonas/administração & dosagem , Piridonas/efeitos adversos , Adolescente , Peso Corporal , Criança , Pré-Escolar , Estudos de Coortes , Cálculos da Dosagem de Medicamento , Europa (Continente)/epidemiologia , Feminino , Infecções por HIV/epidemiologia , Infecções por HIV/virologia , Humanos , Masculino , RNA Viral/genética , África do Sul/epidemiologia , Tailândia/epidemiologia , Resultado do Tratamento , Uganda/epidemiologia , Carga Viral/efeitos dos fármacos , Organização Mundial da Saúde , Zimbábue/epidemiologia
15.
Mol Cell ; 81(2): 355-369.e10, 2021 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-33321093

RESUMO

Ferroptosis is a form of necrotic cell death caused by iron-dependent peroxidation of polyunsaturated phospholipids on cell membranes and is actively suppressed by the cellular antioxidant systems. We report here that oxidoreductases, including NADPH-cytochrome P450 reductase (POR) and NADH-cytochrome b5 reductase (CYB5R1), transfer electrons from NAD(P)H to oxygen to generate hydrogen peroxide, which subsequently reacts with iron to generate reactive hydroxyl radicals for the peroxidation of the polyunsaturated fatty acid (PUFA) chains of membrane phospholipids, thereby disrupting membrane integrity during ferroptosis. Genetic knockout of POR and CYB5R1 decreases cellular hydrogen peroxide generation, preventing lipid peroxidation and ferroptosis. Moreover, POR knockdown in mouse liver prevents ConA-induced liver damage. Ferroptosis, therefore, is a result of incidental electron transfer carried out by POR/CYB5R1 oxidoreductase and thus needs to be constitutively countered by the antioxidant systems.


Assuntos
Membrana Celular/química , Sistema Enzimático do Citocromo P-450/genética , Citocromo-B(5) Redutase/genética , Ácidos Graxos Insaturados/metabolismo , Ferroptose/genética , NADP/metabolismo , Animais , Linhagem Celular Tumoral , Membrana Celular/efeitos dos fármacos , Membrana Celular/metabolismo , Concanavalina A/farmacologia , Sistema Enzimático do Citocromo P-450/deficiência , Citocromo-B(5) Redutase/deficiência , Transporte de Elétrons/efeitos dos fármacos , Ferroptose/efeitos dos fármacos , Células HEK293 , Células HeLa , Humanos , Peróxido de Hidrogênio/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Nus , Oxigênio/metabolismo , Compostos de Fenilureia/farmacologia , Piperazinas/farmacologia , Piridinas/farmacologia , Sorafenibe/farmacologia
16.
Biochim Biophys Acta Gen Subj ; 1865(1): 129760, 2021 01.
Artigo em Inglês | MEDLINE | ID: mdl-33035602

RESUMO

BACKGROUND: Cancer cells show highly increased glucose utilization which, among other cancer-essential functions, was found to facilitate DNA repair. Lactate dehydrogenase (LDH) activity is pivotal for supporting the high glycolytic flux of cancer cells; to our knowledge, a direct contribution of this enzyme in the control of DNA integrity was never investigated. In this paper, we looked into a possible LDH-mediated regulation of homologous recombination (HR) repair. METHODS: We identified two cancer cell lines with different assets in energy metabolism: either based on glycolytic ATP or on oxidative reactions. In cells with inhibited LDH, we assessed HR function by applying four different procedures. RESULTS: Our findings revealed an LDH-mediated control of HR, which was observed independently of cell metabolic asset. Since HR inhibition is known to make cancer cells responsive to PARP inhibitors, in both the cellular models we finally explored the effects of a combined inhibition of LDH and PARP. CONCLUSIONS: The obtained results suggest for LDH a central role in cancer cell biology, not merely linked to the control of energy metabolism. The involvement of LDH in the DNA damage response could suggest new drug combinations to obtain improved antineoplastic effects. GENERAL SIGNIFICANCE: Several evidences have correlated the metabolic features of cancer cells with drug resistance and LDH inhibition has been repeatedly shown to increase the antineoplastic power of chemotherapeutics. By shedding light on the processes linking cell metabolism to the control of DNA integrity, our findings also give a mechanistic explanation to these data.


Assuntos
Antineoplásicos/farmacologia , Inibidores Enzimáticos/farmacologia , L-Lactato Desidrogenase/antagonistas & inibidores , Neoplasias/tratamento farmacológico , Ftalazinas/farmacologia , Piperazinas/farmacologia , Reparo de DNA por Recombinação/efeitos dos fármacos , Linhagem Celular Tumoral , Glicólise/efeitos dos fármacos , Humanos , L-Lactato Desidrogenase/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia
17.
Virus Res ; 293: 198259, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33309913

RESUMO

BACKGROUND: The large number of people infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has plunged the world into fear in recent times. In Japan, 18,769 novel coronavirus disease 2019 (COVID-19) cases have been reported as of June 30, 2020. This study aimed to assess whether cluster infection prevention is possible by evaluating the association between viral transmission and meteorological factors. METHODS: This study included 1263 people who were successively diagnosed with COVID-19 in Hokkaido, Japan between January 24, 2020 and June 30, 2020. After obtaining the values from the Japanese Meteorological Agency, the average scores of air temperature and humidity were calculated and compared with COVID-19 reproduction numbers, and the association between COVID-19 incidence or reproduction number and meteorological factors was assessed. RESULTS: The COVID-19 reproduction number in Hokkaido had three peaks that came several days before the surge in COVID-19 cases. The peaks are indicative of cluster infections. There was a strong negative correlation between the kinematic viscosity of atmospheric air and the reproduction number. DISCUSSION AND CONCLUSION: Analysis of the reproduction number is important for predicting or suppressing COVID-19 infection clusters. The authors found a strong association between meteorological factors, such as kinematic viscosity of atmospheric air and the incidence of COVID-19 infection. Meteorological forecasts could provide foreknowledge about COVID-19 infection clusters in the future.


Assuntos
Esquizofrenia , Método Duplo-Cego , Humanos , Japão/epidemiologia , Piperazinas , Piperidinas , Adesivo Transdérmico , Viscosidade
18.
Curr Opin Obstet Gynecol ; 33(1): 53-58, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33337614

RESUMO

PURPOSE OF REVIEW: The present review summarizes recent original publications addressing the topic of risk-adapted adjuvant therapy in early breast cancer (EBC). As neoadjuvant therapy has become a standard for triple negative and HER2+ EBC, it focusses on luminal EBC. RECENT FINDINGS: Gene expression assays have become standard of care in luminal EBC, at least for patients with node negative disease. Two prospective randomized clinical trials, TAILORx (Oncotype DX) and MINDACT (MammaPrint) have presented additional analyses underlining the clinical utility of the tests. In times of COVID-19, immunohistochemically determined ER, PR, and Ki67 and early Ki67 response to endocrine therapy can be used to safely allocate patients for preoperative endocrine therapy and delay surgeries if resources are scarce. In patients with luminal high-risk disease, adding a CDK 4/6 inhibitor (abemaciclib) improves patient outcome already after short-term follow-up. SUMMARY: Determination of recurrence risk will remain important in luminal EBC for optimal therapy decisions. In the future, risk-adapted treatment concepts will include decision making for chemotherapy but also for endocrine-based approaches.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Inibidores de Proteínas Quinases/uso terapêutico , Aminopiridinas/uso terapêutico , Benzimidazóis/uso terapêutico , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Feminino , Perfilação da Expressão Gênica , Humanos , Antígeno Ki-67/metabolismo , Terapia Neoadjuvante , Piperazinas/uso terapêutico , Piridinas/uso terapêutico , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores Estrogênicos/genética , Receptores Estrogênicos/metabolismo , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Medição de Risco
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...