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3.
SAGE Open Nurs ; 10: 23779608241231172, 2024.
Artigo em Inglês | MEDLINE | ID: mdl-38384386

RESUMO

Introduction: Parental stress related to their infants' hospitalization is a significant concern that affects both parents and their infants. Fathers' experiences tend to be understudied compared to mothers. Further research on fathers' stress levels is necessary. While parental stress has been correlated with infant health severity, the specific causes and risk factors contributing to heightened stress levels in parents of neonatal intensive care unit (NICU) infants are not yet fully understood and require further investigation. Objective: This study aimed to examine the stress levels experienced by parents of premature infants in the NICU and to explore the factors associated with parental stress in this specific context. Methods: A cross-sectional observational design was used to accomplish this study, which was carried out on 743 parents from nine different NICUs located in governmental hospitals across various locations in Egypt. We used characteristics of parents and premature infants, and Parent Stress Scale was used for data collection. Results: A majority of parents reported experiencing high stress in the following domains: sight and sound (80.3%), infants' appearance (69%), and the parent-infant relationship (81.4%). Additionally, about three-quarters (73.6%) of parents experienced high stress overall, with a mean score of 167.56 (21.3). Conclusion: About three-quarters of the parents experienced high overall stress levels. Also, factors that were found to affect parents' stress levels included premature infants connected to mechanical ventilators, previous neonatal death, parents living far from hospitals, infants delivered through cesarean section, insufficient income, and prolonged hospitalization beyond 5 days.

4.
BMC Surg ; 24(1): 8, 2024 Jan 03.
Artigo em Inglês | MEDLINE | ID: mdl-38172774

RESUMO

BACKGROUND: Bile duct injury (BDI) is still a major worrisome complication that is feared by all surgeons undergoing cholecystectomy. The overall incidence of biliary duct injuries falls between 0.2 and 1.3%. BDI classification remains an important method to define the type of injury conducted for investigation and management. Recently, a Consensus has been taken to define BDI using the ATOM classification. Early management brings better results than delayed management. The current perspective in biliary surgery is the laparoscopic role in diagnosing and managing BDI. Diagnostic laparoscopy has been conducted in various entities for diagnostic and therapeutic measures in minor and major BDIs. METHODS: 35 cases with iatrogenic BDI following cholecystectomy (after both open and laparoscopic approaches) both happened in or were referred to Alexandria Main University Hospital surgical department from January 2019 till May 2022 and were analyzed retrospectively. Patients were classified according to the ATOM classification. Management options undertaken were mentioned and compared to the timing of diagnosis, and the morbidity and mortality rates (using the Clavien-Dindo classification). RESULTS: 35 patients with BDI after both laparoscopic cholecystectomy (LC) (54.3%), and Open cholecystectomy (OC) (45.7%) (20% were converted and 25.7% were Open from the start) were classified according to ATOM classification. 45.7% were main bile duct injuries (MBDI), and 54.3% were non-main bile duct injuries (NMBDI), where only one case 2.9% was associated with vasculobiliary injury (VBI). 28% (n = 10) of the cases were diagnosed intraoperatively (Ei), 62.9% were diagnosed early postoperatively (Ep), and 8.6% were diagnosed in the late postoperative period (L). LC was associated with 84.2% of the NMBDI, and only 18.8% of the MBDI, compared to OC which was associated with 81.3% of the MBDI, and 15.8% of the NMBDI. By the Clavien-Dindo classification, 68.6% fell into Class IIIb, 20% into Class I, 5.7% into Class V (mortality rate), 2.9% into Class IIIa, and 2.9% into Class IV. The Clavien-Dindo classification and the patient's injury (type and time of detection) were compared to investigation and management options. CONCLUSION: Management options should be defined individually according to the mode of presentation, the timing of detection of injury, and the type of injury. Early detection and management are associated with lower morbidity and mortality. Diagnostic Laparoscopy was associated with lower morbidity and better outcomes. A proper Reporting checklist should be designed to help improve the identification of injury types.


Assuntos
Doenças dos Ductos Biliares , Colecistectomia Laparoscópica , Humanos , Estudos Retrospectivos , Ductos Biliares/lesões , Resultado do Tratamento , Colecistectomia/efeitos adversos , Colecistectomia Laparoscópica/efeitos adversos , Colecistectomia Laparoscópica/métodos , Doenças dos Ductos Biliares/cirurgia
5.
Future Med Chem ; 15(11): 937-958, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-37381751

RESUMO

Aim: The previously reported dual histone deacetylase type II (HDAC II) / topoisomerase type I (Topo I) inhibitors suffer pharmacokinetic limitations because of their huge molecular weights. Materials & methods: We report the design and synthesis of a smarter novel set of uracil-linked Schiff bases (19-30) as dual HDAC II/Topo I inhibitors keeping the essential pharmacophoric features. Cytotoxicity of all compounds was assessed against three cancer cell lines. Studies of their effects on the apoptotic BAX and antiapoptotic BCL2 genes, molecular docking studies, and absorption, distribution, metabolism and excretion studies were conducted. Results: Compounds 22, 25 and 30 exhibited significant activities. The bromophenyl derivative 22 displayed the best selectivity index, with IC50 values against HDAC II and Topo I of 1.12 and 13.44 µM, respectively. Conclusion: Compound 22 could be considered a lead HDAC II/Topo I inhibitor.


Assuntos
Antineoplásicos , Inibidores de Histona Desacetilases , Inibidores de Histona Desacetilases/farmacologia , Inibidores da Topoisomerase I/farmacologia , Histona Desacetilases/metabolismo , Linhagem Celular Tumoral , Simulação de Acoplamento Molecular , Bases de Schiff/farmacologia , Relação Estrutura-Atividade , Antineoplásicos/farmacologia , Proliferação de Células , DNA Topoisomerases Tipo II/metabolismo , DNA Topoisomerases Tipo II/farmacologia
6.
Cureus ; 15(1): e33847, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36819447

RESUMO

Latent autoimmune diabetes in adults (LADA) is a common but not well-studied entity and its features overlap between type 1 and type 2 diabetes mellitus (T1D, T2D). Although autoimmunity is a well-known factor associated with this diabetes subtype, environmental factors including excessive weight, physical inactivity, and smoking may also be associated with it. It is commonly misdiagnosed as T2D and generally treated by oral anti-diabetes medications that cause a delay in commencing insulin therapy. There are few cases mentioned in the literature of LADA presenting first time as diabetic ketoacidosis (DKA). Here, we report a case of latent autoimmune diabetes in an adult male who presented with DKA.

7.
QJM ; 116(5): 345-354, 2023 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-36592055

RESUMO

BACKGROUND: Matricellular proteins comprising matrisome and adhesome are responsible for structure integrity and interactions between cells in the tumour microenvironment of breast cancer. Changes in the gene expression of matrisome and adhesome augment metastasis. Since inflammatory breast cancer (IBC) is characterized by high metastatic behaviour. Herein, we compared the gene expression profile of matrisome and adhesome in non-IBC and IBC in fresh tissue and ex vivo patient-derived explants (PDEs) and we also compared the secretory inflammatory mediators of PDEs in non-IBC and IBC to identify secretory cytokines participate in cross-talk between cells via interactions with matrisome and adhisome. METHODS: Fifty patients (31 non-IBC and 19 IBC) were enrolled in the present study. To test their validation in clinical studies, PDEs were cultured as an ex vivo model. Gene expression and cytokine array were used to identify candidate genes and cytokines contributing to metastasis in the examined fresh tissues and PDEs. Bioinformatics analysis was applied on identified differentially expressed genes using GeneMANIA and Metascape gene annotation and analysis resource to identify pathways involved in IBC metastasis. RESULTS: Normal and cancer fresh tissues and PDEs of IBC were characterized by overexpression of CDH1 and MMP14 and downregulation of CTNNA1 and TIMP1 compared with non-IBC. The secretome of IBC cancer PDEs is characterized by significantly high expression of interleukin 6 and monocyte chemoattractant protein-1 (CCL2) compared with non-IBC. CONCLUSION: Genes expressed by adhisome and matrisome play a significant role in IBC metastasis and should be considered novel target therapy.


Assuntos
Neoplasias Inflamatórias Mamárias , Humanos , Neoplasias Inflamatórias Mamárias/genética , Neoplasias Inflamatórias Mamárias/metabolismo , Neoplasias Inflamatórias Mamárias/patologia , Interleucina-6/genética , Quimiocina CCL2/genética , Citocinas , Expressão Gênica , Microambiente Tumoral
8.
BMC Microbiol ; 23(1): 9, 2023 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-36627557

RESUMO

Cytosine deaminase (CDA) is a prodrug mediating enzyme converting 5-flurocytosine into 5-flurouracil with profound broad-range anticancer activity towards various cell lines. Availability, molecular stability, and catalytic efficiency are the main limiting factors halting the clinical applications of this enzyme on prodrug and gene therapies, thus, screening for CDA with unique biochemical and catalytic properties was the objective. Thermotolerant/ thermophilic fungi could be a distinctive repertoire for enzymes with affordable stability and catalytic efficiency. Among the recovered thermotolerant isolates, Aspergillus niger with optimal growth at 45 °C had the highest CDA productivity. The enzyme was purified, with purification 15.4 folds, molecular mass 48 kDa and 98 kDa, under denaturing and native PAGE, respectively. The purified CDA was covalently conjugated with dextran with the highest immobilization yield of 75%. The free and CDA-dextran conjugates have the same optimum pH 7.4, reaction temperature 37 °C, and pI 4.5, and similar response to the inhibitors and amino acids suicide analogues, ensuring the lack of effect of dextran conjugation on the CDA conformational structure. CDA-Dextran conjugates had more resistance to proteolysis in response to proteinase K and trypsin by 2.9 and 1.5 folds, respectively. CDA-Dextran conjugates displayed a dramatic structural and thermal stability than the free enzyme, authenticating the acquired structural and catalytic stability upon dextran conjugation. The thermal stability of CDA was increased by about 1.5 folds, upon dextran conjugation, as revealed from the half-life time (T1/2). The affinity of CDA-conjugates (Km 0.15 mM) and free CDA (Km 0.22 mM) to deaminate 5-fluorocytosine was increased by 1.5 folds. Upon dextran conjugation, the antiproliferative activity of the CDA towards the different cell lines "MDA-MB, HepG-2, and PC-3" was significantly increased by mediating the prodrug 5-FC. The CDA-dextran conjugates strongly reduce the tumor size and weight of the Ehrlich cells (EAC), dramatically increase the titers of Caspase-independent apoptotic markers PARP-1 and AIF, with no cellular cytotoxic activity, as revealed from the hematological and biochemical parameters.


Assuntos
Citosina Desaminase , Pró-Fármacos , Humanos , Aspergillus niger , Citosina Desaminase/metabolismo , Dextranos/metabolismo , Estabilidade Enzimática , Concentração de Íons de Hidrogênio , Cinética , Peptídeo Hidrolases/metabolismo , Pró-Fármacos/farmacologia , Proteólise , Linhagem Celular Tumoral
9.
J Adv Res ; 45: 87-100, 2023 03.
Artigo em Inglês | MEDLINE | ID: mdl-35595215

RESUMO

INTRODUCTION: The structural and dynamic determinants that confer highly selective RET kinase inhibition are poorly understood. OBJECTIVES: To explore the druggability landscape of the RET active site in order to uncover structural and dynamic vulnerabilities that can be therapeutically exploited. METHODS: We apply an integrated structural, computational and biochemical approach in order to explore the druggability landscape of the RET active site. RESULTS: We demonstrate that the that the druggability landscape of the RET active site is determined by the conformational setting of the ATP-binding (P-) loop and its coordination with the αC helix. Open and intermediate P-loop structures display additional druggable vulnerabilities within the active site that were not exploited by first generation RET inhibitors. We identify a cryptic pocket adjacent to the catalytic lysine formed by K758, L760, E768 and L772, that we name the post-lysine pocket, with higher druggability potential than the adenine-binding site and with important implications in the regulation of the phospho-tyrosine kinase activity. Crystal structure and simulation data show that the binding mode of highly-selective RET kinase inhibitors LOXO-292 and BLU-667 is controlled by a synchronous open P-loop and αC-in configuration that allows accessibility to the post-lysine pocket. Molecular dynamics simulations show that these inhibitors efficiently occupy the post-lysine pocket with high stability through the simulation time-scale (300 ns), with both inhibitors forming hydrophobic contacts further stabilized by pi-cation interactions with the catalytic K758. Engineered mutants targeting the post-lysine pocket impact on inhibitor binding and sensitivity, as well as RET tyrosine kinase activity. CONCLUSIONS: The identification of the post-lysine pocket as a new druggable vulnerability in the RET kinase and its exploitation by second generation RET inhibitors have important implications for future drug design and the development of personalized therapies for patients with RET-driven cancers.


Assuntos
Neoplasias , Proteínas Proto-Oncogênicas c-ret , Humanos , Proteínas Proto-Oncogênicas c-ret/química , Proteínas Proto-Oncogênicas c-ret/metabolismo , Lisina , Simulação de Dinâmica Molecular , Conformação Molecular
10.
Biochim Biophys Acta Mol Cell Res ; 1870(1): 119367, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-36202317

RESUMO

Studies suggested that the pathogenesis of inflammatory breast cancer (IBC) is related to inflammatory manifestations accompanied by specific cellular and molecular mechanisms in the IBC tumor microenvironment (TME). IBC is characterized by significantly higher infiltration of tumor-associated macrophages (TAMs) that contribute to its metastatic process via secreting many cytokines such as TNF, IL-6, IL-8, and IL-10 that enhance invasion and angiogenesis. Thus, there is a need to first understand how IBC-TME modulates the polarization of TAMs to better understand the role of TAMs in IBC. Herein, we used gene expression signature and Synchrotron Fourier-Transform Infrared Microspectroscopy (SR-µFTIR) to study the molecular and biochemical changes, respectively of in vitro polarized TAMs stimulated by the secretome of IBC and non-IBC cells. The gene expression signature showed significant differences in the macrophage's polarization-related genes between stimulated TAMs. FTIR spectra showed absorption bands in the region of 1700-1500 cm-1 attributed to the amide I ν(C=O), & νAS (CN), δ (NH), and amide II ν(CN), δ (NH) proteins bands. Moreover, three peaks of different intensities and areas were detected in the lipid region of the νCH2 and νCH3 stretching modes positioned within the 3000-2800 cm-1 range. The PCA analysis for the second derivative spectra of the amide regions discriminates between stimulated IBC and non-IBC TAMs. This study showed that IBC and non-IBC TMEs differentially modulate the polarization of TAMs and SR-µFTIR can determine these biochemical changes which will help to better understand the potential role of TAMs in IBC.


Assuntos
Neoplasias Inflamatórias Mamárias , Macrófagos Associados a Tumor , Humanos , Síncrotrons , Secretoma , Neoplasias Inflamatórias Mamárias/genética , Neoplasias Inflamatórias Mamárias/metabolismo , Neoplasias Inflamatórias Mamárias/patologia , Amidas , Microambiente Tumoral
11.
Plants (Basel) ; 11(22)2022 Nov 08.
Artigo em Inglês | MEDLINE | ID: mdl-36432745

RESUMO

Lack of high-quality irrigation water and soil salinity are two main environmental factors that affect plant development. When both stressors are combined, the soil becomes sterile and constrains plant productivity. Consequently, two field trials were designed to assess whether plant growth-promoting microbes (PGPMs; Bradyrhizobium japonicum (USDA 110) and Trichoderma harzianum) and potassium humate (K-humate) can stimulate soybean growth, productivity, and seed quality under two different watering regimes as follows: (i) well-watered (WW), where plants were irrigated at 12-day intervals (recommended), and (ii) water stress (WS), where plants were irrigated at the 18-day intervals in salt-affected soil during 2020 and 2021 seasons. Results revealed that coupled application of PGPMs and K-humate resulted in a substantial improvement in K+ levels in the leaves compared to Na+ levels, which has a direct positive impact on an enhancement in the antioxidants defense system (CAT, POX, SOD), which caused the decline of the oxidative stress indicators (H2O2, MDA, and EL%) as well as proline content under water stress in salt-affected soil. Hence, a significant increase in root length, nodule weight, soybean relative water content (RWC), stomatal conductance, photosynthetic pigments, net photosynthetic rate, soluble protein, seed carbohydrate content as well as the number of pods plant-1 and seed yield was reported. In conclusion, the combined application of PGPMs and K-humate might be recommended to maximize the soybean growth and productivity under harsh growth conditions (e.g., water stress and soil salinity).

12.
Plants (Basel) ; 11(15)2022 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-35956503

RESUMO

Exploitation of low-quality water or irrigation of field crops with saline water in salt-affected soil is a critical worldwide challenge that rigorously influences agricultural productivity and sustainability, especially in arid and semiarid zones with limited freshwater resources. Therefore, we investigated a synergistic amendment strategy for salt-affected soil using a singular and combined application of plant growth-promoting rhizobacteria (PGPR at 950 g ha-1; Azotobacter chroococcum SARS 10 and Pseudomonas koreensis MG209738) and silica nanoparticles (SiNPs) at 500 mg L-1 to mitigate the detrimental impacts of irrigation with saline water on the growth, physiology, and productivity of barley (Hordum vulgare L.), along with soil attributes and nutrient uptake during 2019/2020 and 2020/2021. Our field trials showed that the combined application of PGPR and SiNPs significantly improved the soil physicochemical properties, mainly by reducing the soil exchangeable sodium percentage. Additionally, it considerably enhanced the microbiological counts (i.e., bacteria, azotobacter, and bacillus) and soil enzyme activity (i.e., urease and dehydrogenase) in both growing seasons compared with the control. The combined application of PGPR and SiNPs alleviated the detrimental impacts of saline water on barley plants grown in salt-affected soil compared to the single application of PGPR or SiNPs. The marked improvement was due to the combined application of PGPR and SiNPs, which enhanced the physiological properties (e.g., relative chlorophyll content (SPAD), relative water content (RWC), stomatal conductance, and K/Na ratio), enzyme activity (superoxide dismutase (SOD), catalase (CAT), and peroxidase (POX)), and yield and yield-related traits and nutrient uptake (N, P, and K) of barley plants. Moreover, the Na+ content, hydrogen peroxide (H2O2) content, lipid peroxidation (MDA), electrolyte leakage (EL), and proline content were reduced upon the application of PGPR + SiNPs. These results could be important information for cultivating barley and other cereal crops in salt-affected soil under irrigation with saline water.

13.
Front Oncol ; 12: 899622, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35847899

RESUMO

Inflammatory breast cancer (IBC) is a highly aggressive phenotype of breast cancer that is characterized by a high incidence early metastasis. We previously reported a significant association of human cytomegalovirus (HCMV) DNA in the carcinoma tissues of IBC patients but not in the adjacent normal tissues. HCMV-infected macrophages serve as "mobile vectors" for spreading and disseminating virus to different organs, and IBC cancer tissues are highly infiltrated by tumor-associated macrophages (TAMs) that enhance IBC progression and promote breast cancer stem cell (BCSC)-like properties. Therefore, there is a need to understand the role of HCMV-infected TAMs in IBC progression. The present study aimed to test the effect of the secretome (cytokines and secreted factors) of TAMs derived from HCMV+ monocytes isolated from IBC specimens on the proliferation, invasion, and BCSC abundance when tested on the IBC cell line SUM149. HCMV+ monocytes were isolated from IBC patients during modified radical mastectomy surgery and tested in vitro for polarization into TAMs using the secretome of SUM149 cells. MTT, clonogenic, invasion, real-time PCR arrays, PathScan Intracellular Signaling array, and cytokine arrays were used to characterize the secretome of HCMV+ TAMs for their effect on the progression of SUM149 cells. The results showed that the secretome of HCMV+ TAMs expressed high levels of IL-6, IL-8, and MCP-1 cytokines compared to HCMV- TAMs. In addition, the secretome of HCMV+ TAMs induced the proliferation, invasion, colony formation, and expression of BCSC-related genes in SUM149 cells compared to mock untreated cells. In addition, the secretome of HCMV+ TAMs activated the phosphorylation of intracellular signaling molecules p-STAT3, p-AMPKα, p-PRAS40, and p-SAPK/JNK in SUM149 cells. In conclusion, this study shows that the secretome of HCMV+ TAMs enhances the proliferation, invasion, colony formation, and BCSC properties by activating the phosphorylation of p-STAT3, p-AMPKα, p-PRAS40, and p-SAPK/JNK intracellular signaling molecules in IBC cells.

14.
Plants (Basel) ; 11(7)2022 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-35406852

RESUMO

The aim of the study was to estimate the impact of soil amendments (i.e., phosphogypsum and plant growth-promoting rhizobacteria (PGPR)) separately or their combination on exchangeable sodium percentage (ESP), soil enzymes' activity (urease and dehydrogenase), pigment content, relative water content (RWC), antioxidant enzymatic activity, oxidative stress, productivity, and quality of quinoa under deficient irrigation conditions in two field experiments during the 2019-2020 and 2020-2021 seasons under salt-affected soil. Results revealed that ESP, soil urease activity, soil dehydrogenase activity, leaf chlorophyll a, b, and carotenoids, leaf K content, RWC, SOD (superoxide dismutase), CAT (catalase), and POD (peroxidase) activities were declined, resulting in overproduction of leaf Na content, proline content, and oxidative stress indicators (H2O2, malondialdehyde (MDA) and electrolyte leakage) under water stress and soil salinity, which negatively influence yield-related traits, productivity, and seed quality of quinoa. However, amendment of salt-affected soil with combined phosphogypsum and seed inoculation with PGPR under deficient irrigation conditions was more effective than singular application and control plots in ameliorating the harmful effects of water stress and soil salinity. Additionally, combined application limited Na uptake in leaves and increased K uptake and leaf chlorophyll a, b, and carotenoids as well as improved SOD, CAT, and POD activities to ameliorate oxidative stress indicators (H2O2, MDA, and electrolyte leakage), which eventually positively reflected on productivity and quality in quinoa. We conclude that the potential utilization of phosphogypsum and PGPR are very promising as sustainable eco-friendly strategies to improve quinoa tolerance to water stress under soil salinity.

15.
mBio ; 13(2): e0370521, 2022 04 26.
Artigo em Inglês | MEDLINE | ID: mdl-35229634

RESUMO

Combinations of direct-acting antivirals are needed to minimize drug resistance mutations and stably suppress replication of RNA viruses. Currently, there are limited therapeutic options against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and testing of a number of drug regimens has led to conflicting results. Here, we show that cobicistat, which is an FDA-approved drug booster that blocks the activity of the drug-metabolizing proteins cytochrome P450-3As (CYP3As) and P-glycoprotein (P-gp), inhibits SARS-CoV-2 replication. Two independent cell-to-cell membrane fusion assays showed that the antiviral effect of cobicistat is exerted through inhibition of spike protein-mediated membrane fusion. In line with this, incubation with low-micromolar concentrations of cobicistat decreased viral replication in three different cell lines including cells of lung and gut origin. When cobicistat was used in combination with remdesivir, a synergistic effect on the inhibition of viral replication was observed in cell lines and in a primary human colon organoid. This was consistent with the effects of cobicistat on two of its known targets, CYP3A4 and P-gp, the silencing of which boosted the in vitro antiviral activity of remdesivir in a cobicistat-like manner. When administered in vivo to Syrian hamsters at a high dose, cobicistat decreased viral load and mitigated clinical progression. These data highlight cobicistat as a therapeutic candidate for treating SARS-CoV-2 infection and as a potential building block of combination therapies for COVID-19. IMPORTANCE The lack of effective antiviral treatments against SARS-CoV-2 is a significant limitation in the fight against the COVID-19 pandemic. Single-drug regimens have so far yielded limited results, indicating that combinations of antivirals might be required, as previously seen for other RNA viruses. Our work introduces the drug booster cobicistat, which is approved by the FDA and typically used to potentiate the effect of anti-HIV protease inhibitors, as a candidate inhibitor of SARS-CoV-2 replication. Beyond its direct activity as an antiviral, we show that cobicistat can enhance the effect of remdesivir, which was one of the first drugs proposed for treatment of SARS-CoV-2. Overall, the dual action of cobicistat as a direct antiviral and a drug booster can provide a new approach to design combination therapies and rescue the activity of compounds that are only partially effective in monotherapy.


Assuntos
Tratamento Farmacológico da COVID-19 , Hepatite C Crônica , Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Animais , Antivirais/farmacologia , Antivirais/uso terapêutico , Cobicistat , Cricetinae , Progressão da Doença , Humanos , Mesocricetus , Pandemias , SARS-CoV-2 , Carga Viral
16.
Biochim Biophys Acta Mol Cell Res ; 1868(6): 118995, 2021 05.
Artigo em Inglês | MEDLINE | ID: mdl-33667527

RESUMO

Locally advanced breast cancer (LABC) is an aggressive disease characterized by late clinical presentation, large tumor size, treatment resistance and low survival rate. Expression of EGFR/HER2 and activation of intracellular tyrosine kinase domains in LABC are associated with poor prognosis. Thus, target therapies such as the anti-receptor tyrosine kinases lapatinib drug have been more developed in the past decade. The response to lapatinib involves the inhibition of RTKs and subsequently signaling molecules such as Src/STAT3/Erk1/2 known also to be activated by the cytokines in the tumor microenvironment (TME). The aim of the present study is to identify the major cytokine that might contribute to lapatinib resistance in EGFR+/HER2+ LABC patients. Indeed, tumor associated macrophages (TAMs) are the main source of cytokines in the TME. Herein, we isolated TAMs from LABC during modified radical mastectomy (MRM). Cytokine profile of TAMs revealed that IL-8 is the most prominent highly secreted cytokine by TAMs of LABC patients. Using in-vitro cell culture model we showed that recombinant IL-8 (50 and 100 ng/mL) at different time intervals interfere with lapatinib action via activation of Src/EGFR and signaling molecules known to be inhibited during treatment. We proposed that to improve LABC patients' response to lapatinib treatment it is preferred to use combined therapy that neutralize or block the action of IL-8.


Assuntos
Neoplasias da Mama/cirurgia , Resistencia a Medicamentos Antineoplásicos , Interleucina-8/metabolismo , Macrófagos Associados a Tumor/imunologia , Adulto , Idoso , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Linhagem Celular Tumoral , Receptores ErbB/metabolismo , Feminino , Humanos , Lapatinib/farmacologia , Sistema de Sinalização das MAP Quinases/efeitos dos fármacos , Mastectomia , Pessoa de Meia-Idade , Receptor ErbB-2/metabolismo , Transdução de Sinais/efeitos dos fármacos
17.
Arch Suicide Res ; 25(3): 641-656, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-32252618

RESUMO

INTRODUCTION: Previous observational cohort studies showed an association between low serum lipid levels and suicide. This study was undertaken to examine the relationship between lipid parameters and impulsivity in suicidal patients with major depressive disorder (MDD). METHODS: The current study included 100 patients with MDD distributed as 50 patients with recent suicidal attempts and 50 patients with no lifetime history of suicide. Participants were subjected to Structured Clinical Interview for DSM-IV Axis I Disorders (SCID I) to confirm the diagnosis. The risk of suicide was assessed through the Suicide Probability Scale (SPS), while the intent and seriousness of suicide were assessed through Beck's Suicidal Intent Scale. assessment of impulsivity was carried out through Barratt Impulsivity Scale. Serum lipid levels were measured in mg/dL after an overnight fast. RESULTS: Total cholesterol (TC) was found significantly lower in the suicidal group compared to the non-suicidal depressed group (p = 0.040). Low high-density lipoprotein (HDL) level was significantly correlated with suicidality and high suicide intent was correlated with hopelessness. Logistic regression for lipid profile in both groups revealed significant TC and low-density lipoprotein (LDL) as predictors for suicide. There was no significant correlation between impulsivity and characteristics of depression, suicide probability, suicide intent, and all elements of the lipid profile. CONCLUSIONS: Low TC and LDL could predict suicidal behavior in patients with MDD. Impulsivity could not be a mediator or predictor of suicide risk in patients with MDD.


Assuntos
Transtorno Depressivo Maior , Humanos , Comportamento Impulsivo , Lipídeos , Ideação Suicida , Tentativa de Suicídio
18.
Molecules ; 25(18)2020 Sep 19.
Artigo em Inglês | MEDLINE | ID: mdl-32961706

RESUMO

Glycosaminoglycans (GAGs)/proteoglycans (PGs) play a pivotal role in the metastasis of inflammatory breast cancer (IBC). They represent biomarkers and targets in diagnosis and treatment of different cancers including breast cancer. Thus, GAGs/PGs could represent potential prognostic/diagnostic biomarkers for IBC. In the present study, non-IBC MDA-MB-231, MCF7, SKBR3 cells and IBC SUM149 cells, as well as their GAG secretome were analyzed. The latter was measured in toto as dried drops with high-throughput (HT) Fourier Transform InfraRed (FTIR) spectroscopy and imaging. FTIR imaging was also employed to investigate single whole breast cancer cells while synchrotron-FTIR microspectroscopy was used to specifically target their cytoplasms. Data were analyzed by hierarchical cluster analysis and principal components analysis. Results obtained from HT-FTIR analysis of GAG drops showed that the inter-group variability enabled us to delineate between cell types in the GAG absorption range 1350-800 cm-1. Similar results were obtained for FTIR imaging of GAG extracts and fixed single whole cells. Synchrotron-FTIR data from cytoplasms allowed discrimination between non-IBC and IBC. Thus, by using GAG specific region, not only different breast cancer cell lines could be differentiated, but also non-IBC from IBC cells. This could be a potential diagnostic spectral marker for IBC detection useful for patient management.


Assuntos
Glicosaminoglicanos/metabolismo , Processamento de Imagem Assistida por Computador , Espectroscopia de Infravermelho com Transformada de Fourier , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Análise por Conglomerados , Meios de Cultivo Condicionados/química , Feminino , Humanos , Análise de Componente Principal
19.
Clin Neurol Neurosurg ; 198: 106138, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32823185

RESUMO

A 61-year-old Caucasian female, with severe obturator neuropathy following a left pubic ramus fracture was treated successfully with dorsal root ganglion stimulation (DRGS). Both conservative management and a dual-lead dorsal column spinal cord stimulator did not provide effective long-term results. The dorsal root ganglion (DRG) trial was completed five years following the initial fracture, resulting in 90 % pain relief. A permanent device was implanted and after one year, 90 % pain relief was still sustained. DRGS has applicability in future treatment algorithms for patients with mixed nociceptive and neuropathic groin pain refractory to conservative management.


Assuntos
Fraturas Ósseas/complicações , Gânglios Espinais/fisiopatologia , Síndromes de Compressão Nervosa/etiologia , Dor Intratável/terapia , Estimulação da Medula Espinal , Nervos Espinhais/lesões , Feminino , Humanos , Pessoa de Meia-Idade , Dor Intratável/etiologia , Osso Púbico/lesões , Resultado do Tratamento
20.
Ortop Traumatol Rehabil ; 22(3): 181-185, 2020 Jun 30.
Artigo em Inglês | MEDLINE | ID: mdl-32732442

RESUMO

BACKGROUND: Anterior cruciate ligament (ACL) reconstruction has remained the gold standard for ACL injuries, especially for young individuals and athletes exposed to high level sporting activities aiming to return to their preinjury level of activity. Cortical suspensory femoral fixation is commonly performed for graft fixation to the femur in anterior cruciate ligament reconstruction using hamstring tendons. The aim of this study was to compare the clinical results of using fixed and adjustable loop cortical suspension devices in arthroscopic ACL reconstruction using the Lysholm Knee Scoring Scale after 12 months postoperatively. MATERIAL AND METHODS: This study included a total of sixty patients who underwent transportal arthroscopic ACL reconstruction using a hamstring tendon autograft from November 2016 to December 2017. For femoral graft fixation, a fixed-length loop device was used in 30 patients (fixed-loop group) and an adjustable-length loop device was used in 30 patients (adjustable-loop group) randomly.For tibial graft fixation, interference screw was used for all patients. RESULTS: The present study shows that there was no statistically significant difference between the two groups regarding the Lysholm score with highly statistically significant difference between preoperative and postoperative Lysholm score in each group separately. CONCLUSION: Both fixed loop and adjustable loop devices in ACL reconstruction provided good clinical outcomes but without significant statistical difference between both groups from the clinical point of view postoperatively using the Lysholm score.


Assuntos
Lesões do Ligamento Cruzado Anterior/cirurgia , Reconstrução do Ligamento Cruzado Anterior/instrumentação , Reconstrução do Ligamento Cruzado Anterior/métodos , Fixadores Internos , Adulto , Feminino , Humanos , Masculino , Resultado do Tratamento
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