Novel thiosemicarbazones induce high toxicity in estrogen-receptor-positive breast cancer cells (MCF7) and exacerbate cisplatin effectiveness in triple-negative breast (MDA-MB231) and lung adenocarcinoma (A549) cells.

Cis-diamminedichloroplatinum(II) (CDDP), known as cisplatin, has been extensively used against breast cancer, which is the most frequent cancer among women, and lung cancer, the leading cancer that causes death worldwide. Novel compounds such as thiazole derivatives have exhibited antiproliferative activity, suggesting they could be useful against cancer treatment. Herein, we synthesized two novel thiosemicarbazones and an aldehyde to combine with CDDP to enhance efficacy against ER-positive breast MCF7 cancer cells, triple-negative/basal-B mammary carcinoma cells (MDA-MB231) and lung adenocarcinoma (A549) human cells. We synthesized 2,3,5,6-tetrafluoro-4-(2-mercaptoetanothiolyl)benzaldehyde (ALD), 5-[(2,3,5,6-tetrafluoro-4-(trifluoromethyl)phenyl)thio]-2-furaldehyde thiosemicarbazone (TSC1) and 5-[(4-(trifluoromethyl)phenyl)thio]-2-furaldehyde thiosemicarbazone (TSC2) and used them alone or in combination with subtoxic CDDP concentrations to evaluate cytotoxicity, cytoskeleton integrity and mitochondrial function. We found that none of the synthesized compounds improved CDDP activity against MCF7 cell cultures; however, TSC2 was effective in enhancing the cytotoxicity of CDDP against MDA-MB231 and A549 cancer cell cultures. We demonstrated that the cytotoxic effect is related to the TSC2 capacity to induce disruption in the cytoskeleton network and to decrease mitochondrial function.

Sodium thiosulphate attenuates brain inflammation induced by systemic lipopolysaccharide administration in C57BL/6J mice.

It has been demonstrated that peripheral infections accompanied by neuroinflammation may modify brain development or affect normal brain aging and represent major risk factors for the development of neurological disorders. A wide range of synthetic and natural compounds with anti-inflammatory properties have been evaluated in animal models of neuroinflammation and neurodegeneration as an adjuvant therapeutic strategy. In the present study we have demonstrated for the first time that sodium thiosulphate (STS), a known antidote approved for treatment of certain medical conditions, is capable of reducing brain inflammation caused by systemic LPS administration. STS reduced brain levels of pro-inflammatory cytokine interleukin-1ß (IL-1ß), cyclooxygenase-2 (COX-2), ionized calcium binding adaptor molecule 1 (Iba-1) and 18 kDa translocator protein (TSPO) in an animal model of systemic LPS-induced neuroinflammation. In addition, we demonstrated for the first time elevated TSPO expression in retinal ganglion cells layer after peripheral LPS challenge and inhibition of ocular TSPO expression after treatment with STS. We think that STS may be used as an adjuvant anti-inflammatory therapy for many pathological conditions associated with inflammation in the brain.

Rosai-Dorfman sphenoorbital histiocytosis with intraparenchymal invasion: Do we have to consider this skull base pathology as a malignant disease?

Background: Rosai-Dorfman disease (RDD) is a rare type of histiocytosis that can manifest with diverse symptoms. It usually presents with systemic involvement, and only a few cases have been reported at the level of the skull base. RDD typically follows a benign course during the progression of the disease. In this particular case reported, after the skull base invasion, the disease started to infiltrate the brain parenchyma. Our objective for this case report was to present this particular progression pattern and the nuances of its surgical treatment. In addition, a revision of the current literature was performed about skull base RDD with intracranial invasion and brain parenchyma infiltration not previously described. Case Description: We are presenting the case study of a 57-year-old male patient who was experiencing severe headaches and an increase in volume in the right fronto-orbital region. On clinical examination, no neurologic clinical symptoms were observed. Contrast computed tomography and magnetic resonance imaging showed a tumor mass that affected the right orbit, frontal paranasal sinus, greater sphenoid wing, and right frontal lobe with moderate adjacent brain edema. The patient underwent surgery using an extended pterional approach with intracranial, orbital decompression, and frontal sinus cranialization, accompanied by frontal lobe tumor resection. Neuropathologic diagnosis revealed a Rosai-Dorfman histiocytosis disease. Conclusion: The etiopathogenesis of RDD is still not completely understood. The current literature considers this disease to have a predominantly benign course. Nevertheless, as we have shown in this case, it may, in some cases, present direct parenchymal invasion. We consider that prompt surgical treatment should be ideal to avoid the local and systemic progression of the disease.

Preliminary tribological results of a new total temporary hip joint prosthesis spacer.

Temporary antibiotic-loaded cement spacers are widely used for treating chronic periprosthetic hip infections. The aim of this study is to evaluate the short-term tribological performance of ultra-high-molecular-weight polyethylene (UHMWPE) and (60Co) gamma-irradiated cross-linked UHMWPE (XLPE) self-mated systems as frictional pairs for temporary total hip spacers. A three-axial hip joint simulator, FIME II, was used to test the UHMWPE and XLPE self-mated systems under variable load profiles. A fetal bovine serum solution was used as a lubricant. After simulation tests, wear measurements of damaged coupled surfaces were made with a coordinate measuring machine. Finally, surfaces were characterized with scanning electron microscopy, Raman spectroscopy, Fourier transform infrared spectroscopy, and nanoindentation tests. The mass loss test results for UHMWPE were 11.91 ± 3.43 mg for the cups and 4.57 ± 0.92 mg for the heads. Whereas, the results for XLPE showed a significant reduction, with mean mass loss values of 6.59 ± 0.14 mg for the cups and 2.82 ± 0.59 mg for the heads, suggesting the viability of the self-mated XLPE contact pair for a temporary total hip spacer.

Effect of sterilization on 3-point dynamic response to in vitro bending of an Mg implant.

BACKGROUND: The aim of the study is to characterize a biomedical magnesium alloy and highlighting the loss of mechanical integrity due to the sterilization method. Ideally, when using these alloys is to delay the onset of degradation so that the implant can support body loads and avoid toxicological effects due to the release of metal ions into the body. METHODS: Standardized procedures according to ASTM F-1264 and ISO-10993-5 were used, respecting detailed methodological controls to ensure accuracy and reproducibility of the results, this testing methodology is carried out in accordance with the monographs of the Pharmacopoeia for the approval of medical devices and obtaining a health registration. An intramedullary implant (IIM) manufactured in magnesium (Mg) WE43 can support loads of the body in the initial period of bone consolidation without compromising the integrity of the fractured area. A system with these characteristics would improve morbidity and health costs by avoiding secondary surgical interventions. RESULTS: As a property, the fatigue resistance of Mg in aggressive environments such as the body environment undergoes progressive degradation, however, the autoclave sterilization method drastically affects fatigue resistance, as demonstrated in tests carried out under in vitro conditions. Coupled with this phenomenon, the relatively poor biocompatibility of Mg WE43 alloys has limited applications where they can be used due to low acceptance rates from agencies such as the FDA. However, Mg alloy with elements such as yttrium and rare earth elements (REEs) have been shown to delay biodegradation depending on the method of sterilization and the physiological solution used. With different sterilization techniques, it may be possible to keep toxicological effects to a minimum while still ensuring a balance between the integrity of fractured bone and implant degradation time. Therefore, the evaluation of fatigue resistance of WE43 specimens sterilized and tested in immersion conditions (enriched Hank's solution) and according to ASTM F-1264, along with the morphological, crystallinity, and biocompatibility characterization of the WE43 alloy allows for a comprehensive evaluation of the mechanical and biological properties of WE43. CONCLUSIONS: These results will support decision-making to generate a change in the current perspective of biomaterials utilized in medical devices (MDs), to be considered by manufacturers and health regulatory agencies. An implant manufactured in WE43 alloy can be used as an intramedullary implant, considering keeping elements such as yttrium-REEs below as specified in its designation and with the help of a coating that allows increasing the life of the implant in vivo.

LINC00460 Is a Dual Biomarker That Acts as a Predictor for Increased Prognosis in Basal-Like Breast Cancer and Potentially Regulates Immunogenic and Differentiation-Related Genes.

Breast cancer (BRCA) is a serious public health problem, as it is the most frequent malignant tumor in women worldwide. BRCA is a molecularly heterogeneous disease, particularly at gene expression (mRNAs) level. Recent evidence shows that coding RNAs represent only 34% of the total transcriptome in a human cell. The rest of the 66% of RNAs are non-coding, so we might be missing relevant biological, clinical or regulatory information. In this report, we identified two novel tumor types from TCGA with LINC00460 deregulation. We used survival analysis to demonstrate that LINC00460 expression is a marker for poor overall (OS), relapse-free (RFS) and distant metastasis-free survival (DMFS) in basal-like BRCA patients. LINC00460 expression is a potential marker for aggressive phenotypes in distinct tumors, including HPV-negative HNSC, stage IV KIRC, locally advanced lung cancer and basal-like BRCA. We show that the LINC00460 prognostic expression effect is tissue-specific, since its upregulation can predict poor OS in some tumors, but also predicts an improved clinical course in BRCA patients. We found that the LINC00460 expression is significantly enriched in the Basal-like 2 (BL2) TNBC subtype and potentially regulates the WNT differentiation pathway. LINC00460 can also modulate a plethora of immunogenic related genes in BRCA, such as SFRP5, FOSL1, IFNK, CSF2, DUSP7 and IL1A and interacts with miR-103-a-1, in-silico, which, in turn, can no longer target WNT7A. Finally, LINC00460:WNT7A ratio constitutes a composite marker for decreased OS and DMFS in Basal-like BRCA, and can predict anthracycline therapy response in ER-BRCA patients. This evidence confirms that LINC00460 is a master regulator in BRCA molecular circuits and influences clinical outcome.

Bio-inspired biomaterial Mg-Zn-Ca: a review of the main mechanical and biological properties of Mg-based alloys.

The toxicity of alloying elements in magnesium alloys used for biomedical purposes is an interesting and innovative subject, due to the great technological advances that would result from their application in medical devices (MDs) in traumatology. Recently promising results have been published regarding the rates of degradation and mechanical integrity that can support Mg alloys; this has led to an interest in understanding the toxicological features of these emerging biomaterials. The growing interest of different segments of the MD market has increased the determination of different research groups to clarify the behavior of alloying elements in vivo. This review covers the influence of the alloying elements on the body, the toxicity of the elements in Mg-Zn-Ca, as well as the mechanical properties, degradation, processes of obtaining the alloy, medical approaches and future perspectives on the use of the Mg in the manufacture of MDs for various medical applications.

Arterial hypertension treatment in octogenarians with dementia according to ESC/ESH-2018: Three-year follow-up. / Tratamiento de la hipertensión arterial en octogenarios con demencia según ESC/ESH-2018: seguimiento a 3 años.

OBJECTIVE: To determine the control of systolic blood pressure (SBP) retrospectively according to the recommendations of the ESC/ESH-2018 guideline and its relationship with mortality in octogenarian patients with dementia. PATIENTS AND METHODS: Preliminary, longitudinal, observational, retrospective study, including 65 patients ≥80 years with diagnosis of dementia and arterial hypertension admitted to a psychogeriatric unit during 2015. The main variables were SBP control according to the recommendations of the ESC/ESH-2018 guideline, considering desirable SBP (130-139mmHg), undesirable SBP (suboptimal <130mmHg and elevated SBP ≥140mmHg) and mortality at 3 years in patients with antihypertensive treatment at discharge (n = 53). RESULTS: Mean age, 86.7±4.31 years (63% women); severe functional dependence (Barthel index <40): 67.7%; severe cognitive impairment (GDS-Riesberg ≥6): 86.3%; high comorbidity: 49%; mortality at 3 years: 41 (63.1%). Patients with arterial hypertension and cardiovascular comorbidity had a higher prescription of antihypertensive drugs (2.07 vs. 1.18, p=.002). Three years mortality was lower in patients with desirable SBP (44.4%) versus undesirable SBP (72.7%) groups, although it was not statistically significant. CONCLUSIONS: The percentage of patients in treatment with suboptimal SBP was elevated especially in hypertensive patients without cardiovascular comorbidity. We found a trend for higher mortality in undesirable SBP groups compared to desirable SBP.

Epidrug Repurposing: Discovering New Faces of Old Acquaintances in Cancer Therapy.

Gene mutations are strongly associated with tumor progression and are well known in cancer development. However, recently discovered epigenetic alterations have shown the potential to greatly influence tumoral response to therapy regimens. Such epigenetic alterations have proven to be dynamic, and thus could be restored. Due to their reversible nature, the promising opportunity to improve chemotherapy response using epigenetic therapy has arisen. Beyond helping to understand the biology of the disease, the use of modern clinical epigenetics is being incorporated into the management of the cancer patient. Potential epidrug candidates can be found through a process known as drug repositioning or repurposing, a promising strategy for the discovery of novel potential targets in already approved drugs. At present, novel epidrug candidates have been identified in preclinical studies and some others are currently being tested in clinical trials, ready to be repositioned. This epidrug repurposing could circumvent the classic paradigm where the main focus is the development of agents with one indication only, while giving patients lower cost therapies and a novel precision medical approach to optimize treatment efficacy and reduce toxicity. This review focuses on the main approved epidrugs, and their druggable targets, that are currently being used in cancer therapy. Also, we highlight the importance of epidrug repurposing by the rediscovery of known chemical entities that may enhance epigenetic therapy in cancer, contributing to the development of precision medicine in oncology.

FAM83H-AS1 is a potential modulator of cancer driver genes across different tumors and a prognostic marker for ER/PR + BRCA patients.

Breast cancer (BRCA) is a serious public health problem, as it is the most frequent malignant tumor in women worldwide. BRCA is a molecularly heterogenic disease, particularly at gene expression (mRNAs) level. Recent evidence shows that coding RNAs represent only 34% of the total transcriptome in a human cell. The rest of the 66% of RNAs are non-coding, so we might be missing relevant biological, clinical or regulatory information. In this report, we identified nine novel tumor types from TCGA with FAM83H-AS1 deregulation. We used survival analysis to demonstrate that FAM83H-AS1 expression is a marker for poor survival in IHC-detected ER and PR positive BRCA patients and found a significant correlation between FAM83H-AS1 overexpression and tamoxifen resistance. Estrogen and Progesterone receptor expression levels interact with FAM83H-AS1 to potentiate its effect in OS prediction. FAM83H-AS1 silencing impairs two important breast cancer related pathways: cell migration and cell death. Among the most relevant potential FAM83H-AS1 gene targets, we found p63 and claudin 1 (CLDN1) to be deregulated after FAM83H-AS1 knockdown. Using correlation analysis, we show that FAM83H-AS1 can regulate a plethora of cancer-related genes across multiple tumor types, including BRCA. This evidence suggests that FAM83H-AS1 is a master regulator in different cancer types, and BRCA in particular.

Nrf2-related gene expression is impaired during a glucose challenge in type II diabetic rat hearts.

Diabetic hearts are susceptible to damage from inappropriate activation of the renin angiotensin system (RAS) and hyperglycemic events both of which contribute to increased oxidant production. Prolonged elevation of oxidants impairs mitochondrial enzyme function, further contributing to metabolic derangement. Nuclear factor erythriod-2-related factor 2 (Nrf2) induces antioxidant genes including those for glutathione (GSH) synthesis following translocation to the nucleus. We hypothesized that an acute elevation in glucose impairs Nrf2-related gene expression in diabetic hearts, while AT1 antagonism would aid in Nrf2-mediated antioxidant production and energy replenishment. We used four groups (n = 6-8/group) of 25-week-old rats: 1) LETO (lean strain-control), 2) type II diabetic OLETF, 3) OLETF + angiotensin receptor blocker (ARB; 10 mg olmesartan/kg/d × 8 wks), and 4) ARBM (4 weeks on ARB, 4 weeks off) to study the effects of acutely elevated glucose on cardiac mitochondrial function and Nrf2 signaling in the diabetic heart. Animals were gavaged with a glucose bolus (2 g/kg) and groups were dissected at T0, T180, and T360 minutes. Nrf2 mRNA was 32% lower in OLETF rats compared to LETO and remained suppressed in response to glucose. LETO Nrf2 mRNA increased 25% at T360 in response to glucose while no changes were observed in diabetic hearts. GCLC and GCLM mRNA decreased in diabetic hearts 33% and 44% respectively and remained suppressed in response to glucose while ARB treatment increased GCLM transcripts 90% at T180. These data illustrate that during T2DM and in response to glucose, cardiac Nrf2's adaptive response to environmental stressors such as glucose is impaired in diabetic hearts and that ARB treatment may aid Nrf2's impaired dynamic response.

Effect of flavonoids on antimicrobial activity of microorganisms present in dental plaque.

PURPOSE: Dental caries is a multi-factorial oral disease, requiring a susceptible host, cariogenic microorganisms and suitable substrate. Caries is extended worldwide in spite of the availability of countless prophylactic means, including fluoride toothpaste and dental sealers. Many efforts have been made to achieve isolation of pure natural products for medicinal use. Flavonoids are bioactive polyphenol compounds possessing multidimensional effects such as antibacterial action. METHODS: The present study targeted the characterization of antibacterial and antifungal activity of various flavonoids (apigenin, catechin, luteolin, morin, myricetin, naringin, quercetin and rutin). Nine strains present in dental plaque were used: Agreggatibacter actinomycetemcomitans, Actinomyces naeslundii, Actinomyces viscosus, Enterococcus faecalis, Escherichia coli, Lactobacillus casei, Staphylococcus aureus, Streptococcus oralis and Streptococcus sanguinis as well as Candida albicans fungal strain. RESULTS: Results revealed that luteolin, morin, naringin, quercetin and rutin effectively inhibited bacterial and fungal growth. However, morin was the most effective flavonoid. CONCLUSION: It might then be concluded that flavonoids show bacteriostatic effect on all of tested bacteria and fungus.

A propósito de un caso. Aspiración de material protésico / Aspiration of prosthetic material. A case report

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Tratamiento de la hipertensión arterial en octogenarios con demencia según ESC/ESH-2018: seguimiento a 3 años / Arterial hypertension treatment in octogenarians with dementia according to ESC/ESH-2018: Three-year follow-up

OBJETIVO: Determinar el control de la presión arterial sistólica (PAS) de forma retrospectiva según las recomendaciones de la guía ESC/ESH-2018 y su probable asociación con la mortalidad en pacientes octogenarios con demencia. PACIENTES Y MÉTODOS: Estudio preliminar, longitudinal, observacional y retrospectivo que incluyó 65 pacientes ≥80 años con diagnóstico de demencia e hipertensión arterial ingresados en una unidad de psicogeriatría durante 2015. Las variables principales fueron: control de la PAS según las recomendaciones de la guía ESC/ESH-2018, considerando PAS deseable (130-139mmHg), PAS no deseable (subóptima <130mmHg, elevada ≥140mmHg) y la mortalidad a 3 años en aquellos pacientes con tratamiento antihipertensivo al alta (n=53). RESULTADOS: Edad media, 86,7±4,31 años (63% mujeres); dependencia funcional severa (índice de Barthel <40): 67,7%; deterioro cognitivo grave (GDS-Riesberg ≥6): 86,3%; elevada comorbilidad: 49%; mortalidad a 3 años: 41 (63,1%). Los pacientes con hipertensión arterial y comorbilidad cardiovascular presentaron mayor prescripción de antihipertensivos (2,07 vs.1,18; p = 0,002). La mortalidad a 3 años fue menor en aquellos con PAS deseable (44,4%) respecto a PAS no deseable (72,7%), aunque no fue estadísticamente significativo. CONCLUSIONES: El porcentaje de pacientes en tratamiento con PAS subóptima fue elevado especialmente en hipertensos sin comorbilidad cardiovascular. Encontramos una tendencia a mayor mortalidad en los grupos de PAS no deseable respecto a PAS deseable

OBJECTIVE: To determine the control of systolic blood pressure (SBP) retrospectively according to the recommendations of the ESC/ESH-2018 guideline and its relationship with mortality in octogenarian patients with dementia. PATIENTS AND METHODS: Preliminary, longitudinal, observational, retrospective study, including 65 patients ≥80 years with diagnosis of dementia and arterial hypertension admitted to a psychogeriatric unit during 2015. The main variables were SBP control according to the recommendations of the ESC/ESH-2018 guideline, considering desirable SBP (130-139mmHg), undesirable SBP (suboptimal <130mmHg and elevated SBP ≥140mmHg) and mortality at 3 years in patients with antihypertensive treatment at discharge (n = 53). RESULTS: Mean age, 86.7±4.31 years (63% women); severe functional dependence (Barthel index <40): 67.7%; severe cognitive impairment (GDS-Riesberg ≥6): 86.3%; high comorbidity: 49%; mortality at 3 years: 41 (63.1%). Patients with arterial hypertension and cardiovascular comorbidity had a higher prescription of antihypertensive drugs (2.07 vs.1.18, p=.002). Three years mortality was lower in patients with desirable SBP (44.4%) versus undesirable SBP (72.7%) groups, although it was not statistically significant. CONCLUSIONS: The percentage of patients in treatment with suboptimal SBP was elevated especially in hypertensive patients without cardiovascular comorbidity. We found a trend for higher mortality in undesirable SBP groups compared to desirable SBP