Novel Titanocene Y derivative with albumin affinity exhibits improved anticancer activity against platinum resistant cells.

The antitumor activity of Ti(IV)-based compounds put them in the spotlight for cancer treatment in the past, but their lack of stability in vivo due to a high rate of hydrolysis has hindered their development as antitumor drugs. As a possible solution for this problem, we have reported a synthesis strategy through which we combined a titanocene fragment, a tridentate ligand, and a long aliphatic chain. This strategy allowed us to generate a titanium compound (Myr-Ti) capable of interacting with albumin, highly stable in water and with cytotoxic activity in tumor cells[1]. Following a similar strategy, now we report the synthesis of a new compound (Myr-TiY) derived from titanocene Y that shows antitumoral activity in a cisplatin resistant model with a 50% inhibitory concentration (IC50) of 41-76 µM. This new compound shows high stability and a strong interaction with human serum albumin. Myr-TiY has a significant antiproliferative and proapoptotic effect on the tested cancer cells and shows potential tumor selectivity when assayed in non-tumor human epithelial cells being more selective (1.3-3.8 times) for tumor cells than cisplatin. These results lead us to think that the described synthesis strategy could be useful to generate compounds for the treatment of both cisplatin-sensitive and cisplatin-resistant cancers.

Biological evaluation of carbohydrate-based aprepitant analogs for neuroblastoma treatment.

Different studies using Aprepitant, a NK1R antagonist currently used as a clinical drug for treating chemotherapy-related nausea and vomiting, have demonstrated that pharmacological inhibition of NK1R effectively reduces the growth of several tumor types such as neuroblastoma (NB). In a previous work, we demonstrated that a series of carbohydrate-based Aprepitant analogs, derived from either d-galactose or l-arabinose, have shown high affinity and NK1R antagonistic activity with a broad-spectrum anticancer activity and an important selectivity. In this new study, we explore the selective cytotoxic effects of these derivatives for the treatment of NB. Furthermore, we describe the design and stereoselective synthesis of a new generation of d-glucose derivatives as Aprepitant analogs, supported by docking studies. This approach showed that most of our carbohydrate-based analogs are significantly more selective than Aprepitant. The galactosyl derivative 2α, has demonstrated a marked in vitro selective cytotoxic activity against NB, with IC50 values in the same range as those of Aprepitant and its prodrug Fosaprepitant. Interestingly, the derivative 2α has shown similar apoptotic effect to that of Aprepitant. Moreover, we can select the glucosyl amino derivative 10α as an interesting hit exhibiting higher in vitro cytotoxic activity against NB than Aprepitant, being 1.2 times more selective.

New titanocene derivative with improved stability and binding ability to albumin exhibits high anticancer activity.

Titanium-based therapies have emerged as a promising alternative for the treatment of cancer patients, particularly those with cisplatin resistant tumors. Unfortunately, some titanium compounds show stability and solubility problems that have hindered their use in clinical practice. Here, we designed and synthesized a new titanium complex containing a titanocene fragment, a tridentate ligand to improve its stability in water, and a long aliphatic chain, designed to facilitate a non-covalent interaction with albumin, the most abundant protein in human serum. The stability and human serum albumin affinity of the resulting titanium complex was investigated by UV-Vis absorption and fluorescence spectroscopy techniques. Complex [TiCp2{(OOC)2py-O-myr}] (3) (myr = C14H29, py = pyridine) and its analogous [TiCp2{(OOC)2py-OH}] (4), lacking the aliphatic chain, showed improved stability in phosphate saline buffer compared with [TiCp2Cl2] (1). 3 showed a strong interaction with human serum albumin in a 1:1 stoichiometry. The cytotoxic effect of 3 was higher compared to [TiCp2Cl2] in tumor cell lines and showed potential tumor selectivity when assayed in non-tumor human epithelial cells. Finally, 3 showed an antiproliferative effect on cancer cells, decreasing the population in the S phase, and increasing apoptotic cells in a significant manner. All this makes the novel Ti(IV) compound 3 a firm candidate to continue further studies of its therapeutic potential in vitro and in vivo.

Music Therapy in the Treatment of Dementia: A Systematic Review and Meta-Analysis.

Background: Dementia is a neurological condition characterized by deterioration in cognitive, behavioral, social, and emotional functions. Pharmacological interventions are available but have limited effect in treating many of the disease's features. Several studies have proposed therapy with music as a possible strategy to slow down cognitive decline and behavioral changes associated with aging in combination with the pharmacological therapy. Objective: We performed a systematic review and subsequent meta-analysis to check whether the application of music therapy in people living with dementia has an effect on cognitive function, quality of life, and/or depressive state. Methods: The databases used were Medline, PubMed Central, Embase, PsycINFO, and the Cochrane Library. The search was made up of all the literature until present. For the search, key terms, such as "music," "brain," "dementia," or "clinical trial," were used. Results: Finally, a total of eight studies were included. All the studies have an acceptable quality based on the score on the Physiotherapy Evidence Database (PEDro) and Critical Appraisal Skills Program (CASP) scales. After meta-analysis, it was shown that the intervention with music improves cognitive function in people living with dementia, as well as quality of life after the intervention and long-term depression. Nevertheless, no evidence was shown of improvement of quality of life in long-term and short-term depression. Conclusion: Based on our results, music could be a powerful treatment strategy. However, it is necessary to develop clinical trials aimed to design standardized protocols depending on the nature or stage of dementia so that they can be applied together with current cognitive-behavioral and pharmacological therapies.

Usos diversos de los epónimos en Medicina / Various uses of eponyms in Medicine

Los epónimos vienen siendo utilizados desde hace siglos. Su uso habitual constituye una de las características del lenguaje de las ciencias médicas y está extendido a todas las especialidades, formando parte de su cultura y de la historia de la Medicina. Se abordan los epónimos en el campo de varias especialidades médicas, así como el debate científico a favor y en contra de su uso, considerando que no son pocas las voces que apoyan su erradicación total; esto es algo que todavía resulta difícil pensar, ya que se cree que los epónimos aportan más de lo que podrían ofrecer otros recursos lingüísticos. Se reconoce la existencia de epónimos cubanos, que no se han estudiado lo suficiente (AU).

Eponyms have been used during centuries. Their common use is one of the characteristics of the medical sciences language, reaches all the specialties, and is part of the Medicine culture and history. The use of eponyms in the field of several medical specialties is approached and also the scientific dispute in favor or against their use, taking into consideration that no few voices back their total eradication; it is still something difficult to understand because it is believed that eponyms are more fruitful than what is offered by other linguistic resources. The existence of Cuban eponyms that are still not sufficiently studied is recognized (AU).

Usos diversos de los epónimos en Medicina / Various uses of eponyms in Medicine

Los epónimos vienen siendo utilizados desde hace siglos. Su uso habitual constituye una de las características del lenguaje de las ciencias médicas y está extendido a todas las especialidades, formando parte de su cultura y de la historia de la Medicina. Se abordan los epónimos en el campo de varias especialidades médicas, así como el debate científico a favor y en contra de su uso, considerando que no son pocas las voces que apoyan su erradicación total; esto es algo que todavía resulta difícil pensar, ya que se cree que los epónimos aportan más de lo que podrían ofrecer otros recursos lingüísticos. Se reconoce la existencia de epónimos cubanos, que no se han estudiado lo suficiente (AU).

Eponyms have been used during centuries. Their common use is one of the characteristics of the medical sciences language, reaches all the specialties, and is part of the Medicine culture and history. The use of eponyms in the field of several medical specialties is approached and also the scientific dispute in favor or against their use, taking into consideration that no few voices back their total eradication; it is still something difficult to understand because it is believed that eponyms are more fruitful than what is offered by other linguistic resources. The existence of Cuban eponyms that are still not sufficiently studied is recognized (AU).

La familia homoparental en la realidad y la diversidad familiar actual / Homoparental family in real life and current family diversity

Son muchas las definiciones de familia desde algunas clásicas como que es "la célula o núcleo básico de la sociedad, la institución social primaria, un subsistema social o una relación social", hasta otras más complejas que, la consideran un grupo de personas relacionadas entre sí y que viven juntas. La familia es el grupo de intermediación entre el individuo, la comunidad y la sociedad. Es la familia, a pesar de las grandes transformaciones del mundo contemporáneo, hábitat natural del ser humano. En el presente siglo XXI, la familia se diversifica estructuralmente y una de las variantes de familia nuclear, puede ser las homoparentales, las cuales, están formadas por padres con orientación sexual homosexual; y si bien no se trata de un fenómeno nuevo, es en la actualidad donde se vive una intensa aceleración a partir del reconocimiento legal del matrimonio entre personas del mismo sexo en muchas naciones. Las familias homoparentales están capacitadas para educar y criar satisfactoriamente a sus hijos e hijas. La orientación sexual de los progenitores, no es un indicador que sirva para evaluar la función educadora de los padres y madres. Padres e hijos de las familias homoparentales, deben apropiarse de elementos resilientes, que les permitan crecerse, ante cualquier manifestación social, potencialmente negativa hacia ellos (AU).

There are many definitions of a family, from some classic ones like that saying that it is ". the basic cell or nucleus of the society, the primary social institution, a social sub-system and a social relation", to others, more complexes, considering it a group of inter-related persons living together. The family is the intermediary group between the individual, community and society. It is, despite the great transformation of the contemporary world, the natural habitat of the human being. In the current century, the family gets structurally diverse, and one of the variants of the nuclear family may be the homoparental one, that is formed by parents with homosexual sexual orientation. Although it is not a new phenomenon, it is nowadays when it is having an intense acceleration beginning from the legal recognition of the marriage between persons of the same sex in many nations. Homoparental families are able to educate and grow their children up satisfactorily. Parents´ sexual orientation is not an indicator useful to assess the educative function of the parents. Parents and children of homoparental families should incorporate resilient elements allowing affronting any potentially negative social manifestation against them (AU).

La familia homoparental en la realidad y la diversidad familiar actual / Homoparental family in real life and current family diversity

Son muchas las definiciones de familia desde algunas clásicas como que es "la célula o núcleo básico de la sociedad, la institución social primaria, un subsistema social o una relación social", hasta otras más complejas que, la consideran un grupo de personas relacionadas entre sí y que viven juntas. La familia es el grupo de intermediación entre el individuo, la comunidad y la sociedad. Es la familia, a pesar de las grandes transformaciones del mundo contemporáneo, hábitat natural del ser humano. En el presente siglo XXI, la familia se diversifica estructuralmente y una de las variantes de familia nuclear, puede ser las homoparentales, las cuales, están formadas por padres con orientación sexual homosexual; y si bien no se trata de un fenómeno nuevo, es en la actualidad donde se vive una intensa aceleración a partir del reconocimiento legal del matrimonio entre personas del mismo sexo en muchas naciones. Las familias homoparentales están capacitadas para educar y criar satisfactoriamente a sus hijos e hijas. La orientación sexual de los progenitores, no es un indicador que sirva para evaluar la función educadora de los padres y madres. Padres e hijos de las familias homoparentales, deben apropiarse de elementos resilientes, que les permitan crecerse, ante cualquier manifestación social, potencialmente negativa hacia ellos (AU).

There are many definitions of a family, from some classic ones like that saying that it is ". the basic cell or nucleus of the society, the primary social institution, a social sub-system and a social relation", to others, more complexes, considering it a group of inter-related persons living together. The family is the intermediary group between the individual, community and society. It is, despite the great transformation of the contemporary world, the natural habitat of the human being. In the current century, the family gets structurally diverse, and one of the variants of the nuclear family may be the homoparental one, that is formed by parents with homosexual sexual orientation. Although it is not a new phenomenon, it is nowadays when it is having an intense acceleration beginning from the legal recognition of the marriage between persons of the same sex in many nations. Homoparental families are able to educate and grow their children up satisfactorily. Parents´ sexual orientation is not an indicator useful to assess the educative function of the parents. Parents and children of homoparental families should incorporate resilient elements allowing affronting any potentially negative social manifestation against them (AU).

Wnt/ß-catenin pathway regulates MGMT gene expression in cancer and inhibition of Wnt signalling prevents chemoresistance.

The DNA repair enzyme O6-methylguanine-DNA methyltransferase (MGMT) is commonly overexpressed in cancers and is implicated in the development of chemoresistance. The use of drugs inhibiting MGMT has been hindered by their haematologic toxicity and inefficiency. As a different strategy to inhibit MGMT we investigated cellular regulators of MGMT expression in multiple cancers. Here we show a significant correlation between Wnt signalling and MGMT expression in cancers with different origin and confirm the findings by bioinformatic analysis and immunofluorescence. We demonstrate Wnt-dependent MGMT gene expression and cellular co-localization between active ß-catenin and MGMT. Pharmacological or genetic inhibition of Wnt activity downregulates MGMT expression and restores chemosensitivity of DNA-alkylating drugs in mouse models. These findings have potential therapeutic implications for chemoresistant cancers, especially of brain tumours where the use of temozolomide is frequently used in treatment.

Effects of epigenetic modificators in combination with small molecule inhibitors of receptor tyrosine kinases on medulloblastoma growth.

Epigenetic alterations and aberrant expression of genes controlling epigenetic mechanisms have been identified in several cancers, including medulloblastoma, the most common brain tumor in children. Here we show that combining drugs that inhibit two of the most important epigenetic factors, gene methylation and post-translational modifications of protein histone-associated DNA, with small molecule inhibitors of receptor tyrosine kinases induces apoptosis. The histone deacetylation inhibitor, 4-phenylbutyrate (4-PB) and the demethylation agent, 5-Aza-2'deoxycytidine (5-Aza-dC) had minor effects on medulloblastoma cell cytotoxity in single agent treatment whereas a significant enhancement in cell cytotoxity was seen when these drugs were combined with Gleevec. Triple treatment of medulloblastoma cells with 4-PB, 5-Aza and Gleevec were associated with reduced DNA methyltransferase activity, reduced global methylation and induction of apoptosis. Taken together these results suggest that a combination of these drugs may be beneficial in the treatment of medulloblastoma.

Sunitinib suppress neuroblastoma growth through degradation of MYCN and inhibition of angiogenesis.

Neuroblastoma, a tumor of the peripheral sympathetic nervous system, is the most common and deadly extracranial tumor of childhood. The majority of high-risk neuroblastoma exhibit amplification of the MYCN proto-oncogene and increased neoangiogenesis. Both MYCN protein stabilization and angiogenesis are regulated by signaling through receptor tyrosine kinases (RTKs). Therefore, inhibitors of RTKs have a potential as a treatment option for high-risk neuroblastoma. We used receptor tyrosine kinase antibody arrays to profile the activity of membrane-bound RTKs in neuroblastoma and found the multi-RTK inhibitor sunitinib to tailor the activation of RTKs in neuroblastoma cells. Sunitinib inhibited several RTKs and demonstrated potent antitumor activity on neuroblastoma cells, through induction of apoptosis and cell cycle arrest. Treatment with sunitinib decreased MYCN protein levels by inhibition of PI3K/AKT signaling and GSK3ß. This effect correlates with a decrease in VEGF secretion in neuroblastoma cells with MYCN amplification. Sunitinib significantly inhibited the growth of established, subcutaneous MYCN-amplified neuroblastoma xenografts in nude mice and demonstrated an anti-angiogenic effect in vivo with a reduction of tumor vasculature and a decrease of MYCN expression. These results suggest that sunitinib should be tested as a treatment option for high risk neuroblastoma patients.

An update on the biology of cancer stem cells in breast cancer.

Breast cancer stem cells are defined as cancer cells with self-renewal capacity. These cells represent a small subpopulation endowed with the ability to form new tumours when injected in nude mice. Markers of differentiation have been used to identify these cancer cells. In the case of breast cancer, CD44+/CD24- select a population with stem cell properties. The fact that these cells have self-renewal ability has suggested that this population could be responsible for new tumour formation and cancer relapse. These cells have been shown to be more resistant to chemotherapy and radiotherapy than normal cancer cells. The identification of the molecular druggable alterations responsible for the initiation and maintenance of cancer stem cells is an important goal. In this article we will review all these points with special emphasis on the possible role of new drugs designed to interact with molecular pathways of cancer stem cells.