Scipion-Chem: An Open Platform for Virtual Drug Screening.

Virtual drug screening (VDS) tackles the problem of drug discovery by computationally reducing the number of potential pharmacological molecules that need to be tested experimentally to find a new drug. To do so, several approaches have been developed through the years, typically focusing on either the physicochemical characteristics of the receptor structure (structure-based virtual screening) or those of the potential ligands (ligand-based virtual screening). Scipion is a workflow engine well suited for structural studies of biological macromolecules. Here, we present Scipion-chem, a new branch oriented to VDS. A total of 11 plugins have already been integrated from the most common programs used in the field. They can be used through the Scipion graphical user interface to execute and analyze typical VDS tasks. In addition, we have developed several consensus protocols that combine results from the different integrated programs to generate more robust predictions. Backstage, Scipion also facilitates the interoperability of those different software packages while tracking all of the intermediate files, parameters, and user decisions. In summary, in this article, we present Scipion-chem. This accessible, interoperable, and traceable platform provides the user with all of the tools to carry out a successful VDS workflow. Scipion-chem is openly available at https://github.com/scipion-chem.

Nuevo caso de disfunción neurológica y microdeleción 15q11.2 / Neurological dysfunction and 15q11.2 microdeletion: report of a new case

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The neurokinin-1 receptor antagonist aprepitant is a promising candidate for the treatment of breast cancer.

The substance P (SP)/neurokinin (NK)-1 receptor system plays an important role in the development of cancer. No in-depth studies of the involvement of this system in breast cancer (BC) have been carried out, and the action exerted by the drug aprepitant on BC cells is currently unknown. We show the involvement of this system in human BC cell lines: i) these cells express mRNA for the NK-1 receptor; ii) they overexpress NK-1 receptors; iii) the NK-1 receptor is involved in their viability; iv) SP induces their proliferation; v) NK-1 receptor antagonists block SP-induced mitogen stimulation of these cells; vi) the specific antitumor action of such antagonists on these cells occurs through the NK-1 receptor; and vii) BC cell death is due to apoptosis. We also found NK-1 receptors and SP in all human BC samples studied. The NK-1 receptor may be a promising target in the treatment of BC and NK-1 receptor antagonists could be candidates as a new antitumor drug in the treatment of BC.

Uveal melanoma expresses NK-1 receptors and cyclosporin A induces apoptosis in human melanoma cell lines overexpressing the NK-1 receptor.

Substance P and neurokinin-1 (NK-1) receptor antagonists respectively induce proliferation and growth inhibition in human melanoma cell lines. The presence of NK-1 receptors in human melanoma cell lines and samples has been reported, but the presence of NK-1 receptors has not been demonstrated in uveal melanomas. It is known that melanoma express the tachykinin 1 receptor (TAC1R) gene. This gene is overexpressed in several human cancer cell lines, but such overexpression is currently unknown in human malignant melanoma cell lines (COLO 858, MEL HO, COLO 679). In this study, we attempt to demonstrate the overexpression of the TAC1R gene in such cells. We performed an in vitro study by real-time quantitative RT-PCR for TAC1R and found that the NK-1 receptor was overexpressed in the three human melanoma cell lines studied. Using a knockdown method, we demonstrate that the NK-1 receptor is involved in the viability of the COLO 858 melanoma cell line. Immunohistochemistry was also used to demonstrate NK-1 receptors in uveal melanoma samples. We observed that NK-1 receptors were present in the 21/21 uveal melanomas. In addition, cyclosporin A inhibited the growth of the three melanoma cell lines studied in a dose-dependent manner, and after the administration of this immunosuppresive drug apoptosis was observed. This indicates at least that the antitumor action of cyclosporin A is mediated by the NK-1 receptor. Our findings suggest that the NK-1 receptor could be a promising target in the treatment of human melanomas.

Hepatoblastoma cells express truncated neurokinin-1 receptor and can be growth inhibited by aprepitant in vitro and in vivo.

BACKGROUND & AIMS: Multidrug resistance presents a major problem in hepatoblastoma (HB), and new anti-tumor strategies are desperately needed. The substance P (SP)/neurokinin-1 receptor (NK1R) complex has been discovered to be pivotal in the development of a variety of human cancers, and NK1R antagonists, such as the clinical drug aprepitant, are promising future anticancer agents. Yet, the role of the SP/NK1R complex as a potential anticancer target in HB is unknown. METHODS: Human HB cell lines HepT1, HepG2, and HuH6, human tumor samples from 17 children with HB as well as mice xenografted with human HB cell line HuH6 were analyzed regarding the SP/NK1R complex as a potential new anti-tumor target in HB. RESULTS: Therapeutic targeting with the NK1R antagonists aprepitant, L-733,060, and L-732,138 led to growth inhibition and apoptosis in HepT1, HepG2, and HuH6 cells in a dose-dependent manner. Intriguingly, HB cells predominantly expressed the truncated splice variant of NK1R. Human fibroblasts showed only dismal NK1R expression and were significantly more resistant. Stimulation of HB cells with SP, NK1R's natural ligand, caused increased growth rates and abrogated the anti-proliferative effect of NK1R antagonists. Expression analysis of 17 human HB samples confirmed the clinical relevance of NK1R. Most importantly, oral treatment of a HuH6 xenograft mouse model with 80mg/kg/day aprepitant for 24days resulted in a striking reduction of tumor growth, as evidenced by reduced tumor volume and weight, lowered tumor-specific alpha-fetoprotein (AFP) serum levels, and decreased number of Ki-67 positive cells. Furthermore, aprepitant treatment inhibited in vivo angiogenesis. CONCLUSIONS: For the first time, we describe the NK1R in its truncated splice variant as a potent target in human HB and an inhibitory effect in vivo and in vitro by NK1R antagonists. Therefore, NK1R antagonists should be considered promising new candidates for innovative therapeutic strategies against HB.

The substance P/neurokinin-1 receptor system in lung cancer: focus on the antitumor action of neurokinin-1 receptor antagonists.

The last decades have seen no significant progress in extending the survival of lung cancer patients and there is an urgent need to improve current therapies. The substance P (SP)/neurokinin-1 receptor (NK-1R) system plays an important role in the development of cancer: SP and NK-1R antagonists respectively induce cell proliferation and inhibition in human cancer cell lines. No study of the involvement of this system in non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) cells has been carried out in depth. Here, we demonstrate the involvement of the SP/NK-1R system in human H-69 (SCLC) and COR-L23 (NSCLC) cell lines: (1) they express isoforms of the NK-1R and mRNA for the NK-1R; (2) they overexpress the tachykinin 1 gene; (3) the NK-1R is involved in their viability; (4) SP induces their proliferation; (5) NK-1R antagonists (Aprepitant (Emend), L-733,060, L-732,138) inhibit the growth of both cell lines in a concentration-dependent manner; (6) the specific antitumor action of these antagonists against such cells occurs through the NK-1R; and (7) lung cancer cell death is due to apoptosis. We also demonstrate the presence of NK-1Rs and SP in all the human SCLC and NSCLC samples studied. Our findings indicate that the NK-1R may be a promising new target in the treatment of lung cancer and that NK-1R antagonists could be new candidate antitumor drugs in the treatment of SCLC and NSCLC.

Problemas diagnósticos en tumores del nervio periférico (II) / Diagnostic problems of peripheral nerve tumours (II)

En esta segunda parte se revisan los criterios diferenciales entre mixomas de vainas neurales y neurotekeomas, neuromas mucosos y neuromas traumáticos y las lesiones neurales pigmentadas (neurofibroma pigmentado y schwannoma pigmentado). Asimismo, se describen los criterios de malignidad en las lesiones precursoras del tumor maligno de vaina neural periférica, los distintos tipos de lesiones de células granulares y los hallazgos diferenciales más significativos de las lesiones neurales de células fusiformes que asientan en piel y tubo digestivo(AU)

In the second part of this study, the criteria for the differentiation between neural sheath myxomas and neurothekeomas, mucous neuromas and traumatic neuromas and pigmented neural lesions (pigmented neurofibroma and pigmented schwannoma) are discussed. Furthermore, the criteria for malignancy in precursor lesions of malignant peripheral nerve sheath tumours, the various types of granular cell lesions and the most significant differential findings in neural lesions with fusiform cells occurring in the skin and digestive tract are examined(AU)

Problemas diagnósticos en tumores del nervio periférico (I) / Diagnostic problems of peripheral nerve tumours (I)

Los tumores del nervio periférico son lesiones relativamente comunes que con frecuencia plantean problemas diagnósticos de marcada trascendencia. En la presente revisión se estudian de modo comparativo lesiones con nombres o con características morfológicas parecidas para poner en relieve los hallazgos diferenciales más significativos. En esta primera parte se revisan los siguientes diagnósticos: schwannoma convencional de tejidos blandos vs. neurofibroma intraneural; neurofibroma plexiforme vs. schwannoma plexiforme; schwannoma celular vs. tumor maligno de la vaina neural periférica (TMVNP); TMVNP vs. Melanoma, y TMVNP vs. sarcoma sinovial monofásico(AU)

Peripheral nerve tumours are relatively common and often pose important diagnostic problems. The present review makes a comparative study of lesions with similar names or morphological characteristics, highlighting the most significant findings. In this first part, the following diagnoses are considered: Conventional soft tissue schwannoma vs. intraneural neurofibroma; plexiform neurofibroma vs. plexiform schwannoma; cellular schwannoma vs. malignant peripheral neural sheath tumour (MPNST); MPNST vs. melanoma; and MPNST vs. monophasic synovial sarcoma(AU)

A strategy for conversion from subcutaneous to oral ketamine in cancer pain patients: effect of a 1:1 ratio.

CONTEXT: No consensus exists about the most appropriate dose ratio for conversion from parenteral to oral ketamine. OBJECTIVES: To confirm that a 1:1 dose ratio is suitable for converting subcutaneous (s.c.) to oral ketamine in cancer patients. METHODS: Patients with opioid poorly responsive cancer pain, who responded to 0.4, 0.6, or 0.8 mg s.c. ketamine bolus, were treated with 0.1, 0.15, or 0.2mg/kg/h ketamine infusion, respectively. Switching to the oral route, by applying a 1:1 dose ratio, was carried out in patients who experienced adequate pain relief and continued to need ketamine as a coanalgesic. Pain, somnolence, feelings of insobriety, confusion, and cardiovascular parameters were assessed throughout the process. RESULTS: Twenty-nine patients were enrolled in the study. Ketamine infusion decreased pain intensity from severe to no pain or slight pain in 23 of 29 and six of 29 patients, respectively. The median of s.c. ketamine doses was 0.2mg/kg/h (range 0.1-0.5). After oral switching, 27 of 29 patients remained as successfully controlled as when receiving s.c. ketamine. The other two patients needed a slight dose ratio readjustment, to 1:1.3 and 1:1.5, to maintain pain control. The median of oral ketamine doses was 300 mg/day (interquartile range 240-382.5). Seven of 29 patients receiving s.c. ketamine developed moderate and transitory side effects, such as feelings of insobriety and somnolence. No side effects were present while receiving oral ketamine. No significant changes were observed in cardiovascular parameters. CONCLUSION: A 1:1 dose ratio for conversion from s.c. to oral ketamine is safe and effective in cancer pain patients.

Temporomandibular joint synovial chondromatosis with a traumatic etiology.

Synovial chondromatosis (SC) is a metaplastic disorder characterized by the formation of cartilaginous nodules inside the articular space. SC is uncommon in the temporomandibular joint (TMJ). A few reports suggest a correlation between a traumatic episode and the development of SC. The authors describe the diagnosis, treatment and follow-up of a patient with unilateral SC of the left TMJ in conjunction with bony resorption on the mandibular condyle and a clear traumatic etiology. They review and comment on previous reports in the literature.

Neonatal fulminant type 2 infantile hepatic hemangioendothelioma involving skin, viscera and soft tissue.

We present the fulminant case of a neonate whose symptoms, lesions, imaging, and laboratory tests perfectly simulated a neonatal neuroblastoma and the definitive diagnosis was finally given by necropsy as follows: Infantile hepatic hemangioendothelioma type 2 with extrahepatic extension affecting skin, lung, intestine, suprarenal, and soft tissue.

The NK-1 receptor is expressed in human melanoma and is involved in the antitumor action of the NK-1 receptor antagonist aprepitant on melanoma cell lines.

Melanoma, the most deadly form of skin cancer, is aggressive and resistant to current therapies. It has been previously reported that the substance P and neurokinin-1 (NK-1) receptor antagonists induce cell proliferation and cell inhibition, respectively, in human melanoma cell lines. Aprepitant is a selective high-affinity antagonist of the human NK-1 receptor. Until now, this drug has been used as an anxiolytic, antidepressant and antiemetic. Moreover, the antitumor action of aprepitant has been previously reported. However, the presence of NK-1 receptors in human melanomas and whether the antitumor action of the NK-1 receptor antagonist aprepitant is exerted on human malignant melanomas have not been previously described. The aims of this study are to show the presence of NK-1 receptors in human malignant melanomas and the antitumoral action of aprepitant against several human melanoma cell lines. Immunoblot analysis was used to determine the presence of NK-1 receptors in human melanoma cell lines, and immunohistochemistry was used to demonstrate NK-1 receptors in human melanoma samples. We performed an in vitro study of the cytotoxicity of the NK-1 receptor antagonist aprepitant on human melanoma cell lines. A coulter counter was used to determine viable cell numbers, followed by application of the tetrazolium compound MTS. The DAPI method was applied to demonstrate apoptosis. We observed that NK-1 receptors were present in all the melanoma samples studied as well as in human melanoma cell lines. We also showed that melanoma cell lines expressed mRNA for the NK-1 receptor. Moreover, after using a knockdown method, we showed that NK-1 receptors are involved in the viability of tumor cells. In this study, we also report that aprepitant, at 10-60 microM concentrations, elicits cell growth inhibition in a concentration-dependent manner in all melanoma cell lines studied, that the specific antitumor action of aprepitant occurs through the NK-1 receptor and that melanoma cell death is due to apoptosis. These findings show for the first time that the NK-1 receptor may be a promising new target and that the NK-1 receptor antagonist aprepitant could be a candidate as a new antitumor drug in the treatment of human melanoma.

Linfoma primario del nervio ciático / Primary Linfoma of the sciatic nerve

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Los cuidados paliativos y el tratamiento del dolor en la solidaridad internacional / No disponible

Los cuidados paliativos (CP) y el tratamiento del dolor (TD) son elementos esenciales para mejorar o mantener la calidad de vida de muchos enfermos afectados por procesos incurables, crónicos o terminales. Su necesidad se acentúa en países con bajos y medianos recursos donde la incidencia del cáncer y de otras enfermedades como el sida va en aumento con una alta proporción de pacientes diagnosticados en fase avanzada y con un muy difícil acceso a un CP o TD adecuado a pesar de que son la única alternativa realista y humana al abandono que sufren la gran mayoría de estos enfermos. Además el perfil epidemiológico de muchos países del sur está cambiando con un aumento de enfermedades crónicas y el acceso a niveles más altos de cobertura de antirretrovirales. Para modificar esta situación, los CP y el TD deben ser incorporados por los gobiernos a sus sistemas de salud. Es también necesario que estos sean considerados una forma más de cooperación internacional. Se revisan diversos aspectos para una mayor colaboración sanitaria española en este campo con Latinoamérica y África y se sugieren vías para hacerlo a distintos niveles institucionales y asociativos (AU)

Palliative Care (PC) and pain management (PM) are key elements for improved or sustained quality of life in many patients suffering from incurable, chronic, or end-stage conditions. Their need is more critical in low- and mid-resource countries where the incidence of cancer and other diseases such as AIDS is on the rise, with a high percentage of patients diagnosed in advanced stages, and with a difficult access to adequate PC and PM despite they are the only realistic, humane option to relieve the high levels of neglect seen in a great majority of these individuals. Also, the epidemiological profile of many Southern countries is changing, with an increase in chronic conditions and access to higher antiretroviral coverage levels. To modify this situation PC and PM must be incorporated by governments into their healthcare systems. It is also necessary that PC and PM be considered an additional means of international cooperation. The various aspects required for greater Spanish cooperation with LatinAmerica and Africa in this field are reviewed, and ways towards this end are suggested at various institutional and associational levels (AU)

Cuidados paliativos y tratamiento del dolor en la solidaridad internacional / Palliative care and pain treatment: international solidarity

Los cuidados paliativos (CP) y el tratamiento del dolor (TD) son elementos esenciales para mejorar o mantener la calidad de vida de muchos enfermos afectados por procesos incurables, crónicos o terminales. Su necesidad se acentúa en países con bajos y medianos recursos donde la incidencia del cáncer y de otras enfermedades como el sida va en aumento, con una alta proporción de pacientes diagnosticados en fase avanzada y con un muy difícil acceso a unos CP o TD adecuados, a pesar de que son la única alternativa realista y humana al abandono que sufren la gran mayoría de estos enfermos. Además el perfil epidemiológico de muchos países del sur está cambiando con un aumento de enfermedades crónicas y el acceso a niveles más altos de cobertura de antirretrovirales. Para modificar esta situación, los gobiernos deben incorporar los CP y el TD en sus sistemas de salud. También es necesario que éstos se consideren una forma más de cooperación internacional. Se revisan diversos aspectos para una mayor colaboración sanitaria española en este campo con Latinoamérica y África, y se sugieren vías para hacerlo a distintos niveles institucionales y asociativos (AU)

Palliative care and pain treatment are essential to improve or maintain quality of life in many patients with incurable, chronic or terminal diseases. The need for palliative careis more pressing in countries with scarce or medium resources and where the incidence of cancer and other diseases such as AIDS is increasing. In these countries, a high proportion of patients are diagnosed in the advanced stage of the disease and access to appropriate palliative care and pain treatment is difficult, even though these options are the only realistic and human alternatives to the abandonment experienced by most of these patients. Moreover, the epidemiological profile of many southern countries is changing, with an increase of chronic diseases and access to higher levels of antiretroviral coverage. To modify this situation, governments should incorporate palliative care and pain treatment in their health systems and these options should also be seen as one more form of international cooperation. The present article reviews several factors required for greater healthcare collaboration between Spain and Latin America and Africa and suggests ways to achieve this collaboration through distinct institutions and associations (AU)

Perspectivas futuras para la autopsia clínica en los pacientes procedentes de la unidad de cuidados críticos y urgencias / Future perspectives for clinical autopsy in patients from critic and urgent care units

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