New Drug Design Avenues Targeting Alzheimer's Disease by Pharmacoinformatics-Aided Tools.

Neurodegenerative diseases (NDD) have been of great interest to scientists for a long time due to their multifactorial character. Among these pathologies, Alzheimer's disease (AD) is of special relevance, and despite the existence of approved drugs for its treatment, there is still no efficient pharmacological therapy to stop, slow, or repair neurodegeneration. Existing drugs have certain disadvantages, such as lack of efficacy and side effects. Therefore, there is a real need to discover new drugs that can deal with this problem. However, as AD is multifactorial in nature with so many physiological pathways involved, the most effective approach to modulate more than one of them in a relevant manner and without undesirable consequences is through polypharmacology. In this field, there has been significant progress in recent years in terms of pharmacoinformatics tools that allow the discovery of bioactive molecules with polypharmacological profiles without the need to spend a long time and excessive resources on complex experimental designs, making the drug design and development pipeline more efficient. In this review, we present from different perspectives how pharmacoinformatics tools can be useful when drug design programs are designed to tackle complex diseases such as AD, highlighting essential concepts, showing the relevance of artificial intelligence and new trends, as well as different databases and software with their main results, emphasizing the importance of coupling wet and dry approaches in drug design and development processes.

Susceptibility to endemic Aedes-borne viruses among pregnant women in Risaralda, Colombia.

OBJECTIVES: Aedes-borne viruses (ABV) affect humans on every inhabited continent and frequently cause epidemics. Recent epidemics of chikungunya and Zika viruses (ZIKV) highlight that preparedness for future epidemics requires assessment of susceptibility, particularly among high-risk groups. We sought to determine immunity against the three major circulating ABV among pregnant women in an ABV-endemic area of Colombia. METHODS: A cross-sectional seroprevalence study was performed, enrolling women presenting to Labor and Delivery. Cord blood and maternal peripheral blood samples were obtained. IgG seroprevalence to flaviviruses and chikungunya was determined by ELISA. An abbreviated neutralization test was used to estimate the frequency and magnitude of immunity to Zika and four dengue serotypes. Cluster analyses explored epidemiologic factors associated with seroprevalence. RESULTS: Most women exhibited high levels of neutralizing antibodies to one or more ABV; however, nearly 20% were seronegative for flaviviruses. Our research took place after the epidemic peak of the ZIKV outbreak in Colombia in 2016. However, only 20% of pregnant women had high levels of Zika-neutralizing antibodies consistent with likely protective immunity to ZIKV. CONCLUSION: Hence, a high proportion of pregnant women in Risaralda remain susceptible to one or more ABV including the teratogenic ZIKV, indicating a risk for future epidemics in this region.

Leucemia linfoblástica aguda en niños con síndrome de Down: análisis comparativo con pacientes sin síndrome de Down / Acute lymphoblastic leukemia in children with Down syndrome: Comparative analysis versus patients without Down syndrome

Introducción: Los niños con síndrome de Down (SD) tienen mayor frecuencia de leucemia linfoblástica aguda (LLA) y menor supervivencia que pacientes sin síndrome de Down (NSD). Analizamos las características clínicas, demográficas-biológicas y respuestas al tratamiento en SD-LLA versus NSD-LLA. Pacientes y métodos: Pacientes (0-19 años) con LLA desde enero de 1990 a noviembre de 2016. Se compararon características demográficas biológicas y respuestas al tratamiento con chi cuadrado y Wilcoxon rank sum. La supervivencia global y el intervalo libre de eventos (ILE) se analizaron con Kaplan-Meier y el test log-rank. Resultados: Se incluyeron 1795 pacientes, 54 con SD. Los SD-LLA presentaron edad mayor (p= 0,0189). T odos inmuno fenotipo precursor-B, con menor incidencia de anomalías recurrentes (p < 0,0001). Demostraron mejor tasa de respuesta a prednisona (p= 0,09) y mayor mortalidad en inducción y remisión completa (p < 0,0001). Todas las muertes de los SD-LLA fueron relacionadas con el tratamiento. La sobrevida libre de eventos en niños SD-LLA vs.NSD-LLA fue 47 (± 8)% vs. 73 (± 1)% (p= 0,006) y el ILE de los SD-LLA vs. NSD-LLA fue 54 (± 9)% vs. 75 (± 1)% (p= 0,0297). La tasa de recaídas fue similar en ambos grupos (p= 0,6894). El ILE de los SD-LLA fue menor en el grupo de 6-9 años: 39 (± 19)% (p= 0,7885). Conclusiones: Los niños de 6-9 años con SD-LLA años presentó menor sobrevida. Aunque estos niños presentaron una mejor respuesta temprana, la sobrevida libre de eventos e ILE fueron menores debido a la mortalidad relacionada con el tratamiento.

Introduction. Children with Down syndrome (DS) more commonly have acute lymphoblastic leukemia (ALL) and a lower survival rate than those without Down syndrome (WDS). We analyzed the clinical, demographic, and biological characteristics and treatment response of children with DS-ALL versus those WDS-ALL. Patients and methods: Patients with ALL between January 1990 and November 2016. The demographic and biologic characteristics and treatment response were compared using the χ² and Wilcoxon rank-sum tests. The overall survival and event-free interval (EFI) were analyzed using the Kaplan-Meier and log-rank tests. Results. 1795 patients were included; 54 had DS. Patients with DS-ALL were older (p= 0.0189). All had B-cell precursor immunophenotype and a lower incidence of recurrent abnormalities (p < 0.0001). They showed a better response rate to prednisone (p= 0.09) and a higher mortality in induction and complete remission (p < 0.0001). All deaths of patients with DS-ALL were treatment-related. The event-free survival (EFS) was 47% (± 8%) versus 73% (± 1%) (p= 0.006) and the EFI was 54% (± 9%) versus 75% (± 1%) (p= 0.0297) among patients with DS-ALL versus those WDS-ALL, respectively. The rate of relapse was similar in both groups (p= 0.6894). The EFI of patients with DS-ALL was lower in the group aged 6-9 years: 39% (± 19%) (p= 0.7885). Conclusions. A lower survival was observed among children aged 6-9 years with DS-ALL. Although these children showed a better early response, their EFS and EFI were lower due to treatment-related mortality.

Acute lymphoblastic leukemia in children with Down syndrome: Comparative analysis versus patients without Down syndrome. / Leucemia linfoblástica aguda en niños con síndrome de Down: análisis comparativo con pacientes sin síndrome de Down.

INTRODUCTION: Children with Down syndrome (DS) more commonly have acute lymphoblastic leukemia (ALL) and a lower survival rate than those without Down syndrome (WDS). We analyzed the clinical, demographic, and biological characteristics and treatment response of children with DS-ALL versus those WDS-ALL. Patients and methods: Patients with ALL between January 1990 and November 2016. The demographic and biologic characteristics and treatment response were compared using the χ² and Wilcoxon rank-sum tests. The overall survival and event-free interval (EFI) were analyzed using the Kaplan-Meier and log-rank tests. RESULTS: 1795 patients were included; 54 had DS. Patients with DS-ALL were older (p= 0.0189). All had B-cell precursor immunophenotype and a lower incidence of recurrent abnormalities (p < 0.0001). They showed a better response rate to prednisone (p= 0.09) and a higher mortality in induction and complete remission (p < 0.0001). All deaths of patients with DS-ALL were treatment-related. The event-free survival (EFS) was 47% (± 8%) versus 73% (± 1%) (p= 0.006) and the EFI was 54% (± 9%) versus 75% (± 1%) (p= 0.0297) among patients with DS-ALL versus those WDS-ALL, respectively. The rate of relapse was similar in both groups (p= 0.6894). The EFI of patients with DS-ALL was lower in the group aged 6-9 years: 39% (± 19%) (p= 0.7885). CONCLUSIONS: A lower survival was observed among children aged 6-9 years with DS-ALL. Although these children showed a better early response, their EFS and EFI were lower due to treatment-related mortality.

Introducción: Los niños con síndrome de Down (SD) tienen mayor frecuencia de leucemia linfoblástica aguda (LLA) y menor supervivencia que pacientes sin síndrome de Down (NSD). Analizamos las características clínicas, demográficas-biológicas y respuestas al tratamiento en SD-LLA versus NSD-LLA. Pacientes y métodos: Pacientes (0-19 años) con LLA desde enero de 1990 a noviembre de 2016. Se compararon características demográficas biológicas y respuestas al tratamiento con chi cuadrado y Wilcoxon rank sum. La supervivencia global y el intervalo libre de eventos (ILE) se analizaron con Kaplan-Meier y el test log-rank. Resultados: Se incluyeron 1795 pacientes, 54 con SD. Los SD-LLA presentaron edad mayor (p= 0,0189). Todos inmuno fenotipo precursor-B, con menor incidencia de anomalías recurrentes (p < 0,0001). Demostraron mejor tasa de respuesta a prednisona (p= 0,09) y mayor mortalidad en inducción y remisión completa (p < 0,0001). Todas las muertes de los SD-LLA fueron relacionadas con el tratamiento. La sobrevida libre de eventos en niños SD-LLA vs.NSD-LLA fue 47 (± 8)% vs. 73 (± 1)% (p= 0,006) y el ILE de los SD-LLA vs. NSD-LLA fue 54 (± 9)% vs. 75 (± 1)% (p= 0,0297). La tasa de recaídas fue similar en ambos grupos (p= 0,6894). El ILE de los SD-LLA fue menor en el grupo de 6-9 años: 39 (± 19)% (p= 0,7885). Conclusiones: Los niños de 6-9 años con SD-LLA años presentó menor sobrevida. Aunque estos niños presentaron una mejor respuesta temprana, la sobrevida libre de eventos e ILE fueron menores debido a la mortalidad relacionada con el tratamiento.

Acute and sub-acute neurological toxicity in children treated for acute lymphoblastic leukemia.

Eighty percent of children with acute lymphoblastic leukemia (ALL) survive with current treatments. Neurotoxicity is an infrequent adverse event. We describe clinical presentations of neurological toxicity, phases of treatment when these adverse events were more frequent and patients ́ outcome. From January-1995 to December-2015, 1379 ALL cases were admitted. Neurotoxicity was diagnosed in 49 patients (3.6%) and classified according to neurological syndromes. Medical records, laboratory-tests and images were reviewed. The diagnosed syndromes were: a) Methotrexate-leukoencephalopathy (MLE) (35.4%); b) Cerebral-venous-sinus thrombosis following L-Asparaginase administration (26.5%); c) Vincristine-induced-vocal-cord paralysis (VVCP) (14.2%); d) Stroke-associated vasospasm (14%), after high-dose methotrexate e) Severe polyneuropathy (6.1%); f) Methotrexate myelopathy (2%); and g) Pseudotumor-cerebri (2%) associated with corticosteroid therapy. Neurotoxicity was diagnosed during induction in 55% of cases. We conclude that MLE was the most frequent syndrome. VVCP was observed in infants and Down patients. Seizure was the most common symptom and toxicity occurred mainly during induction phase.

Children and Adolescent Hodgkin Lymphoma in Argentina: Long-term Results After Combined ABVD and Restricted Radiotherapy.

OBJECTIVE: Prospective analysis of clinical characteristics and long-term treatment results of a pediatric cohort with Hodgkin lymphoma (HL) treated in a single institution with ABVD and restricted radiotherapy (RT). PATIENTS AND METHODS: Between September 2000 and December 2015, 165 new consecutive assessable patients with HL were registered at our institution. Lymphocyte predominant nodular HL was excluded. Low risk (LR) patients were stage I and IIA (no bulky disease, <4 involved ganglionar areas and no lung hilar nodes), high risk (HR) was assigned to stage IV and any other stage with bulky mediastinum. The rest of the cohort was treated as intermediate risk (IR). Chemotherapy for LR and IR patients was 4 and 6 courses of ABVD regimen, respectively. These subsets received Low-dose involved field radiotherapy only in case of partial remission at the end of chemotherapy (21 Gy in initially involved areas, plus 14 Gy boost on residual disease). The HR group was treated with 6 courses of ABVD followed always with 21 Gy involved field radiotherapy if complete remission (CR) was achieved. A boost of 14 Gy was added to residual disease in case of partial remission. RESULTS: Median age was 10.6 years (range, 2.7 to 17 y). Males: 117 (71%); females: 48 (29%). Eighteen (11%) patients were stage I, 76 (46%) stage II, 35 (21%) stage III, and 35 (21%) stage IV. Forty-nine (30%) patients were assigned to LR, 49 (30%) to IR, and 67 (40%) to HR. Forty-three patients (26%) had "bulky" mediastinum involvement. One hundred thirty (79%) patients achieved CR after chemotherapy and 161 (98%) after RT. Four patients (all HR), did not respond to initial therapy and died of disease. One patient died in first CR due to adenovirus infection on previously therapy-related damaged lungs. Seventeen (10%) patients relapsed and 13 of them remained in second CR after further therapy. Seventy-six (46%) patients could be spared from RT and cured of disease (88% of LR patients and 67% of IR patients). With a median follow-up of 5 years, event free and overall survival were 0.84 (SE: 0.03) and 0.95 (SE: 0.02), respectively. Overall survival according to risk group was 1 for LR, 0.93 for IR, and 0.85 for HR. Acute toxicity and late effects due to therapy were not significant. CONCLUSIONS: The strategy of avoiding RT for LR and IR patients that responded completely to ABVD chemotherapy achieved very good results. For the HR group, the combination of 6 cycles of ABVD and Low-dose involved field radiotherapy was efficacious with similar good results. Nearly half of the patients could be cured without RT.

Second Neoplasms in Children Following a Treatment for Acute Leukemia and/or Lymphoma: 29 Years of Experience in a Single Institution in Argentina.

INTRODUCTION: Childhood acute leukemias (AL) and lymphomas achieve good survival rates. However, second neoplasms (SN) are a devastating event. METHODS: From August 1987 to December 2016, 34 of 3321 (1%) patients with diagnosis of AL or lymphoma developed SN. SN were AL (n=16), CNS tumors (n=5), endocrinal tumors (n=3), lymphomas (n=2), schwannoma (n=2) assorted sarcomas (n=4), retinal melanoma (n=1), and Vanek tumor (n=1). Median latency was 51 (range, 10 to 110) months for hematological malignancies and 119 (range, 25 to 236) months for solid tumors (P=0.001). RESULTS: A total of 33 patients with SN were treated taking into account cumulative doses of anthracyclines and radiotherapy. Twenty-three (67.6%) patients achieved complete remission (CR), 5 died early during therapy and 5 were refractory or partial responders. Six patients presented relapses of the SN and 1 died in CR. Seventeen patients remain alive in CR, with a median follow-up of 110 (range, 4 to 276) months. CONCLUSIONS: (1) The latency period was significantly longer for patients developing solid tumors than for those developing AL. (2) AL was the most frequent SN. (3) Our results strongly encourage giving standard therapy to SN, considering cumulative doses of previous treatment, since similar probabilities of surviving as "de novo" counterparts can be achieved.

Intra-arterial chemotherapy is more effective than sequential periocular and intravenous chemotherapy as salvage treatment for relapsed retinoblastoma.

BACKGROUND: Treatment of eyes with retinoblastoma failing systemic chemoreduction and external beam radiotherapy is seldom efficacious. This study compares the efficacy and toxicity of intra-arterial ophthalmic artery chemotherapy (IAO) to our historical cohort of sequential periocular and systemic chemotherapy in such patients. PATIENTS AND METHODS: Eighteen eyes (15 consecutive patients) were retrospectively evaluated. Eight eyes received IAO for a median of four cycles (range: 2-9) including melphalan alone (n = 3) or after topotecan and carboplatin (n = 4) or topotecan and carboplatin without melphalan (n = 1). Ten eyes received a median of two cycles (range: 1-3) of periocular topotecan (n = 9) or carboplatin (n = 1) followed by intravenous topotecan and cyclophosphamide in three patients if at least stable disease was achieved. Both groups were comparable for disease extension and prior therapy. RESULTS: No extraocular dissemination or second malignancy occurred and all patients are alive. The probability of enucleation-free eye survival at 12 months was 0.87 (95% CI: 0.42-0.97) for the IAO group, compared to 0.1 (95% CI: 0.06-0.35) for the periocular group (P < 0.01). Ocular toxicity was mild and similar in both groups (mostly mild orbital edema). Systemic toxicity was low for IAO and periocular injection, but children who received sequentially intravenous chemotherapy (n = 12 cycles) had five episodes of grade 4 neutropenia, three of which resulted in hospitalizations. No case in the IAO group presented these complications. CONCLUSIONS: IAO is significantly superior to sequential periocular-intravenous topotecan-containing regimens in eyes with relapsed intraocular retinoblastoma with a more favorable toxicity profile.