Drug design of novel molecules using a bioisosteric and de novo techniques - a comparison

Rational drug design is an area of science that evolves continuously in order to answer contemporary demands for a decrease in novel drug discovery turnover time. Multiple drug design modalities exist which may be exploited in response to the parameters of specific drug design projects. Bioisosteric modification of existing molecules and de novo design are two such approaches, both of which were employed in parallel in this study which aimed to compare their scope and efficiency using Tricyclic Antidepressants (TCAs) and Selective Serotonin Reuptake Inhibiting (SSRIs) molecules as case studies. Results indicated that bioisosterically modified structures did not have a higher affinity for their cognate receptor when compared to the template structure while the de novo design yielded molecules that were markedly different to the template from a structural perspective, and which also bound to the cognate receptor with an affinity superior to that of the template. This study showed therefore that bioisosteric modification is of utility when minor structural variations are considered sufficiently relative to a template molecule, and could consequently be of utility in the acquisition of new patents, in the reduction of toxicity, or in the attainment of improved biological profiles. It indicated furthermore, the role of the de novo approach in the successful exploration of novel pharmacophoric space and in the generation of molecular structures with an affinity significantly greater than that of lead molecules for a target receptor.peer-reviewe

The histology of ovarian cancer: worldwide distribution and implications for international survival comparisons (CONCORD-2)

Objective Ovarian cancers comprise several histologically distinct tumour groups with widely different prognosis. We aimed to describe the worldwide distribution of ovarian cancer histology and to understand what role this may play in international variation in survival. Methods The CONCORD programme is the largest population-based study of global trends in cancer survival. Data on 681,759 women diagnosed during 1995â\u80\u932009 with cancer of the ovary, fallopian tube, peritoneum and retroperitonum in 51 countries were included. We categorised ovarian tumours into six histological groups, and explored the worldwide distribution of histology. Results During 2005â\u80\u932009, type II epithelial tumours were the most common. The proportion was much higher in Oceania (73.1%), North America (73.0%) and Europe (72.6%) than in Central and South America (65.7%) and Asia (56.1%). By contrast, type I epithelial tumours were more common in Asia (32.5%), compared with only 19.4% in North America. From 1995 to 2009, the proportion of type II epithelial tumours increased from 68.6% to 71.1%, while the proportion of type I epithelial tumours fell from 23.8% to 21.2%. The proportions of germ cell tumours, sex cord-stromal tumours, other specific non-epithelial tumours and tumours of non-specific morphology all remained stable over time. Conclusions The distribution of ovarian cancer histology varies widely worldwide. Type I epithelial, germ cell and sex cord-stromal tumours are generally associated with higher survival than type II tumours, so the proportion of these tumours may influence survival estimates for all ovarian cancers combined. The distribution of histological groups should be considered when comparing survival between countries and regions

Worldwide comparison of survival from childhood leukaemia for 1995–2009, by subtype, age, and sex (CONCORD-2): a population-based study of individual data for 89 828 children from 198 registries in 53 countries

Background Global inequalities in access to health care are reflected in differences in cancer survival. The CONCORD programme was designed to assess worldwide differences and trends in population-based cancer survival. In this population-based study, we aimed to estimate survival inequalities globally for several subtypes of childhood leukaemia. Methods Cancer registries participating in CONCORD were asked to submit tumour registrations for all children aged 0-14 years who were diagnosed with leukaemia between Jan 1, 1995, and Dec 31, 2009, and followed up until Dec 31, 2009. Haematological malignancies were defined by morphology codes in the International Classification of Diseases for Oncology, third revision. We excluded data from registries from which the data were judged to be less reliable, or included only lymphomas, and data from countries in which data for fewer than ten children were available for analysis. We also excluded records because of a missing date of birth, diagnosis, or last known vital status. We estimated 5-year net survival (ie, the probability of surviving at least 5 years after diagnosis, after controlling for deaths from other causes [background mortality]) for children by calendar period of diagnosis (1995-99, 2000-04, and 2005-09), sex, and age at diagnosis (< 1, 1-4, 5-9, and 10-14 years, inclusive) using appropriate life tables. We estimated age-standardised net survival for international comparison of survival trends for precursor-cell acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML). Findings We analysed data from 89 828 children from 198 registries in 53 countries. During 1995-99, 5-year agestandardised net survival for all lymphoid leukaemias combined ranged from 10.6% (95% CI 3.1-18.2) in the Chinese registries to 86.8% (81.6-92.0) in Austria. International differences in 5-year survival for childhood leukaemia were still large as recently as 2005-09, when age-standardised survival for lymphoid leukaemias ranged from 52.4% (95% CI 42.8-61.9) in Cali, Colombia, to 91.6% (89.5-93.6) in the German registries, and for AML ranged from 33.3% (18.9-47.7) in Bulgaria to 78.2% (72.0-84.3) in German registries. Survival from precursor-cell ALL was very close to that of all lymphoid leukaemias combined, with similar variation. In most countries, survival from AML improved more than survival from ALL between 2000-04 and 2005-09. Survival for each type of leukaemia varied markedly with age: survival was highest for children aged 1-4 and 5-9 years, and lowest for infants (younger than 1 year). There was no systematic difference in survival between boys and girls. Interpretation Global inequalities in survival from childhood leukaemia have narrowed with time but remain very wide for both ALL and AML. These results provide useful information for health policy makers on the effectiveness of health-care systems and for cancer policy makers to reduce inequalities in childhood survival

Avaliação radiográfica da localização de caninos superiores não irrompidos Radiographic evaluation of localization for non-erupted upper canines

A erupção ectópica e a impacção de caninos superiores são problemas bastante comuns na população. A excelência do tratamento ortod��ntico traduz-se na correção da oclusão, harmonia do sorriso, saúde periodontal e estabilidade pós-tratamento. Para obtermos tais condições, a manutenção dos caninos é fundamental. Portanto, o objetivo deste estudo foi avaliar radiograficamente a localização de caninos superiores não irrompidos utilizando-se radiografias panorâmicas. Foram selecionadas setenta radiografias panorâmicas de pacientes com impacção uni ou bilateral de caninos, candidatos a tratamento cirúrgico. Para determinação da posição espacial dos caninos superiores não irrompidos foram selecionados métodos descritos na literatura e uma avaliação proposta neste trabalho. A localização de caninos não irrompidos é fundamental para estabelecer o plano de tratamento, auxiliando no acesso cirúrgico e na direção das forças ortodônticas a serem aplicadas no dente impactado. Os pacientes que tiveram suas radiografias utilizadas neste estudo serão tratados pelas disciplinas de Ortodontia e Cirurgia, com exodontia do canino ou exposição cirúrgica para colagem do dispositivo de tracionamento associada ao tratamento ortodôntico corretivo.<br>Ectopic eruption and the impaction of upper canines are problems quite commonly presented by the population. An excellent orthodontic treatment encompasses occlusal correction, smile harmony, periodontal health and posttreatment stability. Such conditions can be obtained upon the due maintenance of the canines, therefore, the aim of this study is to assess the radiographic localization of non-erupted upper canines using panoramic radiographs. In this study, seventy panoramic radiographs of patients presented with uni or bilateral canine impaction, applying for surgical treatment, were selected. Methods described in the literature and an evaluation proposed in this work were chosen to determine the spatial position for non-erupted upper canines. The localization of non-erupted canines is fundamental to establish the treatment plan, aiding in the surgical access and in the direction of orthodontic forces to be applied on the impacted tooth. The patients whose radiographs were utilized in this study will be treated at the Orthodontics and Surgery Departments, by means of surgeries for canine exodontics or surgical exposure for the bonding of a wire traction device, associated with corrective orthodontic treatment

Reasons for low cervical cancer survival in new accession European Union countries: a EUROCARE-5 study

Purpose: With better access to early diagnosis and appropriate treatment, cervical cancer (CC) burden decreased in several European countries. In Eastern European (EE) countries, which accessed European Union in 2004, CC survival was worse than in the rest of Europe. The present study investigates CC survival differences across five European regions, considering stage at diagnosis (local, regional and metastatic), morphology (mainly squamous versus glandular tumours) and patients’ age. Methods: We analysed 101,714 CC women diagnosed in 2000–2007 and followed-up to December 2008. Age-standardised 5-year relative survival (RS) and the excess risks of cancer death in the 5&nbsp;years after diagnosis were computed. Results: EE women were older and less commonly diagnosed with glandular tumours. Proportions of local stage cancers were similar across Europe, while morphology- and stage-specific RS (especially for non-metastatic disease) were lower in Eastern Europe. Adjusting for age and morphology, excess risk of local stage CC death for EE patients remained higher than that for other European women. Conclusion: Stage, age and morphology alone do not explain worse survival in Eastern Europe: less effective care may play a role, probably partly due to fewer or inadequate resources being allocated to health care in this area, compared to the rest of Europe

Worldwide comparison of survival from childhood leukaemia for 1995\u20132009, by subtype, age, and sex (CONCORD-2): a population-based study of individual data for 89\u2008828 children from 198 registries in 53 countries

Background Global inequalities in access to health care are reflected in differences in cancer survival. The CONCORD programme was designed to assess worldwide differences and trends in population-based cancer survival. In this population-based study, we aimed to estimate survival inequalities globally for several subtypes of childhood leukaemia. Methods Cancer registries participating in CONCORD were asked to submit tumour registrations for all children aged 0\u201314 years who were diagnosed with leukaemia between Jan 1, 1995, and Dec 31, 2009, and followed up until Dec 31, 2009. Haematological malignancies were defined by morphology codes in the International Classification of Diseases for Oncology, third revision. We excluded data from registries from which the data were judged to be less reliable, or included only lymphomas, and data from countries in which data for fewer than ten children were available for analysis. We also excluded records because of a missing date of birth, diagnosis, or last known vital status. We estimated 5-year net survival (ie, the probability of surviving at least 5 years after diagnosis, after controlling for deaths from other causes [background mortality]) for children by calendar period of diagnosis (1995\u201399, 2000\u201304, and 2005\u201309), sex, and age at diagnosis (&lt;1, 1\u20134, 5\u20139, and 10\u201314 years, inclusive) using appropriate life tables. We estimated age-standardised net survival for international comparison of survival trends for precursor-cell acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML). Findings We analysed data from 89\u2008828 children from 198 registries in 53 countries. During 1995\u201399, 5-year age-standardised net survival for all lymphoid leukaemias combined ranged from 10\ub76% (95% CI 3\ub71\u201318\ub72) in the Chinese registries to 86\ub78% (81\ub76\u201392\ub70) in Austria. International differences in 5-year survival for childhood leukaemia were still large as recently as 2005\u201309, when age-standardised survival for lymphoid leukaemias ranged from 52\ub74% (95% CI 42\ub78\u201361\ub79) in Cali, Colombia, to 91\ub76% (89\ub75\u201393\ub76) in the German registries, and for AML ranged from 33\ub73% (18\ub79\u201347\ub77) in Bulgaria to 78\ub72% (72\ub70\u201384\ub73) in German registries. Survival from precursor-cell ALL was very close to that of all lymphoid leukaemias combined, with similar variation. In most countries, survival from AML improved more than survival from ALL between 2000\u201304 and 2005\u201309. Survival for each type of leukaemia varied markedly with age: survival was highest for children aged 1\u20134 and 5\u20139 years, and lowest for infants (younger than 1 year). There was no systematic difference in survival between boys and girls. Interpretation Global inequalities in survival from childhood leukaemia have narrowed with time but remain very wide for both ALL and AML. These results provide useful information for health policy makers on the effectiveness of health-care systems and for cancer policy makers to reduce inequalities in childhood cancer survival. Funding Canadian Partnership Against Cancer, Cancer Focus Northern Ireland, Cancer Institute New South Wales, Cancer Research UK, US Centers for Disease Control and Prevention, Swiss Re, Swiss Cancer Research foundation, Swiss Cancer League, and the University of Kentucky

Worldwide comparison of ovarian cancer survival: Histological group and stage at diagnosis (CONCORD-2)

Objective Ovarian cancer comprises several histological groups with widely differing levels of survival. We aimed to explore international variation in survival for each group to help interpret international differences in survival from all ovarian cancers combined. We also examined differences in stage-specific survival. Methods The CONCORD programme is the largest population-based study of global trends in cancer survival, including data from 60 countries for 695,932 women (aged 15\u201399&nbsp;years) diagnosed with ovarian cancer during 1995\u20132009. We defined six histological groups: type I epithelial, type II epithelial, germ cell, sex cord-stromal, other specific non-epithelial and non-specific morphology, and estimated age-standardised 5-year net survival for each country by histological group. We also analysed data from 67 cancer registries for 233,659 women diagnosed from 2001 to 2009, for whom information on stage at diagnosis was available. We estimated age-standardised 5-year net survival by stage at diagnosis (localised or advanced). Results Survival from type I epithelial ovarian tumours for women diagnosed during 2005\u201309 ranged from 40 to 70%. Survival from type II epithelial tumours was much lower (20\u201345%). Survival from germ cell tumours was higher than that of type II epithelial tumours, but also varied widely between countries. Survival for sex-cord stromal tumours was higher than for the five other groups. Survival from localised tumours was much higher than for advanced disease (80% vs. 30%). Conclusions There is wide variation in survival between histological groups, and stage at diagnosis remains an important factor in ovarian cancer survival. International comparisons of ovarian cancer survival should incorporate histology

Erratum to "The histology of ovarian cancer: Worldwide distribution and implications for international survival comparisons (CONCORD-2)" [Gynecol. Oncol. 144 (2017) 405-413]

Objective. Ovarian cancers comprise several histologically distinct tumour groups with widely different prognosis. We aimed to describe the worldwide distribution of ovarian cancer histology and to understand what role this may play in international variation in survival. Methods. The CONCORD programme is the largest population-based study of global trends in cancer survival. Data on 681,759 women diagnosed during 1995\u20132009 with cancer of the ovary, fallopian tube, peritoneum and retroperitonum in 51 countries were included.We categorised ovarian tumours into six histological groups, and explored the worldwide distribution of histology. Results. During 2005\u20132009, type II epithelial tumours were the most common. The proportion was much higher in Oceania (73.1%), North America (73.0%) and Europe (72.6%) than in Central and South America (65.7%) and Asia (56.1%). By contrast, type I epithelial tumours were more common in Asia (32.5%), compared with only 19.4% in North America. From 1995 to 2009, the proportion of type II epithelial tumours increased from 68.6% to 71.1%, while the proportion of type I epithelial tumours fell from 23.8% to 21.2%. The proportions of germ cell tumours, sex cord-stromal tumours, other specific non-epithelial tumours and tumours of non-specific morphology all remained stable over time. Conclusions. The distribution of ovarian cancer histology varieswidely worldwide. Type I epithelial, germcell and sex cord-stromal tumours are generally associated with higher survival than type II tumours, so the proportion of these tumours may influence survival estimates for all ovarian cancers combined. The distribution of histological groups should be considered when comparing survival between countries and regions

Erratum to "Worldwide comparison of ovarian cancer survival: Histological group and stage at diagnosis (CONCORD-2)" [Gynecol. Oncol. 144 (2017) 396-404]

Objective. Ovarian cancer comprises several histological groups with widely differing levels of survival. We aimed to explore international variation in survival for each group to help interpret international differences in survival from all ovarian cancers combined. We also examined differences in stage-specific survival. Methods. The CONCORD programme is the largest population-based study of global trends in cancer survival, including data from 60 countries for 695,932 women (aged 15\u201399 years) diagnosed with ovarian cancer during 1995\u20132009. We defined six histological groups: type I epithelial, type II epithelial, germ cell, sex cord-stromal, other specific non-epithelial and non-specific morphology, and estimated age-standardised 5-year net survival for each country by histological group. We also analysed data from67 cancer registries for 233,659 women diagnosed from 2001 to 2009, for whom information on stage at diagnosis was available. We estimated agestandardised 5-year net survival by stage at diagnosis (localised or advanced). Results. Survival fromtype I epithelial ovarian tumours for women diagnosed during 2005\u201309 ranged from40 to 70%. Survival from type II epithelial tumours was much lower (20\u201345%). Survival fromgermcell tumours was higher than that of type II epithelial tumours, but also varied widely between countries. Survival for sex-cord stromal tumours was higher than for the five other groups. Survival from localised tumours was much higher than for advanced disease (80% vs. 30%). Conclusions. There is wide variation in survival between histological groups, and stage at diagnosis remains an important factor in ovarian cancer survival. International comparisons of ovarian cancer survival should incorporate histology