Interactions of Phenylalanine Derivatives with Human Tyrosinase: Lessons from Experimental and Theoretical tudies.

The pigmentation of the skin, modulated by different actors in melanogenesis, is mainly due to the melanins (protective pigments). In humans, these pigments' precursors are synthetized by an enzyme known as tyrosinase (TyH). The regulation of the enzyme activity by specific modulators (inhibitors or activators) can offer a means to fight hypo- and hyper-pigmentations responsible for medical, psychological and societal handicaps. Herein, we report the investigation of phenylalanine derivatives as TyH modulators. Interacting with the binuclear copper active site of the enzyme, phenylalanine derivatives combine effects induced by combination with known resorcinol inhibitors and natural substrate/intermediate (amino acid part). Computational studies including docking, molecular dynamics and free energy calculations combined with biological activity assays on isolated TyH and in human melanoma MNT-1 cells, and X-ray crystallography analyses with the TyH analogue Tyrp1, provide conclusive evidence of the interactions of phenylalanine derivatives with human tyrosinase. In particular, our findings indicate that an analogue of L-DOPA, namely (S)-3-amino-tyrosine, stands out as an amino phenol derivative with inhibitory properties against TyH.

Computational methods to analyze and predict the binding mode of inhibitors targeting both human and mushroom tyrosinase.

Tyrosinase, a copper-containing enzyme critical in melanin biosynthesis, is a key drug target for hyperpigmentation and melanoma in humans. Testing the inhibitory effects of compounds using tyrosinase from Agaricus bisporus (AbTYR) has been a common practice to identify potential therapeutics from synthetic and natural sources. However, structural diversity among human tyrosinase (hTYR) and AbTYR presents a challenge in developing drugs that are therapeutically effective. In this study, we combined retrospective and computational analyses with experimental data to provide insights into the development of new inhibitors targeting both hTYR and AbTYR. We observed contrasting effects of Thiamidol™ and our 4-(4-hydroxyphenyl)piperazin-1-yl-derivative (6) on both enzymes; based on this finding, we aimed to investigate their binding modes in hTYR and AbTYR to identify residues that significantly improve affinity. All the information led to the discovery of compound [4-(4-hydroxyphenyl)piperazin-1-yl](2-methoxyphenyl)methanone (MehT-3, 7), which showed comparable activity on AbTYR (IC50 = 3.52 µM) and hTYR (IC50 = 5.4 µM). Based on these achievements we propose the exploitation of our computational results to provide relevant structural information for the development of newer dual-targeting molecules, which could be preliminarily tested on AbTYR as a rapid and inexpensive screening procedure before being tested on hTYR.

Percepción del aborto en alumnado de primer año de la Facultad de Medicina posterior al curso de embriología humana / Perception of abortion in first-year students of the Faculty of Medicine after the Human Embryology course

Resumen Antecedentes: Actualmente se han registrado diversos estudios sobre la percepción del aborto en el alumnado del área de la salud. Objetivo: Conocer si la formación médico-científica puede generar un cambio en la percepción del alumnado que cursa el primer año en la Facultad de Medicina de la Universidad Nacional Autónoma de México. Material y métodos: Se aplicó una encuesta transversal en dos tiempos y se analizó el nivel de relación de los ítems de cada dimensión mediante coeficiente V de Crámer. Los resultados se compararon para identificar si existió un cambio de percepción acerca del aborto después del curso de embriología humana. Resultados: Con una población inicial de 2150 alumnos, se realizaron 393 encuestas previas al curso y 394 encuestas posteriores. Los resultados indicaron que a pesar de existir cambios en la percepción de los alumnos de la Facultad de Medicina sobre el aborto, no fueron significativos. Conclusiones: La formación médico-científica que proporciona el curso de embriología humana no es suficiente para fundamentar la percepción del alumnado en temas como el aborto o la objeción de conciencia.

Abstract Background: Multiple studies have been recorded regarding the perception of abortion among students in the health area. Objective: To know if medical-scientific training is sufficient to generate a change in the perception of first-year students of the National Autonomous University of Mexico Faculty of Medicine. Material and methods: A cross-sectional survey was applied in two times, with the level of relationship between the items of each dimension being analyzed using Cramer's V test. The results were compared to analyze if there was a change in the perception of abortion after the human embryology course. Results: With an initial population of 2,150 students, 393 pre-course and 394 post-course surveys were conducted. The results indicated that despite the existence of changes in the perception of Faculty of Medicine students with regard to abortion, they are not significant. Conclusions: The medical-scientific training provided by the human embryology course is not enough to provide foundations to the perception of students on issues such as abortion or conscientious objection.

In Combo Studies for the Optimization of 5-Aminoanthranilic Acid Derivatives as Potential Multitarget Drugs for the Management of Metabolic Syndrome.

Metabolic syndrome is a set of risk factors that consist of abdominal obesity, arterial hypertension, alterations in the lipid profile, and hyperglycemia. The current therapeutic strategy includes polypharmacy, using three or more drugs to control each syndrome component. However, this approach has drawbacks that could lead to therapeutic failure. Multitarget drugs are molecules with the ability to act on different targets simultaneously and are an attractive alternative for treating complex diseases such as metabolic syndrome. Previously, we identified a triamide derivative of 5-aminoanthranilic acid that exhibited hypoglycemic, hypolipemic, and antihypertensive activities simultaneously. In the present study, we report the synthesis and in combo evaluation of new derivatives of anthranilic acid, intending to identify the primary structural factors that improve the activity over metabolic syndrome-related parameters. We found that substitution on position 5, incorporation of 3,4-dimethoxyphenyl substituents, and having a free carboxylic acid group lead to the in vitro inhibition of HMG-CoA reductase, and simultaneously the diminution of the serum levels of glucose, triglycerides, and cholesterol in a diet-induced in vivo model.

Malignancies in Deceased Organ Donors: The Spanish Experience.

BACKGROUND: To better define the risk of malignancy transmission through organ transplantation, we review the Spanish experience on donor malignancies. METHODS: We analyzed the outcomes of recipients of organs obtained from deceased donors diagnosed with a malignancy during 2013-2018. The risk of malignancy transmission was classified as proposed by the Council of Europe. RESULTS: Of 10 076 utilized deceased donors, 349 (3.5%) were diagnosed with a malignancy. Of those, 275 had a past (n = 168) or current (n = 107) history of malignancy known before the transplantation of organs into 651 recipients. Ten malignancies met high-risk criteria. No donor-transmitted cancer (DTC) was reported after a median follow-up of 24 (interquartile range [IQR]: 19-25) mo. The other 74 donors were diagnosed with a malignancy after transplantation. Within this group, 64 donors (22 with malignancies of high or unacceptable risk) whose organs were transplanted into 126 recipients did not result in a DTC after a median follow-up of 26 (IQR: 22-37) mo, though a prophylactic transplantectomy was performed in 5 patients. The remaining 10 donors transmitted an occult malignancy to 16 of 25 recipients, consisting of lung cancer (n = 9), duodenal adenocarcinoma (n = 2), renal cell carcinoma (n = 2), extrahepatic cholangiocarcinoma (n = 1), prostate cancer (n = 1), and undifferentiated cancer (n = 1). After a median follow-up of 14 (IQR: 11-24) mo following diagnosis, the evolution was fatal in 9 recipients. In total, of 802 recipients at risk, 16 (2%) developed a DTC, which corresponds to 6 cases per 10 000 organ transplants. CONCLUSIONS: Current standards may overestimate the risk of malignancy transmission. DTC is an infrequent but difficult to eliminate complication.

The Impact of COVID-19 on the Lifestyles of University Students: A Spanish Online Survey.

The present study aimed to investigate the perceived changes in lifestyle behaviors among Spanish university students during COVID-19-related confinement. An observational, descriptive, and cross-sectional survey study was conducted during April 2020. Sociodemographic and anthropometric data were then obtained. The FANTASTIC questionnaire was used to assess the lifestyles of the 488 participants who took part in the study. Of the participants, 76.3% were female. Overall, the lifestyles of university students significantly deteriorated during the period of confinement caused by the COVID-19 pandemic in Spain. University female students were especially affected compared to their male fellows (p = 0.010). For women, social and family relationships (p < 0.001), personality (p < 0.001), interior (p < 0.001), and career (p < 0.001) were the aspects that worsened during confinement. For men, lack of physical exercise (p < 0.001), social and family relationships (p < 0.001), and career (p = 0.002) were affected to a greater extent. In both cases, confinement was a protective factor against the consumption of tobacco, toxins (p < 0.001), and alcohol (p < 0.001). Gender (p = 0.008) and obesity (p = 0.044) were the two factors that most affected the change in the score of the FANTASTIC questionnaire. Spanish university students' lifestyles worsened during the lockdown caused by the COVID-19 pandemic, especially those of women, who were the most affected. Some aspects, such as those related to social and emotional behaviors, were deeply affected, while confinement could be a protective factor against previous toxic habits.

Differential Characteristics of Patients With Squamous Cell Carcinoma of the Head and Neck According to Gender.

OBJECTIVE: To analyse the trend in the percentage of patients with squamous cell carcinoma of the head and neck (SCCHN) of female gender over the last decades, and differences in survival according to gender. MATERIAL AND METHODS: Retrospective study of 5828 SCCHN diagnosed during the period 1985-2019. In the survival analysis we only included only patients with more than two years of follow-up. RESULTS: The proportion of tumours in female patients increased significantly over the study period. There was greater increase of tumours located in the oral cavity, oropharynx and larynx in the percentage of female patients. When considering the total number of patients, there were no significant differences in disease-specific survival according to gender. We observed a variable behaviour of disease-specific survival according to gender depending on the primary location of the tumour. For tumours of the larynx and oropharynx the female patients had a disease-specific survival significantly higher than that of men, while for tumours of the oral cavity, the female patients had a significant reduction of disease-specific survival. CONCLUSIONS: In our setting, the percentage of female patients with HNSCC has been increasing steadily over recent decades. There were differences in disease-specific survival according to gender depending on the location of the primary tumour.

Head and neck squamous cell carcinoma in cigar smokers. Distinctive epidemiological and prognostic characteristics.

OBJECTIVE: The objective of this study is to assess the existence of differences in the epidemiological characteristics and prognosis of patients with head and neck squamous cell carcinoma (HNSCC) who smoke cigars. MATERIAL AND METHODS: We carried out a retrospective study of a cohort of 4500 patients with HNSCC treated during the period 1985-2017. RESULT: The proportion of cigar smokers was 2.4%, compared with 88.3% of cigarette smokers and 9.3% of non-smokers. There was an increase in the proportion of cigar smokers throughout the study period. With respect to cigarette smokers, cigar smokers had a higher proportion of male patients, a higher average age at diagnosis, and they had a higher frequency of tumours located in the oral cavity and hypopharynx. The results of a univariate analysis showed that the disease-specific survival of cigar smokers was lower than that of the other patients. Five-year disease-specific survival of cigar smokers was 60.9%, compared to 69.0% for non-smokers, 72.8% for smokers of less than 20 cigarettes/day, and 67.2% for smokers of more than 20 cigarettes/day. There were differences in the pattern of survival depending on tobacco consumption based on the location of the primary tumour. CONCLUSIONS: A 2.4% of patients with HNSCC had a history of regular consumption of cigars. Disease-specific survival of cigar smokers was lower than that of other patients.

Tendency and seasonality of suicide in Chihuahua, México. A retrospective analysis from 2008 to 2018 / Tendencia y estacionalidad del suicidio en el Estado de Chihuahua, México. Un análisis retrospectivo de 2008-2018

Abstract Introduction Suicide has shown an international and national trend to increase, mainly in young people, together with seasonal behavior associated with high temperatures. Although Chihuahua saw the highest number of suicides and suicide attempts in 2016, there are no studies documenting their seasonal and trend behavior. Objective This study sought to analyze the trend and seasonality of completed suicides in the state of Chihuahua from 2008 to 2018. Method The number of deaths from intentionally self-inflicted injuries was obtained from INEGI. The absolute suicide rate was estimated, and a time series model applied to identify its trend and seasonality. In addition, environmental temperature was used as a predictor variable for the number of suicides through a Poisson model. Results A trend was found in the completed suicide rate from 2008 to 2018 in men and women, both separately and together (stationary R2 .73, .66 and .69, respectively), together with seasonality in both sexes (p < .002), with the highest figures being recorded in June and July. An increase of 1,028 suicides was found for every 1°C rise in temperature. In the 10-24 and 25-34 age groups, a linear increase in the suicide rate was observed during the period studied (R² > .7, p = .001). Discussion and conclusion Between 2008 and 2018, the suicide rate increased in the state of Chihuahua, mainly among those aged between 10 and 34. Moreover, suicide rates tend to increase during the months of June and July because of temperature.

Resumen Introducción El suicidio ha presentado una tendencia a la alta a nivel internacional y nacional, principalmente en jóvenes, y un comportamiento estacional, asociado a altas temperaturas. Aunque Chihuahua presentó la mayor cantidad de suicidios e intentos de suicidio durante 2016; no hay estudios que evidencien su comportamiento tendencial y estacional. Objetivo El objetivo fue analizar la tendencia y estacionalidad de suicidios consumados en el estado de Chihuahua de 2008 a 2018. Método Se obtuvieron las defunciones por lesiones autoinfligidas intencionalmente del repositorio del INEGI. Se estimó la tasa de suicidio absoluta y se aplicó un modelo de series de tiempo para identificar su tendencia y estacionalidad; además, se utilizó la temperatura ambiental como variable predictora en el número de suicidios por medio de un modelo Poisson. Resultados Se encontró una tendencia en la tasa de suicidios consumados de 2008 a 2018 en hombres, mujeres y en conjunto (R2 estacionaria .73, .66 y .69, respectivamente); y estacionalidad en ambos sexos (p < .002), donde los mayores registros fueron en junio y julio. Se encontró una asociación en un incremento de 1,028 suicidios por cada incremento de 1°C de la temperatura. En los grupos etarios de 10-24 y 25-34 se observó un incremento lineal en la tasa de suicidio durante el periodo estudiado (R2 > .7, p = .001). Discusión y conclusión De 2008 a 2018, la tasa de suicidios se ha incrementado en el estado de Chihuahua, principalmente entre los 10 y 34 años de edad. Además, la tasa de suicidio tiende a incrementarse durante los meses de junio y julio, asociándose a la temperatura.

Differential characteristics of patients with squamous cell carcinoma of the head and neck according to gender. / Características diferenciales de los pacientes con carcinomas escamosos de cabeza y cuello en función del género.

OBJECTIVE: To analyse the trend in the percentage of patients with squamous cell carcinoma of the head and neck of female gender over the last decades, and differences in survival according to gender. MATERIAL AND METHODS: Retrospective study of 5,828 squamous cell carcinoma of the head and neck diagnosed during the period 1985-2019. In the survival analysis we only included only patients with more than two years of follow-up. RESULTS: The proportion of tumours in female patients increased significantly over the study period. There was greater increase of tumours located in the oral cavity, oropharynx and larynx in the percentage of female patients. When considering the total number of patients, there were no significant differences in disease-specific survival according to gender. We observed a variable behaviour of disease-specific survival according to gender depending on the primary location of the tumour. For tumours of the larynx and oropharynx the female patients had a disease-specific survival significantly higher than that of men, while for tumours of the oral cavity, the female patients had a significant reduction of disease-specific survival. CONCLUSIONS: In our setting, the percentage of female patients with squamous cell carcinoma of the head and neck has been increasing steadily over recent decades. There were differences in disease-specific survival according to gender depending on the location of the primary tumour.

Organ preservation after treatment with induction chemotherapy in patients with locally advanced carcinomas (T3-T4) of oral cavity and oropharynx. / Preservación de órgano tras un tratamiento con quimioterapia de inducción en pacientes con carcinomas localmente avanzados (T3-T4) de cavidad oral y orofaringe.

INTRODUCTION AND OBJECTIVES: With the goal of achieving functional preservation, one of the treatment strategies for patients with locally advanced squamous cell carcinomas of the head and neck is to initiate treatment with induction chemotherapy (CT) and decide the second therapeutic manoeuvre depending on the response. The objective of this study is to evaluate organ preservation capacity based on this therapeutic approach in patients with tumours of the oral cavity and oropharynx. METHODS: A retrospective study of 246 patients with locally advanced carcinomas of the oral cavity or oropharynx (cT3-T4) initially treated with induction CT. RESULTS: After induction CT 28% of patients achieved a complete response of the primary location of the tumour, 43.1% a partial response greater than 50%, and 28.9% a reduction less than 50% or persistence. After the induction CT treatment 70 patients (28.5%) underwent surgical treatment, and 176 (71.5%) radiotherapy (RT) or chemoradiotherapy (CRT). Considering the patients treated non-surgically (n=176), organ preservation for patients with a complete response (n=66) was 65.2%, for those patients with a partial response greater than 50% (n=75) it was 30.7%, and for patients with a partial response less than 50% or persistence (n=35) it was 14.3%. CONCLUSION: The response to treatment with induction CT has prognostic value in patients with locally advanced carcinomas of the oral cavity and oropharynx. Patients who are candidates for conservative treatment with RT or CRT would be those who achieve a complete response after induction treatment.

Oncological results of salvage treatment in patients with hypopharyngeal carcinoma. / Resultados oncológicos del tratamiento de rescate en pacientes con carcinomas de hipofaringe.

INTRODUCTION AND OBJECTIVE: The aim of this study is to analyse the variables related to the feasibility of salvage surgery with radical intention in patients with a local recurrence of hypopharyngeal carcinoma, and to evaluate the oncological performance of this type of surgery. METHODS: Retrospective study of 96 patients with hypopharyngeal carcinoma with local tumour recurrence RESULT: Only 27 patients (28.1%) were considered for surgical salvage treatment. The variables related to feasibility of salvage surgery were non-surgical initial treatment of the tumour and a disease-free interval greater than 6 months. All 69 patients non-candidates for salvage surgery died as a result of tumour progression in a period of less than 2.5 years. The 5-year disease-specific survival rate for the patients treated with salvage surgery was 39.5%. The only variable significantly related to disease-specific survival was the status of the resection margins. Patients with extensive tumour recurrence (rT3-T4) or with simultaneous nodal involvement had a lower survival rate, but the differences did not reach statistical significance. CONCLUSION: Only 28% of the patients with hypopharyngeal carcinoma with local recurrence of the tumour were eligible for salvage surgery with radical intention. The patients treated with salvage surgery had a 5 -year disease-specific survival of 39.5%.

Organ preservation in patients with advanced laryngeal tumours. Results of induction chemotherapy versus chemoradiotherapy in actual clinical practice. / Preservación de órgano en pacientes con tumores avanzados de laringe. Resultados de la quimioterapia de inducción versus quimio-radioterapia en la práctica clínica real.

INTRODUCTION AND OBJECTIVES: A high percentage of patients with locally advanced larynx carcinomas are candidates for inclusion in organ preservation protocols. The objective of this study is to compare the results of two schemes of preservation, induction chemotherapy versus chemoradiotherapy, in patients with locally advanced larynx carcinomas in the context of actual clinical practice. METHODS: Our retrospective study included 157 patients with locally advanced tumours of the larynx (T3-T4) treated with induction chemotherapy (n = 121) or chemoradiotherapy (n = 36). RESULTS: From 121 patients who began treatment with induction chemotherapy, 6 died due to toxicity, 37 were treated with surgery, and 78 completed the preservation scheme; 36 patients received treatment with chemoradiotherapy. There were no significant differences in 5-year disease-specific survival between both treatments: 68.9% in induction chemotherapy versus 75.7% in chemoradiotherapy (p = 0.259). In 45.9% of patients the laryngeal function was preserved. Patients treated with chemoradiotherapy had a tendency to have better 5-year laryngeal dysfunction-free survival than patients treated with induction chemotherapy (55.6% versus 44.8%, p = 0.079). CONCLUSION: Patients included in a protocol of organ preservation achieved a 5-year laryngeal dysfunction-free survival of 45.9%. There were no significant differences in disease-specific survival among patients treated with induction chemotherapy or chemoradiotherapy.

Salvage surgery in head and neck cancer: External validation of predictors of disease-specific survival.

OBJECTIVE: Salvage surgery in recurrent head and neck squamous cell carcinoma (HNSCC) is associated with poor outcomes. There is great interest to better identify suitable surgical patients. This study aimed to validate the proposal of Hamoir et al. to use three items to predict the outcomes of salvage surgery. MATERIALS AND METHODS: Single-center analysis of 577 patients undergoing salvage surgery for recurrent HNSCC during the period 1985-2016, with a minimal follow-up of 2 years. Patients were classified according to the prediction modeling proposed by Hamoir et al. This prediction modeling is based on three predictors: the tumor site (larynx vs non-larynx), initial staging (stage I-II vs stage III-IV), and site of recurrence (local or regional vs locoregional). RESULTS: Five-year disease-specific survival after salvage surgery was 54.0% (95% CI: 49.6-58.4%). Applying the prediction modeling tested, a total of 212 patients (36.7%) patients had no predictors of poor prognosis, 185 (32.1%) had one predictor, 146 (25.3%) two predictors, and 34 (5.9%) three predictors. Five-year disease-specific survival for patients with none, one, two and three predictors were 82.2%, 47.2%, 29.5% and 20.2% respectively (P = 0.0001). CONCLUSIONS: We have validated the prediction modeling based on the location of the tumor, initial staging and locoregional recurrence proposed by Hamoir et al. This prediction model is easy to apply and provides good information about the possibilities of success of salvage surgery.

Prognostic capacity of the lymph node ratio in squamous cell carcinomas of the head and neck. / Capacidad pronóstica de la densidad ganglionar en los carcinomas escamosos de cabeza y cuello.

INTRODUCTION AND OBJECTIVES: Lymph node density or lymph node ratio (LNR), defined as the quotient between the total number of positive lymph nodes and the total number of dissected lymph nodes, has demonstrated a prognostic capacity in several tumour models, including patients with head and neck squamous cell carcinomas (HNSCC). The aim of the present study is to analyse the prognostic value of LNR in a wide cohort of patients with HNSCC. METHODS: We carried out a retrospective study of a cohort of 1,311 patients with HNSCC treated with unilateral or bilateral neck dissections. Of the patients included in the study, 55.0% had lymph node metastases (pN+). We proceeded to calculate the value of the LNR, and its categorization through a recursive partition analysis considering specific survival as the dependent variable. RESULTS: Three categories were defined according to the value of the LNR with a cut-off point at the values < of .025 and .118. The 5-year specific survival for patients with an LNR less than .025 (n=654, 49.8%) was 87.2%, for patients with a LNR .025-.118 (n=394, 30.1%) it was 51.6%, and for patients with a LNR greater than .188 (n=263, 20.1%) it was 27.3% (P=.0001). According to the results of a multivariate analysis, the LNR significantly related to specific survival. CONCLUSION: The LNR can be a prognostic variable to be considered in the pathological staging of the lymph nodes.

Weighted lymph node ratio: New tool in the assessment of postoperative staging of the neck dissection in HPV-negative head and neck squamous cell carcinoma patients.

BACKGOUND: The objective of this study is to assess a new parameter, the weighted lymph node ratio (WLNR), which incorporates prognostic information regarding the number of metastatic nodes with extracapsular spread and the lymph node yield for pN0 patients to the lymph node ratio. METHODS: We studied retrospectively 1118 patients with head and neck squamous cell carcinoma (HNSCC) treated with a neck dissection. RESULTS: We obtained a classification with four categories based on the WLNR values. WLNR classification had a higher prognostic discrimination capacity and a more homogeneous distribution in the number of patients included in each of the categories than the pTNM classification. CONCLUSION: The WLNR improved the predictive capacity of the eighth edition of the pTNM classification and it can be a useful tool in the assessment of the postoperative staging of the neck dissections in HNSCC patients.

Prognostic value of nodal involvement in patients with oropharyngeal carcinoma according to the HPV status. / Valoración de la capacidad pronóstica de la afectación ganglionar de los pacientes con carcinoma de orofaringe en función del estatus HPV.

BACKGROUND AND OBJECTIVE: Different studies performed in populations with a high incidence of HPV infection have found no prognostic capacity of clinical nodal involvement (cN+) in patients with HPV-positive oropharyngeal carcinomas. The objective of this study was to assess the prognostic ability of nodal involvement in patients with oropharyngeal carcinomas according to HPV status in a cancer population with a low incidence of HPV infection. MATERIAL AND METHODS: Retrospective study of a cohort of 420 patients with oropharyngeal carcinomas treated during the period 1990-2016 for whom information on HPV status was available. RESULTS: 14.8% of the patients included in the study had HPV-positive tumours. In relation to patients without nodal involvement (cN0), nodal involvement at diagnosis (cN+) significantly decreased the specific survival of patients with HPV-negative oropharyngeal carcinomas. Conversely, no differences in survival were found for patients with HPV-positive tumours according to the presence of nodal involvement. A history of toxic consumption did not change the absence of prognostic significance of nodal involvement for patients with HPV-positive tumours. CONCLUSIONS: Regional involvement at the time of diagnosis is not a prognostic variable for patients with HPV-positive oropharyngeal carcinomas.

Discovery, affinity maturation and multimerization of small molecule ligands against human tyrosinase and tyrosinase-related protein 1.

Human tyrosinase (hTYR) and tyrosinase-related protein 1 (hTYRP1) are closely-related enzymes involved in the synthesis of melanin, which are selectively expressed in melanocytes and, in a pathological context, in melanoma lesions. We used a previously described tyrosinase inhibitor (Thiamidol™) and DNA-encoded library technology for the discovery of novel hTYR and hTYRP1 ligands, that could be used as vehicles for melanoma targeting. Performing de novo selections with DNA-encoded libraries, we discovered novel ligands capable of binding to both hTYR and hTYRP1. More potent ligands were obtained by multimerizing Thiamidol™ moieties, leading to homotetrameric structures that avidly bound to melanoma cells, as revealed by flow cytometry. These findings suggest that melanoma lesions may, in the future, be targeted not only by monoclonal antibody reagents but also by small organic ligands.

Analysis of specific survival and local control through a recursive partitioning analysis in patients with head and neck carcinoma. / Análisis de la supervivencia específica y el control local mediante un análisis de partición recursiva en pacientes con carcinomas de cabeza y cuello.

INTRODUCTION AND OBJECTIVES: Recursive partitioning analysis (RPA) is a technique that allows prognostic classification in oncological patients. The aim of the present study is to analyse by means of an RPA a cohort of patients with squamous carcinomas of the head and neck (SCHN). METHODS: 5,226 SCHN were retrospectively analysed with an RPA, considering the specific survival and local control of the disease as dependent variables. A cohort of patients was used for the creation of the classification model, and another cohort was used to carry out its internal validation. RESULTS: Considering specific survival as a dependent variable we obtained a classification tree with 14 terminal nodes that were grouped into 5 categories, including as partition variables the local and regional extent of the tumour, and the location of the tumour. When considering the local control of the disease as a dependent variable we obtained a classification tree with 10 terminal nodes that were grouped into 4 categories, including as partition variables the local extension and location of the tumour, the type of treatment performed, the age of the patient, and if it was a first tumour or a subsequent neoplasm. The validation study confirmed the prognostic capacity of the models developed with the RPA. One of the advantages of the RPA is that it allows the identification of groups of patients with specific behaviour. CONCLUSION: RPA is shown to be an effective technique for the prognostic classification of patients with a SCHN.