102 research outputs found
Characterization of potential therapeutic targets in Leishmania infantum
Leishmaniasis is a parasitic disease caused by various species of Leishmania, which affects
millions of people worldwide. Current treatments for leishmaniasis often present adverse
effects and may not be effective against every Leishmania strain or form of the disease.
Therefore, it is essential to explore new therapeutic approaches to combat the parasite. In this
study, we focused on the PeBoW complex proteins homologous in Leishmania, which is
involved in ribosomal biogenesis and plays a critical role in cancer development in mammalian
cells. Recently, a homologue of the oncogene PES1 was found in Leishmania major, which
plays a crucial role in parasite infectivity. Given this, we analyzed the possibility of using other
PeBoW complex partner genes in Leishmania as therapeutic targets for leishmaniasis treatment.
Specifically, our investigation aimed to characterize the partner WDR12 homologous in
Leishmania infantum (LmjWDR12) as new therapeutic approach
Trajectories of alcohol consumption during life and the risk of developing breast cancer
Background: Whether there are lifetime points of greater sensitivity to the deleterious effects of alcohol intake on the breasts remains inconclusive. Objective: To compare the influence of distinctive trajectories of alcohol consumption throughout a woman’s life on development of breast cancer (BC). Methods: 1278 confirmed invasive BC cases and matched (by age and residence) controls from the Epi-GEICAM study (Spain) were used. The novel group-based trajectory modelling was used to identify different alcohol consumption trajectories throughout women’s lifetime. Results: Four alcohol trajectories were identified. The first comprised women (45%) with low alcohol consumption (<5 g/day) throughout their life. The second included those (33%) who gradually moved from a low alcohol consumption in adolescence to a moderate in adulthood (5 to <15 g/day), never having a high consumption; and oppositely, women in the third trajectory (16%) moved from moderate consumption in adolescence, to a lower consumption in adulthood. Women in the fourth (6%) moved from a moderate alcohol consumption in adolescence to the highest consumption in adulthood (=15 g/day), never having a low alcohol consumption. Comparing with the first trajectory, the fourth doubled BC risk (OR 2.19; 95% CI 1.27, 3.77), followed by the third (OR 1.44; 0.96, 2.16) and ultimately by the second trajectory (OR 1.17; 0.86, 1.58). The magnitude of BC risk was greater in postmenopausal women, especially in those with underweight or normal weight. When alcohol consumption was independently examined at each life stage, =15 g/day of alcohol consumption in adolescence was strongly associated with BC risk followed by consumption in adulthood. Conclusions: The greater the alcohol consumption accumulated throughout life, the greater the risk of BC, especially in postmenopausal women. Alcohol consumption during adolescence may particularly influence BC risk. © 2021, The Author(s)
Multiple myeloma and SARS-CoV-2 infection : clinical characteristics and prognostic factors of inpatient mortality
There is limited information on the characteristics, prognostic factors, and outcomes of patients with multiple myeloma (MM) hospitalized with COVID-19. This retrospective case series investigated 167 patients reported from 73 hospitals within the Spanish Myeloma Collaborative Group network in March and April, 2020. Outcomes were compared with 167 randomly selected, contemporary, age-/sex-matched noncancer patients with COVID-19 admitted at six participating hospitals. Among MM and noncancer patients, median age was 71 years, and 57% of patients were male; 75 and 77% of patients, respectively, had at least one comorbidity. COVID-19 clinical severity was moderate-severe in 77 and 89% of patients and critical in 8 and 4%, respectively. Supplemental oxygen was required by 47 and 55% of MM and noncancer patients, respectively, and 21%/9% vs 8%/6% required noninvasive/invasive ventilation. Inpatient mortality was 34 and 23% in MM and noncancer patients, respectively. Among MM patients, inpatient mortality was 41% in males, 42% in patients aged >65 years, 49% in patients with active/progressive MM at hospitalization, and 59% in patients with comorbid renal disease at hospitalization, which were independent prognostic factors on adjusted multivariate analysis. This case series demonstrates the increased risk and identifies predictors of inpatient mortality among MM patients hospitalized with COVID-19
Reliability of a novel electro-medical device for wheal size measurement in allergy skin testing: An exploratory clinical trial
Skin prick testing (SPT) is the cornerstone of IgE-mediated allergy diagnosis,1 due to its high sensitivity and specificity.2 However, a uniform method for wheal measurement does not exist. Ansotegui et al.2 recommends to measure wheals in millimeters with a ruler, in many centers they are outlined with a pen and transfer by tape to a paper and then measured. Subsequently, the specialist is able to manually measure the maximum (MD) and orthogonal diameter (OD) of the wheal. This procedure is time consuming and makes repro-ducible measurements difficult.2,3 Knowing the wheal's area could help make a more accurate diagnosis.4 Over the last 30 years, many attempts have been made to develop a device to measure the size of SPT.3 Nexkin DSPT® (Figure S1A,B) is a novel mechatronic system based on 3D laser technology, that automatically locates allergen's wheal and measures its size (MD, OD and area in square millimeters) (Figure S1C)
Immunologic evaluation and validation of methods using synthetic peptides derived from Mycobacterium tuberculosis for the diagnosis of tuberculosis infection
A randomized phase 3 trial of zanubrutinib vs ibrutinib in symptomatic Waldenström macroglobulinemia: the ASPEN study
Se trata de la publicación del estudio de fase 3 ASPEN que comparó en pacientes con macro-globulinemia de Waldenström (WM) la eficacia y la seguridad de ibrutinib, un inhibidor de la tirosi-na quinasa Bruton (BTK) de primera generación, familia que ha demostrado ser un tratamiento eficaz en estos pacientes, frente a zanubrutinib, un nuevo inhibidor de BTK de 2ª generación, altamente selectivo. Los pacientes con enfermedad MYD88L265P se asignaron al azar 1:1 al tratamiento con ibrutinib o zanubrutinib. El criterio principal de valoración fue la proporción de pa-cientes que lograron una respuesta completa (RC) o una respuesta parcial muy buena (RPMB) mediante una revisión independiente. Los criterios secundarios clave de valoración incluyeron la tasa de respuesta mayor (RM), la supervivencia libre de progresión (SLP), la duración de la res-puesta (DR), la carga de la enfermedad y la seguridad. Se randomizaron 201 pacientes y 199 recibieron al menos 1 dosis del tratamiento del estudio. Veintinueve (28%) pacientes tratados con zanubrutinib y 19 (19%) pacientes tratados con ibrutinib lograron una RPMB, diferencia que no alcanzó la significación estadística (P = 0,09). Las RM fueron del 77% y del 78%, respectivamen-te. No se alcanzó la mediana de DR y SLP, ya que el 84% y el 85% de los pacientes tratados con ibrutinib y zanubrutinib estaban libres de progresión a los 18 meses. La fibrilación auricular, hema-tomas, diarrea, edema periférico, hemorragia, espasmos musculares y neumonía, así como los eventos adversos que condujeron a interrumpir el tratamiento, fueron menos frecuentes entre los receptores de zanubrutinib. La incidencia de neutropenia fue mayor con zanubrutinib, aunque las tasas de infección de grado ≥3 fueron similares en ambos grupos (1,2 y 1,1 eventos por 100 me-ses-persona). Estos resultados demuestran que zanubrutinib e ibrutinib son altamente efectivos en el tratamiento de la WM, pero zanubrutinib se asoció con menor toxicidad y una tendencia hacia una mejor calidad de respuesta y menos toxicidad, particularmente toxicidad cardiovascular.[EN]Bruton tyrosine kinase (BTK) inhibition is an effective treatment approach for patients with Waldenström macroglobulinemia (WM). The phase 3 ASPEN study compared the efficacy and safety of ibrutinib, a first-generation BTK inhibitor, with zanubrutinib, a novel highly selective BTK inhibitor, in patients with WM. Patients with MYD88L265P disease were randomly assigned 1:1 to treatment with ibrutinib or zanubrutinib. The primary end point was the proportion of patients achieving a complete response (CR) or a very good partial response (VGPR) by independent review. Key secondary end points included major response rate (MRR), progression-free survival (PFS), duration of response (DOR), disease burden, and safety. A total of 201 patients were randomized, and 199 received ≥1 dose of study treatment. No patient achieved a CR. Twenty-nine (28%) zanubrutinib patients and 19 (19%) ibrutinib patients achieved a VGPR, a nonstatistically significant difference (P = .09). MRRs were 77% and 78%, respectively. Median DOR and PFS were not reached; 84% and 85% of ibrutinib and zanubrutinib patients were progression free at 18 months. Atrial fibrillation, contusion, diarrhea, peripheral edema, hemorrhage, muscle spasms, and pneumonia, as well as adverse events leading to treatment discontinuation, were less common among zanubrutinib recipients. Incidence of neutropenia was higher with zanubrutinib, although grade ≥3 infection rates were similar in both arms (1.2 and 1.1 events per 100 person-months). These results demonstrate that zanubrutinib and ibrutinib are highly effective in the treatment of WM, but zanubrutinib treatment was associated with a trend toward better response quality and less toxicity, particularly cardiovascular toxicity.BeiGene CoBeiGene C
Substrate translocation involves specific lysine residues of the central channel of the conjugative coupling protein TrwB
Conjugative transfer of plasmid R388 requires the coupling protein TrwB for protein and DNA transport, but their molecular role in transport has not been deciphered. We investigated the role of residues protruding into the central channel of the TrwB hexamer by a mutational analysis. Mutations affecting lysine residues K275, K398, and K421, and residue S441, all facing the internal channel, affected transport of both DNA and the relaxase protein in vivo. The ATPase activity of the purified soluble variants was affected significantly in the presence of accessory protein TrwA or DNA, correlating with their behaviour in vivo. Alteration of residues located at the cytoplasmic or the inner membrane interface resulted in lower activity in vivo and in vitro, while variants affecting residues in the central region of the channel showed increased DNA and protein transfer efficiency and higher ATPase activity, especially in the absence of TrwA. In fact, these variants could catalyze DNA transfer in the absence of TrwA under conditions in which the wild-type system was transfer deficient. Our results suggest that protein and DNA molecules have the same molecular requirements for translocation by Type IV secretion systems, with residues at both ends of the TrwB channel controlling the opening?closing mechanism, while residues embedded in the channel would set the pace for substrate translocation (both protein and DNA) in concert with TrwA
International Myeloma Working Group risk stratification model for smoldering multiple myeloma (SMM)
Smoldering multiple myeloma (SMM) is an asymptomatic precursor state of multiple myeloma (MM). Recently, MM
was redefined to include biomarkers predicting a high risk of progression from SMM, thus necessitating a redefinition
of SMM and its risk stratification. We assembled a large cohort of SMM patients meeting the revised IMWG criteria to
develop a new risk stratification system. We included 1996 patients, and using stepwise selection and multivariable
analysis, we identified three independent factors predicting progression risk at 2 years: serum M-protein >2 g/dL (HR:
2.1), involved to uninvolved free light-chain ratio >20 (HR: 2.7), and marrow plasma cell infiltration >20% (HR: 2.4). This
translates into 3 categories with increasing 2-year progression risk: 6% for low risk (38%; no risk factors, HR: 1); 18% for
intermediate risk (33%; 1 factor; HR: 3.0), and 44% for high risk (29%; 2–3 factors). Addition of cytogenetic abnormalities
(t(4;14), t(14;16), +1q, and/or del13q) allowed separation into 4 groups (low risk with 0, low intermediate risk with 1,
intermediate risk with 2, and high risk with ≥3 risk factors) with 6, 23, 46, and 63% risk of progression in 2 years,
respectively. The 2/20/20 risk stratification model can be easily implemented to identify high-risk SMM for clinical
research and routine practice and will be widely applicable
Cómo poner puertas al campo : tres revisiones panorámicas sobre el uso de biomarcadores en prevención personalizada de enfermedades crónicas
Se incluye PDF de la presentación y vídeo del seminario.El seminario trata de dar respuesta a qué biomarcadores hay disponibles o en desarrollo para la prevención personalizada de enfermedades crónicas en la población general. Las revisiones realizadas resumen las principales características y conclusiones de la bibliografía sobre este tema. Abarca los tres principales grupos de enfermedades crónicas:11 tipos de cáncer, 9 enfermedades cardiovasculares y 7 enfermedades neurodegenerativas.N
Menstrual and Reproductive Factors and Risk of Gastric and Colorectal Cancer in Spain
BACKGROUND:
Sex hormones play a role in gastric cancer and colorectal cancer etiology, however, epidemiological evidence is inconsistent. This study examines the influence of menstrual and reproductive factors over the risk of both tumors.
METHODS:
In this case-control study 128 women with gastric cancer and 1293 controls, as well as 562 female and colorectal cancer cases and 1605 controls were recruited in 9 and 11 Spanish provinces, respectively. Population controls were frequency matched to cases by age and province. Demographic and reproductive data were directly surveyed by trained staff. The association with gastric, colon and rectal cancer was assessed using logistic and multinomial mixed regression models.
RESULTS:
Our results show an inverse association of age at first birth with gastric cancer risk (five-year trend: OR = 0.69; p-value = 0.006). Ever users of hormonal contraception presented a decreased risk of gastric (OR = 0.42; 95%CI = 0.26-0.69), colon (OR = 0.64; 95%CI = 0.48-0.86) and rectal cancer (OR = 0.61; 95%CI = 0.43-0.88). Postmenopausal women who used hormone replacement therapy showed a decreased risk of colon and rectal tumors. A significant interaction of educational level with parity and months of first child lactation was also observed.
CONCLUSION:
These findings suggest a protective role of exogenous hormones in gastric and colorectal cancer risk. The role of endogenous hormones remains unclear
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