Longitudinal profiling identifies co-occurring BRCA1/2 reversions, TP53BP1, RIF1 and PAXIP1 mutations in PARP inhibitor-resistant advanced breast cancer.

BACKGROUND: Resistance to therapies that target homologous recombination deficiency (HRD) in breast cancer limits their overall effectiveness. Multiple, preclinically validated, mechanisms of resistance have been proposed, but their existence and relative frequency in clinical disease are unclear, as is how to target resistance. PATIENTS AND METHODS: Longitudinal mutation and methylation profiling of circulating tumour (ct)DNA was carried out in 47 patients with metastatic BRCA1-, BRCA2- or PALB2-mutant breast cancer treated with HRD-targeted therapy who developed progressive disease-18 patients had primary resistance and 29 exhibited response followed by resistance. ctDNA isolated at multiple time points in the patient treatment course (before, on-treatment and at progression) was sequenced using a novel >750-gene intron/exon targeted sequencing panel. Where available, matched tumour biopsies were whole exome and RNA sequenced and also used to assess nuclear RAD51. RESULTS: BRCA1/2 reversion mutations were present in 60% of patients and were the most prevalent form of resistance. In 10 cases, reversions were detected in ctDNA before clinical progression. Two new reversion-based mechanisms were identified: (i) intragenic BRCA1/2 deletions with intronic breakpoints; and (ii) intragenic BRCA1/2 secondary mutations that formed novel splice acceptor sites, the latter being confirmed by in vitro minigene reporter assays. When seen before commencing subsequent treatment, reversions were associated with significantly shorter time to progression. Tumours with reversions retained HRD mutational signatures but had functional homologous recombination based on RAD51 status. Although less frequent than reversions, nonreversion mechanisms [loss-of-function (LoF) mutations in TP53BP1, RIF1 or PAXIP1] were evident in patients with acquired resistance and occasionally coexisted with reversions, challenging the notion that singular resistance mechanisms emerge in each patient. CONCLUSIONS: These observations map the prevalence of candidate drivers of resistance across time in a clinical setting, information with implications for clinical management and trial design in HRD breast cancers.

Family Planning Concerns Among Women With Psoriasis: A Descriptive, Cross-Sectional, Multicenter Study. / Percepción de la mujer con psoriasis en la planificación familiar: Estudio descriptivo, transversal y multicéntrico.

BACKGROUND AND OBJECTIVE: A significant proportion of women of childbearing age have psoriasis. The aim of this study was to examine family planning concerns in this population. MATERIAL AND METHODS: Observational, descriptive, cross-sectional, multicenter study conducted between March 2020 and October 2021. We collected sociodemographic data and analyzed responses to a family planning questionnaire administered to women aged 18 to 45 years with plaque psoriasis who were candidates for systemic treatment. RESULTS: We studied 153 patients (mean [SD] age, 35.4 [8.0] years; mean disease duration, 16.7 years) being treated at 11 Spanish hospitals. Overall, 38.4% of women were considered to have moderate to severe psoriasis by their physicians; perceived severity ratings were significantly higher among women. Psoriasis affected the women's desire to become pregnant or led to their delaying pregnancy in 1 in 3 respondents. They were concerned that their condition might worsen if they had to discontinue or switch treatment or that the treatment might harm the baby. Approximately half of the women had not received family planning counseling from their physicians, and this was more likely to be the case among never-pregnant women. Women on biologic therapy (58.7%) had better psoriasis control and a better quality of life than women on other treatments. Their sexual health was also less affected. CONCLUSIONS: Women with psoriasis have numerous family planning concerns, which in some cases can lead them to delay pregnancy or affect their desire to become pregnant. Dermatologists need to receive better training regarding family planning in women with psoriasis so that they can provide their patients with more and better information.

[Translated article] Family Planning Concerns Among Women With Psoriasis: A Descriptive, Cross-Sectional, Multicenter Study.

BACKGROUND AND OBJECTIVE: A significant proportion of women of childbearing age have psoriasis. The aim of this study was to examine family planning concerns in this population. MATERIAL AND METHODS: Observational, descriptive, cross-sectional, multicenter study conducted between March 2020 and October 2021. We collected sociodemographic data and analyzed responses to a family planning questionnaire administered to women aged 18 to 45 years with plaque psoriasis who were candidates for systemic treatment. RESULTS: We studied 153 patients (mean [SD] age, 35.4 [8.0] years; mean disease duration, 16.7 years) being treated at 11 Spanish hospitals. Overall, 38.4% of women were considered to have moderate to severe psoriasis by their physicians; perceived severity ratings were significantly higher among women. Psoriasis affected the women's desire to become pregnant or led to their delaying pregnancy in 1 in 3 respondents. They were concerned that their condition might worsen if they had to discontinue or switch treatment or that the treatment might harm the baby. Approximately half of the women had not received family planning counseling from their physicians, and this was more likely to be the case among never-pregnant women. Women on biologic therapy (58.7%) had better psoriasis control and a better quality of life than women on other treatments. Their sexual health was also less affected. CONCLUSIONS: Women with psoriasis have numerous family planning concerns, which in some cases can lead them to delay pregnancy or affect their desire to become pregnant. Dermatologists need to receive better training regarding family planning in women with psoriasis so that they can provide their patients with more and better information.

Tuning the aspect ratio of silver nanospheroids embedded in silica: erratum.

We present a corrigendum to our Letter [Opt. Lett.35, 703 (2010)10.1364/OL.35.000703]. In the original Letter we inadvertently included in Fig. 2(a) a TEM micrograph corresponding to a different, but very similar, sample. This corrigendum replaces Fig. 2(a) with a correct version. Since the main results are rather based in optical absorption measurements, and their modeling by using the T-matrix method, this correction does not affect the results and conclusions of the original Letter.

Pharmacogenetic biomarkers for secukinumab response in psoriasis patients in real-life clinical practice.

BACKGROUND: Prediction of the response to a biological treatment in psoriasis patients would allow efficient treatment allocation. OBJECTIVE: To identify polymorphisms associated with secukinumab response in psoriasis patients in a daily practice setting. METHODS: We studied 180 SNPs in patients with moderate-to-severe plaque psoriasis recruited from 15 Spanish hospitals. Treatment effectiveness was evaluated by absolute PASI ≤3 and ≤1 at 6 and 12 months. Individuals were genotyped using a custom Taqman array. Multiple logistic regression models were generated. Sensitivity, specificity and area under the curve (AUC) were analysed. RESULTS: A total of 173 patients were studied at 6 months, (67% achieved absolute PASI ≤ 3 and 65% PASI ≤ 1) and 162 at 12 months (75% achieved absolute PASI ≤ 3 and 64% PASI ≤ 1). Multivariable analysis showed the association of different sets of SNPs with the response to secukinumab. The model of absolute PASI≤3 at 6 months showed best values of sensitivity and specificity. Four SNPs were associated with the capability of achieving absolute PASI ≤ 3 at 6 months. rs1801274 (FCGR2A), rs2431697 (miR-146a) and rs10484554 (HLCw6) were identified as risk factors for failure to achieve absolute PASI≤3, while rs1051738 (PDE4A) was protective. AUC including these genotypes, weight of patients and history of biological therapy was 0.88 (95% CI 0.83-0.94), with a sensitivity of 48.6% and specificity of 95.7% to discriminate between both phenotypes. CONCLUSION: We have identified a series of polymorphisms associated with the response to secukinumab capable of predicting the potential response/non-response to this drug in patients with plaque psoriasis.

Obesity status and obesity-associated gut dysbiosis effects on hypothalamic structural covariance.

BACKGROUND: Functional connectivity alterations in the lateral and medial hypothalamic networks have been associated with the development and maintenance of obesity, but the possible impact on the structural properties of these networks remains largely unexplored. Also, obesity-related gut dysbiosis may delineate specific hypothalamic alterations within obese conditions. We aim to assess the effects of obesity, and obesity and gut-dysbiosis on the structural covariance differences in hypothalamic networks, executive functioning, and depressive symptoms. METHODS: Medial (MH) and lateral (LH) hypothalamic structural covariance alterations were identified in 57 subjects with obesity compared to 47 subjects without obesity. Gut dysbiosis in the subjects with obesity was defined by the presence of high (n = 28) and low (n = 29) values in a BMI-associated microbial signature, and posthoc comparisons between these groups were used as a proxy to explore the role of obesity-related gut dysbiosis on the hypothalamic measurements, executive function, and depressive symptoms. RESULTS: Structural covariance alterations between the MH and the striatum, lateral prefrontal, cingulate, insula, and temporal cortices are congruent with previously functional connectivity disruptions in obesity conditions. MH structural covariance decreases encompassed postcentral parietal cortices in the subjects with obesity and gut-dysbiosis, but increases with subcortical nuclei involved in the coding food-related hedonic information in the subjects with obesity without gut-dysbiosis. Alterations for the structural covariance of the LH in the subjects with obesity and gut-dysbiosis encompassed increases with frontolimbic networks, but decreases with the lateral orbitofrontal cortex in the subjects with obesity without gut-dysbiosis. Subjects with obesity and gut dysbiosis showed higher executive dysfunction and depressive symptoms. CONCLUSIONS: Obesity-related gut dysbiosis is linked to specific structural covariance alterations in hypothalamic networks relevant to the integration of somatic-visceral information, and emotion regulation.

Pustular lesions in patients with Crohn disease and treatment with tumour necrosis factor-α inhibitors.

We present seven new cases of patients with Crohn disease who developed lesions clinically compatible with amicrobial pustulosis of the flexures during their treatment with anti-tumour necrosis factor therapy.

Nematicidal activity of leaf extract of Moringa oleifera Lam. against Haemonchus contortus and Nacobbus aberrans.

In the present study, the nematicidal activity of a Moringa oleifera ethyl acetate leaf extract against the eggs and larvae of Haemonchus contortus and Nacobbus aberrans, nematodes of agricultural importance, was evaluated. The experimental design for the evaluation of the effects against both nematodes consisted of eight treatments (n = 4). Distilled water, Tween (4%) and a commercial anthelmintic agent (ivermectin, 5 mg/mL) were used as controls, and for treatments 4-8, the concentrations of the extract were 20, 10, 5, 2.5 and 1.25 mg/mL, respectively. Readings were taken at 12 h and 24 h for N. aberrans and 48 h and 72 h for H. contortus post-treatment under an optical microscope (10× and 40×). The data obtained were analysed by analysis of variance through a completely randomized factorial design using the SAS V9 program. The results show that, for H. contortus egg hatching, 85.88% inhibition was obtained at a concentration of 20 mg/mL at 48 h, while for third-stage larva (L3) mortality, the highest percentage was 68.19% at 1.25 mg/mL at 72 h. In the case of N. aberrans, the greatest inhibition of egg hatching was 90.69% at 5 mg/mL at 12 h post-treatment, and for larval mortality, it was 100% at 10 mg/mL at 24 h post-treatment. The main major compounds identified by qualitative analysis and by gas chromatography coupled to mass spectrometry were 9,12,15-octadecatrienoic acid, (Z,Z,Z)-, n-hexadecanoic acid and 2,4-di-tert-butylphenol, and the minor compounds included phytol, γ-sitosterol and α-tocopheryl acetate. It was demonstrated that the ethyl acetate leaf extract of M. oleifera Lam. shows great potential for combating agricultural nematodes.

Moderate to Severe Psoriasis in Pediatric and Young Patients: The BIOBADADERM Registry Experience. / Psoriasis moderada-grave en pacientes pediátricos y jóvenes: experiencia en el registro BIOBADADERM.

Childhood-onset psoriasis generally follows an indolent course but patients with moderate or severe disease may require systemic treatment. The aim of this study was to determine the relative proportion of children and young people aged up to 21 years with moderate to severe psoriasis in the BIOBADADERM registry and to analyze the characteristics of these patients, treatments used, and adverse events. Of the 3946 patients in the registry, 24 were aged 21 years or younger. They had mean age of 16.1 years on starting treatment. When the registry was started, they had a Psoriasis Area and Severity Index of 9.4 and 67% were being treated with a conventional systemic drug. Treatment was discontinued in 14 patients (58%) due to adverse events or a loss or lack of effectiveness. In conclusion, the BIOBADADERM registry shows that young people account for a small proportion of psoriasis patients receiving systemic treatment, and they are more likely to be treated using conventional systemic drugs.

Risk stratification and outreach to hematology/oncology patients during the COVID-19 pandemic.

PURPOSE: Cancer patients have many medical and psychosocial needs, which may increase during the COVID-19 pandemic. We sought to (1) risk-stratify hematology/oncology patients using general medicine and cancer-specific methods to identify those at high risk for acute care utilization, (2) measure the correlation between two risk stratification methods, and (3) perform a telephone-based needs assessment with intervention for high-risk patients. METHODS: Patients were risk-stratified using a general medical health composite score (HCS) and a cancer-specific risk (CSR) stratification based on disease and treatment characteristics. The correlation between HCS and CSR was measured using Spearman's correlation. A multi-disciplinary team developed a focused needs assessment script with recommended interventions for patients categorized as high-risk by either method. The number of patient needs identified and referrals for services made in the first month of outreach are reported. RESULTS: A total of 1697 patients were risk-stratified, with 17% high-risk using HCS and 22% high-risk using CSR. Correlation between HCS and CSR was modest (ρ = 0.41). During the first month of the pilot, 286 patients were called for outreach with 245 contacted (86%). Commonly identified needs were financial difficulties (17%), uncontrolled symptoms (15%), and interest in advance care planning (13%), resulting in referral for supportive services for 33% of patients. CONCLUSION: There is a high burden of unmet medical and psychosocial needs in hematology/oncology patients during the COVID-19 pandemic. A telephone-based outreach program results in the identification of and intervention for these needs; however, additional cancer-specific risk models are needed to improve targeting to high-risk patients.

Molecular detection and identification of spotted fever group rickettsiae in ticks collected from horses in Cuba.

Spotted fever group (SFG) rickettsiae are obligatory intracellular bacteria that cause disease in humans and other animals. Ixodid ticks are the principal vectors of SFG rickettsiae. The present study aimed to determine the prevalence and species identity of SFG rickettsiae in ticks and horses from urban and rural areas of western Cuba using PCR assays. Tick samples, collected from 79 horses, consisted of 14 Amblyomma mixtum adults, 111 Dermacentor nitens adults and 19 pools of D. nitens nymphs (2-5 individuals/pool). The PCR results revealed the presence of Rickettsia spp. in 64% of the A. mixtum adults, 16% of the D. nitens adults, and 11% of the pooled samples of D. nitens nymphs. In contrast, Rickettsia spp. was not detected in any of the 200 horse blood samples included in this study. DNA sequence data of the rickettsial 17 kDa antigen gene showed that Rickettsia amblyommatis was present in A. mixtum; and Rickettsia felis in D. nitens. This is the first report of R. felis in D. nitens in Cuba. The present study extends our knowledge of the potential vector spectrum and distribution of SFG rickettsiae pathogens in western Cuba.

Genome-wide association study for feed efficiency in collective cage-raised rabbits under full and restricted feeding.

Feed efficiency (FE) is one of the most economically and environmentally relevant traits in the animal production sector. The objective of this study was to gain knowledge about the genetic control of FE in rabbits. To this end, GWASs were conducted for individual growth under two feeding regimes (full feeding and restricted) and FE traits collected from cage groups, using 114 604 autosome SNPs segregating in 438 rabbits. Two different models were implemented: (1) an animal model with a linear regression on each SNP allele for growth trait; and (2) a two-trait animal model, jointly fitting the performance trait and each SNP allele content, for FE traits. This last modeling strategy is a new tool applied to GWAS and allows information to be considered from non-genotyped individuals whose contribution is relevant in the group average traits. A total of 189 SNPs in 17 chromosomal regions were declared to be significantly associated with any of the five analyzed traits at a chromosome-wide level. In 12 of these regions, 20 candidate genes were proposed to explain the variation of the analyzed traits, including genes such as FTO, NDUFAF6 and CEBPA previously associated with growth and FE traits in monogastric species. Candidate genes associated with behavioral patterns were also identified. Overall, our results can be considered as the foundation for future functional research to unravel the actual causal mutations regulating growth and FE in rabbits.

Modeling and prediction of COVID-19 in Mexico applying mathematical and computational models.

This work presents the modeling and prediction of cases of COVID-19 infection in Mexico through mathematical and computational models using only the confirmed cases provided by the daily technical report COVID-19 MEXICO until May 8th. The mathematical models: Gompertz and Logistic, as well as the computational model: Artificial Neural Network were applied to carry out the modeling of the number of cases of COVID-19 infection from February 27th to May 8th. The results show a good fit between the observed data and those obtained by the Gompertz, Logistic and Artificial Neural Networks models with an R2 of 0.9998, 0.9996, 0.9999, respectively. The same mathematical models and inverse Artificial Neural Network were applied to predict the number of cases of COVID-19 infection from May 9th to 16th in order to analyze tendencies and extrapolate the projection until the end of the epidemic. The Gompertz model predicts a total of 47,576 cases, the Logistic model a total of 42,131 cases, and the inverse artificial neural network model a total of 44,245 as of May 16th. Finally, to predict the total number of COVID-19 infected until the end of the epidemic, the Gompertz, Logistic and inverse Artificial Neural Network model were used, predicting 469,917, 59,470 and 70,714 cases, respectively.

In vitro nematicidal activity of two ferrocenyl chalcones against larvae of Haemonchus contortus (L3) and Nacobbus aberrans (J2).

The main goal of this work was to evaluate the in vitro biological activity of two ferrocenyl chalcones (FcC-1 and FcC-2) against Haemonchus contortus (third-stage larvae (L3)) and Nacobbus aberrans (second-stage juveniles (J2)). Both compounds were synthesized and characterized by usual spectroscopic methods and their molecular structures were confirmed by single-crystal X-ray diffractometry. Nematode strains were examined in terms of percentage mortality of H. contortus (L3) by the action of FcC-1, which showed an effectivity of 100% at a concentration of 342 µM in 24 h, with EC50 = 20.33 µM and EC90 = 162.76 µM, whereas FcC-2 had an effectivity of 72% at a concentration of 342 µM in 24 h, with EC50 = 167.39 µM and EC90 = 316.21 µM. The effect of FcC-1 against nematode phytoparasite N. aberrans showed a better percentage of 95% at a concentration of 342 µM, with EC50 = 7.18 µM and EC90 = 79.25 µM, whereas the effect of FcC-2 was 87% at 342 µM, with EC50 = 168 µM and EC90 = 319.56 µM at 36 h. After treatment, the scanning electron micrographs revealed deformities in the dorsal flank and posterior part close to the tail of H. contortus L3. They showed moderate in vitro nematicidal activity against H. contortus L3 and N. aberrans J2.

Determination of the seroprevalence of Leptospira spp. and the main serovars circulating in cattle in the province of Manabí, Ecuador. / Determinación de la seroprevalencia de Leptospira spp. y los principales serovares circulantes en el ganado bovino en la provincia de Manabí, Ecuador.

Leptospirosis is a transmissible zoonotic disease caused by pathogenic strains of the genus Leptospira. Clinical signs in cattle are fever, haematuria, haemoglobinuria, meningitis, abortion, birth of weak calves and infertility; in the most severe cases, it can cause death to the animal. The few studies conducted in Ecuador, and in particular the province of Manabí, have revealed varying prevalence rates, ranging from 35.8% to 75%. The objective of this study is to determine the seroprevalence of leptospirosis in cattle and to ascertain the main serovars circulating in the province of Manabí. A cross-sectional epidemiological study was conducted from November 2015 to March 2016, for which seven cantons were selected at random and a total of 854 animals from 67 herds were investigated. The samples were processed in the laboratories of the Animal Diagnostics Directorate of the Ecuadorian Agency for Agriculture Quality Assurance (AGROCALIDAD) in Tumbaco, using the microscopic agglutination test. The sera were analysed to check whether they contained any of the eight serovars of Leptospira interrogans circulating most frequently in the country: Canicola, Hardjo, Pomona, Icterohaemorrhagiae, Grippotyphosa, Wolffi, Bratislava and Copenhageni. Overall seroprevalence at herd level was 97.01%, with the most common serovars being Pomona, Icterohaemorrhagiae, Grippotyphosa, Bratislava and Canicola. It was concluded that there is high seroprevalence at herd level in the province of Manabí.

La leptospirose est une maladie zoonotique infecto-contagieuse causée par des souches pathogènes du genre Leptospira. Chez les bovins, le tableau clinique de la maladie se caractérise par de la fièvre, une hématurie, une hémoglobinurie, une méningite, des cas d'avortement ou la naissance de veaux faibles et une infertilité ; dans les cas les plus graves, la maladie peut provoquer la mort de l'animal. En Équateur et plus précisément dans la province de Manabí, les rares études effectuées jusqu'à ce jour ont rapporté des taux de prévalence allant de 35,8 % à 75 %. Les auteurs présentent les résultats d'une étude visant à déterminer la prévalence sérologique de la leptospirose dans le cheptel bovin de la province de Manabí ainsi que les principaux sérovars présents. Une enquête épidémiologique transversale a été conduite de novembre 2015 à mars 2016 dans sept cantons choisis de manière aléatoire. Au total, 854 animaux appartenant à 67 élevages ont été testés. Les prélèvement ont été préparés par les laboratoires de la Direction du diagnostic vétérinaire de l'Agence équatorienne de la qualité agricole (AGROCALIDAD) de Tumbaco et soumis à une épreuve d'agglutination microscopique afin de déterminer s'ils contenaient l'un ou plusieurs des huit sérovars de Leptospira interrogans présents dans le pays, à savoir Canicola, Hardjo, Pomona, Icterohaemorrhagiae, Grippotyphosa, Wolffi, Bratislava et Copenhageni. La séroprévalence globale au niveau des troupeaux était de 97,01 %, les sérovars les plus fréquents étant Pomona, Icterohaemorrhagiae, Grippotyphosa, Bratislava et Canicola. Les auteurs en concluent que la séroprévalence au niveau des troupeaux est élevée dans la province de Manabí.

La leptospirosis es una enfermedad zoonótica infectocontagiosa causada por cepas patógenas del género Leptospira. En el ganado bovino, clínicamente se caracteriza por fiebre, hematuria, hemoglobinuria, meningitis, abortos y/o nacimiento de animales débiles e infertilidad, y, en los casos más graves, puede provocar la muerte de los animales. En Ecuador, y en concreto en la provincia de Manabí, los escasos estudios realizados denotan prevalencias variables, que van del 35,8% al 75%. El objetivo del presente estudio es determinar la seroprevalencia de la leptospirosis en el ganado bovino y conocer los principales serovares circulantes en la provincia de Manabí. Se realizó un estudio epidemiológico de tipo transversal en el período comprendido entre noviembre de 2015 y marzo de 2016, para el cual se seleccionaron siete cantones al azar y se investigaron un total 854 animales pertenecientes a 67 hatos. Las muestras se procesaron en los Laboratorios de la Dirección de Diagnóstico Animal de la Agencia Ecuatoriana para la Calidad del Agro (AGROCALIDAD) de Tumbaco utilizando la técnica de aglutinación microscópica, y los sueros se analizaron para comprobar si contenían cada uno de los ocho serovares de Leptospira interrogans de mayor circulación en el país: Canicola, Hardjo, Pomona, Icterohaemorrhagiae, Grippotyphosa, Wolffi, Bratislava y Copenhageni. La seroprevalencia general a nivel de hatos fue del 97,01%, siendo los más frecuentes los serovares Pomona, Icterohaemorrhagiae, Grippotyphosa, Bratislava y Canicola. Se llegó a la conclusión de que en la provincia de Manabí existe una alta seroprevalencia a nivel de hatos.

RAD51 foci as a functional biomarker of homologous recombination repair and PARP inhibitor resistance in germline BRCA-mutated breast cancer.

Background: BRCA1 and BRCA2 (BRCA1/2)-deficient tumors display impaired homologous recombination repair (HRR) and enhanced sensitivity to DNA damaging agents or to poly(ADP-ribose) polymerase (PARP) inhibitors (PARPi). Their efficacy in germline BRCA1/2 (gBRCA1/2)-mutated metastatic breast cancers has been recently confirmed in clinical trials. Numerous mechanisms of PARPi resistance have been described, whose clinical relevance in gBRCA-mutated breast cancer is unknown. This highlights the need to identify functional biomarkers to better predict PARPi sensitivity. Patients and methods: We investigated the in vivo mechanisms of PARPi resistance in gBRCA1 patient-derived tumor xenografts (PDXs) exhibiting differential response to PARPi. Analysis included exome sequencing and immunostaining of DNA damage response proteins to functionally evaluate HRR. Findings were validated in a retrospective sample set from gBRCA1/2-cancer patients treated with PARPi. Results: RAD51 nuclear foci, a surrogate marker of HRR functionality, were the only common feature in PDX and patient samples with primary or acquired PARPi resistance. Consistently, low RAD51 was associated with objective response to PARPi. Evaluation of the RAD51 biomarker in untreated tumors was feasible due to endogenous DNA damage. In PARPi-resistant gBRCA1 PDXs, genetic analysis found no in-frame secondary mutations, but BRCA1 hypomorphic proteins in 60% of the models, TP53BP1-loss in 20% and RAD51-amplification in one sample, none mutually exclusive. Conversely, one of three PARPi-resistant gBRCA2 tumors displayed BRCA2 restoration by exome sequencing. In PDXs, PARPi resistance could be reverted upon combination of a PARPi with an ataxia-telangiectasia mutated (ATM) inhibitor. Conclusion: Detection of RAD51 foci in gBRCA tumors correlates with PARPi resistance regardless of the underlying mechanism restoring HRR function. This is a promising biomarker to be used in the clinic to better select patients for PARPi therapy. Our study also supports the clinical development of PARPi combinations such as those with ATM inhibitors.

Autologous dental pulp mesenchymal stem cells for inferior third molar post-extraction socket healing: A split-mouth randomised clinical trial.

BACKGROUND: Since the discovery of adult mesenchymal stem cells extensive research has been conducted to determine their mechanisms of differentiation and effectiveness in cell therapy and regenerative medicine. MATERIAL AND METHODS: To assess the efficacy of autologous dental pulp mesenchymal stem cells delivered in a collagen matrix for post-extraction socket healing, a single-centre, double-blind, randomised, split-mouth, controlled clinical trial was performed. Both impacted mandibular third molars were extracted from 32 patients. Dental pulp was collected and dissociated; the resulting cell suspension, obtained by centrifugation, was incorporated into a resorbable collagen matrix and implanted in 32 experimental post-extraction sockets. Collagen matrices alone were implanted in 32 contralateral, control post-extraction sockets. Two neuroradiologists independently assessed the extent of bone repair at 6 months after the extractions. Computed tomography (CT, Philips Brilliance) and an advanced display platform (IntelliSpace Portal) was used to record extraction socket density, expressed as Hounsfield units (HU) and height (mm) of the distal interdental bone septum of the second molar. Measurements at 6 months post-extraction were compared with measurements obtained immediately after extraction. Data were analysed with the statistical program STATA 14. RESULTS: Two patients dropped out of the study. The final sample consisted of 22 women and 8 men (mean age, 23 years; range: 18-30 years). Clinical, radiological, and surgical characteristics of impacted third molars of the control and experimental groups were homogeneous. Measurements obtained by the two neuroradiologists showed agreement. No significant differences were found in the extent of bone repair during analyses of density (p=0.4203 neuroradiologist 1; p=0.2525 neuroradiologist 2) or interdental septum height (p=0.2280 neuroradiologist 1; p=0.4784 neuroradiologist 2). CONCLUSIONS: In our clinical trial, we were unable to demonstrate that autologous dental pulp mesenchymal stem cells reduce socket bone resorption after inferior third molar extraction.

Diagnostic performance of the measurement of nitric oxide in exhaled air in the diagnosis of COPD phenotypes.

INTRODUCTION: COPD is a highly heterogeneous disease that has a serious impact on affected populations. Patients share some of the features of bronchial asthma, often summarized under the term ACOS (asthma-COPD overlap syndrome). The objective of this study is to evaluate the utility of the measurement of nitric oxide in exhaled air (FENO50) in the diagnosis of COPD phenotypes. MATERIAL AND METHODS: The study comprised cross-sectional observation of patients receiving assistance during a respiratory outpatient visit. Patient data was collected on lung function, FENO, questionnaires scoring CAT®(COPD Assessment Test), and COPD clinical phenotype. RESULTS: 192 patients were studied: 103 with COPD; 16 healthy non-smokers; 30 healthy smokers; and 43 asthmatics. COPD patients were grouped by phenotype: 34 non exacerbators (33.0%); 22 ACOS (21.3%); 13 frequent exacerbators with emphysema (12.6%); and 34 frequent exacerbators with chronic bronchitis (33.0%). ACOS patients showed significantly higher FENO50 values compared to the others after adjustments for confounding factors. FENO50 demonstrated greater diagnostic accuracy than the bronchodilator test (BT) in the diagnosis of ACOS and COPD phenotypes (AUC 0.79 vs 0.74), with an optimal cut-off value of 19 ppb (sensitivity 0.68, specificity 0.75). CONCLUSIONS: Patients with COPD have different levels of FENO50 depending on the COPD phenotype. FENO50 measurement provides better diagnostic accuracy than BT, with an optimal cut-off value of 19 ppb.

Mass spectrometry applied to the identification of Mycobacterium tuberculosis and biomarker discovery.

An adequate and effective tuberculosis (TB) diagnosis system has been identified by the World Health Organization as a priority in the fight against this disease. Over the years, several methods have been developed to identify the bacillus, but bacterial culture remains one of the most affordable methods for most countries. For rapid and accurate identification, however, it is more feasible to implement molecular techniques, taking advantage of the availability of public databases containing protein sequences. Mass spectrometry (MS) has become an interesting technique for the identification of TB. Here, we review some of the most widely employed methods for identifying Mycobacterium tuberculosis and present an update on MS applied for the identification of mycobacterial species.