TRIM33 loss in multiple myeloma is associated with genomic instability and sensitivity to PARP inhibitors.

Deletions of chromosome 1p (del(1p)) are a recurrent genomic aberration associated with poor outcome in Multiple myeloma (MM.) TRIM33, an E3 ligase and transcriptional co-repressor, is located within a commonly deleted region at 1p13.2. TRIM33 is reported to play a role in the regulation of mitosis and PARP-dependent DNA damage response (DDR), both of which are important for maintenance of genome stability. Here, we demonstrate that MM patients with loss of TRIM33 exhibit increased chromosomal instability and poor outcome. Through knockdown studies, we show that TRIM33 loss induces a DDR defect, leading to accumulation of DNA double strand breaks (DSBs) and slower DNA repair kinetics, along with reduced efficiency of non-homologous end joining (NHEJ). Furthermore, TRIM33 loss results in dysregulated ubiquitination of ALC1, an important regulator of response to PARP inhibition. We show that TRIM33 knockdown sensitizes MM cells to the PARP inhibitor Olaparib, and this is synergistic with the standard of care therapy bortezomib, even in co-culture with bone marrow stromal cells (BMSCs). These findings suggest that TRIM33 loss contributes to the pathogenesis of high-risk MM and that this may be therapeutically exploited through the use of PARP inhibitors.

Prevalence of Homologous Recombination Deficiency Among Patients With Germline RAD51C/D Breast or Ovarian Cancer.

Importance: RAD51C and RAD51D are involved in DNA repair by homologous recombination. Germline pathogenic variants (PVs) in these genes are associated with an increased risk of ovarian and breast cancer. Understanding the homologous recombination deficiency (HRD) status of tumors from patients with germline PVs in RAD51C/D could guide therapeutic decision-making and improve survival. Objective: To characterize the clinical and tumor characteristics of germline RAD51C/D PV carriers, including the evaluation of HRD status. Design, Setting, and Participants: This retrospective cohort study included 91 index patients plus 90 relatives carrying germline RAD51C/D PV (n = 181) in Spanish hospitals from January 1, 2014, to December 31, 2021. Genomic and functional HRD biomarkers were assessed in untreated breast and ovarian tumor samples (n = 45) from June 2022 to February 2023. Main Outcomes and Measures: Clinical and pathologic characteristics were assessed using descriptive statistics. Genomic HRD by genomic instability scores, functional HRD by RAD51, and gene-specific loss of heterozygosity were analyzed. Associations between HRD status and tumor subtype, age at diagnosis, and gene-specific loss of heterozygosity in RAD51C/D were investigated using logistic regression or the t test. Results: A total of 9507 index patients were reviewed, and 91 patients (1.0%) were found to carry a PV in RAD51C/D; 90 family members with a germline PV in RAD51C/D were also included. A total of 157 of carriers (86.7%) were women and 181 (55.8%) had received a diagnosis of cancer, mainly breast cancer or ovarian cancer. The most prevalent PVs were c.1026+5_1026+7del (11 of 56 [19.6%]) and c.709C>T (9 of 56 [16.1%]) in RAD51C and c.694C>T (20 of 35 [57.1%]) in RAD51D. In untreated breast cancer and ovarian cancer, the prevalence of functional and genomic HRD was 55.2% (16 of 29) and 61.1% (11 of 18) for RAD51C, respectively, and 66.7% (6 of 9) and 90.0% (9 of 10) for RAD51D. The concordance between HRD biomarkers was 91%. Tumors with the same PV displayed contrasting HRD status, and age at diagnosis did not correlate with the occurrence of HRD. All breast cancers retaining the wild-type allele were estrogen receptor positive and lacked HRD. Conclusions and Relevance: In this cohort study of germline RAD51C/D breast cancer and ovarian cancer, less than 70% of tumors displayed functional HRD, and half of those that did not display HRD were explained by retention of the wild-type allele, which was more frequent among estrogen receptor-positive breast cancers. Understanding which tumors are associated with RAD51C/D and HRD is key to identify patients who can benefit from targeted therapies, such as PARP (poly [adenosine diphosphate-ribose] polymerase) inhibitors.

Potential of Cricket (Acheta domesticus) Flour as a Lean Meat Replacer in the Development of Beef Patties.

This study examined the incorporation of cricket (Acheta domesticus) flour (CF) (0, control; 5.0%, CF5.0; 7.5%, CF7.5; and 10.0%, CF10.0) as a lean meat replacer in beef patties and its impact on composition, microbiological, sensory, and technological properties, as well as its influence on the cooking process. The inclusion of CF led to beef patties with significantly higher protein levels than the control group. Additionally, an elevation in total viable (TVC) and lactic acid bacteria (LAB) counts was observed. However, Enterobacteriaceae counts remained at safe levels. CF5.0 demonstrated similar sensory scores and purchase intention to the control treatment. CF7.5 and CF10.0 showed comparable sensory scores to the control except for texture attributes. The inclusion of CF significantly reduced cooking loss and diameter reduction values. Beef patties with CF were notably firmer and had a browner color than the control. In general, the cooking process impacted the technological properties similarly in both the control and beef patties with CF. In all cooked samples, no significant differences in pH, redness (a*), or texture were observed. This study demonstrated that incorporating up to 5.0% CF into beef patties is optimal in terms of composition, technological, sensorial, and cooking properties.

Exploring the influence of density-dependence and weather on the spatial and temporal variation in common vole (Microtus arvalis) abundance in Castilla y León, NW Spain.

BACKGROUND: The common vole has invaded the agroecosystems of northwestern Spain, where outbreaks cause important crop damage and management costs. Little is yet known about the factors causing or modulating vole fluctuations. Here, we used 11 years of vole abundance monitoring data in 40 sites to study density-dependence and weather influence on vole dynamics. Our objective was to identify the population dynamics structure and determine whether there is direct or delayed density-dependence. An evaluation of climatic variables followed, to determine whether they influenced vole population peaks. RESULTS: First- and second-order outbreak dynamics were detected at 7 and 33 study sites, respectively, together with second-order variability in periodicity (2-3 to 4-5-year cycles). Vole population growth was explained by previous year abundance (mainly numbers in summer and spring) at 21 of the sites (52.5%), by weather variables at 11 sites (27.5%; precipitation or temperature in six and five sites, respectively), and by a combination of previous abundance and weather variables in eight sites (20%). CONCLUSIONS: We detected variability in vole spatiotemporal abundance dynamics, which differs in cyclicity and period. We also found regional variation in the relative importance of previous abundances and weather as factors modulating vole fluctuations. Most vole populations were cyclical, with variable periodicity across the region. Our study is a first step towards the development of predictive modeling, by disclosing relevant factors that might trigger vole outbreaks. It improves decision-making processes within integrated management dealing with mitigation of the agricultural impacts caused by voles. © 2023 Society of Chemical Industry.

Resistance mechanism to fibroblast growth factor receptor (FGFR) inhibitors in cholangiocarcinoma.

Precision medicine is a major achievement that has impacted on management of patients diagnosed with advanced cholangiocarcinoma (CCA) over the last decade. Molecular profiling of CCA has identified targetable alterations, such as fibroblast growth factor receptor-2 (FGFR-2) fusions, and has thus led to the development of a wide spectrum of compounds. Despite favourable response rates, especially with the latest generation FGFRi, there are still a proportion of patients who will not achieve a radiological response to treatment, or who will have disease progression as the best response. In addition, for patients who do respond to treatment, secondary resistance frequently develops and mechanisms of such resistance are not fully understood. This review will summarise the current state of development of FGFR inhibitors in CCA, their mechanism of action, activity, and the hypothesised mechanisms of resistance.

Autophagy, Oxidative Stress, and Alcoholic Liver Disease: A Systematic Review and Potential Clinical Applications.

Ethanol consumption triggers oxidative stress by generating reactive oxygen species (ROS) through its metabolites. This process leads to steatosis and liver inflammation, which are critical for the development of alcoholic liver disease (ALD). Autophagy is a regulated dynamic process that sequesters damaged and excess cytoplasmic organelles for lysosomal degradation and may counteract the harmful effects of ROS-induced oxidative stress. These effects include hepatotoxicity, mitochondrial damage, steatosis, endoplasmic reticulum stress, inflammation, and iron overload. In liver diseases, particularly ALD, macroautophagy has been implicated as a protective mechanism in hepatocytes, although it does not appear to play the same role in stellate cells. Beyond the liver, autophagy may also mitigate the harmful effects of alcohol on other organs, thereby providing an additional layer of protection against ALD. This protective potential is further supported by studies showing that drugs that interact with autophagy, such as rapamycin, can prevent ALD development in animal models. This systematic review presents a comprehensive analysis of the literature, focusing on the role of autophagy in oxidative stress regulation, its involvement in organ-organ crosstalk relevant to ALD, and the potential of autophagy-targeting therapeutic strategies.

Scaffold coupling: ERK activation by trans-phosphorylation across different scaffold protein species.

RAS-ERK (extracellular signal-regulated kinase) pathway signals are modulated by scaffold proteins that assemble the components of different kinase tiers into a sequential phosphorylation cascade. In the prevailing model scaffold proteins function as isolated entities, where the flux of phosphorylation events progresses downstream linearly, to achieve ERK phosphorylation. We show that different types of scaffold proteins, specifically KSR1 (kinase suppressor of Ras 1) and IQGAP1 (IQ motif-containing guanosine triphosphatase activating protein 1), can bind to each other, forming a complex whereby phosphorylation reactions occur across both species. MEK (mitogen-activated protein kinase kinase) bound to IQGAP1 can phosphorylate ERK docked at KSR1, a process that we have named "trans-phosphorylation." We also reveal that ERK trans-phosphorylation participates in KSR1-regulated adipogenesis, and it also underlies the modest cytotoxicity exhibited by KSR-directed inhibitors. Overall, we identify interactions between scaffold proteins and trans-phosphorylation as an additional level of regulation in the ERK cascade, with broad implications in signaling and the design of scaffold protein-aimed therapeutics.

Effect of calcium silicate-based endodontic sealers on tooth color: A 3-year in vitro experimental study.

Objective: To analyze the change in tooth color produced by two hydraulic and one resin-based sealers by means of spectrophotometry for 3 years. Methods: Forty maxillary anterior teeth were selected (n = 10 per group). Root canals were prepared by rotary instrumentation and irrigation was performed with NaOCl, which was also used in the final irrigation, followed by saline and activated with Endoactivator. Root canals were then filled using single cone technique. Negative control (NC): gutta-percha filling; Positive control: gutta-percha and AH Plus; experimental groups: gutta-percha and Bioroot RCS/TotalFill BC Sealer. Gutta-percha was cut 2 mm below the cementoenamel junction, the pulp chamber was sealed with flowable composite. The teeth were kept in PBS. Color was measured in the cervical and incisal halves before root canal treatment (RCT), one and six months after RCT, and after one, two and three years, with the Vita EasyShade spectrophotometer; positioned using an individualized splint. ΔEab and ΔE00 were calculated. Two-way ANOVA repeated measures test followed by Bonferroni post-test were performed to analyze the ΔL, Δa*, Δb*, ΔEab, and ΔE00, considering treatment groups and evaluation periods. Statistical significance was set at p < 0.05. Results: In the incisal half, in decreasing order of darkening, the groups at three years were ordered according to the ΔEab: AH Plus > NC > TotalFill > Bioroot. ΔE00 values were: 1.38 ± 0.61 NC, 2.37 ± 0.70 AH Plus, 1.86 ± 0.60 BioRoot and 1.53 ± 0.85 TotalFill. In the cervical half, the ΔEab values, showed the same descending order, except for Bioroot and TotalFill which alternated the order. The ΔE00 values were 1.86 ± 0.61 NC, 3.01 ± 0.70 AH Plus,1.89 ± 0.58 Bioroot and 1.65 ± 0.41 TotalFill, with no significant differences between groups and times in both locations. Conclusions: All groups presented some degree of discoloration. Lightness and b* component were the most influential. Calcium silicate-based cements (Bioroot RCS and TotalFill BC Sealer) produced acceptable levels of discoloration at the end of follow-up.

DNA Damage Response Alterations in Ovarian Cancer: From Molecular Mechanisms to Therapeutic Opportunities.

The DNA damage response (DDR), a set of signaling pathways for DNA damage detection and repair, maintains genomic stability when cells are exposed to endogenous or exogenous DNA-damaging agents. Alterations in these pathways are strongly associated with cancer development, including ovarian cancer (OC), the most lethal gynecologic malignancy. In OC, failures in the DDR have been related not only to the onset but also to progression and chemoresistance. It is known that approximately half of the most frequent subtype, high-grade serous carcinoma (HGSC), exhibit defects in DNA double-strand break (DSB) repair by homologous recombination (HR), and current evidence indicates that probably all HGSCs harbor a defect in at least one DDR pathway. These defects are not restricted to HGSCs; mutations in ARID1A, which are present in 30% of endometrioid OCs and 50% of clear cell (CC) carcinomas, have also been found to confer deficiencies in DNA repair. Moreover, DDR alterations have been described in a variable percentage of the different OC subtypes. Here, we overview the main DNA repair pathways involved in the maintenance of genome stability and their deregulation in OC. We also recapitulate the preclinical and clinical data supporting the potential of targeting the DDR to fight the disease.

Real-world safety and effectiveness of maintenance niraparib for platinum-sensitive recurrent ovarian cancer: A GEICO retrospective observational study within the Spanish expanded-access programme.

AIM: To describe patient characteristics, effectiveness and safety in a real-world population treated with niraparib in the Spanish expanded-access programme. PATIENTS AND METHODS: This retrospective observational study included women with platinum-sensitive recurrent high-grade serous ovarian cancer who received maintenance niraparib within the Spanish niraparib expanded-access programme. Eligible patients had received ≥2 previous lines of platinum-containing therapy, remained platinum-sensitive after the penultimate line of platinum and had responded to the most recent platinum-containing therapy. Niraparib dosing was at the treating physician's discretion (300 mg/day fixed starting dose or individualised starting dose [ISD] according to baseline body weight and platelet count). Safety, impact of dose adjustments, patient characteristics and effectiveness were analysed using data extracted from medical records. RESULTS: Among 316 eligible patients, 80% had BRCA wild-type tumours and 66% received an ISD. Median niraparib duration was 7.8 months. The most common adverse events typically occurred within 3 months of starting niraparib. Median progression-free survival was 8.6 (95% confidence interval [CI] 7.6-10.0) months. One- and 2-year overall survival rates were 86% (95% CI 81-89%) and 65% (95% CI 59-70%), respectively. Dose interruptions, dose reductions, haematological toxicities and asthenia/fatigue were less common with ISD than fixed starting dose niraparib, but progression-free survival was similar irrespective of dosing strategy. Subsequent therapy included platinum in 71% of patients who received further treatment. CONCLUSION: Outcomes in this large real-world dataset of niraparib-treated patients are consistent with phase III trials, providing reassuring evidence of the tolerability and activity of niraparib maintenance therapy for platinum-sensitive recurrent ovarian cancer. GOV REGISTRATION: NCT04546373.

Análise vacinal de estudantes em uma faculdade de medicina / Analysis of the vaccination status of students at a medical school / Análisis de vacunación de estudiantes de una facultad de medicina

Objetivo: O estudo analisa a situação vacinal dos estudantes de medicina de uma faculdade do interior de São Paulo, além de verificar seu conhecimento em relação à imunização. Método: Foi realizada a análise na carteira vacinal de 277 estudantes de medicina e disponibilizado um questionário autoaplicável. A análise dos dados foi conduzida de maneira estatística descritiva para interpretação dos resultados. Resultados: Verificou-se que mais da metade dos estudantes apresentam carteiras vacinais desatualizadas e poucos conhecem quais vacinas são indicadas aos profissionais de saúde, embora mais da metade dos estudantes reconheça o risco de contágio e transmissão de doenças relacionadas ao esquema vacinal incompleto. Conclusão: Esses resultados demonstram a necessidade de conscientização dos acadêmicos de medicina quanto à atualização de seus cartões vacinais e do aprofundamento do conhecimento e domínio sobre o tema vacinação (AU).

Objective: The study analyzes the vaccination status of medical students at a college in the interior of São Paulo, in addition to verifying their knowledge regarding immunization. Method: An analysis was carried out on the vaccination records of 277 medical students and a self-administered questionnaire was made available. Data analysis was conducted in a descriptive statistical manner to interpret the results. Results: It was found that more than half of the students have outdated vaccination records and few know which vaccines are indicated to health professionals, although more than half of the students recognize the risk of contagion and transmission of diseases related to an incomplete vaccination schedule. Conclusion: These results demonstrate the need for medical students to be aware of updating their vaccination cards and deepening their knowledge and mastery of the topic of vaccination (AU).

Objetivo: El estudio analiza el estado de vacunación de estudiantes de medicina de una facultad del interior de São Paulo, además de verificar sus conocimientos sobre vacunación. Método: Se realizó un análisis de los registros de vacunación de 277 estudiantes de medicina y se dispuso de un cuestionario autoadministrado. El análisis de datos se realizó de manera estadística descriptiva para interpretar los resultados. Resultados: Se encontró que más de la mitad de los estudiantes tienen cartilla de vacunación desactualizada y pocos saben qué vacunas están indicadas a los profesionales de la salud, aunque más de la mitad de los estudiantes reconocen el riesgo de contagio y transmisión de enfermedades relacionadas con un esquema de vacunación incompleto. Conclusión: Estos resultados demuestran la necesidad de que los estudiantes de medicina estén atentos a la actualización de sus carnés de vacunación y profundicen en el conocimiento y dominio del tema de la vacunación (AU).

Plant Antioxidants in Dry Fermented Meat Products with a Healthier Lipid Profile.

Consumers' perception of meat products has changed in recent years, which has led to an increased interest in healthier meat products. In response to this demand, academia and industry have made efforts to reformulate meat products, especially dry fermented meat products, which are known for their high fat contents, mainly saturated fat. The use of plant or marine oils stabilized in emulsion gels (EGs) or oil-bulking agents (OBAs) as animal fat replacers has been one of the most advantageous strategies to reformulate dry fermented meat products with a healthier lipid content (quality and quantity), but an increase in their polyunsaturated fatty acid content can trigger a significant increase in lipid oxidation, negatively affecting sensory and nutritional quality. The use of antioxidants is the main strategy to delay this deteriorative reaction, but the controversy around the safety and toxicity of synthetic antioxidants has driven consumers and industry toward the use of plant antioxidants, such as phenolic compounds, carotenoids, and some vitamins and minerals. This review provides information about the use of plant antioxidants to control lipid oxidation of dry fermented meat products with healthier lipids.

Immune Checkpoint Inhibitors and RAS-ERK Pathway-Targeted Drugs as Combined Therapy for the Treatment of Melanoma.

Metastatic melanoma is a highly immunogenic tumor with very poor survival rates due to immune system escape-mechanisms. Immune checkpoint inhibitors (ICIs) targeting the cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and the programmed death-1 (PD1) receptors, are being used to impede immune evasion. This immunotherapy entails an increment in the overall survival rates. However, melanoma cells respond with evasive molecular mechanisms. ERK cascade inhibitors are also used in metastatic melanoma treatment, with the RAF activity blockade being the main therapeutic approach for such purpose, and in combination with MEK inhibitors improves many parameters of clinical efficacy. Despite their efficacy in inhibiting ERK signaling, the rewiring of the melanoma cell-signaling results in disease relapse, constituting the reinstatement of ERK activation, which is a common cause of some resistance mechanisms. Recent studies revealed that the combination of RAS-ERK pathway inhibitors and ICI therapy present promising advantages for metastatic melanoma treatment. Here, we present a recompilation of the combined therapies clinically evaluated in patients.

Panobinostat Synergistically Enhances the Cytotoxicity of Microtubule Destabilizing Drugs in Ovarian Cancer Cells.

Ovarian cancer (OC) is one of the most common gynecologic neoplasia and has the highest mortality rate, which is mainly due to late-stage diagnosis and chemotherapy resistance. There is an urgent need to explore new and better therapeutic strategies. We have previously described a family of Microtubule Destabilizing Sulfonamides (MDS) that does not trigger multidrug-mediated resistance in OC cell lines. MDS bind to the colchicine site of tubulin, disrupting the microtubule network and causing antiproliferative and cytotoxic effects. In this work, a novel microtubule-destabilizing agent (PILA9) was synthetized and characterized. This compound also inhibited OC cell proliferation and induced G2/M cell cycle arrest and apoptosis. Interestingly, PILA9 was significantly more cytotoxic than MDS. Here, we also analyzed the effect of these microtubule-destabilizing agents (MDA) in combination with Panobinostat, a pan-histone deacetylase inhibitor. We found that Panobinostat synergistically enhanced MDA-cytotoxicity. Mechanistically, we observed that Panobinostat and MDA induced α-tubulin acetylation and that the combination of both agents enhanced this effect, which could be related to the observed synergy. Altogether, our results suggest that MDA/Panobinostat combinations could represent new therapeutic strategies against OC.

Rucaparib in recurrent ovarian cancer: real-world experience from the rucaparib early access programme in Spain - A GEICO study.

BACKGROUND: Rucaparib is a poly(ADP-ribose) polymerase inhibitor approved in Europe as maintenance therapy for recurrent platinum-sensitive (Pt-S) ovarian cancer (OC). The Rucaparib Access Programme (RAP) was designed to provide early access to rucaparib for the above-mentioned indication, as well as for patients with BRCA-mutated Pt-S or platinum-resistant (Pt-R) OC and no therapeutic alternatives. METHODS: In this observational, retrospective study we analysed the efficacy and safety of rucaparib within the RAP in Spain. Hospitals associated with the Spanish Ovarian Cancer Research Group (GEICO) recruited patients with high-grade epithelial ovarian, fallopian tube, or primary peritoneal cancer treated with rucaparib 600 mg twice daily as maintenance or treatment (Pt-S/Pt-R) in the RAP. Baseline characteristics, efficacy, and safety data were collected. RESULTS: Between July 2020 and February 2021, 51 patients treated in 22 hospitals in the RAP were included in the study. Eighteen patients with a median of 3 (range, 1-6) prior treatment lines received rucaparib as maintenance; median progression-free survival (PFS) for this group was 9.1 months (95% confidence interval [CI], 4.2-11.6 months). Among 33 patients (median 5 [range, 1-9] prior treatment lines) who received rucaparib as treatment, 7 and 26 patients had Pt-S and Pt-R disease, respectively. Median PFS was 10.6 months (95% CI, 2.5 months-not reached) in the Pt-S group and 2.2 months (95% CI, 1.1-3.2 months) in the Pt-R group. Grade ≥ 3 treatment-emergent adverse events were reported in 39% of all patients, the most common being anaemia (12% and 15% in the maintenance and treatment groups, respectively). At data cut-off, 5 patients remained on treatment. CONCLUSION: Efficacy results in these heavily pre-treated patients were similar to those from previous trials. The safety profile of rucaparib in real life was predictable and manageable.

Two-Way Twisting of a Confined Monolayer: Orientational Ordering within the van der Waals Gap between Graphene and Its Crystalline Substrate.

Two-dimensional confinement of lattices produces a variety of order and disorder phenomena. When the confining walls have atomic granularity, unique structural phases are expected, of relevance in nanotribology, porous materials, or intercalation compounds where, e.g., electronic states can emerge accordingly. The interlayer's own order is frustrated by the competing interactions exerted by the two confining surfaces. We revisit the concept of orientational ordering, introduced by Novaco and McTague to describe the twist of incommensurate monolayers on crystalline surfaces. We predict a two-way twist of the monolayer as its density increases. We discover such a behavior in alkali atom monolayers (sodium, cesium) confined between graphene and an iridium surface, using scanning tunneling microscopy and electron diffraction.

Recurrent NOMO1 Gene Deletion Is a Potential Clinical Marker in Early-Onset Colorectal Cancer and Is Involved in the Regulation of Cell Migration.

The incidence of early-onset colorectal cancer (EOCRC; age younger than 50 years) has been progressively increasing over the last decades globally, with causes unexplained. A distinct molecular feature of EOCRC is that compared with cases of late-onset colorectal cancer, in EOCRC cases, there is a higher incidence of Nodal Modulator 1 (NOMO1) somatic deletions. However, the mechanisms of NOMO1 in early-onset colorectal carcinogenesis are currently unknown. In this study, we show that in 30% of EOCRCs with heterozygous deletion of NOMO1, there were pathogenic mutations in this gene, suggesting that NOMO1 can be inactivated by deletion or mutation in EOCRC. To study the role of NOMO1 in EOCRC, CRISPR/cas9 technology was employed to generate NOMO1 knockout HCT-116 (EOCRC) and HS-5 (bone marrow) cell lines. NOMO1 loss in these cell lines did not perturb Nodal pathway signaling nor cell proliferation. Expression microarrays, RNA sequencing, and protein expression analysis by LC-IMS/MS showed that NOMO1 inactivation deregulates other signaling pathways independent of the Nodal pathway, such as epithelial-mesenchymal transition and cell migration. Significantly, NOMO1 loss increased the migration capacity of CRC cells. Additionally, a gut-specific conditional NOMO1 KO mouse model revealed no subsequent tumor development in mice. Overall, these findings suggest that NOMO1 could play a secondary role in early-onset colorectal carcinogenesis because its loss increases the migration capacity of CRC cells. Therefore, further study is warranted to explore other signalling pathways deregulated by NOMO1 loss that may play a significant role in the pathogenesis of the disease.

Prospective Longitudinal Study of Putative Agents Involved in Complex Gill Disorder in Atlantic salmon (Salmo salar).

Complex gill disorder (CGD) is an important condition in Atlantic salmon aquaculture, but the roles of the putative aetiological agents in the pathogenesis are uncertain. A longitudinal study was undertaken on two salmon farms in Scotland to determine the variations in loads of CGD-associated pathogens (Desmozoon lepeophtherii, Candidatus Branchiomonas cysticola, salmon gill pox virus (SGPV) and Neoparamoeba perurans) estimated by quantitative PCR. In freshwater, Ca. B. cysticola and SGPV were detected in both populations, but all four pathogens were detected on both farms during the marine stage. Candidatus B. cysticola and D. lepeophtherii were detected frequently, with SGPV detected sporadically. In the marine phase, increased N. perurans loads associated significantly (p < 0.05) with increases in semi-quantitative histological gill-score (HGS). Increased Ca. B. cysticola load associated significantly (p < 0.05) with increased HGS when only Farm B was analysed. Higher loads of D. lepeophtherii were associated significantly (p < 0.05) with increased HGS on Farm B despite the absence of D. lepeophtherii-type microvesicles. Variations in SGPV were not associated significantly (p > 0.05) with changes in HSG. This study also showed that water temperature (season) and certain management factors were associated with higher HGS. This increase in histological gill lesions will have a deleterious impact on fish health and welfare, and production performance.

Chloroquine-Induced DNA Damage Synergizes with Nonhomologous End Joining Inhibition to Cause Ovarian Cancer Cell Cytotoxicity.

Ovarian cancer (OC) is the most lethal gynecological malignancy; therefore, more effective treatments are urgently needed. We recently reported that chloroquine (CQ) increased reactive oxygen species (ROS) in OC cell lines (OCCLs), causing DNA double-strand breaks (DSBs). Here, we analyzed whether these lesions are repaired by nonhomologous end joining (NHEJ), one of the main pathways involved in DSB repair, and if the combination of CQ with NHEJ inhibitors (NHEJi) could be effective against OC. We found that NHEJ inhibition increased the persistence of γH2AX foci after CQ-induced DNA damage, revealing an essential role of this pathway in the repair of the lesions. NHEJi decreased the proliferation of OCCLs and a strong in vitro synergistic effect on apoptosis induction was observed when combined with CQ. This effect was largely abolished by the antioxidant N-Acetyl-L-cysteine, revealing the critical role of ROS and DSB generation in CQ/NHEJi-induced lethality. We also found that the NHEJ efficiency in OCCLs was not affected by treatment with Panobinostat, a pan-histone deacetylase inhibitor that also synergizes with CQ in OCCLs by impairing homologous recombination. Accordingly, the triple combination of CQ-NHEJi-Panobinostat exerted a stronger in vitro synergistic effect. Altogether, our data suggest that the combination of these drugs could represent new therapeutic strategies against OC.

Characterisation of a nucleo-adhesome.

In addition to central functions in cell adhesion signalling, integrin-associated proteins have wider roles at sites distal to adhesion receptors. In experimentally defined adhesomes, we noticed that there is clear enrichment of proteins that localise to the nucleus, and conversely, we now report that nuclear proteomes contain a class of adhesome components that localise to the nucleus. We here define a nucleo-adhesome, providing experimental evidence for a remarkable scale of nuclear localisation of adhesion proteins, establishing a framework for interrogating nuclear adhesion protein functions. Adding to nuclear FAK's known roles in regulating transcription, we now show that nuclear FAK regulates expression of many adhesion-related proteins that localise to the nucleus and that nuclear FAK binds to the adhesome component and nuclear protein Hic-5. FAK and Hic-5 work together in the nucleus, co-regulating a subset of genes transcriptionally. We demonstrate the principle that there are subcomplexes of nuclear adhesion proteins that cooperate to control transcription.