Identifying and targeting key driver genes for collagen production within the 11q13/14 breast cancer amplicon.

Genetic studies indicate that breast cancer can be divided into several basic molecular groups. One of these groups, termed IntClust-2, is characterized by amplification of a small portion of chromosome 11 and has a median survival of only five years. Several cancer-relevant genes occupy this portion of chromosome 11, and it is thought that overexpression of a combination of driver genes in this region is responsible for the poor outcome of women in this group. In this study we used a gene editing method to knock out, one by one, each of 198 genes that are located within the amplified region of chromosome 11 and determined how much each of these genes contributed to the survival of breast cancer cells. In addition to well-known drivers such as CCND1 and PAK1 , we identified two different genes ( SERPINH1 and P4HA3 ), that encode proteins involved in collagen synthesis and organization. Using both in vitro and in vivo functional analyses, we determined that P4HA3 and/or SERPINH1 provide a critical driver function on IntClust-2 basic processes, such as viability, proliferation, and migration. Inhibiting these enzymes via genetic or pharmacologic means reduced collagen synthesis and impeded oncogenic signaling transduction in cell culture models, and a small-molecule inhibitor of P4HA3 was effective in treating 11q13 tumor growth in an animal model. As collagen has a well-known association with tissue stiffness and aggressive forms of breast cancer, we believe that the two genes we identified provide an opportunity for a new therapeutic strategy in IntClust-2 breast cancers.

Trabectedin and low-dose radiation therapy in patients with advanced leiomyosarcoma.

Background and objectives: Dimensional response is an unmet need in second lines of advanced soft tissue sarcomas (STS). Indeed, the three approved drugs, pazopanib, trabectedin, and eribulin, achieved an overall response rate (ORR) of less than 10%. This fact potentially hinders the options for fast symptomatic relief or surgical rescue. The combination of trabectedin plus low-dose radiation therapy (T-XRT) demonstrated a response rate of 60% in phase I/II trial, while real-life data achieved 32.5% ORR, probably due to a more relaxed timing between treatments. These results were obtained in progressing and advanced STS. In this study, the merged databases (trial plus real life) have been analyzed, with a special focus on leiomyosarcoma patients. Design and methods: As responses were seen in a wide range of sarcoma histologies (11), this study planned to analyze whether leiomyosarcoma, the largest subtype with 26 cases (30.6%) in this series, exhibited a better clinical outcome with this therapeutic strategy. In addition, four advanced and progressing leiomyosarcoma patients, all with extraordinarily long progression-free survival of over 18 months, were collected. Results: A total of 847 cycles of trabectedin were administered to 85 patients, with the median number of cycles per patient being 7 (1-45+). A trend toward a longer progression-free survival (PFS) was observed in leiomyosarcoma patients with median PFS (mPFS) of 9.9 months [95% confidence interval (CI): 1.1-18.7] versus 5.6 months (95% CI: 3.2-7.9) for the remaining histologies, p = 0.25. When leiomyosarcoma and liposarcoma were grouped, this difference reached statistical significance, probably due to the special sensitivity of myxoid liposarcoma. The mPFS for L-sarcomas was 12.7 months (95% CI: 7-18.5) versus 4.3 months (95% CI: 3.3-5.3) for the remaining histologies, p = 0.001. Cases with long-lasting disease control are detected among leiomyosarcoma patients. Conclusion: Even when extraordinarily long-lasting responses do exist among leiomyosarcoma patients treated with T-XR, we were unable to demonstrate a significant difference favoring leiomyosarcoma patients in clinical outcomes.

Unique vulnerability of RAC1-mutant melanoma to combined inhibition of CDK9 and immune checkpoints.

RAC1P29S is the third most prevalent hotspot mutation in sun-exposed melanoma. RAC1 alterations in cancer are correlated with poor prognosis, resistance to standard chemotherapy, and insensitivity to targeted inhibitors. Although RAC1P29S mutations in melanoma and RAC1 alterations in several other cancers are increasingly evident, the RAC1-driven biological mechanisms contributing to tumorigenesis remain unclear. Lack of rigorous signaling analysis has prevented identification of alternative therapeutic targets for RAC1P29S-harboring melanomas. To investigate the RAC1P29S-driven effect on downstream molecular signaling pathways, we generated an inducible RAC1P29S expression melanocytic cell line and performed RNA-sequencing (RNA-seq) coupled with multiplexed kinase inhibitor beads and mass spectrometry (MIBs/MS) to establish enriched pathways from the genomic to proteomic level. Our proteogenomic analysis identified CDK9 as a potential new and specific target in RAC1P29S-mutant melanoma cells. In vitro, CDK9 inhibition impeded the proliferation of in RAC1P29S-mutant melanoma cells and increased surface expression of PD-L1 and MHC Class I proteins. In vivo, combining CDK9 inhibition with anti-PD-1 immune checkpoint blockade significantly inhibited tumor growth only in melanomas that expressed the RAC1P29S mutation. Collectively, these results establish CDK9 as a novel target in RAC1-driven melanoma that can further sensitize the tumor to anti-PD-1 immunotherapy.

Virtual Pedagogy and Care: Systematic Review on Educational Innovation with Mobile Applications for the Development of Healthy Habits in the Adolescent Population.

BACKGROUND: The scientific literature was reviewed to determine the state of the art regarding innovative educational practices that employ mobile health applications with the aim of establishing healthy habits in the adolescent population, following a strategy based on spiral curriculum. METHODS: The search was conducted in the WOS, Scopus and PubMed databases, discarding any articles that were not published in English, Spanish or French. The search was limited to studies performed in the last 6 years, that is, from 1 January 2017 to 18 March 2023. RESULTS: From the initial sample of 132 articles selected, the final sample included 9 articles that met the eligibility criteria after a more exhaustive analysis. This systematic review identified one application (11.11%) with topics about sex and reproductive health, two applications (22.22%) that tackled mental health, six applications (66.66%) with topics about nutrition, three applications (33.33%) that contemplate physical activity, and two applications (22.22%) with aspects related to the prevention of harmful habits. The results show a positive relationship between the use of mobile health applications used as innovative didactic resources and the establishment of healthy habits in the adolescent population. CONCLUSIONS: Digital devices have been incorporated to the lives of humans as fundamental tools for their daily living. Specifically, adolescents are especially attracted to mobile phones. If this resource is used in this population to improve health, it is possible to attain very satisfactory objectives. The results of this review indicate that these devices can be used as a didactic resource in the promotion of health by implementing healthy habits at early ages, thereby contributing to the prevention of chronic diseases in future adulthood.

Ultrasound-Guided Ethanol Percutaneous Ablation Versus Rescue Surgery in Patients With Locoregional Recurrence of Papillary Thyroid Cancer.

OBJECTIVES: Neck recurrence of papillary thyroid cancer (PTC) is frequently detected after initial surgery. The management of these lesions may include rescue surgery (RS) or minimally invasive techniques in selected patients, but comparative studies evaluating the effectiveness and safety of these techniques are lacking. In this paper, we compared ultrasound-guided ethanol ablation (EA) in selected patients to RS in a matched cohort. METHODS: We retrospectively compared 41 patients and 41 matched PTC patients without known distant metastases, who underwent ultrasound-guided EA or RS (matched reference group), who had 63 and 75 thyroid bed and/or lymph node confirmed PTC recurrences during a median follow-up of 72.8 and 89.6 months, respectively. The primary outcome was time until structural recurrence, compared using Kaplan-Meier survival curves. The secondary outcomes included time until biochemical recurrence, plasma thyroglobulin (Tg) levels, American Thyroid Association (ATA) response-to-therapy categories by the last available observation, and treatment-derived complications in each group. RESULTS: No significant differences were found between the EA and RS groups for time until structural recurrence (log-rank test, P=0.94). The time until biochemical recurrence was also similar (P=0.51); and the plasma Tg concentration reduction and proportions of patients in the ATA reclassification categories were also similar. A significantly higher proportion of patients in the RS group presented treatment-derived complications (29.27% vs. 9.75%, P<0.05). CONCLUSION: In this retrospective analysis, the treatment of PTC neck recurrence with EA in selected patients was comparable to RS in a matched reference group for the long-term risk of structural or biochemical relapse, but with a lower risk of treatment-derived complications. These. RESULTS: support the effectiveness and safety of this minimally invasive technique in the management of selected patients with recurrent PTC.

Unique vulnerability of RAC1-mutant melanoma to combined inhibition of CDK9 and immune checkpoints.

RAC1P29S is the third most prevalent hotspot mutation in sun-exposed melanoma. RAC1 alterations in cancer are correlated with poor prognosis, resistance to standard chemotherapy, and insensitivity to targeted inhibitors. Although RAC1P29S mutations in melanoma and RAC1 alterations in several other cancers are increasingly evident, the RAC1-driven biological mechanisms contributing to tumorigenesis remain unclear. Lack of rigorous signaling analysis has prevented identification of alternative therapeutic targets for RAC1P29S-harboring melanomas. To investigate the RAC1P29S-driven effect on downstream molecular signaling pathways, we generated an inducible RAC1P29S expression melanocytic cell line and performed RNA-sequencing (RNA-seq) coupled with multiplexed kinase inhibitor beads and mass spectrometry (MIBs/MS) to establish enriched pathways from the genomic to proteomic level. Our proteogenomic analysis identified CDK9 as a potential new and specific target in RAC1P29S-mutant melanoma cells. In vitro, CDK9 inhibition impeded the proliferation of in RAC1P29S-mutant melanoma cells and increased surface expression of PD-L1 and MHC Class I proteins. In vivo, combining CDK9 inhibition with anti-PD-1 immune checkpoint blockade significantly inhibited tumor growth only in melanomas that expressed the RAC1P29S mutation. Collectively, these results establish CDK9 as a novel target in RAC1-driven melanoma that can further sensitize the tumor to anti-PD-1 immunotherapy.

Isomeric Aromatic Polyimides Containing Biphenyl Moieties for Gas Separation Applications.

An optimized synthesis of the monomer 2,2'3,3'-biphenyltetracarboxylic dianhydride, iBPDA, was performed to obtain high molecular weight polymers. This monomer has a contorted structure that produces a non-linear shape, hindering the packing of the polymer chain. Aromatic polyimides of high molecular weight were obtained by reaction with the commercial diamine 2,2-bis(4-aminophenyl) hexafluoropropane, 6FpDA, which is a very common monomer in gas separation applications. This diamine has hexafluoroisopropylidine groups which introduce rigidity in the chains, hindering efficient packing. The thermal treatment of the polymers processed as dense membranes had two targets: on the one hand, to achieve the complete elimination of the solvent used, which could remain occluded in the polymeric matrix, and on the other hand to ensure the complete cycloimidization of the polymer. A thermal treatment exceeding the glass transition temperature was performed to ensure the maximum degree of imidization at 350 °C. The good mechanical properties of these materials allow for their use in high-pressure gas purification applications. Moreover, models of the polymers exhibited an Arrhenius-like behavior characteristic of secondary relaxations, normally associated with local motions of the molecular chain. The gas productivity of these membranes was high.

Age-standardized incidence, mortality rate, and trend changes of thyroid cancer in the Balearic Islands during the 2000-2020 period: a population-based study.

Objective: Global thyroid cancer (TC) incidence is growing worldwide, but great heterogenicity exists among published studies, and thus, population-specific epidemiological studies are needed to adequate health resources and evaluate the impact of overdiagnosis. Methods: We conducted a Public Health System database retrospective review of TC incident cases from 2000 to 2020 in the Balearic Islands region and evaluated age-standardized incidence rate (ASIR), age at diagnosis, gender distribution, tumor size and histological subtype, mortality rate (MR), and cause of death. Estimated annual percent changes (EAPCs) were also evaluated and data from the 2000-2009 period were compared to the 2010-2020 period when neck ultrasound (US) was routinely performed by clinicians at Endocrinology Departments. Results: A total of 1387 incident cases of TC were detected. Overall, ASIR (×105) was 5.01 with a 7.82% increment in EAPC. A significant increase in the 2010-2020 period was seen for ASIR (6.99 vs 2.82, P < 0.001) and age at diagnosis (52.11 vs 47.32, P < 0.001) compared to the 2000-2009 period. A reduction in tumor size (2.00 vs 2.78 cm, P < 0.001) and a 6.31% increase in micropapillary TC (P < 0.05) were also seen. Disease-specific MR remained stable at 0.21 (×105). The mean age at diagnosis for all mortality groups was older than survivors (P < 0.001). Conclusion: The incidence of TC has grown in the 2000-2020 period in the Balearic Islands, but MR has not changed. Beyond other factors, a significant contribution of overdiagnosis to this increased incidence is likely due to changes in the routine management of thyroid nodular disease and increased availability of neck US.

Aromatic Polyimide Membranes with tert-Butyl and Carboxylic Side Groups for Gas Separation Applications-Covalent Crosslinking Study.

A set of aromatic copolyimides was obtained by reaction of 4,4'-(hexafluoroisopropylidene) diphthalic anhydride (6FDA), and mixtures of the diamines 1,4-bis(4-amino-2-trifluoromethylphenoxy)-2,5-di-tert-butylbenzene (CF3TBAPB) and 3,5-diamino benzoic acid (DABA). These polymers were characterized and compared with the homopolymer derived from 6FDA and CF3TBAPB. All copolyimides showed high molecular weight values and good mechanical properties. The presence of carboxylic groups in these copolymers allowed their chemical crosslinking by reaction with 1,4-butanediol. Glass transition temperatures (Tg) were higher than 260 °C, showing the non-crosslinked copolyimides had the highest Tg values. Degradation temperature of crosslinked copolyimides was lower than their corresponding non-crosslinked ones. Mechanical properties of all polymers were good, and thus, copolyimide (precursor, and crosslinked ones) films could be tested as gas separation membranes. It was observed that CO2 permeability values were around 100 barrer. Finally, the plasticization resistance of the crosslinked material having a large number of carboxylic groups was excellent.

Free triiodothyronine levels and age influences the metabolic profile and COVID-19 severity parameters in euthyroid and levothyroxine-treated patients.

Metabolic reprogramming is required to fight infections and thyroid hormones are key regulators of metabolism. We have analyzed in hospitalized COVID-19 patients: 40 euthyroid and 39 levothyroxine (LT4)-treated patients in the ward and 29 euthyroid and 9 LT4-treated patients in the intensive care unit (ICU), the baseline characteristics, laboratory data, thyroid-stimulating hormone (TSH), free thyroxine (FT4), free triiodothyronine (FT3), the FT3/FT4 ratio, 11 antiviral cytokines and 74 metabolomic parameters. No evidence for significant differences between euthyroid and LT4-treated patients were found in the biochemical, metabolomic and cytokines parameters analyzed. Only TSH (p=0.009) and ferritin (p=0.031) showed significant differences between euthyroid and LT4-treated patients in the ward, and TSH (p=0.044) and FT4 (p=0.012) in the ICU. Accordingly, severity and mortality were similar in euthyroid and LT4-treated patients. On the other hand, FT3 was negatively related to age (p=0.012), independently of sex and body mass index in hospitalized COVID-19 patients. Patients with low FT3 and older age showed a worse prognosis and higher levels of the COVID-19 severity markers IL-6 and IL-10 than patients with high FT3. IL-6 negatively correlated with FT3 (p=0.023) independently of age, body mass index and sex, whereas IL-10 positively associated with age (p=0.035) independently of FT3, body mass index and sex. A metabolomic cluster of 6 parameters defined low FT3 ward patients. Two parameters, esterified cholesterol (p=4.1x10-4) and small HDL particles (p=6.0x10-5) correlated with FT3 independently of age, body mass index and sex, whereas 3-hydroxybutyrate (p=0.010), acetone (p=0.076), creatinine (p=0.017) and high-density-lipoprotein (HDL) diameter (p=8.3x10-3) were associated to FT3 and also to age, with p-values of 0.030, 0.026, 0.017 and 8.3x10-3, respectively. In conclusion, no significant differences in FT3, cytokines, and metabolomic profile, or in severity and outcome of COVID-19, were found during hospitalization between euthyroid patients and hypothyroid patients treated with LT4. In addition, FT3 and age negatively correlate in COVID-19 patients and parameters that predict poor prognosis were associated with low FT3, and/or with age. A metabolomic cluster indicative of a high ketogenic profile defines non-critical hospitalized patients with low FT3 levels.

Thermally Rearranged Mixed Matrix Membranes from Copoly(o-hydroxyamide)s and Copoly(o-hydroxyamide-amide)s with a Porous Polymer Network as a Filler-A Comparison of Their Gas Separation Performances.

Copoly(o-hydroxyamide)s (HPA) and copoly(o-hydroxyamide-amide)s (PAA) have been synthesized to be used as continuous phases in mixed matrix membranes (MMMs). These polymeric matrices were blended with different loads (15 and 30 wt.%) of a relatively highly microporous porous polymer network (PPN). SEM images of the manufactured MMMs exhibited good compatibility between the two phases for all the membranes studied, and their mechanical properties have been shown to be good enough even after thermal treatment. The WAX results show that the addition of PPN as a filler up to 30% does not substantially change the intersegmental distance and the polymer packing. It seems that, for all the membranes studied, the free volume that determines gas transport is in the high end of the possible range. This means that gas flow occurs mainly between the microvoids in the polymer matrix around the filler. In general, both HPA- and PAA-based MMMs exhibited a notable improvement in gas permeability, due to the presence of PPN, for all gases tested, with an almost constant selectivity. In summary, although the thermal stability of the PAA is limited by the thermal stability of the polyamide side chain, their mechanical properties were better. The permeability was higher for the PAA membranes before their thermal rearrangement, and these values increased after the addition of moderate amounts of PPN.

Kidney Autotransplantation and Orthotopic Kidney Transplantation: Two Different Approaches for Complex Cases.

Introduction: Transplantation surgery teams often have to face complex cases. In certain circumstances, such as occlusion of the iliac vessels or prior pelvic surgery, heterotopic kidney transplantation may not be feasible and orthotopic kidney transplantation (OKT) could be a good alternative. Kidney autotransplantation (KAT) has been described as a potential treatment for complex renovascular, ureteral, or neoplastic conditions. There are scarce data regarding the complications and outcomes of these procedures; therefore, we present our experience. Materials and Methods: We retrospectively analysed the medical records of both 21 patients who had received OKT and 19 patients who underwent KAT between 1993 and 2020. We collected demographic features and data regarding surgical technique, complications, and graft outcomes. Kidney graft survival was calculated using Kaplan-Meier survival analysis. Results: Regarding OKT, in 15 (71.43%) cases, it was the first kidney transplantation. The most common indication was the unsuitable iliac region due to vascular abnormalities (57.14%). The early postoperative complication rate was high (66.67%), with 23.81% of Clavien grade 3b complications. During the follow-up period (mean 5.76 -SD 6.15- years), we detected 9 (42.85%) graft losses. At 1 year, the survival rate was 84.9%. Concerning KAT, the most frequent indication was ureteral pathology (52.63%), followed by vascular lesions (42.11%). The overall early complication rate was 42.11%. During the follow-up period (mean of 4.47 years), 4 (15.79%) graft losses were reported. Conclusions: Although OKT and KAT have high complication rates, these techniques can be considered as two valuable approaches for complex cases, in the absence of other therapeutic options.

Development of Thermo- and pH-Sensitive Liposomal Magnetic Carriers for New Potential Antitumor Thienopyridine Derivatives.

The development of stimuli-sensitive drug delivery systems is a very attractive area of current research in cancer therapy. The deep knowledge on the microenvironment of tumors has supported the progress of nanosystems' ability for controlled and local fusion as well as drug release. Temperature and pH are two of the most promising triggers in the development of sensitive formulations to improve the efficacy of anticancer agents. Herein, magnetic liposomes with fusogenic sensitivity to pH and temperature were developed aiming at dual cancer therapy (by chemotherapy and magnetic hyperthermia). Magnetic nanoparticles of mixed calcium/manganese ferrite were synthesized by co-precipitation with citrate and by sol-gel method, and characterized by X-ray diffraction (XRD), scanning electron microscopy in transmission mode (STEM), and superconducting quantum interference device (SQUID). The citrate-stabilized nanoparticles showed a small-sized population (around 8 nm, determined by XRD) and suitable magnetic properties, with a low coercivity and high saturation magnetization (~54 emu/g). The nanoparticles were incorporated into liposomes of dipalmitoylphosphatidylcholine/cholesteryl hemisuccinate (DPPC:CHEMS) and of the same components with a PEGylated lipid (DPPC:CHEMS:DSPE-PEG), resulting in magnetoliposomes with sizes around 100 nm. Dynamic light scattering (DLS) and electrophoretic light scattering (ELS) measurements were performed to investigate the pH-sensitivity of the magnetoliposomes' fusogenic ability. Two new antitumor thienopyridine derivatives were efficiently encapsulated in the magnetic liposomes and the drug delivery capability of the loaded nanosystems was evaluated, under different pH and temperature conditions.

The "diagnose and leave in" strategy for diminutive rectosigmoid polyps in Lynch syndrome: a post hoc analysis from a randomized controlled trial.

BACKGROUND: The "diagnose-and-leave-in" policy has been established to reduce the risks and costs related to unnecessary polypectomies in the average-risk population. In individuals with Lynch syndrome, owing to accelerated carcinogenesis, the general recommendation is to remove all polyps, irrespective of size, location, and appearance. We evaluated the feasibility and safety of the diagnose-and-leave-in strategy in individuals with Lynch syndrome. METHODS : We performed a post hoc analysis based on per-polyp data from a randomized, clinical trial conducted by 24 dedicated colonoscopists at 14 academic centers, in which 256 patients with confirmed Lynch syndrome underwent surveillance colonoscopy from July 2016 to January 2018. In vivo optical diagnosis with confidence level for all detected lesions was obtained before polypectomy using virtual chromoendoscopy alone or with dye-based chromoendoscopy. Primary outcome was the negative predictive value (NPV) for neoplasia of high-confidence optical diagnosis among diminutive (≤ 5 mm) rectosigmoid lesions. Histology was the reference standard. RESULTS: Of 147 rectosigmoid lesions, 128 were diminutive. In 103 of the 128 lesions (81 %), the optical diagnostic confidence was high and showed an NPV of 96.0 % (95 % confidence interval [CI] 88.9 %-98.6 %) and accuracy of 89.3 % (95 %CI 81.9 %-93.9 %). By following the diagnose-and-leave-in policy, we would have avoided 59 % (75/128) of polypectomies at the expense of two diminutive low grade dysplastic adenomas and one diminutive sessile serrated lesion that would have been left in situ. CONCLUSION: In patients with Lynch syndrome, the diagnose-and-leave-in strategy for diminutive rectosigmoid polyps would be feasible and safe.

[Effectiveness of smoking cessation programs of roll-your-own tobacco smokers in Galicia.] / Efectividad de los programas de cesación tabáquica en fumadores de tabaco de liar en Galicia.

OBJECTIVE: Currently in developed countries there is an increase in the consumption of roll your own tobacco, which is associated with a higher proportion of users of this form of tobacco who wish to make an attempt to quit. The objective of this study was to analyze the effectiveness of tobacco cessation interventions based on the type of tobacco consumed. METHODS: Longitudinal study of a cohort of 641 smokers recruited between 2015 and 2018 in a health area of Galicia included in smoking cessation programs, based on psychological counseling and pharmacological treatment. The characteristics and success of the intervention were evaluated in two groups: roll your own tobacco smokers (RYO) and manufactured tobacco smokers (MT). A logistic regression was performed to determine the probability of success in smoking cessation. The risk measure was the odds ratio (OR) with its 95% confidence interval. RESULTS: RYO users started at a younger age and had a lower sociocultural stratum than MT users. Interventions to quit smoking in RYO users were associated with less abstinence at 4 weeks (52% MT vs 38% LT) (OR: 0.5; 95% CI 0.35-0.99; p=0.045;) and at 3 months (42% TM vs 30% TL) (OR:0.6; 95% CI 0.33-0.98; p=0.04). CONCLUSIONS: Smoking cessation programs are less effective in short-term RYO users. There are no differences in long-term abstinence between the two groups.

OBJETIVO: Actualmente en los países desarrollados existe un aumento del consumo de tabaco de liar lo que se asocia a una mayor proporción de usuarios de esta forma de tabaco que desean realizar un intento de abandono. El objetivo de este estudio fue analizar la efectividad de las intervenciones de cesación tabáquica en función del tipo de tabaco consumido. METODOS: Estudio longitudinal de una cohorte de 641 fumadores reclutados entre 2015 y 2018 en un área sanitaria de Galicia incluidos en programas de deshabituación tabáquica, basados en el asesoramiento psicológico y en el tratamiento farmacológico. Se evaluaron las características y el éxito de la intervención en dos grupos: fumadores de tabaco de liar (TL) y fumadores de tabaco manufacturado (TM). Se realizó una regresión logística para determinar la probabilidad de éxito en la cesación tabáquica. La medida de riesgo fue el odds ratio (OR) con su intervalo de confianza al 95%. RESULTADOS: Los consumidores de TL se iniciaron a una edad más temprana y tenían un estrato sociocultural más bajo que los consumidores de TM. Las intervenciones para abandonar el tabaco en los consumidores de TL se asociaron a una menor abstinencia a las 4 semanas (52%TM vs 38% TL) (OR: 0,5; 95%IC 0,35-0,99; p=0,045;) y a los 3 meses (42%TM vs 30%TL) (OR:0,6; 95%IC 0,33-0,98; p=0,04). CONCLUSIONES: Los programas de cesación tabáquica son menos efectivas en los consumidores de TL a corto plazo. No se observan diferencias en la abstinencia a largo plazo entre ambos grupos.

Targeting effector pathways in RAC1P29S-driven malignant melanoma.

Malignant melanoma is characterized by mutations in a number of driver genes, most notably BRAF and NRAS. Recent genomic analyses revealed that 4-9% of sun-exposed melanomas bear activating mutations in RAC1, which encodes a small GTPase that is known to play key roles in cell proliferation, survival, and migration. The RAC1 protein activates several effector pathways, including Group A p21-activated kinases (PAKs), phosphoinositol-3-kinases (PI3Ks), in particular the beta isoform, and the serum-response factor/myocardin-related transcription factor (SRF/MRTF). Having previously shown that inhibition of Group A PAKs impedes oncogenic signalling from RAC1P29S, we here extend this analysis to examine the roles of PI3Ks and SRF/MRTF in melanocytes and/or in a zebrafish model. We demonstrate that a selective Group A PAK inhibitor (Frax-1036), a pan-PI3K (BKM120), and two PI3Kß inhibitors (TGX221, GSK2636771) impede the growth of melanoma cells driven by mutant RAC1 but not by mutant BRAF, while other PI3K selective inhibitors, including PI3Kα, δ and γ, are less effective. Using these compounds as well as an SRF/MRTF inhibitor (CCG-203,971), we observed similar results in vivo, using embryonic zebrafish development as a readout. These results suggest that targeting Group A PAKs, PI3Kß, and/or SRF/MRTF represent a promising approach to suppress RAC1 signalling in malignant melanoma.

Gastric plexiform fibromyxoma, an uncommon mesenchymal tumor.

Plexiform fibromyxoma (PF) is an uncommon primary tumor of the gastrointestinal tract, with a mesenchymal origin and a benign behavior. Herein, we report a case and provide a literature review. A 41-year-old male patient underwent surgery in our unit for a PF at the gastric antrum, after being admitted due to vomiting and weight loss. As illustrated by our case, the mean age at presentation is around 40 years, the antrum is the most common location and abdominal pain the most widely reported manifestation. None of the reviewed cases involved regional or distant spread.

RAC1 as a Therapeutic Target in Malignant Melanoma.

Small GTPases of the RAS and RHO families are related signaling proteins that, when activated by growth factors or by mutation, drive oncogenic processes. While activating mutations in KRAS, NRAS, and HRAS genes have long been recognized and occur in many types of cancer, similar mutations in RHO family genes, such as RAC1 and RHOA, have only recently been detected as the result of extensive cancer genome-sequencing efforts and are linked to a restricted set of malignancies. In this review, we focus on the role of RAC1 signaling in malignant melanoma, emphasizing recent advances that describe how this oncoprotein alters melanocyte proliferation and motility and how these findings might lead to new therapeutics in RAC1-mutant tumors.