A personalized medicine approach identifies enasidenib as an efficient treatment for IDH2 mutant chondrosarcoma.

BACKGROUND: Sarcomas represent an extensive group of malignant diseases affecting mesodermal tissues. Among sarcomas, the clinical management of chondrosarcomas remains a complex challenge, as high-grade tumours do not respond to current therapies. Mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes are among the most common mutations detected in chondrosarcomas and may represent a therapeutic opportunity. The presence of mutated IDH (mIDH) enzymes results in the accumulation of the oncometabolite 2-HG leading to molecular alterations that contribute to drive tumour growth. METHODS: We developed a personalized medicine strategy based on the targeted NGS/Sanger sequencing of sarcoma samples (n = 6) and the use of matched patient-derived cell lines as a drug-testing platform. The anti-tumour potential of IDH mutations found in two chondrosarcoma cases was analysed in vitro, in vivo and molecularly (transcriptomic and DNA methylation analyses). FINDINGS: We treated several chondrosarcoma models with specific mIDH1/2 inhibitors. Among these treatments, only the mIDH2 inhibitor enasidenib was able to decrease 2-HG levels and efficiently reduce the viability of mIDH2 chondrosarcoma cells. Importantly, oral administration of enasidenib in xenografted mice resulted in a complete abrogation of tumour growth. Enasidenib induced a profound remodelling of the transcriptomic landscape not associated to changes in the 5 mC methylation levels and its anti-tumour effects were associated with the repression of proliferative pathways such as those controlled by E2F factors. INTERPRETATION: Overall, this work provides preclinical evidence for the use of enasidenib to treat mIDH2 chondrosarcomas. FUNDING: Supported by the Spanish Research Agency/FEDER (grants PID2022-142020OB-I00; PID2019-106666RB-I00), the ISC III/FEDER (PI20CIII/00020; DTS18CIII/00005; CB16/12/00390; CB06/07/1009; CB19/07/00057); the GEIS group (GEIS-62); and the PCTI (Asturias)/FEDER (IDI/2021/000027).

Combined PIK3CA and SOX2 Gene Amplification Predicts Laryngeal Cancer Risk beyond Histopathological Grading.

The PIK3CA and SOX2 genes map at 3q26, a chromosomal region frequently amplified in head and neck cancers, which is associated with poor prognosis. This study explores the clinical significance of PIK3CA and SOX2 gene amplification in early tumorigenesis. Gene copy number was analyzed by real-time PCR in 62 laryngeal precancerous lesions and correlated with histopathological grading and laryngeal cancer risk. Amplification of the SOX2 and PIK3CA genes was frequently detected in 19 (31%) and 32 (52%) laryngeal dysplasias, respectively, and co-amplification in 18 (29%) cases. The PIK3CA and SOX2 amplifications were predominant in high-grade dysplasias and significantly associated with laryngeal cancer risk beyond histological criteria. Multivariable Cox analysis further revealed PIK3CA gene amplification as an independent predictor of laryngeal cancer development. Interestingly, combined PIK3CA and SOX2 amplification allowed us to distinguish three cancer risk subgroups, and PIK3CA and SOX2 co-amplification was found the strongest predictor by ROC analysis. Our data demonstrate the clinical relevance of PIK3CA and SOX2 amplification in early laryngeal tumorigenesis. Remarkably, PIK3CA amplification was found to be an independent cancer predictor. Furthermore, combined PIK3CA and SOX2 amplification is emerging as a valuable and easy-to-implement tool for cancer risk assessment in patients with laryngeal precancerous lesions beyond current WHO histological grading.

Registry-based study of survivorship of cemented femoral components versus collared cementless femoral components in total hip arthroplasty in older patients with osteoarthritis.

Aims: In recent years, the use of a collared cementless femoral prosthesis has risen in popularity. The design intention of collared components is to transfer some load to the resected femoral calcar and prevent implant subsidence within the cancellous bone of the metaphysis. Conversely, the load transfer for a cemented femoral prosthesis depends on the cement-component and cement-bone interface interaction. The aim of our study was to compare the three most commonly used collared cementless components and the three most commonly used tapered polished cemented components in patients aged ≥ 75 years who have undergone a primary total hip arthroplasty (THA) for osteoarthritis (OA). Methods: Data from the Australian Orthopaedic Association National Joint Replacement Registry from 1 September 1999 to 31 December 2022 were analyzed. Collared cementless femoral components and cemented components were identified, and the three most commonly used components in each group were analyzed. We identified a total of 11,278 collared cementless components and 47,835 cemented components. Hazard ratios (HRs) from Cox proportional hazards models, adjusting for age and sex, were obtained to compare the revision rates between the groups. Results: From six months postoperatively onwards, patients aged ≥ 75 years undergoing primary THA with primary diagnosis of OA have a lower risk of all-cause revision with collared cementless components than with a polished tapered cemented component (HR 0.78 (95% confidence interval 0.64 to 0.96); p = 0.018). There is no difference in revision rate prior to six months. Conclusion: Patients aged ≥ 75 years with a primary diagnosis of OA have a significantly lower rate of revision with the most common collared cementless femoral component, compared with the most common polished tapered cemented components from six months postoperatively onwards. The lower revision rate is largely due to a reduction in revisions for fracture and infection.

Impact of post-stroke aphasia on functional communication, quality of life, perception of health and depression: A case-control study.

BACKGROUND AND PURPOSE: Post-stroke aphasia is associated with a reduced quality of life (QoL) and higher risk of depression. Few studies have addressed the effect of coping with aphasia. Our aim is to evaluate the impact of post-stroke aphasia on self-reported QoL and symptoms of depression. METHODS: This was a cross-sectional prospective case-control study. Cases involved patients with post-stroke aphasia included in the DULCINEA trial (NCT04289493). Healthy controls were recruited using snowball sampling. All subjects completed the following questionnaires: General Health Questionnaire (GHQ-12), Stroke Aphasia Quality of Life Scale (SAQOL-39), Communicative Activity Log (CAL) and Stroke Aphasic Depression Questionnaire (SADQ-10). RESULTS: Twenty-three patients (eight women; mean age 62.9 years) and 73 controls (42 women; mean age 53.7 years) were included. Cases scored lower than controls in perception of health (GHQ-12: median 3 [IQR 1; 6] vs. 0 [IQR 0; 2]) and perception of QoL (SAQOL-39: median 3.6 [IQR 3.3; 40] vs. 4.6 [IQR 4.2; 4.8]). Functional communication (CAL: median 135 [IQR 122; 148] vs. 94 [IQR 74; 103]) and SAQOL-39 communication subscale (median 2.7 [IQR 2.1; 3.2] vs. 4.8 [IQR 4.6; 5.0]) were also significantly lower in the case group. Notably, cases reported fewer depressive symptoms than controls (SADQ-10: median 11 [IQR 9; 15] vs. 13 [IQR 11; 16]; p = 0.016). A mediational analysis revealed that the relationship between post-stroke aphasia and depression was not mediated by functional communication. CONCLUSIONS: Although communication difficulties impact the QoL of patients with post-stroke aphasia, such patients report fewer depressive symptoms on the SADQ-10 scale than healthy people, with no differences in scores related to social participation.

Cold plasma-treated medium preferentially eliminates doxorubicin-resistant osteosarcoma cells.

Osteosarcoma (OS) is an aggressive bone cancer with poor prognosis, largely due to the limited effectiveness of current treatments such as doxorubicin (DX). Developing ways to overcome DX resistance is a significant clinical challenge. Here, we used two DX-resistant models to study the potential of Cold Plasma Treated Medium (PTM) to prevent DX resistance in OS. During the acquisition of the resistant phenotype upon long-term DX exposure, OS resistant cells became less proliferative, overexpressed the drug resistance-related efflux pump MDR1 and displayed a concomitant loss of SOD2 or GPX1. According to the reduced expression of these antioxidant enzymes, PTM treatment produced higher levels of oxidative express and was more effective in eradicating DX-resistant cells. Moreover, PTM reduced the expression of MDR1, thus sensitizing resistant cells to DX. These findings uncover new vulnerabilities of DX-resistant cells related with their inability to cope with excessive oxidative stress and their dependence on MDR1 that can be exploited using PTM-based treatments to provide new therapeutic approaches for the management of drug resistance in OS.

Addressing Maternal Health Disparities: Building a Novel Two-Generation Approach to Comprehensive Postpartum Care.

The United States is facing a maternal health crisis with increasing rates of severe maternal morbidity and mortality. To improve maternal health and promote health equity, the authors developed a novel 2-generation model of postpartum and pediatric care. This article describes the Two-Generation Clinic (Two-Gen) and model of care. The model combines a dyadic strategy for simultaneous maternal and pediatric care with the collaborative care model in which seamless primary and behavioral health care are delivered to address the physical health, behavioral health, and social service needs of families. The transdisciplinary team includes primary care physicians, nurse practitioners, psychiatrists, obstetrician-gynecologists, social workers, care navigators, and lactation specialists. Dyad clinic visits are coscheduled (at the same time) and colocated (in the same examination room) with the same primary care provider. In the Two-Gen, the majority (89%) of the mothers self-identify as racial and ethnic minorities. More than 40% have a mental health diagnosis. Almost all mothers (97.8%) completed mental health screenings, >50.0% have received counseling from a social worker, 17.2% had a visit with a psychiatrist, and 50.0% received lactation counseling. Over 80% of the children were up to date with their well-child visits and immunizations. The Two-Gen is a promising model of care that has the potential to inform the design of postpartum care models and promote health equity in communities with the highest maternal health disparities.

Screening fathers for postpartum depression in a maternal-child health clinic: a program evaluation in a midwest urban academic medical center.

BACKGROUND: Postpartum depression (PPD) impacts fathers as well as mothers, and is estimated to affect between 8 and 13% of fathers. Paternal PPD is a risk factor for worsened quality of life, poor physical and mental health, and developmental and relational harms in the father-mother-child triad. There are no current recommendations for PPD screening among fathers. Paternal PPD screening was piloted in an intergenerational postpartum primary care clinic. METHODS: The pilot was carried out in an intergenerational postpartum primary care clinic located at a Midwest urban academic safety net health system from October 2021 to July 2022. Fathers actively involved in relationships with mothers or infants receiving primary care in the clinic were approached with mothers' permission. A novel survey instrument was used to collect demographic/social data, as well as mental health history and current stress levels; an Edinburgh Postnatal Depression Scale (EPDS) was also administered. Screenings were completed by social workers; data were collected in REDCap and descriptive statistics were calculated in SAS. RESULTS: 29 fathers were contacted and 24 completed screening (83%). Mean age was 31 years (range 19-48). Most (87%) identified as belonging to a racial or ethnic minority group. Fathers self-reported low rates of stress and preexisting mental health conditions, but 30% screened positive for PPD on EPDS (score of ≥ 8, or suicidal ideation). Gaps in health care were found, as one-quarter (26%) of fathers were uninsured and half (54%) did not have a primary care provider. After screening, two requested mental health services, and three established new primary care with a physician. CONCLUSIONS: Participation was high in a PPD screening pilot for fathers in a primary care setting. This small sample of fathers demonstrated significant peripartum mental health challenges unlikely to have been identified otherwise. For some participants, engaging in PPD screening was an effective tool to prompt their subsequent engagement with general health care. This pilot is a step toward incorporating the health of fathers into models for supporting the health of families. Expanding screening for paternal PPD into routine primary care is necessary to reach more affected fathers.

Quantitative Indices of Student Social Media Engagement in Tertiary Education: A Systematic Review and a Taxonomy.

Recent studies have evaluated the use of social media as learning aids in tertiary education. Emerging research in this area has focused primarily on non-quantitative approaches to student social media engagement. However, quantitative engagement outcomes may be extracted from student posts, comments, likes, and views. The goal of the present review was to provide a research-informed taxonomy of quantitative and behavior-based metrics of student social media engagement. We selected 75 empirical studies comprising a pooled sample of 11,605 tertiary education students. Included studies used social media for educational purposes and reported student social media engagement outcomes (source databases: PsycInfo and ERIC). We used independent raters and stringent interrater agreement and data extraction processes to mitigate bias during the screening of references. Over half of the studies (52%, n = 39) utilized ad hoc interviews and surveys to estimate student social media engagement, whereas thirty-three studies (44%) used some form of quantitative analysis of engagement. Based on this literature, we present a selection of count-based, time-based, and text-analysis metrics. The proposed taxonomy of engagement metrics resulting provides the methodological basis for the analysis of social media behavior in educational settings, particularly, for human operant and behavioral education studies. Implications for future research are discussed. Supplementary Information: The online version contains supplementary material available at 10.1007/s10864-023-09516-6.

Reducing face touching through haptic feedback: A treatment evaluation against fomite-mediated self-infection.

Fomite-mediated self-infection via face touching is an understudied transmission pathway for infectious diseases. We evaluated the effect of computer-mediated vibrotactile cues (presented through experimental bracelets located on one or both hands of the participant) on the frequency of face touching among eight healthy adults in the community. We conducted a treatment evaluation totaling over 25,000 min of video observation. The treatment was evaluated through a multiple-treatment design and hierarchical linear modeling. The one-bracelet intervention did not produce significantly lower levels of face touching across both hands, whereas the two-bracelet intervention did result in significantly lower face touching. The effect increased over repeated presentations of the two-bracelet intervention, with the second implementation producing, on average, 31 fewer face-touching percentual points relative to baseline levels. Dependent on the dynamics of fomite-mediated self-infection via face touching, treatment effects could be of public health significance. The implications for research and practice are discussed.

Abrogation of stemness in osteosarcoma by the mithramycin analog EC-8042 is mediated by its ability to inhibit NOTCH-1 signaling.

Osteosarcomas are frequently associated to a poor prognosis and a modest response to current treatments. EC-8042 is a well-tolerated mithramycin analog that has demonstrated an efficient ability to eliminate tumor cells, including cancer stem cell subpopulations (CSC), in sarcomas. In transcriptomic and protein expression analyses, we identified NOTCH1 signaling as one of the main pro-stemness pathways repressed by EC-8042 in osteosarcomas. Overexpression of NOTCH-1 resulted in a reduced anti-tumor effect of EC-8042 in CSC-enriched 3D tumorspheres cultures. On the other hand, the depletion of the NOTCH-1 downstream target HES-1 was able to enhance the action of EC-8042 on CSCs. Moreover, HES1 depleted cells failed to recover after treatment withdrawal and showed reduced tumor growth potential in vivo. In contrast, mice xenografted with NOTCH1-overexpressing cells responded worse than parental cells to EC-8042. Finally, we found that active NOTCH1 levels in sarcoma patients was associated to advanced disease and lower survival. Overall, these data highlight the relevant role that NOTCH1 signaling plays in mediating stemness in osteosarcoma. Moreover, we demonstrate that EC-8042 is powerful inhibitor of NOTCH signaling and that the anti-CSC activity of this mithramycin analog highly rely on its ability to repress this pathway.

Cold plasma and inhibition of STAT3 selectively target tumorigenicity in osteosarcoma.

Osteosarcoma (OS) is a malignant type of bone cancer that arises in periods of increased bone formation. Curative strategies for these types of tumors have remained essentially unchanged for decades and the overall survival for most advanced cases is still dismally low. This is in part due to the existence of drug resistant Cancer Stem Cells (CSC) with progenitor properties that are responsible for tumor relapse and metastasis. In the quest for therapeutic alternatives for OS, Cold Atmospheric Plasmas and Plasma-Treated Liquids (PTL) have come to the limelight as a source of Reactive Oxygen and Nitrogen Species displaying selectivity towards a variety of cancer cell lines. However, their effects on CSC subpopulations and in vivo tumor growth have been barely studied to date. By employing bioengineered 3D tumor models and in vivo assays, here we show that low doses of PTL increase the levels of pro-stemness factors and the self-renewal ability of OS cells, coupled to an enhanced in vivo tumor growth potential. This could have critical implications to the field. By proposing a combined treatment, our results demonstrate that the deleterious pro-stemness signals mediated by PTL can be abrogated when this is combined with the STAT3 inhibitor S3I-201, resulting in a strong suppression of in vivo tumor growth. Overall, our study unveils an undesirable stem cell-promoting function of PTL in cancer and supports the use of combinatorial strategies with STAT3 inhibitors as an efficient treatment for OS avoiding critical side effects. We anticipate our work to be a starting point for wider studies using relevant 3D tumor models to evaluate the effects of plasma-based therapies on tumor subpopulations of different cancer types. Furthermore, combination with STAT3 inhibition or other suitable cancer type-specific targets can be relevant to consolidate the development of the field.

Accuracy of paper-and-pencil systematic observation versus computer-aided systems.

Computer-aided behavior observation is gradually supplanting paper-and-pencil approaches to behavior observation, but there is a dearth of evidence on the relative accuracy of paper-and-pencil versus computer-aided behavior observation formats in the literature. The current study evaluated the accuracy resulting from paper-and-pencil observation and from two computer-aided behavior observation methods: The Observer XT® desktop software and the Big Eye Observer® smartphone application. Twelve postgraduate students without behavior observation experience underwent a behavior observation training protocol. As part of a multi-element design, participants recorded 60 real clinical sessions randomly assigned to one of the three observation methods. All three methods produced high levels of accuracy (paper-and-pencil, .88 ± .01; The Observer XT, .84 ± .01; Big Eye Observer, .84 ± .01). A mixed linear model analysis indicated that paper-and-pencil observation produced marginally superior accuracy values, whereas the accuracy produced by The Observer XT and Big Eye Observer did not differ. The analysis suggests that accuracy of recording was mediated by the number of recordable events in the observation videos. The implications of these findings for research and practice are discussed.

Addressing Doxorubicin Resistance in Bone Sarcomas Using Novel Drug-Resistant Models.

Bone sarcomas have not shown a significant improvement in survival for decades, due, in part, to the development of resistance to current systemic treatments, such as doxorubicin. To better understand those mechanisms mediating drug-resistance we generated three osteosarcoma and one chondrosarcoma cell lines with a stable doxorubicin-resistant phenotype, both in vitro and in vivo. These resistant strains include a pioneer model generated from a patient-derived chondrosarcoma line. The resistant phenotype was characterized by a weaker induction of apoptosis and DNA damage after doxorubicin treatment and a lower migratory capability. In addition, all resistant lines expressed higher levels of ABC pumps; meanwhile, no clear trends were found in the expression of anti-apoptotic and stem cell-related factors. Remarkably, upon the induction of resistance, the proliferation potential was reduced in osteosarcoma lines but enhanced in the chondrosarcoma model. The exposure of resistant lines to other anti-tumor drugs revealed an increased response to cisplatin and/or methotrexate in some models. Finally, the ability to retain the resistant phenotype in vivo was confirmed in an osteosarcoma model. Altogether, this work evidenced the co-existence of common and case-dependent phenotypic traits and mechanisms associated with the development of resistance to doxorubicin in bone sarcomas.

Proof of concept for the use of trained sniffer dogs to detect osteosarcoma.

Sarcomas are mesenchymal cancers which often show an aggressive behavior and patient survival largely depends on an early detection. In last years, much attention has been given to the fact that cancer patients release specific odorous volatile organic compounds (VOCs) that can be efficiently detected by properly trained sniffer dogs. Here, we have evaluated for the first time the ability of sniffer dogs (n = 2) to detect osteosarcoma cell cultures and patient samples. One of the two dogs was successfully trained to discriminate osteosarcoma patient-derived primary cells from mesenchymal stem/stromal cells (MSCs) obtained from healthy individuals. After the training phase, the dog was able to detect osteosarcoma specific odor cues in a different panel of 6 osteosarcoma cell lines with sensitivity and specificity rates between 95 and 100%. Moreover, the same VOCs were also detected by the sniffer dog in saliva samples from osteosarcoma patients (n = 2) and discriminated from samples from healthy individuals with a similar efficacy. Altogether, these results indicate that there are common odor profiles shared by cultures of osteosarcoma cells and body fluid samples from patients and provide a first proof of concept about the potential of canine odor detection as a non-invasive screening method to detect osteosarcomas.

DUbbing Language-therapy CINEma-based in Aphasia post-Stroke (DULCINEA): study protocol for a randomized crossover pilot trial.

BACKGROUND: Communication is one of the most important predictors of social reintegration after stroke. Approximately 15-42% of stroke survivors experience post-stroke aphasia. Helping people recover from aphasia is one of the research priorities after a stroke. Our aim is to develop and validate a new therapy integrating dubbing techniques to improve functional communication. METHODS: The research project is structured as three work packages (WP). WP1: development of the dubbed language cinema-based therapy: Two research assistants (a speech therapist and a dubbing actor) will select the clips, mute specific words/sentences in progressive speech difficulty, and guide patients to dub them across sessions. Words to be dubbed will be those considered to be functionally meaningful by a representative sample of aphasic patients and relatives through an online survey. WP2: a randomized, crossover, interventional pilot study with the inclusion of 54 patients with post-stroke non-fluent aphasia. Patients will be treated individually in 40-min sessions twice per week for 8 weeks. Primary outcomes will be significant pre/post differences in scores in the Communicative Activity Log (CAL) questionnaire and Boston Diagnostic Aphasia Examination (BDAE) administered by a psychologist blinded to the patients' clinical characteristics. SECONDARY OUTCOMES: General Health Questionnaire (GHQ)-12, Stroke Aphasia Quality of Life Scale (SAQOL-39), Western Aphasia Battery Revised (WAB-R), and the Stroke Aphasic Depression Questionnaire (SADQ10). WP3: educational activities and dissemination of results. WP3 includes educational activities to improve public knowledge of aphasia and dissemination of the results, with the participation of the Spanish patients' association Afasia Activa. DISCUSSION: This pilot clinical trial will explore the efficacy of a new therapeutic tool based on dubbing techniques and computer technology to improve functional communication of patients suffering from post-stroke aphasia with the use of standardized test assessment. TRIAL REGISTRATION: ClinicalTrials.gov NCT04289493 . Registered on 28 February 2020.

Western Honduras Copán Population-Based Cancer Registry: Initial Estimates and a Model for Rural Central America.

PURPOSE: Population-based cancer registries (PBCRs) are critical for national cancer control planning, yet few low- and middle-income countries (LMICs) have quality PBCRs. The Central America Four region represents the principal LMIC region in the Western hemisphere. We describe the establishment of a PBCR in rural Western Honduras with first estimates for the 2013-2017 period. METHODS: The Western Honduras PBCR was established through a collaboration of academic institutions and the Honduras Ministry of Health for collection of incident cancer data from public and private health services. Data were recorded using the Research Electronic Data Capture (REDCap) web-based platform with data monitoring and quality checks. Crude and age-standardized rates (ASRs) were calculated at the regional level, following WHO methodology. RESULTS: The web-based platform for data collection, available ancillary data services (eg, endoscopy), and technical support from international centers (United States and Colombia) were instrumental for quality control. Crude cancer incidence rates were 112.2, 69.8, and 154.6 per 100,000 habitants overall, males, and females, respectively (excluding nonmelanoma skin cancer). The adjusted ASRs were 84.2, 49.6, and 118.9 per 100,000 overall habitants, males, and females, respectively. The most common sites among men were stomach (ASR 26.0, 52.4%), colorectal (ASR 5.11, 10.15%), and prostate (ASR 2.7, 5.4%). The most common sites in women were cervix (ASR 34.2, 36.7%), breast (ASR 11.2, 12.3%), and stomach (ASR 10.8, 11.7%). CONCLUSION: The Copán-PBCR represents a successful model to develop cancer monitoring in rural LMICs. Innovations included the use of the REDCap platform and leverage of Health Ministry resources. This provides the first PBCR data for Honduras and the Central America Four and confirms that infection-driven cancers, such as gastric and cervical, should be priority targets for cancer control initiatives.

Mithramycin delivery systems to develop effective therapies in sarcomas.

BACKGROUND: Sarcomas comprise a group of aggressive malignancies with very little treatment options beyond standard chemotherapy. Reposition of approved drugs represents an attractive approach to identify effective therapeutic compounds. One example is mithramycin (MTM), a natural antibiotic which has demonstrated a strong antitumour activity in several tumour types, including sarcomas. However, its widespread use in the clinic was limited by its poor toxicity profile. RESULTS: In order to improve the therapeutic index of MTM, we have loaded MTM into newly developed nanocarrier formulations. First, polylactide (PLA) polymeric nanoparticles (NPs) were generated by nanoprecipitation. Also, liposomes (LIP) were prepared by ethanol injection and evaporation solvent method. Finally, MTM-loaded hydrogels (HG) were obtained by passive loading using a urea derivative non-peptidic hydrogelator. MTM-loaded NPs and LIP display optimal hydrodynamic radii between 80 and 105 nm with a very low polydispersity index (PdI) and encapsulation efficiencies (EE) of 92 and 30%, respectively. All formulations show a high stability and different release rates ranging from a fast release in HG (100% after 30 min) to more sustained release from NPs (100% after 24 h) and LIP (40% after 48 h). In vitro assays confirmed that all assayed MTM formulations retain the cytotoxic, anti-invasive and anti-stemness potential of free MTM in models of myxoid liposarcoma, undifferentiated pleomorphic sarcoma and chondrosarcoma. In addition, whole genome transcriptomic analysis evidenced the ability of MTM, both free and encapsulated, to act as a multi-repressor of several tumour-promoting pathways at once. Importantly, the treatment of mice bearing sarcoma xenografts showed that encapsulated MTM exhibited enhanced therapeutic effects and was better tolerated than free MTM. CONCLUSIONS: Overall, these novel formulations may represent an efficient and safer MTM-delivering alternative for sarcoma treatment.

Cancer Stem Cells as a Source of Drug Resistance in Bone Sarcomas.

Bone sarcomas are commonly characterized by a high degree of intra-tumor heterogeneity, which in part is due to the presence of subpopulations of tumor cells presenting stem cell properties. Similar to normal stem cells, these cancer stem cells (CSCs) display a drug resistant phenotype and therefore are responsible for relapses and tumor dissemination. Drug resistance in bone sarcomas could be enhanced/modulated during tumor evolution though the acquisition of (epi)-genetic alterations and the adaptation to changing microenvironments, including drug treatments. Here we summarize findings supporting the involvement of pro-stemness signaling in the development of drug resistance in bone sarcomas. This include the activation of well-known pro-stemness pathways (Wnt/ß-Cat, NOTCH or JAT/STAT pathways), changes in the metabolic and autophagic activities, the alteration of epigenetic pathways, the upregulation of specific non-coding RNAs and the crosstalk with different microenvironmental factors. This altered signaling is expected to be translated to the clinic in the form of biomarkers of response and new therapies able to overcome drug resistance.

Cardiovascular risk assessment in the resource limited setting of Western Honduras: An epidemiological perspective.

Cardiovascular Disease (CVD) epidemiology varies significantly among Low and Middle-Income Countries. Honduras is the Central American country with the highest Ischemic Heart Disease and CVD mortality rates. The aim of this study was to assess the individual CVD risk factors and calculate Cardiovascular Risk Assessment Scores (CVRAS) from the population. Methods: A cross-sectional study in western Honduras. Estimation of CV risk was performed using Framingham, MESA, ACC/AHA-PCEs and ESC SCORE calculators. Results: 38% were male. For men and women respectively; 49% and 48% had self-reported hypertension (HTN), on measured blood pressure only 18% and 30% had normal readings. Diabetes Mellitus was reported in 19% and 22%. Tobacco use was 14% and 3%. Self-reported regular exercise was 39.9% and 25%. Obesity was diagnosed in 24% and 24%. Lipid profile; total cholesterol was ≥200 mg/dl in 63% of subjects. LDL-C was elevated (>100 mg/dl) in 74% of participants, 9% had LDL-C levels higher than 190 mg/dl. Triglycerides were high (>160 mg/dl) in 60%, of these subjects 22% were taking lipid-lowering medications. 52% reported family-history of CVD. The risk calculation for men and women respectively for each CVRAS were; AHA/ACC-PCEs high risk (score ≥ 7.5%) in 62% and 30%, FRS high risk (score ≥ 20%) 46% and 15%, MESA high risk (Score ≥ 7.5%) in 70.6% and 17.7%, ESC SCORE high risk (score ≥ 5% in 32.4% and 11.8%). Conclusions: CV risk calculations revealed higher than rates than expected with consequently reflected on higher than estimated CVRAS. This represents the first report of its kind in Honduras.

Standardized protocol for determination of biohydrogen potential.

Biohydrogen production potential (BHP) depends on several factors like inoculum source, substrate, pH, among many others. Batch assays are the most common strategy to evaluate such parameters, where the comparison is a challenging task due to the different procedures used. The present method introduces the first internationally validated protocol, evaluated by 8 independent laboratories from 5 different countries, to assess the biohydrogen potential. As quality criteria, a coefficient of variation of the cumulative hydrogen production (H max) was defined to be <15 %. Two options to run BHP batch tests were proposed; a manual protocol with periodic measurements of biogas production, needing conventional laboratory materials and analytical equipment for biogas characterization; and an automatic protocol, which is run in a device developed for online measurements of low biogas production. The detailed procedures for both protocol options are presented, as well as data validating them. The validation showed acceptable repeatability and reproducibility, measured as intra- and inter-laboratory coefficient of variation, which can be reduced up to 9 %.