Quasi-Diabatic Propagation Scheme for Direct Simulation of Proton-Coupled Electron Transfer Reaction.

We apply a recently developed quasi-diabatic (QD) propagation scheme to simulate proton-coupled electron transfer (PCET) reactions. This scheme enables a direct interface between an accurate diabatic dynamics approach and the adiabatic vibronic states of the coupled electron-proton subsystem. It explicitly avoids theoretical efforts to preconstruct diabatic states for the transferring electron and proton or reformulate a diabatic dynamics method to the adiabatic representation, both of which are nontrivial tasks. Using a partial linearized path-integral approach and symmetrical quasi-classical approach as the diabatic dynamics methods, we demonstrate that the QD propagation scheme provides accurate vibronic dynamics of PCET reactions and reliably predicts the correct reaction mechanism without any a priori assumptions. This work demonstrates the possibility to directly simulate challenging PCET reactions by using accurate diabatic dynamics approaches and adiabatic vibronic information.

Effectiveness of Workplace-Based Muscle Resistance Training Exercise Program in Preventing Musculoskeletal Dysfunction of the Upper Limbs in Manufacturing Workers.

Aims Given the high levels of absenteeism due to musculoskeletal disorders of the upper limbs, there is a need for preventive strategies to protect workers exposed to high risk levels. The purpose of this study was to determine the effect of a workplace-based muscle resistance training exercise program in the presence of pain and musculoskeletal dysfunction of the upper extremities in manufacturing workers exposed to repetitive movements and excessive effort in the workplace. Method Randomized controlled trial in manufacturing workers. A sample of 120 healthy workers was allocated at random to an experimental group, which received a resistance-based exercise program, and a control group, which performed stretching exercises. Results The muscle resistance training exercise had a protective effect on the intensity of pain perceived by workers in their upper limbs (RR: 0.62 95% CI 0.44-0.87) compared with the group of workers who performed stretching exercises. Conclusion A workplace-based muscle resistance training exercise program is an effective preventive strategy in factory workers exposed to risk; however, it is necessary for companies initially to adopt mechanisms to minimize exposure as a prevention strategy.

Symmetric quasi-classical dynamics with quasi-diabatic propagation scheme.

We apply a recently developed quasi-diabatic (QD) scheme to the symmetric quasi-classical (SQC) approach for accurate quantum dynamics propagation. By using the adiabatic states as the QD states during a short-time quantum dynamics propagation, the QD scheme allows for directly interfacing the diabatic SQC method with commonly used adiabatic electronic structure calculations, thus alleviating any non-trivial theoretical efforts to reformulate SQC in the adiabatic representation. Furthermore, the QD scheme ensures a stable propagation of the dynamics and allows using a much larger time step compared to directly propagating SQC dynamics in the adiabatic representation. This is due to the fact that the QD scheme does not explicitly require non-adiabatic couplings that could exhibit highly peaked values during non-adiabatic dynamics propagation. We perform the QD-SQC calculations with a wide range of model non-adiabatic systems to demonstrate the accuracy of the proposed scheme. This study opens up the possibility for combining accurate diabatic quantum dynamics methods such as SQC with any adiabatic electronic structure calculations for non-adiabatic on-the-fly propagations.

Contribution of polymorphisms in the LEP, LEPR and RETN genes on serum leptin and resistin levels in young adults from Mexico.

Polymorphisms in the LEP (G-2548A and A19G), LEPR (A326G, A668G and G3057A) and RETN (C-420G and G+62A) genes were documented according to their association with alterations in biochemical parameters such as glucose, insulin and lipid profiles, along with serum leptin and resistin concentrations. The aim of the study was to establish any contribution of the G-2548A and A19G polymorphisms of the LEP gene, the A326G, A668G and G3057A polymorphisms of the LEPR gene, and the C-420G and G+62A polymorphisms of the RETN gene to serum leptin and resistin levels in Mexican young adults. Clinical and biochemical variables, serum leptin and resistin levels, and genotype profiles were analysed in 66 Mexican young adults. Seven polymorphisms in the LEP, LEPR and RETN genes were genotyped using polymerase chain reaction-restriction fragment length polymorphisms analysis. Individuals carrying allele 3057A of the G3057A polymorphism in the LEPR gene showed significantly higher leptin concentrations than those bearing the genotype G/G (43.78 ± 39.11 vs 28.20 ± 14.12 ng/mL; p = 0.021). There were no associations of serum leptin or resistin levels according to the genotype of the other six analysed polymorphisms. Our results suggest that the allele 3057A of the LEPR G3057A polymorphism contributes to increased serum leptin levels in Mexican young adults.

Characterization of ascaris from ecuador and zanzibar.

To shed light on the epidemiology of ascariasis in Ecuador and Zanzibar, 177 adult worms retrieved by chemo-expulsion from either people or pigs were collected, measured and subjected to polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis of the ribosomal internal transcribed spacer (ITS) region. Upon double digestion with RsaI and HaeIII, PCR-RFLP analysis revealed the presence of A. lumbricoides in people and A. suum in pigs in Ecuador. In contrast, while there are no pigs on Zanzibar, of the 56 worms obtained from people, one was genotyped as A. suum. No additional genetic variation was detected upon further PCR-RFLP analysis with several other restriction enzymes. Upon measurement, worm mass and length differed by location and by species, A. suum being lighter and longer. While there is no evidence to suggest zoonotic transmission in Ecuador, an enduring historical signature of previous zoonotic transmission remains on Zanzibar.

Treatment patterns among Canadian men diagnosed with localized low-risk prostate cancer.

In general, guideline-recommended treatment options for men with low-risk prostate cancer (pca) include active surveillance, radical prostatectomy, and external-beam radiation therapy or brachytherapy. Because of the concern about overdiagnosis and consequent overtreatment of pca, patients with low-risk disease are increasingly being managed with active surveillance. Using data from six provincial cancer registries, we examined treatment patterns within a year of a diagnosis of localized low-risk pca, and we assessed differences by age. Of patients diagnosed in 2010 in four of the six reporting provinces, most received surgery or radiation therapy within 1 year of diagnosis. Depending on the province, either surgery or radiation therapy was the most commonly used primary treatment. In the other two provinces, most patients had no record of treatment within a year of diagnosis. Examining treatment patterns by age demonstrated a lesser likelihood of receiving surgery or radiation therapy within 1 year of diagnosis among men more than 75 years of age than among men 75 years of age or younger (no record of treatment in 69.1% and 46.3% respectively). In conclusion, we observed interprovincial and age-specific variations in the patterns of care for men with low-risk pca. The findings presented in this report are intended to identify opportunities for improvement in clinical practice that could lead to improved care and experience.

Wait times for prostate cancer treatment and patient perceptions of care in Canada: a mixed-methods report.

BACKGROUND: Access to cancer care is a significant concern for Canadians. Prolonged delays between cancer diagnosis and treatment have been associated with anxiety, stress, and perceived powerlessness for patients and their family members. Longer wait times can also be associated with poorer prognosis, although the evidence is inconclusive. Here, we report national wait times for radiation therapy and surgery for localized prostate cancer (pca) and the effect of wait time on patient perceptions of their care. RESULTS: Treatment wait times showed substantial interprovincial variation. The longest 90th percentile wait times for radiation therapy and surgery were, respectively, 40 days and 105 days. In all provinces, waits for radiation therapy were longer for pca patients than for patients with breast, colorectal, or lung cancer. In the focus groups and interviews conducted with 47 men treated for pca, many participants did not perceive that wait times for treatment were prolonged. Those who experienced delays between diagnosis and treatment voiced issues with a lack of communication about when they would receive treatment and a lack of support or information to make an informed decision about treatment. Minimizing treatment delays was an aspect of the cancer journey that participants would like to change because of the stress it caused. CONCLUSIONS: Although wait time statistics are useful, a review of cancer control in Canada cannot be considered complete unless an effort is made to give voice to the experiences of individuals with cancer. The findings presented here are intended to provide a snapshot of national care delivery for localized pca and to identify opportunities for improvement in clinical practice.

Anticaries effect of an antioxidant-rich apple concentrate on enamel in an experimental biofilm-demineralization model.

AIMS: To assess the anticaries activity of an antioxidant-rich apple concentrate (ARAC) in an experimental biofilm caries model on enamel. METHODS AND RESULTS: A validated caries model with Streptococcus mutans UA159 biofilms was used. Biofilms were formed on enamel slabs during 5 days. To mimic cariogenic challenges, triplicate slabs were exposed three times per day for 5 min to 10% sucrose followed by five additional minutes of exposure to serial dilutions of ARAC in 0·9% NaCl. A triplicate slab exposed to 10% sucrose followed by 0·9% NaCl served as caries-positive control. Acidogenicity was estimated by medium pH twice per day. After the experimental phase, biofilms were recovered to determine biomass, viable bacteria and intra- and extracellular polysaccharides. Slabs were used to estimate demineralization by the percentage of surface microhardness loss (%SHL). Differences among treatments were analysed by anova and Bonferroni test (P < 0·05). Streptococcus mutans biofilms were exposed to ARAC after a cariogenic challenge with sucrose-induced lower enamel demineralization than the positive control. The highest dilution of ARAC at 1 : 100 000 (v/v) showed the most marked reduction in demineralization of about 57%. Although no differences were observed in the number of bacterial cells, the intracellular polysaccharides or in the biomass (P > 0·05), the highest dilution of the apple concentrate induced significantly lower extracellular polysaccharide formation by the biofilm. CONCLUSIONS: An apple concentrate in low concentrations appears to have a potential anticaries activity on enamel. Data suggest a metabolic rather than an antimicrobial mechanism, but further research is needed. SIGNIFICANCE AND IMPACT OF THE STUDY: Phenolic compounds contained in apple concentrates seem to have anticaries properties that may be effective even in the presence of sucrose and in very low doses. Nutritional interventions that do not require rescinding from sucrose might be derived from these findings.

[Early congenital syphilis: a case report]. / Sífilis congénita precoz: a propósito de 2 casos clínicos.

INTRODUCTION: Congenital syphilis (CS) is a multisystemic infection of the newborn (NB) which can produce severe symptoms, and in some cases, even be fatal. In recent years, the incidence of syphilis has increased worldwide and similarly, the cases of CS in neonates have increased. OBJECTIVE: To report two cases of early and severe presentation of CS, focusing on the importance of prevention of vertical transmission and monitoring of treated mothers. The diagnostic difficulties are discussed. CLINICAL CASES: Two premature newborns that were diagnosed with probable CS present in the newborn period are presented. In the first case, due to a high index of suspicion, but without confirmatory testing, treatment was started with good clinical response. In the second case, CS was confirmed through positive serology and the specific treatment was given. CONCLUSION: CS has significant diagnostic challenges as there is no test for early confirmation, therefore, a high index of suspicion might be key in the treatment and consequent prognosis. Due to the current epidemiology of the condition, it is also important to focus on preventive measures.

Bone marrow mesenchymal/fibroblastic stromal cells induce a distinctive EMT-like phenotype in AML cells.

The development of epithelial-to-mesenchymal transition (EMT) like features is emerging as a critical factor involved in the pathogenesis of acute myeloid leukaemia (AML). However, the extracellular signals and the signalling pathways in AML that may regulate EMT remain largely unstudied. We found that the bone marrow (BM) mesenchymal/fibroblastic cell line HS5 induces an EMT-like migratory phenotype in AML cells. AML cells underwent a strong increase of vimentin (VIM) levels that was not mirrored to the same extent by changes of expression of the other EMT core proteins SNAI1 and SNAI2. We validated these particular pattern of co-expression of core-EMT markers in AML cells by performing an in silico analysis using datasets of human tumours. Our data showed that in AML the expression levels of VIM does not completely correlate with the co-expression of core EMT markers observed in epithelial tumours. We also found that vs epithelial tumours, AML cells display a distinct patterns of co-expression of VIM and the actin binding and adhesion regulatory proteins that regulate F-actin dynamics and integrin-mediated adhesions involved in the invasive migration in cells undergoing EMT. We conclude that the BM stroma induces an EMT related pattern of migration in AML cells in a process involving a distinctive regulation of EMT markers and of regulators of cell adhesion and actin dynamics that should be further investigated. Understanding the tumour specific signalling pathways associated with the EMT process may contribute to the development of new tailored therapies for AML as well as in different types of cancers.

Effect of treatment with paliperidone palmitate versus oral antipsychotics on frontal lobe intracortical myelin volume in participants with recent-onset schizophrenia: Magnetic resonance imaging results from the DREaM study.

OBJECTIVE: We investigated changes in brain intracortical myelin (ICM) volume in the frontal lobe after 9 months of treatment with paliperidone palmitate (PP) compared with 9 months of treatment with oral antipsychotics (OAP) in participants with recent-onset schizophrenia or schizophreniform disorder from the Disease Recovery Evaluation and Modification (DREaM) study, a randomized, open-label, delayed-start trial. METHODS: DREaM included 3 phases: Part I, a 2-month oral run-in; Part II, a 9-month disease progression phase (PP or OAP); and Part III, 9 months of additional treatment (participants receiving PP continued PP [PP/PP] and participants receiving OAP were rerandomized to receive either PP [OAP/PP] or OAP [OAP/OAP]). In Part II, magnetic resonance imaging (MRI) and functional and symptomatic assessment was performed at baseline, day 92, and day 260. ICM volume as a fraction of the entire brain volume was quantified by subtraction of a proton density image from an inversion recovery image. Within-treatment-group changes from baseline were assessed by paired t-tests. Analysis of covariance was used to analyze ICM volume changes between treatment groups, adjusting for country. RESULTS: The MRI analysis sample size included 71 DREaM participants (PP, 23; OAP, 48) and 64 healthy controls. At baseline, mean adjusted ICM fraction values did not differ between groups (PP, 0.057; OAP, 0.058, p = 0.79). By day 92, the adjusted ICM fraction in the OAP group had decreased significantly (change from baseline, -0.002; p = 0.001), whereas the adjusted ICM fraction remained unchanged from baseline in the PP group (0.000; p = 0.80). At day 260, the change from baseline in adjusted ICM fraction was -0.004 (p = 0.004) in the OAP group and -0.001 (p = 0.728) in the PP group. The difference between treatment groups did not reach statistical significance (p = 0.147). CONCLUSIONS: In participants with recent-onset schizophrenia or schizophreniform disorder, frontal ICM volume was preserved at baseline levels in those treated with PP over 9 months. However, a decrease of frontal ICM volume was observed among participants treated with OAPs. TRIAL REGISTRATION: clinicaltrials.gov identifier NCT02431702.

Effect of fluoridated milk on enamel and root dentin demineralization evaluated by a biofilm caries model.

Although some studies suggest an anticaries effect of fluoridated bovine milk (F-milk) on enamel, evidence is still considered weak. Even more uncertain, the effect of F-milk on root caries remains largely unknown. This study evaluated the effect of F-milk on enamel and on root dentin demineralization using a validated Streptococcus mutans biofilm model, simulating a high cariogenic challenge. S. mutans (UA159) biofilms were formed on bovine enamel and root dentin saliva-coated slabs after measuring initial surface microhardness (SH). Biofilms were exposed to 10% sucrose 8×/day and treated 2×/day with either: (1) 0.9% NaCl (negative control), (2) bovine milk, (3) F-milk (5.0 ppm F as NaF) or (4) NaF 0.05% (anticaries-positive control). Medium pH was monitored twice/day, as a biofilm acidogenicity indicator. After 5 days for enamel and 4 days for dentin, biofilms were recovered to analyze: biomass, soluble proteins, viable microorganisms, and extra- and intracellular polysaccharides. Enamel and dentin demineralization were estimated by percentage of SH loss. Results were compared by ANOVA and Tukey's test. Neither acidogenicity nor biofilm composition differed among treatment groups in biofilms formed on enamel or dentin (p > 0.05). F-milk, however, significantly reduced enamel and dentin demineralization when compared with the negative control (p < 0.05). Also, F-milk was as efficient as 0.05% NaF to reduce enamel (p > 0.05), but not dentin demineralization (p < 0.05). These findings suggest that milk containing 5.0 ppm of fluoride is effective to control enamel caries and that it may be effective on root dentin caries prevention.

Axonal quantification of the white matter association fasciculi in cerebral hemispheres of cow (Bos taurus), pig (Sus scrofa domesticus) and rabbit (Oryctolagus cuniculus).

BACKGROUND: Cerebral white matter consists mainly of axons surrounded by myelin sheaths, which are grouped to form association, commissural, and projection fasciculi. The aim of our work was to quantify and compare under the microscope the axons of the white matter association fasciculi in the cerebral hemispheres of cow (Bos taurus), pig (Sus scrofa domesticus) and rabbit (Oryctolagus cuniculus) indirectly by identification of their myelin sheaths. MATERIALS AND METHODS: The samples were taken from 30 cerebral hemispheres: 10 cow, 10 pig and 10 rabbit (15 right and 15 left). They were obtained following a protocol based on the Talairach-Tournoux coordinate system for human and primate brains. The slides were stained with Luxol Fast Blue, observed by optical microscopy, and photographed at 600×. Samples were also prepared for observation in scanning transmission electron microscopy with osmium tetroxide. The myelin sheaths/axons were counted with the ImageJ software. RESULTS: Statistically significant differences in the number of myelin sheaths per 410 µm² were found in the inferior and superior longitudinal fasciculi between the left and right hemispheres of cows, with predominance of the right hemisphere; and in the inferior occipitofrontal fasciculus of the rabbit with predominance of the left hemisphere. CONCLUSIONS: The use of animal models for experiments in the cerebral fasciculi, especially pig, could give us a greater understanding of the behaviour of demyelinating and neurodegenerative diseases in humans.

[Attentional focus instructions for therapeutic exercise in people with musculoskeletal disorders. A scoping review]. / Instrucciones con foco atencional durante el ejercicio terapéutico en personas con trastornos musculoesqueléticos. Una revisión de alcance.

Attentional focus instructions are verbal strategies that could maximize the effects of exercise. The objective of this review was to explore and synthesize the available evidence on the incorporation of attentional focus instruction in the exercise of people with musculoskeletal disorders. A search of 11 databases was carried out until October 2020. Of 4,227 studies identified in the searches, 15 were included. The studies showed deficiencies in the conceptualization and definition of attentional focus instructions. The available evidence indicates that external focus is effective in improving motor learning and function. However, methodological limitations, clinical heterogeneity, the small number of articles included, and new experimental studies challenge the conclusions of the systematic reviews available to date. Attentional focus instructions in musculoskeletal disorders is an emerging field and requires further research. This review is a guide for future studies.

Membrane lipids of the stallion spermatozoon in relation to sperm quality and susceptibility to lipid peroxidation.

Lipids were extracted from ejaculated spermatozoa from seven individual stallions to distinguish neutral lipids (NL) and polar lipids (PL) and determine their variation among stallions and their relationship with sperm quality and sperm susceptibility to lipid peroxidation. The isolated fatty acids were correlated with sperm quality (membrane integrity, mitochondrial membrane potential (ΔΨm) and expression of active caspases) and the sensitivity of the sperm plasma membrane to LPO. The miristic (C14: 0), palmitic (C16: 0), stearic (C18: 0) and oleic (C18: 1n9) acids were predominant among the NLs. Within the phospholipid fraction, the docosapentanoic acid (C22: 5n6) was dominant, albeit varying among stallions. Surprisingly, the percentage of polyunsaturated fatty acids was positively correlated with sperm quality and a low propensity for LPO, probably because these particular fatty acids provide a higher fluidity of the plasma membrane. The stallion showing the poorest sperm membrane integrity plus a high level of LPO in his ejaculate had a lower percentage (p<0.05) of this fatty acid in his sperm plasma membranes.

[Sepsis due to Pseudomonas aeruginosa in a previously healthy infant]. / Sepsis por Pseudomonas aeruginosa en un lactante previamente sano.

Pseudomonas aeruginosa, is an opportunistic organism widely distributed in both environmental and nosocomial settings. Invasive infections typically occur in immunocompromised patients, but this agent can also produce sepsis in the immunocompetent host. We report the case of an 8 months old infant, previous healthy, who presented septic shock by P. aeruginosa. Lesions of ecthyma gangrenosum in his limbs required surgical debridement. The patient presented transitory neutropenia and reduced C4 levels but subsequent study of immune defects was normal.

Effect of maternal nutrient restriction on expression of glucose transporters (SLC2A4 and SLC2A1) and insulin signaling in skeletal muscle of SGA and Non-SGA sheep fetuses.

Maternal nutrient restriction (NR) causes small for gestational age (SGA) offspring, which are at higher risk for accelerated postnatal growth and developing insulin resistance in adulthood. Skeletal muscle is essential for whole-body glucose metabolism, as 80% of insulin-mediated glucose uptake occurs in this tissue. Maternal NR can alter fetal skeletal muscle mass, expression of glucose transporters, insulin signaling, and myofiber type composition. It also leads to accumulation of intramuscular triglycerides (IMTG), which correlates to insulin resistance. Using a 50% NR treatment from gestational day (GD) 35 to GD 135 in sheep, we routinely observe a spectral phenotype of fetal weights within the NR group. Thus, we classified those fetuses into NR(Non-SGA; n = 11) and NR(SGA; n = 11). The control group (n = 12) received 100% of nutrient requirements throughout pregnancy. At GD 135, fetal plasma and gastrocnemius and soleus muscles were collected. In fetal plasma, total insulin was lower in NR(SGA) fetuses compared NR(Non-SGA) and control fetuses (P < 0.01), whereas total IGF-1 was lower in NR(SGA) fetuses compared with control fetuses (P < 0.05). Within gastrocnemius, protein expression of insulin receptor (INSRB; P < 0.05) and the glucose transporters, solute carrier family 2 member 1 and solute carrier family 2 member 4, was higher (P < 0.05) in NR(SGA) fetuses compared with NR(Non-SGA) fetuses; IGF-1 receptor protein was increased (P < 0.01) in NR(SGA) fetuses compared with control fetuses, and a lower (P < 0.01) proportion of type I myofibers (insulin sensitive and oxidative) was observed in SGA fetuses. For gastrocnemius muscle, the expression of lipoprotein lipase (LPL) messenger RNA (mRNA) was upregulated (P < 0.05) in both NR(SGA) and NR(Non-SGA) fetuses compared with control fetuses, whereas carnitine palmitoyltransferase 1B (CPT1B) mRNA was higher (P < 0.05) in NR(Non-SGA) fetuses compared with control fetuses, but there were no differences (P > 0.05) for protein levels of LPL or CPT1B. Within soleus, there were no differences (P > 0.05) for any characteristic except for the proportion of type I myofibers, which was lower (P < 0.05) in NR(SGA) fetuses compared with control fetuses. Accumulation of IMTG did not differ (P > 0.05) in gastrocnemius or soleus muscles. Collectively, the results indicate molecular differences between SGA and Non-SGA fetuses for most characteristics, suggesting that maternal NR induces a spectral phenotype for the metabolic programming of those fetuses.

[Antimicrobials in neonatology. Part II: Recommendations for the dilution and administration of antimicrobials in the newborn]. / Antimicrobianos en neonatología. Parte II: Recomendaciones para la dilución y administración de antimicrobianos utilizados en el recién nacido.

Antimicrobials are among the most commonly prescribed classes of medications in Neonatal Intensive Care Units; however, its use has been constantly associated with a number of medication errors in clinical practice. In contrast to this situation, there is no common agreement when it comes to determining the right dosing, administration, or handling of antibiotics in this population. In order to help improve the use of antibiotics, decrease the rate of medication errors and optimize clinical results in the newborn, this review aims to provide recommendations to support and guide the correct preparation of some of the most relevant antibiotics used in neonatal wards.

Prognostic value of molecular biomarkers in patients with metastatic colorectal cancer: a real-world study.

PURPOSE: Outcomes for patients with metastatic colorectal cancer (mCRC) have been improved by the identification of biomarkers predictive and prognostic of clinical outcome. The present retrospective analysis was undertaken to assess the utility of key biomarkers and clinical parameters in predicting outcomes in Spanish patients with mCRC. METHODS: We retrospectively analyzed tumor samples from a series of patients aged > 18 years with mCRC who were treated at the Hospital General Universitario Gregorio Marañón Spain. Real-time polymerase chain reaction was used to detect KRAS, NRAS, BRAF, and PIK3CA mutations. The key outcome of interest was overall survival (OS). Survival curves were estimated using the Kaplan-Meier method and stratified by the variables of greatest clinical interest. Differences were tested using the log-rank test. RESULTS: Median OS in the overall population was 24.4 months. Triple WT patients (WT KRAS, NRAS, and BRAF) and quadruple WT patients (WT KRAS, NRAS, BRAF, and PIK3CA) had significantly better OS than those who did not have triple or quadruple WT tumors. OS was significantly better in patients with left- vs. right-sided tumors, patients with resected primary tumors and metastases vs. those without resection, and patients with isolated hepatic and isolated pulmonary metastases. CONCLUSIONS: This retrospective, observational study has confirmed the prognostic value of the location and resection status of the primary tumor and metastases in Spanish patients with mCRC. Triple WT status, in particular, was prognostic in this patient population, with PIK3CA adding to the prognostic value in the quadruple WT population.

Polyglutamine-expanded androgen receptor truncation fragments activate a Bax-dependent apoptotic cascade mediated by DP5/Hrk.

Spinal and bulbar muscular atrophy (SBMA) is an inherited neuromuscular disorder caused by a polyglutamine (polyQ) repeat expansion in the androgen receptor (AR). PolyQ-AR neurotoxicity may involve generation of an N-terminal truncation fragment, as such peptides occur in SBMA patients and mouse models. To elucidate the basis of SBMA, we expressed N-terminal truncated AR in motor neuron-derived cells and primary cortical neurons. Accumulation of polyQ-AR truncation fragments in the cytosol resulted in neurodegeneration and apoptotic, caspase-dependent cell death. Using primary neurons from mice transgenic or deficient for apoptosis-related genes, we determined that polyQ-AR apoptotic activation is fully dependent on Bax. Jun N-terminal kinase (JNK) was required for apoptotic pathway activation through phosphorylation of c-Jun. Expression of polyQ-AR in DP5/Hrk null neurons yielded significant protection against apoptotic activation, but absence of Bim did not provide protection, apparently due to compensatory upregulation of DP5/Hrk or other BH3-only proteins. Misfolded AR protein in the cytosol thus initiates a cascade of events beginning with JNK and culminating in Bax-dependent, intrinsic pathway activation, mediated in part by DP5/Hrk. As apoptotic mediators are candidates for toxic fragment generation and other cellular processes linked to neuron dysfunction, delineation of the apoptotic activation pathway induced by polyQ-expanded AR may shed light on the pathogenic cascade in SBMA and other motor neuron diseases.