Interactions between the principal risk factors for reduction of the eGFR in unvaccinated COVID­19 survivors: Normal pre-COVID­19 eGFR, not having diabetes and being hospitalized.

There are contradictory results regarding changes in estimated glomerular filtration rate (eGFR) in coronavirus disease 2019 (COVID-19) survivors. An analysis of eGFR changes and clinical characteristics associated with those changes was conducted among COVID-19 survivors. eGFR values were compared at different time points (before and 4-, 8- and 12-months after COVID-19 infection). A multivariate generalized linear mixed model (GENLINMIXED procedure) with a binary logistic regression link was used to determine factors associated with eGFR reduction of ≥10 ml/min/1.73 m2. Being hospitalized (RR=2.90, 95% CI=1.10-7.68, P=0.032), treated with Ivermectin (RR=14.02, 95% CI=4.11-47.80, P<0.001) or anticoagulants (RR=6.51, 95% CI=2.69-15.73, P<0.001) are risk factors for a reduced eGFR. Having a low eGFR (<90 ml/min/1.73 m2) before COVID-19 infection, having B-positive blood type, diabetes, taking vitamin C during the acute phase of COVID-19 or suffering from chronic COVID-19 symptoms, were identified as protective factors. Analysis involving a two-way interaction (A x B, where A and B are factors) demonstrated that the combination of patients with a normal eGFR value before COVID-19 infection without diabetes (RR=58.60, 95% CI=11.62-295.38, P<0.001), or a normal eGFR value with being hospitalized for COVID-19 (RR=38.07, 95% CI=8.68-167.00, P<0.001), increased the probability of a reduced eGFR. The changes in eGFR in COVID-19 survivors varied depending on patient characteristics. Furthermore, the principal risk factors for post-COVID-19 eGFR reduction were analyzed in separate models.

Evaluation of the adenocarcinoma-associated gene AGR2 and the intestinal stem cell marker LGR5 as biomarkers in colorectal cancer.

We aim to estimate the diagnostic performances of anterior gradient homolog-2 (AGR2) and Leucine-rich repeat-containing-G-protein-coupled receptor 5 (LGR5) in peripheral blood (PB) as mRNA biomarkers in colorectal cancer (CRC) and to explore their prognostic significance. Real-time PCR was used to analyze AGR2 and LGR5 in 54 stages I-IV CRC patients and 19 controls. Both mRNAs were significantly increased in PB from CRC patients compared to controls. The area under the receiver-operating characteristic curves were 0.722 (p = 0.006), 0.376 (p = 0.123) and 0.767 (p = 0.001) for AGR2, LGR5 and combined AGR2/LGR5, respectively. The AGR2/LGR5 assay resulted in 67.4% sensitivity and 94.7% specificity. AGR2 correlated with pT3-pT4 and high-grade tumors. LGR5 correlated with metastasis, R2 resections and high-grade. The progression-free survival (PFS) of patients with high AGR2 was reduced (p = 0.037; HR, 2.32), also in the stage I-III subgroup (p = 0.046). LGR5 indicated a poor prognosis regarding both PFS (p = 0.007; HR, 1.013) and overall survival (p = 0.045; HR, 1.01). High AGR2/LGR5 was associated with poor PFS (p = 0.014; HR, 2.8) by multivariate analysis. Our findings indicate that the assessment of AGR2 and LGR5 in PB might reflect the presence of circulating tumor cells (CTC) and stem cell like CTC in CRC. Increased AGR2 and LGR5 are associated with poor outcomes.

Preclinical Characterization of an Antibody-Drug Conjugate Targeting CS-1 and the Identification of Uncharacterized Populations of CS-1-Positive Cells.

Multiple myeloma is a hematologic cancer that disrupts normal bone marrow function and has multiple lines of therapeutic options, but is incurable as patients ultimately relapse. We developed a novel antibody-drug conjugate (ADC) targeting CS-1, a protein that is highly expressed on multiple myeloma tumor cells. The anti-CS-1 mAb specifically bound to cells expressing CS-1 and, when conjugated to a cytotoxic pyrrolobenzodiazepine payload, reduced the viability of multiple myeloma cell lines in vitro In mouse models of multiple myeloma, a single administration of the CS-1 ADC caused durable regressions in disseminated models and complete regression in a subcutaneous model. In an exploratory study in cynomolgus monkeys, the CS-1 ADC demonstrated a half-life of 3 to 6 days; however, no highest nonseverely toxic dose was achieved, as bone marrow toxicity was dose limiting. Bone marrow from dosed monkeys showed reductions in progenitor cells as compared with normal marrow. In vitro cell killing assays demonstrated that the CS-1 ADC substantially reduced the number of progenitor cells in healthy bone marrow, leading us to identify previously unreported CS-1 expression on a small population of progenitor cells in the myeloid-erythroid lineage. This finding suggests that bone marrow toxicity is the result of both on-target and off-target killing by the ADC.

The relative activity of "function sparing" HIV-1 entry inhibitors on viral entry and CCR5 internalization: is allosteric functional selectivity a valuable therapeutic property?

Six allosteric HIV-1 entry inhibitor modulators of the chemokine (C-C motif) receptor 5 (CCR5) receptor are compared for their potency as inhibitors of HIV-1 entry [infection of human osteosarcoma (HOS) cells and peripheral blood mononuclear cells (PBMC)] and antagonists of chemokine (C-C motif) ligand 3-like 1 [CCL3L1]-mediated internalization of CCR5. This latter activity has been identified as a beneficial action of CCL3L1 in prolonging survival after HIV-1 infection ( Science 307: 1434-1440, 2005 ). The allosteric nature of these modulators was further confirmed with the finding of a 58-fold (HOS cells) and 282-fold (PBMC) difference in relative potency for blockade of CCL3L1-mediated internalization versus HIV-1 entry. For the CCR5 modulators, statistically significant differences in this ratio were found for maraviroc, vicriviroc, aplaviroc, Sch-C, TAK652, and TAK779. For instance, although TAK652 is 13-fold more potent as an HIV-1 inhibitor (over blockade of CCL3L1-mediated CCR5 internalization), this ratio of potency is reversed for Sch-C (22-fold more potent for CCR5-mediated internalization over HIV-1 entry). Quantitative analyses of the insurmountable antagonism of CCR5 internalization by these ligands suggest that all of them reduce the efficacy of CCL3L1 for CCR5 internalization. The relatively small magnitude of dextral displacement accompanying the depression of maximal responses for aplaviroc, maraviroc and vicriviroc suggests that these modulators have minimal effects on CCL3L1 affinity, although possible receptor reserve effects obscure complete interpretation of this effect. These data are discussed in terms of the possible benefits of sparing natural CCR5 chemokine function in HIV-1 entry inhibition treatment for AIDS involving allosteric inhibitors.

Hedgehog signalling as a target in cancer stem cells.

Hedgehog (Hh) is one of the most important signalling pathways. Together with the Wnt, TGF-Beta/BMP and Notch pathways, it is involved in both embryonic development and adult tissue homeostasis. This is because Hh plays a central role in the proliferative control and differentiation of both embryonic stem cells and adult stem cells. In this way, an alteration in the Hh pathway, either by misexpression of components of that pathway or by changes in the expression of other cellular components that interfere with the Hh signalling system, may trigger the development of several types of cancer. This occurs because normal stem cells or their intermediaries toward differentiated mature cells are not part of the normal proliferative/ differentiation balance and begin to expand without control, triggering the generation of the so-called cancer stem cells. In this review, we will focus on the molecular aspects and the role of Hh signalling in normal tissues and in tumour development.

Human Relaxin-2 Fusion Protein Treatment Prevents and Reverses Isoproterenol-Induced Hypertrophy and Fibrosis in Mouse Heart.

Background Heart failure is one of the leading causes of death in Western countries, and there is a need for new therapeutic approaches. Relaxin-2 is a peptide hormone that mediates pleiotropic cardiovascular effects, including antifibrotic, angiogenic, vasodilatory, antiapoptotic, and anti-inflammatory effects in vitro and in vivo. Methods and Results We developed RELAX10, a fusion protein composed of human relaxin-2 hormone and the Fc of a human antibody, to test the hypothesis that extended exposure of the relaxin-2 peptide could reduce cardiac hypertrophy and fibrosis. RELAX10 demonstrated the same specificity and similar in vitro activity as the relaxin-2 peptide. The terminal half-life of RELAX10 was 7 days in mouse and 3.75 days in rat after subcutaneous administration. We evaluated whether treatment with RELAX10 could prevent and reverse isoproterenol-induced cardiac hypertrophy and fibrosis in mice. Isoproterenol administration in mice resulted in increased cardiac hypertrophy and fibrosis compared with vehicle. Coadministration with RELAX10 significantly attenuated the cardiac hypertrophy and fibrosis compared with untreated animals. Isoproterenol administration significantly increased transforming growth factor ß1 (TGF-ß1)-induced fibrotic signaling, which was attenuated by RELAX10. We found that RELAX10 also significantly increased protein kinase B/endothelial NO synthase signaling and protein S-nitrosylation. In the reversal study, RELAX10-treated animals showed significantly reduced cardiac hypertrophy and collagen levels. Conclusions These findings support a potential role for RELAX10 in the treatment of heart failure.

Design and characterization of homogenous antibody-drug conjugates with a drug-to-antibody ratio of one prepared using an engineered antibody and a dual-maleimide pyrrolobenzodiazepine dimer.

Most strategies used to prepare homogeneous site-specific antibody-drug conjugates (ADCs) result in ADCs with a drug-to-antibody ratio (DAR) of two. Here, we report a disulfide re-bridging strategy to prepare homogeneous ADCs with DAR of one using a dual-maleimide pyrrolobenzodiazepine (PBD) dimer (SG3710) and an engineered antibody (Flexmab), which has only one intrachain disulfide bridge at the hinge. We demonstrate that SG3710 efficiently re-bridge a Flexmab targeting human epidermal growth factor receptor 2 (HER2), and the resulting ADC was highly resistant to payload loss in serum and exhibited potent anti-tumor activity in a HER2-positive gastric carcinoma xenograft model. Moreover, this ADC was tolerated in rats at twice the dose compared to a site-specific ADC with DAR of two prepared using a single-maleimide PBD dimer (SG3249). Flexmab technologies, in combination with SG3710, provide a platform for generating site-specific homogenous PBD-based ADCs with DAR of one, which have improved biophysical properties and tolerability compared to conventional site-specific PBD-based ADCs with DAR of two.

In silico and in vitro analysis of small breast epithelial mucin as a marker for bone marrow micrometastasis in breast cancer.

Molecular signatures associated with malignant phenotype would be useful for detection of micrometastatic carcinoma cells. The small breast epithelial mucin (SBEM) gene is predicted to code for a low molecular weight glycoprotein. To evaluate its potential role as a marker for bone marrow (BM) micrometastasis in breast cancer (BC) patients, we have studied in silico and in vitro expression profiles of SBEM gene. Digital SBEM expression in libraries obtained from normal and neoplastic tissues and cell-lines (CL) were displayed and counted on the SAGE Anatomic Viewer. Profiles for cytokeratin-19 and mammaglobin (hMAM), commonly targets used for detection of disseminated BC cells were obtained and compared with SBEM data. Human breast and haematopoietic cancer CL and normal BM were examined by RT-PCR for SBEM and hMAM. Bioinformatics tools were used to gain further insights about the biological role of SBEM in normal breast and BC. Genes with expression patterns in breast libraries correlating with SBEM were identified using two-dimensional display. SBEM tag was detected in 40 libraries (21 BC; 8 non-cancerous breast tissues). Intermediate to high expression was found on 15/21 BC libraries and 7/8 non-tumor breast tissue. SBEM tag count was correlated with ERBB2 (0.662), hMAM (0.409), and RRM2 (-0.379). A model system based on RT-PCR for SBEM mRNA was highly sensitive and specific in order to detect isolated tumor cells. Our results demonstrate that SBEM mRNA may be an imp ortant marker for targeting BC micrometastasis.

Context-dependent roles of mutant B-Raf signaling in melanoma and colorectal carcinoma cell growth.

Mutational activation of Ras and a key downstream effector of Ras, the B-Raf serine/threonine kinase, has been observed in melanomas and colorectal carcinomas. These observations suggest that inhibition of B-Raf activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase kinase (MEK) and the extracellular signal-regulated kinase MAPK cascade may be an effective approach for the treatment of RAS and B-RAF mutation-positive melanomas and colon carcinomas. Although recent studies with interfering RNA (RNAi) and pharmacologic inhibitors support a critical role for B-Raf signaling in melanoma growth, whether mutant B-Raf has an equivalent role in promoting colorectal carcinoma growth has not been determined. In the present study, we used both RNAi and pharmacologic approaches to further assess the role of B-Raf activation in the growth of human melanomas and additionally determined if a similar role for mutant B-Raf is seen for colorectal carcinoma cell lines. We observed that RNAi suppression of mutant B-Raf(V600E) expression strongly suppressed the anchorage-dependent growth of B-RAF mutation-positive melanoma, but not colorectal carcinoma, cells. However, the anchorage-independent and tumorigenic growth of B-RAF mutation-positive colorectal carcinomas was dependent on mutant B-Raf function. Finally, pharmacologic inhibition of MEK and Raf was highly effective at inhibiting the growth of B-RAF mutation-positive melanomas and colorectal carcinoma cells, whereas inhibitors of other protein kinases activated by Ras (AKT, c-Jun NH(2)-terminal kinase, and p38 MAPK) were less effective. Our observations suggest that Raf and MEK inhibitors may be effective for the treatment of B-RAF mutation-positive colorectal carcinomas as well as melanomas.

The human XPC DNA repair gene: arrangement, splice site information content and influence of a single nucleotide polymorphism in a splice acceptor site on alternative splicing and function.

XPC DNA repair gene mutations result in the cancer-prone disorder xeroderma pigmentosum. The XPC gene spans 33 kb and has 16 exons (82-882 bp) and 15 introns (0.08-5.4 kb). A 1.6 kb intron was found within exon 5. Sensitive real- time quantitative reverse transcription-polymerase chain reaction methods were developed to measure full-length XPC mRNA (the predominant form) and isoforms that skipped exons 4, 7 or 12. Exon 7 was skipped in approximately 0.07% of XPC mRNAs, consistent with the high information content of the exon 7 splice acceptor and donor sites (12.3 and 10.4 bits). In contrast, exon 4 was skipped in approximately 0.7% of the XPC mRNAs, consistent with the low information content of the exon 4 splice acceptor (-0.1 bits). A new common C/A single nucleotide polymorphism in the XPC intron 11 splice acceptor site (58% C in 97 normals) decreased its information content from 7.5 to 5.1 bits. Fibroblasts homozygous for A/A had significantly higher levels (approximately 2.6-fold) of the XPC mRNA isoform that skipped exon 12 than those homozygous for C/C. This abnormally spliced XPC mRNA isoform has diminished DNA repair function and may contribute to cancer susceptibility.

A Biparatopic HER2-Targeting Antibody-Drug Conjugate Induces Tumor Regression in Primary Models Refractory to or Ineligible for HER2-Targeted Therapy.

Antibody-drug conjugate (ADC) which delivers cytotoxic drugs specifically into targeted cells through internalization and lysosomal trafficking has emerged as an effective cancer therapy. We show that a bivalent biparatopic antibody targeting two non-overlapping epitopes on HER2 can induce HER2 receptor clustering, which in turn promotes robust internalization, lysosomal trafficking, and degradation. When conjugated with a tubulysin-based microtubule inhibitor, the biparatopic ADC demonstrates superior anti-tumor activity over ado-trastuzumab emtansine (T-DM1) in tumor models representing various patient subpopulations, including T-DM1 eligible, T-DM1 ineligible, and T-DM1 relapsed/refractory. Our findings indicate that this biparatopic ADC has promising potential as an effective therapy for metastatic breast cancer and a broader patient population may benefit from this unique HER2-targeting ADC.

The C. elegans Chp/Wrch Ortholog CHW-1 Contributes to LIN-18/Ryk and LIN-17/Frizzled Signaling in Cell Polarity.

Wnt signaling controls various aspects of developmental and cell biology, as well as contributing to certain cancers. Expression of the human Rho family small GTPase Wrch/RhoU is regulated by Wnt signaling, and Wrch and its paralog Chp/RhoV are both implicated in oncogenic transformation and regulation of cytoskeletal dynamics. We performed developmental genetic analysis of the single Caenorhabditis elegans ortholog of Chp and Wrch, CHW-1. Using a transgenic assay of the distal tip cell migration, we found that wild-type CHW-1 is likely to be partially constitutively active and that we can alter ectopic CHW-1-dependent migration phenotypes with mutations predicted to increase or decrease intrinsic GTP hydrolysis rate. The vulval P7.p polarity decision balances multiple antagonistic Wnt signals, and also uses different types of Wnt signaling. Previously described cooperative Wnt receptors LIN-17/Frizzled and LIN-18/Ryk orient P7.p posteriorly, with LIN-17/Fz contributing approximately two-thirds of polarizing activity. CHW-1 deletion appears to equalize the contributions of these two receptors. We hypothesize that CHW-1 increases LIN-17/Fz activity at the expense of LIN-18/Ryk, thus making the contribution of these signals unequal. For P7.p to polarize correctly and form a proper vulva, LIN-17/Fz and LIN-18/Ryk antagonize other Wnt transmembrane systems VANG-1/VanGogh and CAM-1/Ror. Our genetic data suggest that LIN-17/Fz represses both VANG-1/VanGogh and CAM-1/Ror, while LIN-18/Ryk represses only VANG-1. These data expand our knowledge of a sophisticated signaling network to control P7.p polarity, and suggests that CHW-1 can alter ligand gradients or receptor priorities in the system.

Qualidade de vida relacionada com a saúde oral em idosas de um grupo de convivência / Quality of life related to oral health among the elderly of a socialization group

Over the last decades, there has been a substantial increase in interest in the quality of life related to the oral health ofthe elderly. This is due to the fact that oral diseases significantly compromise the physical, emotional and social aspectsof these individuals. Oral health is considered part of the general state of health and well-being. The objective of thisstudy was to evaluate the association of quality of life with oral health in elderly women participating in a socializationgroup. This was a descriptive, analytical, cross-sectional study with women aged 60 years or older, who participate in asocialization group from the city of Santa Maria, RS, Brazil. Data collection was performed using the Oral Health ImpactProfile instrument (OHIP-14). Sixty-six elderly women aged between 60 and 88 years, with a mean of 69.8±7.31 years,participated in the study. The areas that presented the highest values were “Physical Pain”, “Psychological Suffering” and“Physical Disability”. The highest averages of the total OHIP-14 scores occurred in individuals with lower family incomeand low schooling, self-reported depression, altered taste, difficulty in feeling the taste of certain foods and malnutrition.Their low level of education, altered taste and malnutrition assessed by arm circumference were associated with poorer quality of life due to oral disorders

Nas últimas décadas, houve um aumento substancial do interesse sobre a qualidade de vida relacionada à saúde oral deidosos, o que se deve ao fato das doenças orais comprometerem significativamente os aspectos físicos, emocionais e sociaisdestes indivíduos, sendo a saúde oral considerada parte integrante do estado geral de saúde e bem-estar. O objetivo destetrabalho foi avaliar a associação da qualidade de vida com a saúde oral em mulheres idosas participantes de um grupode convivência. É um estudo do tipo descritivo, analítico, transversal, com mulheres com 60 anos ou mais, participantesde um grupo de convivência da cidade de Santa Maria, RS, Brasil. A coleta de dados utilizou o instrumento Oral HealthImpact Profile (OHIP-14). Participaram do estudo 64 mulheres idosas com idade entre 60 e 88 anos, com média de 69,8± 7,31 anos. As áreas que apresentaram os maiores valores foram “Dor Física”, “Sofrimento Psicológico” e “IncapacidadeFísica”. As maiores médias dos escores totais do OHIP-14 ocorreram em indivíduos com menor renda familiar e baixaescolaridade, depressão autorreferida, alterações no paladar, dificuldade de sentir o gosto de determinados alimentos edesnutrição. A baixa escolaridade, a alteração de paladar e a desnutrição avaliadas pela circunferência do braço estavamassociadas com pior qualidade de vida decorrente das desordens orais

A simple method for quantifying functional selectivity and agonist bias.

Activation of seven-transmembrane (7TM) receptors by agonists does not always lead to uniform activation of all signaling pathways mediated by a given receptor. Relative to other ligands, many agonists are "biased" toward producing subsets of receptor behaviors. A hallmark of such "functional selectivity" is cell type dependence; this poses a particular problem for the profiling of agonists in whole cell test systems removed from the therapeutic one(s). Such response-specific cell-based variability makes it difficult to guide medicinal chemistry efforts aimed at identifying and optimizing therapeutically meaningful agonist bias. For this reason, we present a scale, based on the Black and Leff operational model, that contains the key elements required to describe 7TM agonism, namely, affinity (K(A) (-1)) for the receptor and efficacy (τ) in activating a particular signaling pathway. Utilizing a "transduction coefficient" term, log(τ/K(A)), this scale can statistically evaluate selective agonist effects in a manner that can theoretically inform structure-activity studies and/or drug candidate selection matrices. The bias of four chemokines for CCR5-mediated inositol phosphate production versus internalization is quantified to illustrate the practical application of this method. The independence of this method with respect to receptor density and the calculation of statistical estimates of confidence of differences are specifically discussed.

Prognostic impact of disseminated tumor cells and microRNA-17-92 cluster deregulation in gastrointestinal cancer.

The presence of tumor cells in the bone marrow (BM) could be relevant to identifying high risk of disease progression and death in gastrointestinal cancer. However, the molecular profile associated with disseminated tumor cells (DTCs) homing to the BM has yet to be defined. MicroRNAs (miRNA) play key roles in cellular processes implicated in cancer. Thus, we investigated in 38 patients with colorectal, gastric or pancreatic cancer whether the presence of BM-DTCs is associated with a specific miRNA tumor profile and analyzed their potential prognostic impact. DTCs were detected by immunocytochemistry and anti-cytokeratin antibodies in 42.1% of the patients. miRNAs were isolated from formalin-fixed, paraffin-embedded tumors. qRT-PCR was used for miRNA profiling. No significant associations were found among DTC detection and miRNA deregulation. Kaplan-Meier curves demonstrated significantly reduced progression-free survival (PFS) and overall survival (OS) in the DTC-positive patients. Although miR-21 was upregulated in 90.6% of the tumors, no associations with outcomes were found. miR-17 and miR-20a (miRNA-17-92 cluster) were upregulated in 33.3 and 42.4%, respectively. Upregulation of both was correlated and found in 30.3%. Univariate analysis shows that increasing values for miR-20a were significantly associated with reduced PFS (HR 1.022; p=0.016) and OS (HR 1.027; p=0.003). In multivariate Cox models, DTC positivity (HR 4.07; p=0.005) and miR-17 overexpression (HR 2.11; p=0.003) were significantly associated with a higher risk of disease progression. The presence of DTCs in the BM (HR 3.98; p=0.010) and a miR-17 overexpression (HR 2.62; p<0.001) were also associated with a risk of death. Our study suggests that the presence of BM-DTCs and the upregulation of the miR-17-92 cluster in tumors are both significant but independent prognostic markers in gastrointestinal cancer patients.

Análise vocal acústica: efeito do treinamento auditivo-visual para graduandos de Fonoaudiologia / Acoustic voice analysis: effect of an audio-visual training for speech therapy undergraduates

Objetivo Verificar a efetividade de treino para avaliação acústica da voz com graduandos de Fonoaudiologia. Métodos Estudo realizado com 14 estudantes de curso de graduação em Fonoaudiologia, que participaram de seis encontros semanais teóricos e práticos, com duração total de quatro horas e meia. Foram abordados os conceitos básicos para avaliação vocal acústica perceptivo-auditiva e foi praticada a análise espectrográfica de cada parâmetro, visualmente e auditivamente. Para verificar a efetividade da proposta, os graduandos realizaram, antes e ao final do treino, a avaliação das medidas de extração automáticas e de aspectos da espectrografia de banda estreita de uma amostra de 15 vozes, normais e alteradas em variados graus. O desempenho dos alunos foi considerado nos dois momentos, comparando-se os erros e acertos em relação à análise prévia realizada por especialista, com índice Kappa >0,70. Para comparação entre os resultados obtidos pelos graduandos, nos dois momentos, utilizou-se o teste de McNemar. Resultados Para todos os parâmetros analisados, as médias de acerto foram maiores no momento pós-treino, com maioria dos índices acima de 90%; o mesmo observou-se em relação à média geral (24,2% no momento pré-treino e 93,0% no momento pós-treino). Conclusão O treino mostrou-se efetivo para a aprendizagem dos graduandos, podendo ser incorporado às disciplinas que envolvem os conceitos de avaliação da voz e transformado em material didático disponível para outros grupos .

Purpose To verify the effectiveness of a training for acoustic voice assessment with undergraduate students of Speech-Language Pathology. Methods Study conducted with 14 undergraduate students of Speech-Language Pathology who participated in six theoretical/practical weekly encounters, whose total duration was four hours and a half. Basic concepts of acoustic voice assessment was performed; we used spectrographic analysis to each parameter, visually and auditory. In order to verify the proposal;s effectiveness, the undergraduate students assessed before and after de training, the measures of automatic extraction of the evaluation measures and also aspects of narrowband spectrograph of 15 voices, normal and disordered in varying degrees. We considered the performance of students, before and after the training comparing their mistakes and correct scores to a previous analysis performed by a specialist with Kappa index >0.70. To compare the results obtained by the undergraduate students in the two instances McNemar test was performed. Results For all parameters analyzed the average of correct scores was higher after the training, as well as the overall average (24.2% before and 93.0% after). Conclusion The developed training was effective for the learning of undergraduate students, and may be included into subjects which involve concepts of voice assessment and also might be transformed into teaching material available to other groups. .

Evaluation of plakophilin-3 mRNA as a biomarker for detection of circulating tumor cells in gastrointestinal cancer patients.

BACKGROUND: This study aims to assess Plakophilin-3 (PKP3) as a surrogate biomarker of circulating tumor cells in patients with gastrointestinal cancer. METHODS: The primary aim is to estimate the diagnostic accuracy of PKP3 real-time reverse transcriptase-PCR in blood. Receiver operating characteristic curves were constructed. Correlations between the blood PKP3 levels and the clinicopathologic features of the study subjects were analyzed. Logistic regression was used to predict outcomes based on PKP3. RESULTS: Sixty-four patients with gastrointestinal cancer and 23 controls were included. The mean relative PKP3 mRNA expression was 48.45 in cancer patients and 2.8 in controls (P < 0.0001). Comparing the PKP3 levels in patients and controls, the area under the curve was 0.852 (95% confidence interval, 0.76-0.94; P < 0.0001) in receiver operating characteristic analysis. A higher blood level of PKP3 mRNA was associated with a more advanced stage (P = 0.025), pT(3-4) tumors (P = 0.028), metastasis (P = 0.021), and residual (R2) disease (P = 0.037). Higher PKP3 mRNA was associated with the risk of cancer progression and death (odds ratio, 3.875; 95% confidence interval, 1.781-8.430; P = 0.001). CONCLUSIONS: Increased PKP3 mRNA was detected in the blood of gastrointestinal cancer patients. Significant correlations were found with advanced stage, pT(3-4), metastatic disease, and the residual disease status. PKP3 mRNA in blood was associated with the risk of cancer progression and death. IMPACT: PKP3 mRNA can be used as a marker of subclinical disease in gastrointestinal cancer and thus holds potential clinical relevance as a predictor for disease outcome.

Wnt signalling and cancer stem cells.

Intracellular signalling mediated by secreted Wnt proteins is essential for the establishment of cell fates and proper tissue patterning during embryo development and for the regulation of tissue homeostasis and stem cell function in adult tissues. Aberrant activation of Wnt signalling pathways has been directly linked to the genesis of different tumours. Here, the components and molecular mechanisms implicated in the transduction of Wnt signal, along with important results supporting a central role for this signalling pathway in stem cell function regulation and carcinogenesis will be briefl y reviewed.

Comprehensive lung injury pathology induced by mTOR inhibitors.

Interstitial lung disease is a rare side effect of temsirolimus treatment in renal cancer patients. Pulmonary fibrosis is characterised by the accumulation of extracellular matrix collagen, fibroblast proliferation and migration, and loss of alveolar gas exchange units. Previous studies of pulmonary fibrosis have mainly focused on the fibroproliferative process in the lungs. However, the molecular mechanism by which sirolimus promotes lung fibrosis remains elusive. Here, we propose an overall cascade hypothesis of interstitial lung diseases that represents a common, partly underlying synergism among them as well as the lung pathogenesis side effects of mammalian target of rapamycin inhibitors.