Regeneration of periodontal intrabony defects using platelet-rich fibrin (PRF): a systematic review and network meta-analysis.

One of the most promising approaches to correct periodontal bone defects and achieve periodontal regeneration is platelet-rich fibrin (PRF). This systematic review and meta-analysis aimed to evaluate the regeneration of periodontal bone defects using PRF compared to other regenerative treatments. The data search and retrieval process followed the PRISMA guidelines. An electronic search of MEDLINE, Cochrane, and PubMed databases was performed, selecting exclusively randomized clinical trials where the following were measured: probing depth reduction (PD), clinical attachment level gain (CAL), and radiographic bone fill (RBF). Out of 284 selected articles, 32 were chosen based on inclusion criteria. The use of platelet-rich fibrin (PRF) + open flap debridement (OFD), PRF + metformin, PRF + platelet-rich plasma (PRP), and PRF + OFD/bone graft (BG) significantly reduced PD and improved CAL and RBF. However, the combination of PRF + BG, PRF + metformin, and PRF + STATINS reduced CAL. The intervention of PRF combined with different treatments such as metformin, OFD, PRP, BG, and STATINS has a significant impact on improving PD and CAL. The use of PRF significantly improved the regeneration of periodontal bone defects compared to other treatments.

Pyrosequencing Analysis of O-6-Methylguanine-DNA Methyltransferase Methylation at Different Cut-Offs of Positivity Associated with Treatment Response and Disease-Specific Survival in Isocitrate Dehydrogenase-Wildtype Grade 4 Glioblastoma.

The O-6-methylguanine-DNA methyltransferase (MGMT) gene is a critical guardian of genomic integrity. MGMT methylation in diffuse gliomas serves as an important determinant of patients' prognostic outcomes, more specifically in glioblastomas (GBMs). In GBMs, the absence of MGMT methylation, known as MGMT promoter unmethylation, often translates into a more challenging clinical scenario, tending to present resistance to chemotherapy and a worse prognosis. A pyrosequencing (PSQ) technique was used to analyze MGMT methylation status at different cut-offs (5%, 9%, and 11%) in a sample of 78 patients diagnosed with IDH-wildtype grade 4 GBM. A retrospective analysis was provided to collect clinicopathological and prognostic data. A statistical analysis was used to establish an association between methylation status and treatment response (TR) and disease-specific survival (DSS). The patients with methylated MGMT status experienced progressive disease rates of 84.6%, 80%, and 78.4% at the respective cut-offs of 5%, 9%, and 11%. The number was considerably higher when considering unmethylated patients, as all patients (100%), regardless of the cut-off, presented progressive disease. Regarding disease-specific survival (DSS), the Hazard Ratio (HR) was HR = 0.74 (0.45-1.24; p = 0.251); HR = 0.82 (0.51-1.33; p = 0.425); and HR = 0.79 (0.49-1.29; p = 0.350), respectively. Our study concludes that there is an association between MGMT unmethylation and worse TR and DSS. The 9% cut-off demonstrated a greater potential for patient survival as a function of time, which may shed light on the future need for standardization of MGMT methylation positivity parameters in PSQ.

Tumor budding is a prognostic factor in head and neck squamous cell carcinoma: A comprehensive meta-analysis and trial sequential analysis.

BACKGROUND: Mortality is linked to tumor budding (TB) in certain neoplasms. TB as a relevant histopathological feature is conditioned by tumor site, a specific study on head and neck squamous cell carcinoma (HNSCC) is needed. METHODS: A comprehensive meta-analysis was undertaken to investigate the relationship between TB and HNSCC-related outcomes. RESULTS: Overall 42 studies were included. Patients harboring high TB reported an Overall Survival (OS) Hazard Ratio (HR) of 2.63 (95% confidential interval (CI) 2.04-3.39; p-value < 0.001), Disease-free Survival (DFS) HR of 1.88 (95%CI 1.57-2.24; p-value <0.001) and Disease-specific Survival (DSS) HR of 2.14 (95%CI 1.81-2.52; p-value <0.001). Lymph Node Metastasis (LNM) studies harbored null heterogeneity and marked association with TB (Odds Ratio (OR) = 4.48, 95%CI 2.97-6.76; p-value < 0.001). Trial Sequential Analysis (TSA) supported definitive results for DSS. CONCLUSION: The study has provided compelling evidence that there is a significant association between TB and a worse prognosis for HNSCC.

Correlation of Bcl-2 expression with prognosis and survival in patients with head and neck cancer: A systematic review and meta-analysis.

Head and neck cancer (HNC) is a growing disease, affecting more than 700.000 cases per year and ranking as the sixth most prevalent type of cancer worldwide. The impossibility of properly entering into apoptosis directly influences uncontrolled growth and consequently tumor development and progression. Bcl-2 emerged as a key regulator in the balance between cell apoptosis and proliferation in apoptosis machinery. This systematic review and meta-analysis aimed to review all published studies investigating changes in Bcl-2 protein expression assessed by immunohistochemistry (IHC) and related to prognostic and survival values of patients with HNC. After applying the inclusion and exclusion factors, we reached the number of 20 articles included in the meta-analysis. The random-effect pooled HR (CI95%) value of OS related to Bcl-2 IHC expression in tissues from HNC patients was 1.80 (CI95% 1.21-2.67) (p 0.0001) and DFS was 1.90 (CI95% 1.26-2.86 (p 0.0001). The OS value for the specific oral cavity tumors was 1.89 (1.34-2.67), while in the larynx it was 1.77 (0.62-5.06), and the DFS in the pharynx was 2.02 (1.46-2.79). The univariate and multivariate analyses of OS were respectively 1.43 (1.11-1.86) and 1.88 (1.12-3.16), while in DFS it was 1.70 (0.95-3.03) and 2.08 (1.55-2.80). The OS considering a low cut-off for Bcl-2 positivity was 1.19 (0.60-2.37) and DFS was 1.48 (0.91-2.41), while studies with a high cut-off demonstrated OS of 2.28 (1.47-3.52) and DFS of 2.77 (1.74-4.40). Our meta-analysis demonstrates that Bcl-2 protein overexpression can result in worse LNM, OS, and DFS in patients with HNC, however, it is not a reliable conclusion, due to the wide divergences between the original studies and the fact that many studies have a very high range of confidence and also a high risk of bias.

Caspase 3 and Cleaved Caspase 3 Expression in Tumorogenesis and Its Correlations with Prognosis in Head and Neck Cancer: A Systematic Review and Meta-Analysis.

Head and neck cancer (HNC) is an ascending and agressive disease. The search for new molecular markers is emerging to solve difficulties in diagnosis, risk management, prognosis and effectiveness of treatments. Proteins related to apoptotic machinery have been identified as potential biomarkers. Caspase 3 is the main effector caspase and has a key role in apoptosis. The objective of this systematic review and meta-analysis is to review studies that analyze changes in Caspase 3 and Cleaved Caspase 3 expression both in oral premalignant disorders (OPMD) as well as in head and neck cancer (HNC). This study also proposes to review the prognostic values associated with HNC according to the expression of Caspase 3. Medline (via PubMed), EMBASE, Scopus, Cochrane, Web of Science and Grey Literature Database were screened from inception to june of 2022 and 18 studies were selected and 8 were included in the prognostic meta-analysis. Results related to the comparison of Caspase 3 expression demonstrated similar expression of Caspase 3 in HNC, with an average of 51.9% (9.5-98.1) showing high/moderate expression compared to 45.7% (14.6-84.7) in OPMD. Of interest, Cleaved Caspase 3 resulted incresed in HNC when compared with OPMD, being 73.3% (38.6-88.3) versus 22.9% (7.1-38.7). Pooled Fixed effect of HR values (95% CI) for OS related to Caspase 3 IHC expression in HNC patients was 1.48 (95% CI 0.95-2.28); also, the rate of heterogeneity was low, as revealed by I2 = 31%. For DFS was 1.07 (95% CI 0.79-1.45) with I2 = 0% and DSS showed a HR of 0.88 (95% CI 0.69-1.12) with I2 = 37%. Caspase 3 and Cleaved Caspase 3 expression could be linked with malignancy progression, but the expression of Caspase 3 did not influence the prognosis of patients with HNC.

Efficacy of photobiomodulation in reducing pain and improving the quality of life in patients with idiopathic burning mouth syndrome. A systematic review and meta-analysis.

Burning mouth syndrome is a chronic condition, which is characterised by a burning sensation or pain in the mucosa of the oral cavity. Treatment options include antidepressants, antipsychotics, anticonvulsants, analgesics, hormone replacement therapies and more recently photobiomodulation. This study aims to perform a systematic review with meta-analysis in order to determine the effect of photobiomodulation on pain relief and the oral health-related quality of life associated with this condition. A bibliographical search of the Pubmed, Embase, Web of Science and Scopus databases was conducted. Only randomised clinical trials were included. Pain and quality of life were calculated as mean difference and pooled at different treatment points (baseline = T0 and final time point = Tf) and laser modality. From a total of 103 records, 7 articles were retrieved for inclusion. PBM group had a greater decrease in pain than control group at Tf with a mean difference = - 2.536 (IC 95% - 3.662 to - 1.410; I2 = 85.33%, p < 0.001). An improvement in oral health-related quality of life was observed in both groups, although this was more significant in the photobiomodulation group mean difference = - 5.148 (IC 95% - 8.576 to - 1.719; I2 = 84.91%, p = 0.003). For the red laser, a greater improvement than infrared was observed, in pain, mean difference = - 2.498 (IC 95% - 3.942 to - 1.053; I2 = 79.93%, p < 0.001), and in quality of life, mean difference = - 8.144 (IC 95% - 12.082 to - 4.206; I2 = 64.22%, p = 0.027). Photobiomodulation, in particular, red laser protocols, resulted in improvement in pain and in quality of life of burning mouth syndrome patients.

The influence of subtalar axis orientation on the foot posture of older adults in a closed kinetic chain / A influência da orientação do eixo subtalar na postura do pé de idosos em cadeia cinética fechada

Objectives: This study compared the influence of subtalar axis position on foot behavior in a closed kinetic chain in older and younger adults. Methods: The sample included 50 older adults and a control group of 50 younger adults. The variables were initially analyzed for both feet together, and were later analyzed separately, comparing each foot (right and left) between groups. Range of motion was assessed by validated goniometric procedures: the position of subtalar axis was evaluated by the palpation technique, while the Foot Posture Index was used to assess behavior in a closed kinetic chain. Student's t-test / Mann-Whitney test compared the main variables according to sample distribution, while Student's t-test / Wilcoxon test was used for paired samples. A standardized Haberman residuals test was also used to determine the connection between the position of subtalar joint axis and the Foot Posture Index. Results: Data from the right and left feet were similar for all variables. The older group had reduced mobility in the ankle and first metatarsophalangeal joint (5.42º [SD (Standard Deviation), 4.49] and 76.12º [SD, 19.24], respectively) with statistically significant values, (p <0.001), as measured by the Mann-Whitney test for the ankle joint and the t-Sutdent test for the first metatarsophalangeal joint, while the younger group had normal values (11.46º [SD, 6.49] and 97.17º [SD, 13.65], respectively)(p < 0.001). The difference in subtalar axis position was not significant (p = 0.788), with more internal deviations in both groups. There was a significant difference in Foot Posture Index (p = 0.006, by applying the chi-square test), with the normal position more prevalent in the older group and the prone position more prevalent in the younger group. Conclusions: Regarding internal deviations in the subtalar joint axis, the older group had a higher frequency of feet in the normal position, while the younger group had a higher frequency of feet in the prone position which, in this case, agrees with the rotational balance theory. For the normal axis position, a higher frequency of normal position was found in both groups. Regarding external deviations of the subtalar joint axis, neither group followed the pattern expected in rotational balance theory. The most consistent connection in the older group was between external axis position and supine foot position, whereas in the younger group it was between normal axis position and normal foot position.

Objetivos: Este estudo comparou a influência da posição do eixo subtalar no comportamento do pé em cadeia cinética fechada em idosos e adultos jovens. Metodologia: O grupo amostral incluiu 50 idosos e o grupo controle, 50 adultos jovens. As variáveis foram estudadas inicialmente para ambos os pés e comparadas entre os grupos, sendo posteriormente analisadas separadamente, comparando-se cada pé (direito e esquerdo) entre os grupos. A amplitude de movimento articular foi avaliada por procedimentos goniométricos validados; a posição do eixo subtalar foi avaliada pela técnica de palpação; o Foot Posture Index foi utilizado para avaliar o comportamento do pé em uma cadeia cinética fechada. O teste t de Student/teste de Mann-Whitney comparou as principais variáveis de acordo com a distribuição amostral, enquanto o teste t de Student/teste de Wilcoxon foi utilizado para amostras emparelhadas. O teste de resíduais ajustados de Haberman padronizado foi usado para a relação entre a posição do eixo da subtalar e o Foot Posture Index. Resultados: Os dados dos pés direito e esquerdo foram semelhantes para todas as variáveis. O grupo mais velho apresentou mobilidade reduzida no tornozelo e na primeira articulação metatarsofalângica (5,42 [desvio padrão ­ DP, 4,49] e 76,12 [DP, 19,24] graus, respectivamente), enquanto o grupo mais jovem apresentou valores normais (11,46 [DP, 6,49] e 97,17 [DP, 13,65], respetivamente) com valores estatisticamente significativos, (p <0,001), aferidos pelo teste de Mann-Whitney para a articulação do tornozelo e pelo teste t-Sutdent para a primeira articulação metatarsofalângica. A diferença na posição do eixo subtalar não foi significativa (p = 0,788, pela aplicação do teste de Qui-quadrado), com mais desvios internos em ambos os grupos. O Foot Posture Index diferiu significativamente entre os grupos (p = 0,006 pela aplicação do teste de Qui-quadrado), sendo a postura normal mais prevalente no grupo mais velho e a postura pronada mais prevalente no grupo mais jovem. Conclusões: Em relação aos desvios internos do eixo da articulação subtalar, o grupo mais velho apresentou maior frequência de pés na postura normal, enquanto o mais jovem apresentou maior frequência de pés pronados, o que, neste caso, corrobora a teoria do equilíbrio rotacional. Na posição normal do eixo, foi encontrada maior frequência de pés com postura normal em ambos os grupos. Em relação aos desvios externos do eixo da articulação subtalar, nenhum dos grupos seguiu o padrão esperado na teoria do equilíbrio rotacional. A relação mais consistente no grupo mais velho foi entre a posição do eixo externo e a posutra supinada do pé, enquanto no grupo mais jovem se deu entre a posição normal do eixo e a postura normal do pé

miRNAs expression of oral squamous cell carcinoma patients: Validation of two putative biomarkers.

microRNA expression patterns have provided new directions in the search of biomarkers with prognostic value and even in the search of novel therapeutic targets for several neoplasms. Specifically, miRNAs profiling in oral squamous cell carcinoma (OSCC) represents a web of intrigue in the study of oral carcinogenesis. The objective of the present study was twofold:The first study phase comprised case-control groups: A) 8 OSCC-affected patients and 8 healthy controls. Microarray technology (Affymetrix miRNA Array Plate 4.1) was used for miRNAs expression profile. Deregulated miRNAs were studied using Diana Tools miRPath 3.0 to associate miRNA targets with molecular pathways via Kyoto Encyclopedia of Genes and Genomes (KEGG). In a second phase, 2 miRNAs chosen for the subsequent RT-qPCR validation were studied in a second OSSC cohort (n = 8).Microarray analysis identified 80 deregulated miRNAs (35 over-expressed and 45 under-expressed). Two miRNAs (miR-497-5p and miR-4417) were chosen for further validation via RT-qPCR. Prognostic analysis did not ascertain relevant relation between miR-497-5p or miR-4417 expression and clinical or pathological parameters, except high miR-4417 in the case of nodular affectation (P = .035) and diminished miR-497-5p radiotherapy-treated patients (P = .05). KEGG analysis revealed that deregulated miRNAs were implicated in several biological pathways such as Proteoglycans in cancer.Our data suggest an altered miRNAs profiling in OSCC-affected patients. We have verified the altered expression of miR-497-5p and miR-4417 in OSCC samples and related the deregulated miRNAs with the 'proteoglycans in cancer' pathway. Further longitudinal studies with large samples are warranted to confirm the present findings.

Differential expression of snoRNAs in oral squamous cell carcinomas: new potential diagnostic markers.

BACKGROUND: Small nucleolar RNAs (snoRNAs) are small non-coding RNA sequences whose most studied function is ribosome biogenesis. The altered expression of snoRNA is observed in tumoral processes such as breast cancer and multiple myeloma. However, we have not found any references to snoRNAs in oral squamous cell carcinomas (OSCC) in the literature at the time this article was written. MATERIAL AND METHODS: We have analyzed snoRNA expression in frozen OSCC tissue samples and have compared them to healthy controls. RNA was extracted from a total of eight OSCC samples and eight control samples, measuring the differential expression of small RNAs with the Affymetrix® miRNA 4.1 Array Plate microarray platform. RESULTS: Results were analyzed using the Transcriptome Analysis Console 3.0 (TAC) software. We obtained a total of 16 deregulated snoRNAs of which one was over expressed and 15 were under expressed. SnoRNAs expression was altered in OSCC and could serve as a diagnostic marker.

Comparison of RNA Extraction Methods for Molecular Analysis of Oral Cytology.

OBJECTIVE OF WORK: The aim of this study was to compare three methods of RNA extraction for molecular analysis of oral cytology to establish the best technique, considering its concentration and purity for molecular tests of oral lesions such as real-time reverse transcriptase reaction. MATERIAL AND METHODS: The sample included exfoliative cytology from the oral cavity mucosa of patients with no visible clinical changes, using Orcellex Rovers Brush®. The extraction of total RNA was performed using the following three techniques: 30 samples were extracted by Trizol® technique, 30 by the Direct-zolTM RNA Miniprep system and 30 by the RNeasy mini Kit. The absorbance was measured by spectrophotometer to estimate the purity. The estimated RNA concentration was obtained by multiplying the value of A260 (ng/mL) by 40. Statistical analysis of the obtained data was performed using GraphPad Prism 5.03 software with Student t, analysis of variance and Bonferroni tests, considering p ≤0.05. RESULTS: Trizol® group revealed higher average concentration, followed by Direct-zolTM and Rneasy group. It was observed that the RNA Direct-zolTM group had the highest purity, followed by RNeasy and Trizol® groups, allowing for the two ratios. CONCLUSION: Considering all aspects, concentration, purity and time spent in the procedures, the Direct-zolTM group showed the best results.

CA15.3 serum concentrations in older women with infiltrating ductal carcinomas of the breast.

Breast cancer is currently becoming a disease of the elderly. We have studied the relation between CA 15.3 serum concentrations and clinical-pathological parameters in 69 women with IDC aged over 70 years (76.3±4.2; range: 71-88; median 76). A group of 205 women with the same tumor but aged <70 years (62.8±4.0; range: 55-70; median 63) was also considered for comparison. Tumor size, axillary lymph node involvement, distant metastasis and histological grade were taken account. Serum CA 15.3 was determined by luminescence assay. CA 15.3 serum concentrations ranged between 6 and 85 U/mL (median 22.9 U/mL), and were higher only in patients with greater (qualitative and quantitative; p: 0.041) tumor size. Our results show that in women with IDCs, and aged over 70 years, serum CA 15.3 serum concentrations are associated exclusively with a greater tumor size, being these findings different to those described in women with the same subtype of tumor considered as a whole or with lower age.

Prognostic value of changes in the expression of stem cell markers in the peripheral blood of patients with colon cancer.

Cancer stem cells play an important role in carcinogenesis and resistance to treatment and may lead to metastasis. The isolation of circulating stem cells involves cell sorting based on the presence of cell surface markers. Many surface markers such as CD133, c-Kit, SOX, OCT4 and TWIST have been reported. In the present study, we determined the expression of different stem cell markers and their variation in expression at different stages of the treatment process. Samples of EDTA blood were collected from metastatic colorectal cancer patients, and circulating cancer stem cells were isolated for the analysis of the expression of stem cell markers using RT-PCR. These findings were correlated with the response to therapy. All statistical analyses were performed using the GraphPad Prism 5.03 software. Significant differences were found in the expression levels of the markers CD133, SOX2, OCT4 and TWIST1. No differences were found in c-Kit expression. Correlation in the expression levels of most of the markers was observed. Expression of CD133, OCT4, SOX2 and TWIST1 had a predictive value for colon cancer behavior. Evaluation of this stem cell gene expression panel may be useful for predicting the response during the process of treatment, and the relative easy access to samples facilitates this method. Moreover the correlation between CD133 and TWIST1 expression may be associated with tumor regrowth and metastatic relapse.

Stem cells as a tool for breast imaging.

Stem cells are a scientific field of interest due to their therapeutic potential. There are different groups, depending on the differentiation state. We can find lonely stem cells, but generally they distribute in niches. Stem cells don't survive forever. They are affected for senescence. Cancer stem cells are best defined functionally, as a subpopulation of tumor cells that can enrich for tumorigenic property and can regenerate heterogeneity of the original tumor. Circulating tumor cells are cells that have detached from a primary tumor and circulate in the bloodstream. They may constitute seeds for subsequent growth of additional tumors (metastasis) in different tissues. Advances in molecular imaging have allowed a deeper understanding of the in vivo behavior of stem cells and have proven to be indispensable in preclinical and clinical studies. One of the first imaging modalities for monitoring pluripotent stem cells in vivo, magnetic resonance imaging (MRI) offers high spatial and temporal resolution to obtain detailed morphological and functional information. Advantages of radioscintigraphic techniques include their picomolar sensitivity, good tissue penetration, and translation to clinical applications. Radionuclide imaging is the sole direct labeling technique used thus far in human studies, involving both autologous bone marrow derived and peripheral stem cells.

Spontaneous calcium oscillations regulate human cardiac progenitor cell growth.

RATIONALE: The adult heart possesses a pool of progenitor cells stored in myocardial niches, but the mechanisms involved in the activation of this cell compartment are currently unknown. OBJECTIVE: Ca2+ promotes cell growth raising the possibility that changes in intracellular Ca2+ initiate division of c-kit-positive human cardiac progenitor cells (hCPCs) and determine their fate. METHODS AND RESULTS: Ca2+ oscillations were identified in hCPCs and these events occurred independently from coupling with cardiomyocytes or the presence of extracellular Ca2+. These findings were confirmed in the heart of transgenic mice in which enhanced green fluorescent protein was under the control of the c-kit promoter. Ca2+ oscillations in hCPCs were regulated by the release of Ca2+ from the endoplasmic reticulum through activation of inositol 1,4,5-triphosphate receptors (IP3Rs) and the reuptake of Ca2+ by the sarco-/endoplasmic reticulum Ca2+ pump (SERCA). IP3Rs and SERCA were highly expressed in hCPCs, whereas ryanodine receptors were not detected. Although Na+-Ca2+ exchanger, store-operated Ca2+ channels and plasma membrane Ca2+ pump were present and functional in hCPCs, they had no direct effects on Ca2+ oscillations. Conversely, Ca2+ oscillations and their frequency markedly increased with ATP and histamine which activated purinoceptors and histamine-1 receptors highly expressed in hCPCs. Importantly, Ca2+ oscillations in hCPCs were coupled with the entry of cells into the cell cycle and 5-bromodeoxyuridine incorporation. Induction of Ca2+ oscillations in hCPCs before their intramyocardial delivery to infarcted hearts was associated with enhanced engraftment and expansion of these cells promoting the generation of a large myocyte progeny. CONCLUSION: IP3R-mediated Ca2+ mobilization control hCPC growth and their regenerative potential.

Diabetes promotes cardiac stem cell aging and heart failure, which are prevented by deletion of the p66shc gene.

Diabetes leads to a decompensated myopathy, but the etiology of the cardiac disease is poorly understood. Oxidative stress is enhanced with diabetes and oxygen toxicity may alter cardiac progenitor cell (CPC) function resulting in defects in CPC growth and myocyte formation, which may favor premature myocardial aging and heart failure. We report that in a model of insulin-dependent diabetes mellitus, the generation of reactive oxygen species (ROS) leads to telomeric shortening, expression of the senescent associated proteins p53 and p16INK4a, and apoptosis of CPCs, impairing the growth reserve of the heart. However, ablation of the p66shc gene prevents these negative adaptations of the CPC compartment, interfering with the acquisition of the heart senescent phenotype and the development of heart failure with diabetes. ROS elicit 3 cellular reactions: low levels activate cell growth, intermediate quantities trigger cell apoptosis, and high amounts initiate cell necrosis. CPC replication predominates in diabetic p66shc-/-, whereas CPC apoptosis and myocyte apoptosis and necrosis prevail in diabetic wild type. Expansion of CPCs and developing myocytes preserves cardiac function in diabetic p66shc-/-, suggesting that intact CPCs can effectively counteract the impact of uncontrolled diabetes on the heart. The recognition that p66shc conditions the destiny of CPCs raises the possibility that diabetic cardiomyopathy is a stem cell disease in which abnormalities in CPCs define the life and death of the heart. Together, these data point to a genetic link between diabetes and ROS, on the one hand, and CPC survival and growth, on the other.

Nuclear targeting of Akt enhances ventricular function and myocyte contractility.

Cytoplasmic overexpression of Akt in the heart results in a myopathy characterized by organ and myocyte hypertrophy. Conversely, nuclear-targeted Akt does not lead to cardiac hypertrophy, but the cellular basis of this distinct heart phenotype remains to be determined. Similarly, whether nuclear-targeted Akt affects ventricular performance and mechanics, calcium metabolism, and electrical properties of myocytes is unknown. Moreover, whether the expression and state of phosphorylation of regulatory proteins implicated in calcium cycling and myocyte contractility are altered in nuclear-targeted Akt has not been established. We report that nuclear overexpression of Akt does not modify cardiac size and shape but results in an increased number of cardiomyocytes, which are smaller in volume. Additionally, the heart possesses enhanced systolic and diastolic function, which is paralleled by increased myocyte performance. Myocyte shortening and velocity of shortening and relengthening are increased in transgenic mice and are coupled with a more efficient reuptake of calcium by the sarcoplasmic reticulum (SR). This process increases calcium loading of the SR during relengthening. The enhanced SR function appears to be mediated by an increase in SR Ca2+-ATPase2a activity sustained by a higher degree of phosphorylation of phospholamban. This posttranslational modification was associated with an increase in phospho-protein kinase A and a decrease in protein phosphatase-1. Together, these observations provide a plausible biochemical mechanism for the potentiation of myocyte and ventricular function in Akt transgenic mice. Therefore, nuclear-targeted Akt in myocytes may have important implications for the diseased heart.