Heart Rate Variability as a Marker of Distress and Recovery: The Effect of Brief Supportive Expressive Group Therapy With Mindfulness in Cancer Patients.

OBJECTIVES: We aimed to investigate the effects of brief supportive expressive group therapy with mindfulness for cancer patients and to assess the utility of heart rate variability (HRV) as a biomarker of distress and treatment effect. METHODS: A total of 28 female patients with nonmetastatic cancer at a university hospital in South Korea received a 4-week modified group therapy for distress reduction. The BESTMIND (Brief Expression and Support Therapy with Mindfulness) program consisted of supportive-expressive group therapy and mindfulness-based stress reduction. The subjective outcomes of distress, anger, sleep quality, and sense of well-being and the physiological outcome of HRV were assessed before and after the program. RESULTS: After the program, patients showed significantly reduced distress, perceived stress, anger, and sleep disturbance and increased quality of life. No significant change was observed in the degree of mindfulness. A significantly increased SD in the normal beat-to-beat intervals and normalized high-frequency (HF 0.15-0.4 Hz) power from spectral analysis were observed after treatment. According to the correlation analyses, HF power correlated with depression scores, and normalized HF power was associated with depression, anxiety, perceived stress, and anger at baseline. The pretreatment and posttreatment comparison indicated that an increase in HF power was associated with a decrease in anger. CONCLUSIONS: These results suggest the effectiveness of this modified group-based program for distress reduction and also provide preliminary evidence for the use of HRV as a biomarker of distress and recovery. HF power from HRV variables may serve as a quantitative biomarker of the treatment response of distress management, including anger.

Relevance of internal time and circadian robustness for cancer patients.

BACKGROUND: Adequate circadian timing of cancer treatment schedules (chronotherapy) can enhance tolerance and efficacy several-fold in experimental and clinical situations. However, the optimal timing varies according to sex, genetic background and lifestyle. Here, we compute the individual phase of the Circadian Timing System to decipher the internal timing of each patient and find the optimal treatment timing. METHODS: Twenty-four patients (11 male; 13 female), aged 36 to 77 years, with advanced or metastatic gastro-intestinal cancer were recruited. Inner wrist surface Temperature, arm Activity and Position (TAP) were recorded every 10 min for 12 days, divided into three 4-day spans before, during and after a course of a set chronotherapy schedule. Pertinent indexes, I < O and a new biomarker, DI (degree of temporal internal order maintenance), were computed for each patient and period. RESULTS: Three circadian rhythms and the TAP rhythm grew less stable and more fragmented in response to treatment. Furthermore, large inter- and intra-individual changes were found for T, A, P and TAP patterns, with phase differences of up to 12 hours among patients. A moderate perturbation of temporal internal order was observed, but the administration of fixed chronomodulated chemotherapy partially resynchronized temperature and activity rhythms by the end of the study. CONCLUSIONS: The integrated variable TAP, together with the asynchrony among rhythms revealed by the new biomarker DI, would help in the personalization of cancer chronotherapy, taking into account individual circadian phase markers.

AXL is a key regulator of inherent and chemotherapy-induced invasion and predicts a poor clinical outcome in early-stage colon cancer.

PURPOSE: Despite the use of 5-fluorouracil (5-FU)-based adjuvant treatments, a large proportion of patients with high-risk stage II/III colorectal cancer will relapse. Thus, novel therapeutic strategies are needed for early-stage colorectal cancer. Residual micrometastatic disease from the primary tumor is a major cause of patient relapse. EXPERIMENTAL DESIGN: To model colorectal cancer tumor cell invasion/metastasis, we have generated invasive (KRASMT/KRASWT/+chr3/p53-null) colorectal cancer cell subpopulations. Receptor tyrosine kinase (RTK) screens were used to identify novel proteins that underpin the migratory/invasive phenotype. Migration/invasion was assessed using the XCELLigence system. Tumors from patients with early-stage colorectal cancer (N = 336) were examined for AXL expression. RESULTS: Invasive colorectal cancer cell subpopulations showed a transition from an epithelial-to-mesenchymal like phenotype with significant increases in migration, invasion, colony-forming ability, and an attenuation of EGF receptor (EGFR)/HER2 autocrine signaling. RTK arrays showed significant increases in AXL levels in all invasive sublines. Importantly, 5-FU treatment resulted in significantly increased migration and invasion, and targeting AXL using pharmacologic inhibition or RNA interference (RNAi) approaches suppressed basal and 5-FU-induced migration and invasion. Significantly, high AXL mRNA and protein expression were found to be associated with poor overall survival in early-stage colorectal cancer tissues. CONCLUSIONS: We have identified AXL as a poor prognostic marker and important mediator of cell migration/invasiveness in colorectal cancer. These findings provide support for the further investigation of AXL as a novel prognostic biomarker and therapeutic target in colorectal cancer, in particular in the adjuvant disease in which EGFR/VEGF-targeted therapies have failed.

Prognostic impact and targeting of CRM1 in acute myeloid leukemia.

Chromosomal region maintenance 1 (CRM1) is a nuclear export receptor recognizing proteins bearing a leucine-rich nuclear export signal. CRM1 is involved in nuclear export of tumor suppressors such as p53. We investigated the prognostic significance of CRM1 in acute myeloid leukemia (AML) and effects of a novel small-molecule selective inhibitor of CRM1. CRM1 protein expression was determined in 511 newly diagnosed AML patients and was correlated with mouse double minute 2 (MDM2) and p53 levels. High CRM1 expression was associated with short survival of patients and remained an adverse prognostic factor in multivariate analysis. CRM1 inhibitor KPT-185 induced mainly full-length p53 and apoptosis in a p53-dependent manner, whereas inhibition of proliferation was p53 independent. Patient samples with p53 mutations showed low sensitivity to KPT-185. Nuclear retention of p53 induced by CRM1 inhibition synergized with increased levels of p53 induced by MDM2 inhibition in apoptosis induction. KPT-185 and Nutlin-3a, alone and in combination, induced synergistic apoptosis in patient-derived CD34(+)/CD38(-) AML, but not in normal progenitor cells. Data suggest that CRM1 exerts an antiapoptotic function and is highly prognostic in AML. We propose a novel combinatorial approach for the therapy of AML, aimed at maximal activation of p53-mediated apoptosis by concomitant MDM2 and CRM1 inhibition.

Inducing apoptosis in chemotherapy-resistant B-lineage acute lymphoblastic leukaemia cells by targeting HSPA5, a master regulator of the anti-apoptotic unfolded protein response signalling network.

We present previously unknown evidence that the immunoglobulin heavy chain binding protein BIP/HSPA5, also known as glucose regulated protein (GRP)78, serving as a pivotal component of the pro-survival axis of the unfolded protein response (UPR) signalling network, is abundantly expressed in relapsed B-lineage acute lymphoblastic leukaemia (ALL) and contributes to chemotherapy resistance of leukaemic B-cell precursors. The resistance of B-lineage ALL cells to the standard anti-leukaemic drug vincristine was overcome by the HSPA5 inhibitor epigallocatechin gallate, which inhibits the anti-apoptotic function of HSPA5 by targeting its ATP-binding domain. Notably, chemotherapy-resistant B-lineage ALL cells underwent apoptosis within 48 h of exposure to a doxorubicin-conjugated cell-penetrating cyclic anti-HSPA5 peptide targeting surface-expressed HSPA5 molecules on leukaemia cells. The identification of the HSPA5 as a chemoresistance biomarker and molecular target for B-lineage ALL may lead to new anti-leukaemic treatment strategies that are much needed.

Na+/K+-ATPase α3 mediates sensitivity of hepatocellular carcinoma cells to bufalin.

Bufalin, a major bioactive component of the Chinese medicine Chansu, has been reported to exhibit significant antitumor activity against various cancer cell lines. However, the exact mechanism remains unclear. In this study, we demonstrated that bufalin inhibited the growth of hepatocellular carcinoma (HCC) cells in a dose-dependent manner, which correlated with the expression level of Na+/K+-ATPase α3 in HCC cells. The IC50 of bufalin markedly increased when Na+/K+-ATPase α3 was silenced by RNA interference. Furthermore, we show that bufalin increased the phosphorylation of Akt and ERK1/2 while inhibited FoxO3a expression. Thus, our study suggests that Na+/K+-ATPase α3 might serve as a therapeutic target for bufalin in HCC, and its expression status may help predict sensitivity of HCC cells to bufalin treatment.

Improvement of hypertrophic scarring by using topical anti-fibrogenic/anti-inflammatory factors in a rabbit ear model.

This study investigates the scar-reducing efficacy of topical application of stratifin and acetylsalicylic acid (ASA) in a rabbit ear model. A total of five New Zealand white rabbits with four wounds per ear were examined. Either recombinant stratifin (0.002%) or ASA (0.5%) incorporated in carboxymethyl cellulose gel was topically applied on each wound at postwounding Day 5. Scars were harvested at postwounding Day 28 for histological analysis. The wounds treated with stratifin and ASA showed 82 and 73% reduction in scar volume, respectively, compared with that of untreated controls. A reduction of 57 and 41% in total tissue cellularity along with 79 and 91% reduction in infiltrated CD3+ T cells were observed in response to treatment with stratifin and ASA, respectively, compared with those of untreated controls. Wounds treated with stratifin showed a 2.8-fold increase in matrix metalloproteinase-1 expression, which resulted in a 48% decrease in collagen density compared with those of untreated controls. Qualitative wound assessment showed a reduced hypertrophic scarring in stratifin and ASA-treated wounds when compared with the controls. This study showed that topical application of either stratifin or ASA-impregnated carboxymethyl cellulose gel reduced hypertrophic scar formation following dermal injuries in a rabbit ear fibrotic model.

CD133 is a marker of bioenergetic stress in human glioma.

Mitochondria dysfunction and hypoxic microenvironment are hallmarks of cancer cell biology. Recently, many studies have focused on isolation of brain cancer stem cells using CD133 expression. In this study, we investigated whether CD133 expression is regulated by bioenergetic stresses affecting mitochondrial functions in human glioma cells. First, we determined that hypoxia induced a reversible up-regulation of CD133 expression. Second, mitochondrial dysfunction through pharmacological inhibition of the Electron Transport Chain (ETC) produced an up-regulation of CD133 expression that was inversely correlated with changes in mitochondrial membrane potential. Third, generation of stable glioma cells depleted of mitochondrial DNA showed significant and stable increases in CD133 expression. These glioma cells, termed rho(0) or rho(0), are characterized by an exaggerated, uncoupled glycolytic phenotype and by constitutive and stable up-regulation of CD133 through many cell passages. Moreover, these rho(0) cells display the ability to form "tumor spheroids" in serumless medium and are positive for CD133 and the neural progenitor cell marker, nestin. Under differentiating conditions, rho(0) cells expressed multi-lineage properties. Reversibility of CD133 expression was demonstrated by transfering parental mitochondria to rho(0) cells resulting in stable trans-mitochondrial "cybrid" clones. This study provides a novel mechanistic insight about the regulation of CD133 by environmental conditions (hypoxia) and mitochondrial dysfunction (genetic and chemical). Considering these new findings, the concept that CD133 is a marker of brain tumor stem cells may need to be revised.

DNA-dependent protein kinase is a therapeutic target and an indicator of poor prognosis in B-cell chronic lymphocytic leukemia.

PURPOSE: del(17p), del(11q), and associated p53 dysfunction predict for short survival and chemoresistance in B-cell chronic lymphocytic leukemia (CLL). DNA-dependent protein kinase (DNA-PK) is activated by DNA damage and mediates DNA double-strand break repair. We hypothesized that inhibiting DNA-PK would sensitize CLL cells to drug-induced DNA damage and that this approach could increase the therapeutic index of agents used to treat CLL. EXPERIMENTAL DESIGN: Fifty-four CLL cases were characterized for poor prognosis markers [del(17p), del(11q), CD38, and ZAP-70]. In selected cases, DNA-PK catalytic subunit (DNA-PKcs) expression and activity and p53 function were also measured. Ex vivo viability assays established sensitivity to fludarabine and chlorambucil and also tested the ability of a novel DNA-PK inhibitor (NU7441) to sensitize CLL cells to these drugs. The effects of NU7441 on fludarabine-induced DNA damage repair were also assessed (Comet assays and detection of gammaH2AX). RESULTS: DNA-PKcs levels correlated with DNA-PK activity and varied 50-fold between cases but were consistently higher in del(17p) (P = 0.01) and del(11q) cases. NU7441 sensitized CLL cells to chlorambucil and fludarabine, including cases with del(17p), del(11q), p53 dysfunction, or high levels of DNA-PKcs. NU7441 increased fludarabine-induced double-strand breaks and abrogated drug-induced autophosphorylation of DNA-PKcs at Ser2056. High DNA-PK levels predicted for reduced treatment-free interval. CONCLUSIONS: These data validate the concept of targeting DNA-PKcs in poor risk CLL, and demonstrate a mechanistic rationale for use of a DNA-PK inhibitor. The novel observation that DNA-PKcs is overexpressed in del(17p) and del(11q) cases indicates that DNA-PK may contribute to disease progression in CLL.

The role of islet neogenesis-associated protein (INGAP) in islet neogenesis.

Islet Neogenesis-Associated Protein (INGAP) is a member of the Reg family of proteins implicated in various settings of endogenous pancreatic regeneration. The expression of INGAP and other RegIII proteins has also been linked temporally and spatially with the induction of islet neogenesis in animal models of disease and regeneration. Furthermore, administration of a peptide fragment of INGAP (INGAP peptide) has been demonstrated to reverse chemically induced diabetes as well as improve glycemic control and survival in an animal model of type 1 diabetes. Cultured human pancreatic tissue has also been shown to be responsive to INGAP peptide, producing islet-like structures with function, architecture and gene expression matching that of freshly isolated islets. Likewise, studies in normoglycemic animals show evidence of islet neogenesis. Finally, recent clinical studies suggest an effect of INGAP peptide to improve insulin production in type 1 diabetes and glycemic control in type 2 diabetes.

Islet Neogenesis Associated Protein (INGAP) modulates gene expression in cultured neonatal rat islets.

The Islet Neogenesis Associated Protein (INGAP) increases pancreatic beta-cell mass and potentiates glucose-induced insulin secretion. We currently studied the effects of a pentadecapeptide having the 104-118 amino acid sequence of INGAP (INGAP-PP) on insulin secretion and on transcript profile expression in 4-day-cultured normal pancreatic neonatal rat islets. Islets cultured with INGAP-PP released significantly more insulin in response to 2.8 and 16.7 mM glucose than those cultured without the peptide. The macroarray analysis showed that 210 out of 2352 genes spotted in the nylon membranes were up-regulated while only 4 were down-regulated by INGAP-PP-treatment. The main categories of genes modified by INGAP-PP included several related with islet metabolism, insulin secretion mechanism, beta-cell mass and islet neogenesis. RT-PCR confirmed the macroarray results for ten selected genes involved in growing, maturation, maintenance of pancreatic islet-cells, and exocytosis, i.e., Hepatocyte nuclear factor 3beta (HNF3beta), Upstream stimulatory factor 1 (USF1), K(+)-channel proteins (SUR1 and Kir6.2), PHAS-I protein, Insulin 1 gene, Glucagon gene, Mitogen-activated protein kinase 1 (MAP3K1), Amylin (IAPP), and SNAP-25. INGAP-PP also stimulated PDX-1 expression. The expression of three transcripts (HNF3beta, SUR1, and SNAP-25) was confirmed by Western blotting for the corresponding proteins. In conclusion, our results show that INGAP-PP enhances specifically the secretion of insulin and the transcription of several islet genes, many of them directly or indirectly involved in the control of islet metabolism, beta-cell mass and islet neogenesis. These results, together with other previously reported, strongly indicate an important role of INGAP-PP, and possibly of INGAP, in the regulation of islet function and development.

O PSA como marcador tumoral é confiável? / PSA as tumor marker is reliable?

Considerado como um dos melhores marcadores tumorais, o antígeno prostático específico (PSA) é largamente utilizado. Valores acima de 4,ng/ml podem significar câncer de próstata (CaP). No entanto, doenças benignas podem alterar o seu valor e o câncer de próstata pode apresentar-se sem alterá-lo. O exame digital da próstata (EDP) e a dosagem de PSA são as melhores formas de diagnosticar e acompanhar os pacientes com mais de 40 anos.

One of the best tumors markers ever known, the prostate-specific antigen (PSA) is well advantage today. Values above 4.ng/ml can demonstrate prostate cancer. Although benign diseases would change the values of PSA and prostate cancers would not. Digital prostate exam (DPE) and PSA are the best way to diagnostic and watch men with over 40 years.