Return to work after treatment for primary breast cancer over a 6-year period: results from a prospective study comparing patients with the general population.

PURPOSE: Only little research has been conducted on breast cancer survivors returning to work in Germany. This paper explores two questions: (1) Does breast cancer lead to an increased drop-out of paid work? (2) Do other factors, apart from their illness, help explain breast cancer survivors' (temporary) retirement from work? To the best of our knowledge, this is the first comparative and prospective study on breast cancer survivors returning to work in Germany. We consider this work to be a relevant research for three reasons: (1) It exceeds the observation period of previous international studies by another 3 years. (2) By including the comparison with a population sample, it allows to take the specific situation of breast cancer patients into account. This refers to their illness as well as to the socio-economic context. (3) It combines qualitative and quantitative methods in order to receive patients' individual interpretations. METHODS: The analysis is based on a sample of 227 breast cancer patients, participating in a prospective study on the role of psychosocial factors in the long-term course of breast cancer and a random sample of 647 age-matched women living in northern Germany. Employment and demographic data were observed directly before primary surgery (2002-2004), 1 year later (2003-2005) and again 5 years later (2008-2010). In addition, qualitative interviews at the three different observations served as a basis for quantitative data analyses, which were mainly performed by logistic regression models. RESULTS: One year after primary surgery, nearly three times as many cancer survivors had left their job as compared to the women in the reference group. For breast cancer survivors, a lower level of education, part-time employment, the severity of work-related difficulties and participation in inpatient rehabilitation correlated significantly with the failure to return to work. Six years after surgery, the probability of returning to work was still only half as high among breast cancer survivors than among controls. The main predictor for not returning to work was found to be age; tumour stage and the severity of side effects of treatment also seemed to have an impact. CONCLUSIONS: Breast cancer survivorship in Germany increases the risk of dropping out of paid work. The influence of work- and illness-related factors varies considerably between the early and late phases of recovery after breast cancer treatment. The comparative analysis demonstrates the relevance of labour market and pension legislation in Germany.

Anatomic characterization of human ultra-weak photon emission in practitioners of transcendental meditation(TM) and control subjects.

BACKGROUND: Research on human ultra-weak photon emission (UPE, biophoton emission) has raised the question whether a typical human emission anatomic percentage distribution pattern exists in addition to individual subject overall anatomic summation intensity differences. The lowest UPE intensities were observed in two subjects who regularly meditate. Spectral analysis of human UPE has suggested that ultra-weak emission is probably, at least in part, a reflection of free radical reactions in a living system. It has been documented that various physiologic and biochemical shifts follow the long-term practice of meditation and it is inferred that meditation may impact free radical activity. OBJECTIVE: To systematically quantify, in subjects with long-term transcendental meditation (TM) experience and subjects without this experience, the UPE emission of the anterior torso, head and neck plus the hands in an attempt to document the differences by the two groups. SUBJECTS: Subjects were 20 men reported to be healthy and nonsmokers. Each of the subjects in the meditation group had practiced TM twice daily for at least the past 10 years. METHODS: UPE in 20 subjects was recorded in a dark room using a highly sensitive, cooled photomultiplier system designed for manipulation in three directions. The protocol for multisite registration of spontaneous emission includes recording of 12 anatomic locations of anterior torso, head, and hands. RESULTS: Data demonstrate emission intensities that are lower in TM practitioners as compared to control subjects. The percent contribution of emission from most anatomic locations was not significantly different for TM practitioners and control subjects. Exceptions are the contributions of throat and palm. CONCLUSION: In subjects with long-term TM experience, the UPE emission is different from control subjects. Data support the hypothesis that free radical reactions can be influenced by TM.

Characterization of epithelial senescence by serial analysis of gene expression: identification of genes potentially involved in prostate cancer.

Evasion of cellular senescence is required for the immortal phenotype of tumor cells. The tumor suppressor genes p16(INK4A), pRb, and p53 have been implicated in the induction of cellular senescence. To identify additional genes and pathways involved in the regulation of senescence in prostate epithelial cells (PrECs), we performed serial analysis of gene expression (SAGE). The gene expression pattern of human PrECs arrested because of senescence was compared with the pattern of early passage cells arrested because of confluence. A total of 144,137 SAGE tags representing 25,645 unique mRNA species was collected and analyzed: 157 mRNAs (70 with known function) were up-regulated and 116 (65 with known function) were down-regulated significantly in senescent PrECs (P < 0.05; fold difference >2.5). The differential regulation of an exemplary set of genes during senescence was confirmed by quantitative real-time PCR in PrECs derived from three different donors. The results presented here provide the molecular basis of the characteristic changes in morphology and proliferation observed in senescent PrECs. Furthermore, the differentially expressed genes identified in this report will be instrumental in the further analysis of cellular senescence in PrECs and may lead to the identification of tumor suppressor genes and proto-oncogenes involved in the development of prostate cancer.

Diastolic left ventricular function in preterm infants with a patent ductus arteriosus: a serial Doppler echocardiography study.

In very low birth weight neonates, a left-to-right shunt via persistent ductus arteriosus (PDA) may interact with diastolic left ventricular function, but specific changes of Doppler parameters have yet to be reported. In a serial transmitral Doppler study, we investigated the impact of a PDA on diastolic function parameters. Twenty-two patients with and without PDA were examined on day 3.8+/-1 and day 14+/-2 after birth. By the first examination, 13 out of 22 patients had a PDA; by the second examination, the number was still 8 out of 22. Peak early and atrial flow velocities (44.8+/-15 and 50.1+/-13 cm/s, respectively) were higher (p<0.05) for neonates with PDA compared to those with closed duct (30.9+/-6 and 34.2 cm/s, respectively). Isovolumic relaxation time (IVRT) was shorter in neonates with PDA (45+/-7 ms, N=21) compared to those with a closed duct (55.3+/-5 ms, N=23) (p<0.01). IVRT correlated inversely with cardiac index (R=-0.79, p<0.01). All observed changes reversed to the normal range after closure of the PDA. When premature infants with a PDA experience a preload challenge, early and atrial peak velocities increase and IVRT shortens significantly. This coincidence of elevated transvalvular pressure differences and decreased IVRT in neonates with immature diastolic function can best be explained as a result of left atrial pressure elevation. Consequently, pulmonary venous pressure must be elevated, with its inherent effect on pulmonary capillary physiology. Thus, the monitoring of left ventricular diastolic function adds significant information to the care of preterm infants with a PDA.

Doppler-derived parameters of diastolic left ventricular function in preterm infants with a birth weight <1500 g: reference values and differences to term infants.

Transmitral flow parameters in preterm and term infants were compared in order to study differences in signal expression and temporal dynamics of left ventricular diastolic function. In 63 preterm infants between 26 and 33 weeks of gestation and 102 term infants, a Doppler survey was performed during 6 months after birth. Early and atrial filling-time velocity integrals and peak velocities were significantly lower in the preterm neonates. Atrial filling parameters reached the level observed in term infants by 2 months of age. Peak early filling velocity was still lower for 2-month-old preterms and attained the term infants' level by 3 months of age. Preterm infants continued having high atrial filling fraction (AFF) (0.51+/-0.07) during 2 months after birth, while in term infants the fraction decreased continuously from 0.41+/-0.06 to 0.37+/-0.05. Isovolumic relaxation time (IVRT) was the only parameter without differences between preterm and term infants, and it decreased from 54+/-7 ms in neonates to 41+/-4 ms over 3 months. Stroke volume passing the mitral valve doubled in preterm (4+/-1 to 7.9+/-1.5 ml/cm2), but increased by only 37% (6.9+/-1.6 to 9.5+/-2.2 ml/cm2) in term infants. Our observations show that the maturational period of diastolic function appears prolonged in preterm infants. As preterm infants have to cope with a higher physiologic preload augmentation during growth, part of the delay in parameter changes might be caused by preload stress rather than by persistence of functional impairment. Although doing well under physiological conditions, preterm neonates may be at higher risk for diastolic dysfunction than term infants when an additional preload challenge is encountered.

Large-scale identification of c-MYC-associated proteins using a combined TAP/MudPIT approach.

The c-MYC oncogene encodes a transcription factor, which is sufficient and necessary for the induction of cellular proliferation. However, the c-MYC protein is a relatively weak transactivator suggesting that it may have other functions. To identify protein interactors which may reveal new functions or represent regulators of c-MYC we systematically identified proteins associated with c-MYC in vivo using a proteomic approach. We combined tandem affinity purification (TAP) with the mass spectral multidimensional protein identification technology (MudPIT). Thereby, 221 c-MYC-associated proteins were identified. Among them were 17 previously known c-MYC-interactors. Selected new c-MYC-associated proteins (DBC-1, FBX29, KU70, MCM7, Mi2-beta/CHD4, RNA Pol II, RFC2, RFC3, SV40 Large T Antigen, TCP1alpha, U5-116kD, ZNF281) were confirmed independently. For association with MCM7, SV40 Large T Antigen and DBC-1 the functionally important MYC-box II region was required, whereas FBX29 and Mi2-beta interacted via MYC-box II and the BR-HLH-LZ motif. In addition, regulators of c-MYC activity were identified: ectopic expression of FBX29, an E3 ubiquitin ligase, decreased c-MYC protein levels and inhibited c-MYC transactivation, whereas knock-down of FBX29 elevated the concentration of c-MYC. Furthermore, sucrose gradient analysis demonstrated that c-MYC is present in numerous complexes with varying size and composition, which may accommodate the large number of new c-MYC-associated proteins identified here and mediate the diverse functions of c-MYC. Our results suggest that c-MYC, besides acting as a mitogenic transcription factor, regulates cellular proliferation by direct association with protein complexes involved in multiple synthetic processes required for cell division, as for example DNA-replication/repair and RNA-processing. Furthermore, this first comprehensive description of the c-MYC-associated sub-proteome will facilitate further studies aimed to elucidate the biology of c-MYC.

Targeted proteomic analysis of 14-3-3 sigma, a p53 effector commonly silenced in cancer.

To comprehensively identify proteins interacting with 14-3-3 sigma in vivo, tandem affinity purification and the multidimensional protein identification technology were combined to characterize 117 proteins associated with 14-3-3 sigma in human cells. The majority of identified proteins contained one or several phosphorylatable 14-3-3-binding sites indicating a potential direct interaction with 14-3-3 sigma. 25 proteins were not previously assigned to any function and were named SIP2-26 (for 14-3-3 sigma-interacting protein). Among the 92 interactors with known function were a number of proteins previously implicated in oncogenic signaling (APC, A-RAF, B-RAF, and c-RAF) and cell cycle regulation (AJUBA, c-TAK, PTOV-1, and WEE1). The largest functional classes comprised proteins involved in the regulation of cytoskeletal dynamics, polarity, adhesion, mitogenic signaling, and motility. Accordingly ectopic 14-3-3 sigma expression prevented cellular migration in a wounding assay and enhanced mitogen-activated protein kinase signaling. The functional diversity of the identified proteins indicates that induction of 14-3-3 sigma could allow p53 to affect numerous processes in addition to the previously characterized inhibitory effect on G2/M progression. The data suggest that the cancer-specific loss of 14-3-3 sigma expression by epigenetic silencing or p53 mutations contributes to cancer formation by multiple routes.

C/EBPbeta: a major PML-RARA-responsive gene in retinoic acid-induced differentiation of APL cells.

In acute promyelocytic leukemia (APL), the translocation t(15;17) induces a block at the promyelocytic stage of differentiation in an all-trans-retinoic acid (ATRA)-responsive manner. Here we report that upon treatment with ATRA, t(15;17) cells (NB4) reveal a very rapid increase in protein level and binding activity of C/EBPbeta, a C/EBP family member, which was not observed in an ATRA-resistant NB4 cell line. We further provide evidence that ATRA mediates a direct increase of C/EBPbeta, only in PML-RARA (promyelocytic leukemia-retinoic acid receptor alpha)-expressing cells. In addition, transactivation experiments indicate that the PML-RARA fusion protein, but not PML-RARA mutants defective in transactivation, strongly transactivates the C/EBPbeta promoter. These results suggest that PML-RARA mediates ATRA-induced C/EBPbeta expression. Finally, we demonstrate the importance of C/EBPbeta in granulocytic differentiation. We show that not only does C/EBPbeta induce granulocytic differentiation of non-APL myeloid cell lines independent of addition of ATRA or other cytokines, but also that C/EBPbeta induction is required during ATRA-induced differentiation of APL cells. Taken together, C/EBPbeta is an ATRA-dependent PML-RARA target gene involved in ATRA-induced differentiation of APL cells.