Heme-protein vibrational couplings in cytochrome c provide a dynamic link that connects the heme-iron and the protein surface

The active site of cytochrome c (Cyt c) consists of a heme covalently linked to a pentapeptide segment (Cys-X-X-Cys-His), which provides a link between the heme and the protein surface, where the redox partners of Cyt c bind. To elucidate the vibrational properties of heme c, nuclear resonance vibrational spectroscopy (NRVS) measurements were performed on (57)Fe-labeled ferric Hydrogenobacter thermophilus cytochrome c(552), including (13)C(8)-heme-, (13)C(5)(15)N-Met-, and (13)C(15)N-polypeptide (pp)-labeled samples, revealing heme-based vibrational modes in the 200- to 450-cm(-1) spectral region. Simulations of the NRVS spectra of H. thermophilus cytochrome c(552) allowed for a complete assignment of the Fe vibrational spectrum of the protein-bound heme, as well as the quantitative determination of the amount of mixing between local heme vibrations and pp modes from the Cys-X-X-Cys-His motif. These results provide the basis to propose that heme-pp vibrational dynamic couplings play a role in electron transfer (ET) by coupling vibrations of the heme directly to vibrations of the pp at the protein-protein interface. This could allow for the direct transduction of the thermal (vibrational) energy from the protein surface to the heme that is released on protein/protein complex formation, or it could modulate the heme vibrations in the protein/protein complex to minimize reorganization energy. Both mechanisms lower energy barriers for ET. Notably, the conformation of the distal Met side chain is fine-tuned in the protein to localize heme-pp mixed vibrations within the 250- to 400-cm(-1) spectral region. These findings point to a particular orientation of the distal Met that maximizes ET.     

Predictors of Health-related Quality of Life and Adjustment to Prostate Cancer During Active Surveillance

Background

Active surveillance (AS) is emerging as an alternative approach to limit the risk of overtreatment and impairment of quality of life (QoL) in patients with low-risk localised prostate cancer. Although most patients report high levels of QoL, some men may be distressed by the idea of living with untreated cancer.

Objective

To identify factors associated with poor QoL during AS.

Design, setting, and participants

Between September 2007 and March 2012, 103 patients participated in the Prostate Cancer Research International Active Surveillance (PRIAS) QoL study. Mental health (Symptom Checklist-90), demographic, clinical, and decisional data were assessed at entrance in AS. Health-related QoL (HRQoL) Functional Assessment of Cancer Therapy-Prostate version and Mini-Mental Adjustment to Cancer outcomes were assessed after 10 mo of AS.

Outcome measurements and statistical analysis

Multivariate logistic regression models were used to identify predictors of low (<25th percentile) HRQoL, adjustment to cancer, and a global QoL index at 10 mo after enrolment.

Results and limitations

The mean age of the study patients was 67 yr (standard deviation: ±7 yr). Lack of partner (odds ratio [OR]: 0.08; p = 0.009) and impaired mental health (OR: 1.2, p = 0.1) were associated with low HRQoL (p = 0.006; area under the curve [AUC]: 0.72). The maladaptive adjustment to cancer (p = 0.047; AUC: 0.60) could be predicted by recent diagnosis (OR: 3.3; p = 0.072). Poor global QoL (overall p = 0.02; AUC: 0.85) was predicted by impaired mental health (OR: 1.16; p = 0.070) and time from diagnosis to enrolment in AS <5 mo (OR: 5.52; p = 0.009). Influence of different physicians on the choice of AS (OR: 0.17; p = 0.044), presence of a partner (OR: 0.22; p = 0.065), and diagnostic biopsy with >18 core specimens (OR: 0.89; p = 0.029) were predictors of better QoL. Limitations of this study were the small sample size and the lack of a control group.

Conclusions

Factors predicting poor QoL were lack of a partner, impaired mental health, recent diagnosis, influence of clinicians and lower number of core samples taken at diagnostic biopsy. Educational support from physicians and emotional/social support should be promoted in some cases to prevent poor QoL.     

13th St. Gallen International Breast Cancer Conference 2013: Primary Therapy of Early Breast Cancer Evidence,Controversies, Consensus – Opinion of a German Team of Experts (Zurich 2013)

Zusammenfassung

Alle zwei Jahre findet in St. Gallen (Schweiz) die internationale Konsensuskonferenz zur Behandlung des primären Mammakarzinoms statt. Da sich das internationale Panel in St. Gallen aus Experten unterschiedlicher Länder zusammensetzt, spiegelt der Konsensus ein internationales Meinungsbild wider. Vor diesem Hintergrund erscheint es aus deutscher Sicht sinnvoll, die Abstimmungsergebnisse für den Therapiealltag in Deutschland zu konkretisieren. Eine deutsche Arbeitsgruppe mit acht Brustkrebsexperten, von denen zwei Mitglieder des internationalen St. Gallen-Panels sind, hat daher die Abstimmungsergebnisse der St. Gallen-Konsensuskonferenz (2013) für den Klinikalltag in Deutschland kommentiert. Inhaltliche Schwerpunkte der diesjährigen St. Gallen-Konferenz waren operative Fragestellungen der Brust und der Axilla, strahlentherapeutische und systemische Therapieoptionen sowie die klinische Relevanz der Tumorbiologie. Intensiv diskutiert wurde der klinische Einsatz von Multigen-Assays, inkl. ihrer Bedeutung für die individuelle Therapieentscheidung.     

Muscle phenotype in patients with myotonic dystrophy type 1

Introduction: The pathogenesis of muscle involvement in patients with myotonic dystrophy type 1 (DM1) is not well understood. In this study, we characterized the muscle phenotype in patients with confirmed DM1. Methods: In 38 patients, muscle strength was tested by hand‐held dynamometry. Myotonia was evaluated by a handgrip test and by analyzing the decrement of the compound muscle action potential. Muscle biopsies were assessed for morphological changes and Na⁺‐K⁺ pump content. Results: Muscle strength correlated with a decline in Na⁺‐K⁺ pump content (r = 0.60, P < 0.001) and with CTG expansion. CTG expansion did not correlate with severity of myotonia, proximal histopathological changes, or Na⁺‐K⁺ pump content. Histopathologically, we found few centrally placed nuclei (range 0.2–6.9%). Conclusions: The main findings of this study are that muscle weakness correlated inversely with CTG expansion and that central nuclei are not a prominent feature of proximal muscles in DM1. Muscle Nerve 47:409‐415, 2013     

Extent of pelvic lymph node dissection in penile cancer may impact survival

Introduction

Current guidelines on management of penile carcinoma (PC) recommend ipsilateral pelvic lymph node dissection (PLND) in patients with inguinal lymph node metastasis (LNM) who meet specific criteria. The aim of this article was to assess outcomes in patients treated with bilateral PLND in the presence of unilateral metastatic pelvic nodes.

Methods

After IRB approval, four international centers contributed to this study. Men with PC and unilateral inguinal LNM and pelvic node metastases were retrospectively analyzed. Estimates of overall survival (OS) and cancer-specific survival were provided by the Kaplan–Meier method. Comparisons between subgroups were made using the log-rank test, and Cox regression analysis was used to adjust comparisons for covariates of interest.

Results

From 1978 to 2012, fifty-one men with unilateral inguinal LNM and positive pelvic nodes on PLND were identified. Thirty-eight (75 %) had ipsilateral and 13 (25 %) had bilateral PLND. Except the extent of the PLND, patients were comparable with respect to disease and therapeutic interventions. The Kaplan–Meier estimated median OS was significantly longer in the bilateral PLND patients (21.7 vs. 13.1, p = 0.051). On Cox regression analysis, bilateral PLND [HR 0.25, (95 % CI 0.10–0.64)], multiple pelvic node involvement [HR 2.12 (95 % CI 1.02–4.43)], neoadjuvant chemotherapy [HR 0.01, (95 % CI 0.02–0.44)] and adjuvant therapies [HR 0.16, (95 % CI 0.06–0.45)] (compared to no additional therapy) were independent predictors of OS.

Conclusions

Men with PC and pelvic node metastases may benefit from a bilateral PLND. This hypothesis requires further confirmation.

     

Discussing sexual health in spinal care

Background

The possible detrimental effects of spinal disease on sexual health are widely recognized; however, it is not known to what extent neurosurgeons discuss this topic with their patients. The aim of this study is to identify knowledge, attitude and practice patterns of neurosurgeons counseling their patients about sexual health.

Methods

All members of the Dutch Association of Neurosurgery (neurosurgeons and residents) were sent a questionnaire addressing their attitudes, knowledge and practice patterns regarding discussing sexual health.

Results

Response rate was 62 % with 89 questionnaires suitable for analysis. The majority of participants (83 %) were male; mean age, 42.4 years. The mean experience in neurosurgical practice was 9 years. Respondents assumed that in 34 % of their patients, sexual health was affected due to spinal disease. The majority of respondents (64 %) stated that responsibility for discussing sexual health lies (partly) with the neurosurgeon; however, 73 % indicated to (almost) never do this. The main reasons for not discussing sexual health were patients’ old age (42 %), lack of knowledge (38 %) and lack of patients’ initiative to bring up the subject (36 %). Twenty-six percent indicated lack of time as a reason. There was no evidence for gender or doctor’s age discordance as important barriers. Fifty percent of participants wished to gain more knowledge on discussing sexual health with patients.

Conclusion

This study shows that despite high prevalence of sexual dysfunction (SD) in spinal patients, counseling about sexual health is not often done in neurosurgical care. More training on sexual health counseling early in the residency program seems critical. By initiating the discussion, clinicians who deal with spinal patients have the potential to detect sexual dysfunction (SD) and to refer adequately when necessary, thereby improving overall quality of life of their patients.