The damage-associated molecular pattern HMGB1 is released early after clinical hepatic ischemia/reperfusion.

OBJECTIVE AND BACKGROUND: Activation of sterile inflammation after hepatic ischemia/reperfusion (I/R) culminates in liver injury. The route to liver damage starts with mitochondrial oxidative stress and cell death during early reperfusion. The link between mitochondrial oxidative stress, damage-associate molecular pattern (DAMP) release, and sterile immune signaling is incompletely understood and lacks clinical validation. The aim of the study was to validate this relation in a clinical liver I/R cohort and to limit DAMP release using a mitochondria-targeted antioxidant in I/R-subjected mice. METHODS: Plasma levels of the DAMPs high-mobility group box 1 (HMGB1), mitochondrial DNA, and nucleosomes were measured in 39 patients enrolled in an observational study who underwent a major liver resection with (N = 29) or without (N = 13) intraoperative liver ischemia. Circulating cytokine and neutrophil activation markers were also determined. In mice, the mitochondria-targeted antioxidant MitoQ was intravenously infused in an attempt to limit DAMP release, reduce sterile inflammation, and suppress I/R injury. RESULTS: In patients, HMGB1 was elevated following liver resection with I/R compared to liver resection without I/R. HMGB1 levels correlated positively with ischemia duration and peak post-operative transaminase (ALT) levels. There were no differences in mitochondrial DNA, nucleosome, or cytokine levels between the two groups. In mice, MitoQ neutralized hepatic oxidative stress and decreased HMGB1 release by ±50%. MitoQ suppressed transaminase release, hepatocellular necrosis, and cytokine production. Reconstituting disulfide HMGB1 during reperfusion reversed these protective effects. CONCLUSION: HMGB1 seems the most pertinent DAMP in clinical hepatic I/R injury. Neutralizing mitochondrial oxidative stress may limit DAMP release after hepatic I/R and reduce liver damage

The clinical relevance of axillary reverse mapping (ARM): study protocol for a randomized controlled trial

BACKGROUND: Axillary lymph node dissection (ALND) in patients with breast cancer has the potential to induce side-effects, including upper-limb lymphedema. Axillary reverse mapping (ARM) is a technique that enables discrimination of the lymphatic drainage of the breast from that of the upper limb in the axillary lymph node (LN) basin. If lymphedema is caused by removing these lymphatics and nodes in the upper limb, the possibility of identifying these lymphatics would enable surgeons to preserve them. The aim of this study is to determine the clinical relevance of selective axillary LN and lymphatic preservation by means of ARM. To minimize the risk of overlooking tumor-positive ARM nodes and the associated risk of undertreatment, we will only include patients with a tumor-positive sentinel lymph node (SLN). Patients who are candidates for ALND because of a proven positive axillary LN at clinical examination can be included in a registration study. METHODS/DESIGN: The study will enroll 280 patients diagnosed with SLN biopsy-proven metastasis of invasive breast cancer with an indication for a completion ALND. Patients will be randomized to undergo standard ALND or an ALND in which the ARM nodes and their corresponding lymphatics will be left in situ. Primary outcome is the presence of axillary surgery-related lymphedema at 6, 12, and 24 months post-operatively, measured by the water-displacement method. Secondary outcome measures include pain, paresthesia, numbness, and loss of shoulder mobility, quality of life, and axillary recurrence risk. DISCUSSION: The benefit of ALND in patients with a positive SLN is a subject of debate. For many patients, an ALND will remain the treatment of choice. This multicenter randomized trial will provide evidence of whether or not axillary LN preservation by means of ARM decreases the side-effects of an ALND. Enrolment of patients will start in April 2013 in five breast-cancer centers in the Netherlands, and is expected to conclude by April 2016. TRIAL REGISTRATION: TC369

Data from: Endure and call for help: strategies of black mustard plants to deal with a specialised caterpillar

Plants have evolved inducible resistance and tolerance mechanisms against insect herbivores. Resistance mechanisms that affect herbivorous insects directly can be effective against generalist herbivores, but will not deter specialist herbivores from attacking the plant. Tolerance mechanisms and indirect plant resistance are more likely effective strategies used by plants when dealing with specialist herbivores. However, inducible indirect resistance and tolerance mechanisms have rarely been investigated within the same study system. We studied multiple tolerance mechanisms and the role of natural enemies in reducing fitness loss of Brassica nigra plants incurred by feeding by the specialist herbivore Pieris brassicae. For this, we measured the changes in carbon and nitrogen triggered by herbivore attack and quantified plant biomass and seed production under field conditions, in the presence or absence of natural enemies of the herbivores. We also assessed whether B. nigra increased selfing rates when exposed to herbivore infestation, and investigated whether infestation by P. brassicae rendered B. nigra plants more attractive to night-active pollinators than control plants. We found that B. nigra flowers are rarely visited by insects during the night, and exposure to herbivores did not influence selfing rates. Brassica nigra plants compensated for herbivory in terms of vegetative biomass. Seed set was negatively affected by herbivory in the absence of natural enemies, but not in the presence of natural enemies. Plants responded to herbivory with drastic changes in nitrogen contents of leaves and flowers, whereas no changes in carbon concentrations were detected. The investment in reproduction or re-growth of vegetative tissues is not sufficient to sustain plant fitness. Reproductive output of flowering mustard plants is only sustained when interactions with the natural enemies of the herbivores are preserved. We conclude that natural enemies of herbivorous insects play an important role as component of the plant's defence strategy. This study reveals that both tolerance and indirect resistance are strategies of this plant species to sustain fitness

The COSMAM TRIAL a prospective cohort study of quality of life and cosmetic outcome in patients undergoing breast conserving surgery

Abstract Background Cosmetic result in breast cancer surgery is gaining increased interest. Currently, some 30–40% of the patients treated with breast conserving surgery (BCS) are dissatisfied with their final cosmetic result. In order to prevent disturbing breast deformity oncoplastic surgical techniques have been introduced. The extent of different levels of oncoplastic surgery incorporated in breast conserving surgery and its value with regard to cosmetic outcome, patient satisfaction and quality of life remains to be defined. The aim of this prospective cohort study is to investigate quality of life and satisfaction with cosmetic result in patients with breast cancer, undergoing standard lumpectomy versus level I or II oncoplastic breast conserving surgery. Methods Female breast cancer patients scheduled for BCS, from 18 years of age, referred to our outpatient clinic from July 2015 are asked to participate in this study. General, oncologic and treatment information will be collected. Patient satisfaction will be scored preceding surgery, and at 1 month and 1 year follow up. Photographs of the breast will be used to score cosmetic result both by the patient, an independent expert panel and BCCT.Core software. Quality of life will be measured by using the BREAST-Q BCT, EORTC-QLQ and EQ-5D-5 L questionnaires. Discussion The purpose of this prospective study is to determine the clinical value of different levels of oncoplastic techniques in breast conserving surgery, with regard to quality of life and cosmetic result. Analysis will be carried out by objective measurements of the final cosmetic result in comparison with standard breast conserving surgery. The results of this study will be used to development of a clinical decision model to guide the use oncoplastic surgery in future BCS. Trial registration Central Commission of Human Research (CCMO), The Netherlands: NL54888.015.15. Medical Ethical Commission (METC), Maxima Medical Centre, Veldhoven, The Netherlands: 15.107. Dutch Trial Register: NTR5665, retrospectively registered, 02-25-2016

Ervaring met ‘axillary reverse mapping’

Axillary reverse mapping (ARM) is a technique by which the lymphatic drainage system of the upper extremities is mapped, so that the lymph channels and glands can be preserved during axillary lymph node dissection (ALND). This can lead to less postoperative morbidity, such as lymphoedema. A randomised multicentre study showed that there are statistically significantly fewer post-operative symptoms if the lymph channels and glands of the upper extremities are spared with this technique. Despite the declining indication for an ALND, ARM can have added value for the patients who do have to undergo ALND

Endure and call for help : Strategies of black mustard plants to deal with a specialized caterpillar

Plants have evolved inducible resistance and tolerance mechanisms against insect herbivores. Resistance mechanisms that affect herbivorous insects directly can be effective against generalist herbivores, but will not deter specialist herbivores from attacking the plant. Tolerance mechanisms and indirect plant resistance are more likely effective strategies used by plants when dealing with specialist herbivores. However, inducible indirect resistance and tolerance mechanisms have rarely been investigated within the same study system. We studied multiple tolerance mechanisms and the role of natural enemies in reducing fitness loss of Brassica nigra plants incurred by feeding by the specialist herbivore Pieris brassicae. For this, we measured the changes in carbon and nitrogen triggered by herbivore attack and quantified plant biomass and seed production under field conditions, in the presence or absence of natural enemies of the herbivores. We also assessed whether B. nigra increased selfing rates when exposed to herbivore infestation, and investigated whether infestation by P. brassicae rendered B. nigra plants more attractive to night-active pollinators than control plants. We found that B. nigra flowers are rarely visited by insects during the night, and exposure to herbivores did not influence selfing rates. Brassica nigra plants compensated for herbivory in terms of vegetative biomass. Seed set was negatively affected by herbivory in the absence of natural enemies, but not in the presence of natural enemies. Plants responded to herbivory with drastic changes in nitrogen contents of leaves and flowers, whereas no changes in carbon concentrations were detected. The investment in reproduction or re-growth of vegetative tissues is not sufficient to sustain plant fitness. Reproductive output of flowering mustard plants is only sustained when interactions with the natural enemies of the herbivores are preserved. We conclude that natural enemies of herbivorous insects play an important role as component of the plant's defence strategy. This study reveals that both tolerance and indirect resistance are strategies of this plant species to sustain fitness