Origin and significance of clay‐coated fractures in mudrock fragments of the SAFOD borehole (Parkfield, California)

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/95148/1/grl21674.pd

Eculizumab in paraxysmal nocturnal haemogloburinia and atypical haemolytic syndrome 10-year pharmacovigilance analysis

Eculizumab is the first and only medication approved for paroxysmal nocturnal haemoglobinuria (PNH) and atypical haemolytic uraemic syndrome (aHUS) treatment. However, eculizumab safety based on long‐term pharmacovigilance is unknown. This analysis summarises safety data collected from spontaneous and solicited sources from 16 March 2007 through 1 October 2016. Cumulative exposure to eculizumab was 28 518 patient‐years (PY) (PNH, 21 016 PY; aHUS, 7502 PY). Seventy‐six cases of meningococcal infection were reported (0·25/100 PY), including eight fatal PNH cases (0·03/100 PY). Susceptibility to meningococcal infections remained the key risk in patients receiving eculizumab. The meningococcal infection rate decreased over time; related mortality remained steady. The most commonly reported serious nonmeningococcal infections were pneumonia (11·8%); bacteraemia, sepsis and septic shock (11·1%); urinary tract infection (4·1%); staphylococcal infection (2·6%); and viral infection (2·5%). There were 434 reported cases of eculizumab exposure in pregnant women; of 260 cases with known outcomes, 70% resulted in live births. Reporting rates for solid tumours (≈0·6/100 PY) and haematological malignancies (≈0·74/100 PY) remained stable over time. No new safety signals affecting the eculizumab benefit‐risk profile were identified. Continued awareness and implementation of risk mitigation protocols are essential to minimise risk of meningococcal and other Neisseria infections in patients receiving eculizumab

Voluntary exercise can strengthen the circadian system in aged mice

Consistent daily rhythms are important to healthy aging according to studies linking disrupted circadian rhythms with negative health impacts. We studied the effects of age and exercise on baseline circadian rhythms and on the circadian system's ability to respond to the perturbation induced by an 8 h advance of the light:dark (LD) cycle as a test of the system's robustness. Mice (male, mPer2luc/C57BL/6) were studied at one of two ages: 3.5 months (n = 39) and >18 months (n = 72). We examined activity records of these mice under entrained and shifted conditions as well as mPER2::LUC measures ex vivo to assess circadian function in the suprachiasmatic nuclei (SCN) and important target organs. Age was associated with reduced running wheel use, fragmentation of activity, and slowed resetting in both behavioral and molecular measures. Furthermore, we observed that for aged mice, the presence of a running wheel altered the amplitude of the spontaneous firing rate rhythm in the SCN in vitro. Following a shift of the LD cycle, both young and aged mice showed a change in rhythmicity properties of the mPER2::LUC oscillation of the SCN in vitro, and aged mice exhibited longer lasting internal desynchrony. Access to a running wheel alleviated some age-related changes in the circadian system. In an additional experiment, we replicated the effect of the running wheel, comparing behavioral and in vitro results from aged mice housed with or without a running wheel (>21 months, n = 8 per group, all examined 4 days after the shift). The impact of voluntary exercise on circadian rhythm properties in an aged animal is a novel finding and has implications for the health of older people living with environmentally induced circadian disruption

Acquisition of a Unique Onshore/Offshore Geophysical and Geochemical Dataset in the Northern Malawi (Nyasa) Rift

The Study of Extension and maGmatism in Malawi aNd Tanzania (SEGMeNT) project acquired a comprehensive suite of geophysical and geochemical datasets across the northern Malawi (Nyasa) rift in the East Africa rift system. Onshore/offshore active and passive seismic data, long‐period and wideband magnetotelluric data, continuous Global Positioning System data, and geochemical samples were acquired between 2012 and 2016. This combination of data is intended to elucidate the sedimentary, crustal, and upper‐mantle architecture of the rift, patterns of active deformation, and the origin and age of rift‐related magmatism. A unique component of our program was the acquisition of seismic data in Lake Malawi, including seismic reflection, onshore/offshore wide‐angle seismic reflection/refraction, and broadband seismic data from lake‐bottom seismometers, a towed streamer, and a large towed air‐gun source

Atypical PKCiota Contributes to Poor Prognosis Through Loss of Apical-basal Polarity and Cyclin E Overexpression in Ovarian Cancer

We show that atypical PKCι, which plays a critical role in the establishment and maintenance of epithelial cell polarity, is genomically amplified and overexpressed in serous epithelial ovarian cancers. Furthermore, PKCι protein is markedly increased or mislocalized in all serous ovarian cancers. An increased PKCι DNA copy number is associated with decreased progression-free survival in serous epithelial ovarian cancers. In a Drosophila in vivo epithelial tissue model, overexpression of persistently active atypical PKC results in defects in apical-basal polarity, increased Cyclin E protein expression, and increased proliferation. Similar to the Drosophila model, increased PKCι proteins levels are associated with increased Cyclin E protein expression and proliferation in ovarian cancers. In nonserous ovarian cancers, increased PKCι protein levels, particularly in the presence of Cyclin E, are associated with markedly decreased overall survival. These results implicate PKCι as a potential oncogene in ovarian cancer regulating epithelial cell polarity and proliferation and suggest that PKCι is a novel target for therapy

Meta-analysis of tumour burden in pre-operative axillary ultrasound positive and negative breast cancer patients

Management of the axilla in breast cancer is becoming increasingly conservative. Patients identified with a low axillary nodal burden (two or fewer involved nodes) at sentinel node biopsy (SNB) can avoid completion axillary node clearance (cANC). 'Fast track' to ANC in patients with involved nodes on pre-operative ultrasound may be over-treating a subgroup of these patients with low nodal burden, which would have precluded their need for ANC. This systematic review assesses the proportion of patients with involved nodes on pre-operative axillary ultrasound, which would fit low axillary burden criteria. Meta-analysis of studies comparing axillary burden of breast cancer patients identified as pre-operative ultrasound negative versus positive was performed. The primary outcome measure was the number of patients with two or fewer involved nodes (macrometastases only). Pooled odds ratio (OR), 95% confidence intervals (CIs), means and probabilities of identifying two or fewer involved nodes versus greater than two were calculated. Six studies reported the axillary burden in 4271 patients who were either directed straight to ANC or cANC after SNB. There was a significantly greater axillary burden in the ultrasound positive versus negative groups (OR 5.95, 95% CI 5.80-6.11) with mean nodal retrieval values of 2.9 [standard error (SE) 0.2] and 1.6 (SE 0.2) nodes, respectively. Cumulative probabilities identified 78.9% of ultrasound negative and 43.2% of ultrasound positive patients possessed low axillary burden. Pre-operative ultrasound positive patients have significantly higher axillary burden. However, nearly half do fit the criteria of low axillary burden and could be considered for omission of ANC

Breast MRI in nonpalpable breast lesions: a randomized trial with diagnostic and therapeutic outcome – MONET – study

<p>Abstract</p> <p>Background</p> <p>In recent years there has been an increasing interest in MRI as a non-invasive diagnostic modality for the work-up of suspicious breast lesions. The additional value of Breast MRI lies mainly in its capacity to detect multicentric and multifocal disease, to detect invasive components in ductal carcinoma in situ lesions and to depict the tumor in a 3-dimensional image. Breast MRI therefore has the potential to improve the diagnosis and provide better preoperative staging and possibly surgical care in patients with breast cancer. The aim of our study is to assess whether performing contrast enhanced Breast MRI can reduce the number of surgical procedures due to better preoperative staging and whether a subgroup of women with suspicious nonpalpable breast lesions can be identified in which the combination of mammography, ultrasound and state-of-the-art contrast-enhanced Breast MRI can provide a definite diagnosis.</p> <p>Methods/Design</p> <p>The MONET – study (<b><it>M</it></b>R mammography <b><it>O</it></b>f <b><it>N</it></b>onpalpable Br<b><it>E</it></b>ast <b><it>T</it></b>umors) is a randomized controlled trial with diagnostic and therapeutic endpoints. We aim to include 500 patients with nonpalpable suspicious breast lesions who are referred for biopsy. With this number of patients, the expected 12% reduction in surgical procedures due to more accurate preoperative staging with Breast MRI can be detected with a high power (90%). The secondary outcome is the positive and negative predictive value of contrast enhanced Breast MRI. If the predictive values are deemed sufficiently close to those for large core biopsy then the latter, invasive, procedure could possibly be avoided in some women. The rationale, study design and the baseline characteristics of the first 100 included patients are described.</p> <p>Trial registration</p> <p>Study protocol number NCT00302120</p

Endocrine Therapy Synergizes with SMAC Mimetics to Potentiate Antigen Presentation and Tumor Regression in Hormone Receptor-Positive Breast Cancer.

UNLABELLED: Immunotherapies have yet to demonstrate significant efficacy in the treatment of hormone receptor-positive (HR+) breast cancer. Given that endocrine therapy (ET) is the primary approach for treating HR+ breast cancer, we investigated the effects of ET on the tumor immune microenvironment (TME) in HR+ breast cancer. Spatial proteomics of primary HR+ breast cancer samples obtained at baseline and after ET from patients enrolled in a neoadjuvant clinical trial (NCT02764541) indicated that ET upregulated β2-microglobulin and influenced the TME in a manner that promotes enhanced immunogenicity. To gain a deeper understanding of the underlying mechanisms, the intrinsic effects of ET on cancer cells were explored, which revealed that ET plays a crucial role in facilitating the chromatin binding of RelA, a key component of the NF-κB complex. Consequently, heightened NF-κB signaling enhanced the response to interferon-gamma, leading to the upregulation of β2-microglobulin and other antigen presentation-related genes. Further, modulation of NF-κB signaling using a SMAC mimetic in conjunction with ET augmented T-cell migration and enhanced MHC-I-specific T-cell-mediated cytotoxicity. Remarkably, the combination of ET and SMAC mimetics, which also blocks prosurvival effects of NF-κB signaling through the degradation of inhibitors of apoptosis proteins, elicited tumor regression through cell autonomous mechanisms, providing additional support for their combined use in HR+ breast cancer. SIGNIFICANCE: Adding SMAC mimetics to endocrine therapy enhances tumor regression in a cell autonomous manner while increasing tumor immunogenicity, indicating that this combination could be an effective treatment for HR+ patients with breast cancer

Comprehensive Axillary Evaluation in Neoadjuvant Chemotherapy Patients With Ultrasonography and Sentinel Lymph Node Biopsy

There is ongoing debate regarding the optimal sequence of sentinel lymph node (SLN) biopsy and neoadjuvant chemotherapy (CTX) for breast cancer. We report the accuracy of comprehensive pre–neoadjuvant CTX and post–neoadjuvant CTX axillary staging via ultrasound imaging, fine-needle aspiration (FNA) biopsy, and SLN biopsy.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/41405/1/10434_2005_Article_6534.pd