Modeling Ferro- and Antiferromagnetic Interactions in Metal-Organic Coordination Networks

Magnetization curves of two rectangular metal-organic coordination networks formed by the organic ligand TCNQ (7,7,8,8-tetracyanoquinodimethane) and two different (Mn and Ni) 3d transition metal atoms [M(3d)] show marked differences that are explained using first principles density functional theory and model calculations. We find that the existence of a weakly dispersive hybrid band with M(3d) and TCNQ character crossing the Fermi level is determinant for the appearance of ferromagnetic coupling between metal centers, as it is the case of the metallic system Ni-TCNQ but not of the insulating system Mn-TCNQ. The spin magnetic moment localized at the Ni atoms induces a significant spin polarization in the organic molecule; the corresponding spin density being delocalized along the whole system. The exchange interaction between localized spins at Ni centers and the itinerant spin density is ferromagnetic. Based on two different model Hamiltonians, we estimate the strength of exchange couplings between magnetic atoms for both Ni- and Mn-TCNQ networks that results in weak ferromagnetic and very weak antiferromagnetic correlations for Ni- and Mn-TCNQ networks, respectively.Comment: 27 pages, 6 figures, accepted for publication; Journal of Physical Chemistry C (2014

Efficient Transfection of Large Plasmids Encoding HIV-1 into Human Cells—A High Potential Transfection System Based on a Peptide Mimicking Cationic Lipid

One major disadvantage of nucleic acid delivery systems is the low transfection or transduction efficiency of large-sized plasmids into cells. In this communication, we demonstrate the efficient transfection of a 15.5 kb green fluorescent protein (GFP)-fused HIV-1 molecular clone with a nucleic acid delivery system prepared from the highly potent peptide-mimicking cationic lipid OH4 in a mixture with the phospholipid DOPE (co-lipid). For the transfection, liposomes were loaded using a large-sized plasmid (15.5 kb), which encodes a replication-competent HIV type 1 molecular clone that carries a Gag-internal green fluorescent protein (HIV-1 JR-FL Gag-iGFP). The particle size and charge of the generated nanocarriers with 15.5 kb were compared to those of a standardized 4.7 kb plasmid formulation. Stable, small-sized lipoplexes could be generated independently of the length of the used DNA. The transfer of fluorescently labeled pDNA-HIV1-Gag-iGFP in HEK293T cells was monitored using confocal laser scanning microscopy (cLSM). After efficient plasmid delivery, virus particles were detectable as budding structures on the plasma membrane. Moreover, we observed a randomized distribution of fluorescently labeled lipids over the plasma membrane. Obviously, a significant exchange of lipids between the drug delivery system and the cellular membranes occurs, which hints toward a fusion process. The mechanism of membrane fusion for the internalization of lipid-based drug delivery systems into cells is still a frequently discussed topic

Model for Screened, Charge-Regulated Electrostatics of an Eye Lens Protein: Bovine GammaB-Crystallin

We model screened, site-specific charge regulation of the eye lens protein bovine gammaB-crystallin (γB) and study the probability distributions of its proton occupancy patterns. Using a simplified dielectric model, we solve the linearized Poisson-Boltzmann equation to calculate a 54 × 54 work-of-charging matrix, each entry being the modeled voltage at a given titratable site, due to an elementary charge at another site. The matrix quantifies interactions within patches of sites, including γB charge pairs. We model intrinsic pK values that would occur hypothetically in the absence of other charges, with use of experimental data on the dependence of pK values on aqueous solution conditions, the dielectric model, and literature values. We use Monte Carlo simulations to calculate a model grand-canonical partition function that incorporates both the work-of-charging and the intrinsic pK values for isolated γB molecules and we calculate the probabilities of leading proton occupancy configurations, for 4 \u3c pH \u3c 8 and Debye screening lengths from 6 to 20 A. We select the interior dielectric ˚ value to model γB titration data. At pH 7.1 and Debye length 6.0 A, on a given ˚ γB molecule the predicted top occupancy pattern is present nearly 20% of the time, and 90% of the time one or another of the first 100 patterns will be present. Many of these occupancy patterns differ in net charge sign as well as in surface voltage profile. We illustrate how charge pattern probabilities deviate from the multinomial distribution that would result from use of effective pK values alone and estimate the extents to which γB charge pattern distributions broaden at lower pH and narrow as ionic strength is lowered. These results suggest that for accurate modeling of orientation-dependent γB-γB interactions, consideration of numerous pairs of proton occupancy patterns will be needed

Radical nephroureterectomy for pathologic T4 upper tract urothelial cancer: can oncologic outcomes be improved with multimodality therapy?

Purpose To report the outcomes of patients with pathologic T4 UTUC and investigate the potential impact of peri-operative chemotherapy combined with radical nephroureterectomy (RNU) and regional lymph node dissection (LND) on oncologic outcomes. Materials and Methods Patients with pathologic T4 UTUC were identified from the cohort of 1464 patients treated with RNU at 13 academic centers between 1987 and 2007. Oncologic outcomes were stratified according to utilization of perioperative systemic chemotherapy and regional LND as an adjunct to RNU. Results The study included 69 patients, 42 males (61%) with median age 73 (range 43-98). Median follow-up was 17 months (range: 6-88). Lymphovascular invasion was found in 47 (68%) and regional lymph node metastases were found in 31 (45%). Peri-operative chemotherapy was utilized in 29 (42%) patients. Patients treated with peri-operative chemotherapy and RNU with LND demonstrated superior oncologic outcomes compared to those not treated by chemotherapy and/or LND during RNU (3Y-DFS: 35% vs. 10%; P = 0.02 and 3Y-CSS: 28% vs. 14%; P = 0.08). In multivariate Cox regression analysis, administration of peri-operative chemotherapy and utilization of LND during RNU was associated with lower probability of recurrence (HR: 0.4, P = 0.01), and cancer specific mortality (HR: 0.5, P = 0.06). Conclusions Pathological T4 UTUC is associated with poor prognosis. Peri-operative chemotherapy combined with aggressive surgery, including lymph node dissection, may improve oncological outcomes. Our findings support the use of aggressive multimodal treatment in patients with advanced UTUC

Plastic and Reconstructive Surgeons' Knowledge and Comfort of Contralateral Prophylactic Mastectomy: A Survey of the American Society of Plastic Surgeons

Background: Despite limited oncologic benefit, contralateral prophylactic mastectomy (CPM) rates have increased in the United States over the past 15 years. CPM is often accompanied by breast reconstruction, thereby requiring an interdisciplinary approach between breast and plastic surgeons. Despite this, little is known about plastic surgeons' (PS) perspectives of CPM. The purpose of this study was to assess PS practice patterns, knowledge of CPM oncologic benefits, and perceptions of the CPM decision-making process.Methods: An electronic survey was sent to 2,642 members of the American Society of Plastic Surgeons (ASPS). Questions assessed demographics, practice patterns, knowledge of CPM oncologic benefits, and perceptions of the CPM decision-making process.Results: ASPS response rate was 12.5% (n = 329). Most responders worked in private practice (69%), were male (81%) and had been in practice for ≥15 years (60%). The median number of CPM reconstructions performed per month was 2–4. Fifty-five percent of PS reported routine attendance at a breast multidisciplinary conference. Responders reported CPM discussion was most likely to be initiated by the patient (51%) followed by the breast surgeon (38%), and plastic surgeon (7.3%). According to PS, the most common reason patients choose CPM is a perceived increased contralateral cancer risk (86%). Most plastic surgeons (63%) assessed the benefits of CPM as worth the risk of additional surgery and the majority (53%) estimated the complication rate at 2X the risk of unilateral surgery. The majority (61%) of PS estimated risk of contralateral cancer in an average risk patient between <2 and 5% over 10 years, which is consistent with data reported from the current literature. Most plastic surgeons (87%) reported that there was no evidence or limited evidence for breast cancer specific survival benefit with CPM. A minority of PS (18.5%) reported discomfort with a patient's choice for CPM. Of those surgeons reporting discomfort, the most common reasons for their reservations were a concern with the risk/benefit ratio of CPM and with lack of patient understanding of expected outcomes. Common reasons for PS comfort with CPM were a respect for autonomy and non-oncologic benefits of CPM.Discussion: To our knowledge, this is the first survey reporting PS perspectives on CPM. According to PS, CPM dialogue appears to be patient driven and dominated by a perceived increased risk of contralateral cancer. Few PS reported discomfort with CPM. While many PS acknowledge both the limited oncologic benefit of CPM and the increased risk of complications, the majority have the opinion that the benefits of CPM are worth the additional risk. This apparent contradiction may be due to an appreciation of the non-oncologic benefits CPM and a desire to respect patients' choices for treatment

Upper urinary tract urothelial carcinoma with loco‐regional nodal metastases: insights from the Upper Tract Urothelial Carcinoma Collaboration

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/86906/1/j.1464-410X.2011.10075.x.pd

Advanced patient age is associated with inferior cancer-specific survival after radical nephroureterectomy

Study Type – Prognosis (case series) Level of Evidence 4To assess the impact of patient age on outcomes after radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC).Data were collected on 1453 patients treated with RNU at 13 centres. Pathological slides were reviewed by dedicated genitourinary pathologists according to standardized criteria. Age at RNU was analysed both as a continuous and categorical variable (70 years were less likely to undergo lymphadenectomy and to receive adjuvant chemotherapy ( P  ≤ 0.026). In multivariable analyses, being older was associated with decreased all-cause (AC) survival (>60 years) and cancer-specific survival (CSS; >80 years) after controlling for the effects of standard pathological features ( P  ≤ 0.006). However, addition of age did not improve the predictive accuracy of a base model that included standard pathological features for prediction of either disease recurrence, AC survival or CSS.Being older at the time of RNU was associated with decreased survival. This finding could be due to a change in the biological potential of the tumour cell, a decrease in the host’s defence mechanisms, or differences in care patterns. Further work is needed to improve our understanding of UTUC outcomes in this growing segment of the population and to develop strategies to improve cancer control in the elderly.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/78588/1/j.1464-410X.2009.09072.x.pd

Tumour architecture is an independent predictor of outcomes after nephroureterectomy: a multi-institutional analysis of 1363 patients

To assess whether tumour architecture can help to refine the prognosis of patients treated with nephroureterectomy (NU) for urothelial carcinoma (UC) of the upper urinary tract (UT), as the prognostic value of tumour architecture (papillary vs sessile) in UTUC remains elusive. PATIENTS AND METHODS The study included 1363 patients with UTUC and treated with radical NU at 12 centres worldwide. All slides were re-reviewed according to strict criteria by genitourinary pathologists who were unaware of the findings of the original pathology slides and clinical outcomes. Gross tumour architecture was categorized as sessile vs papillary. RESULTS Papillary growth was identified in 983 patients (72.2%) and sessile growth in 380 (27.8%). The sessile growth pattern was associated with higher tumour grade, more advanced stage, lymphovascular invasion, and metastasis to lymph nodes (all P  < 0.001). In multivariable Cox regression analyses that adjusted for the effects of pathological stage, grade and lymph node status, tumour architecture (sessile or papillary) was an independent predictor of cancer recurrence (hazard ratio 1.5, P  = 0.002) and cancer-specific mortality (1.6, P  = 0.001). Adding tumour architecture increased the predictive accuracy of a model that comprised pathological stage, grade and lymph node status for predicting cancer recurrence and cancer-specific death by a minimal but statistically significant margin (gain in predictive accuracy 1% and 0.5%, both P  < 0.001). CONCLUSION The tumour architecture of UTUC is associated with established features of biologically aggressive disease, and more importantly, with prognosis after radical NU. Including tumour architecture in predictive models for disease progression should be considered, aiming to identify patients who might benefit from early systemic therapeutic intervention.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/72257/1/j.1464-410X.2008.08003.x.pd

Prognostic factors for recovery following acute lateral ankle ligament sprain: a systematic review.

BACKGROUND: One-third of individuals who sustain an acute lateral ankle ligament sprain suffer significant disability due to pain, functional instability, mechanical instability or recurrent sprain after recovery plateaus at 1 to 5 years post injury. The identification of early prognostic factors associated with poor recovery may provide an opportunity for early-targeted intervention and improve outcome. METHODS: We performed a comprehensive search of AMED, EMBASE, Psych Info, CINAHL, SportDiscus, PubMed, CENTRAL, PEDro, OpenGrey, abstracts and conference proceedings from inception to September 2016. Prospective studies investigating the association between baseline prognostic factors and recovery over time were included. Two independent assessors performed the study selection, data extraction and quality assessment of the studies. A narrative synthesis is presented due to inability to meta-analyse results due to clinical and statistical heterogeneity. RESULTS: The search strategy yielded 3396 titles/abstracts after duplicates were removed. Thirty-six full text articles were then assessed, nine of which met the study inclusion criteria. Six were prospective cohorts, and three were secondary analyses of randomised controlled trials. Results are presented for nine studies that presented baseline prognostic factors for recovery after an acute ankle sprain. Age, female gender, swelling, restricted range of motion, limited weight bearing ability, pain (at the medial joint line and on weight-bearing dorsi-flexion at 4 weeks, and pain at rest at 3 months), higher injury severity rating, palpation/stress score, non-inversion mechanism injury, lower self-reported recovery, re-sprain within 3 months, MRI determined number of sprained ligaments, severity and bone bruise were found to be independent predictors of poor recovery. Age was one prognostic factor that demonstrated a consistent association with outcome in three studies, however cautious interpretation is advised. CONCLUSIONS: The associations between prognostic factors and poor recovery after an acute lateral ankle sprain are largely inconclusive. At present, there is insufficient evidence to recommend any factor as an independent predictor of outcome. There is a need for well-conducted prospective cohort studies with adequate sample size and long-term follow-up to provide robust evidence on prognostic factors of recovery following an acute lateral ankle sprain. TRIAL REGISTRATION: Prospero registration: CRD42014014471

Network-based atrophy modelling in the common epilepsies: a worldwide ENIGMA study

SUMMARY Epilepsy is increasingly conceptualized as a network disorder. In this cross-sectional mega-analysis, we integrated neuroimaging and connectome analysis to identify network associations with atrophy patterns in 1,021 adults with epilepsy compared to 1,564 healthy controls from 19 international sites. In temporal lobe epilepsy, areas of atrophy co-localized with highly interconnected cortical hub regions, whereas idiopathic generalized epilepsy showed preferential subcortical hub involvement. These morphological abnormalities were anchored to the connectivity profiles of distinct disease epicenters, pointing to temporo-limbic cortices in temporal lobe epilepsy and fronto-central cortices in idiopathic generalized epilepsy. Indices of progressive atrophy further revealed a strong influence of connectome architecture on disease progression in temporal lobe, but not idiopathic generalized, epilepsy. Our findings were reproduced across individual sites and single patients, and were robust across different analytical methods. Through worldwide collaboration in ENIGMA-Epilepsy, we provided novel insights into the macroscale features that shape the pathophysiology of common epilepsies