External validation of nomograms including MRI features for the prediction of side-specific extraprostatic extension

Background: Prediction of side-specific extraprostatic extension (EPE) is crucial in selecting patients for nerve-sparing radical prostatectomy (RP). Multiple nomograms, which include magnetic resonance imaging (MRI) information, are available predict side-specific EPE. It is crucial that the accuracy of these nomograms is assessed with external validation to ensure they can be used in clinical practice to support medical decision-making.// Methods: Data of prostate cancer (PCa) patients that underwent robot-assisted RP (RARP) from 2017 to 2021 at four European tertiary referral centers were collected retrospectively. Four previously developed nomograms for the prediction of side-specific EPE were identified and externally validated. Discrimination (area under the curve [AUC]), calibration and net benefit of four nomograms were assessed. To assess the strongest predictor among the MRI features included in all nomograms, we evaluated their association with side-specific EPE using multivariate regression analysis and Akaike Information Criterion (AIC).// Results: This study involved 773 patients with a total of 1546 prostate lobes. EPE was found in 338 (22%) lobes. The AUCs of the models predicting EPE ranged from 72.2% (95% CI 69.1–72.3%) (Wibmer) to 75.5% (95% CI 72.5–78.5%) (Nyarangi-Dix). The nomogram with the highest AUC varied across the cohorts. The Soeterik, Nyarangi-Dix, and Martini nomograms demonstrated fair to good calibration for clinically most relevant thresholds between 5 and 30%. In contrast, the Wibmer nomogram showed substantial overestimation of EPE risk for thresholds above 25%. The Nyarangi-Dix nomogram demonstrated a higher net benefit for risk thresholds between 20 and 30% when compared to the other three nomograms. Of all MRI features, the European Society of Urogenital Radiology score and tumor capsule contact length showed the highest AUCs and lowest AIC.// Conclusion: The Nyarangi-Dix, Martini and Soeterik nomograms resulted in accurate EPE prediction and are therefore suitable to support medical decision-making

Intraspecific Trait Variation and Phenotypic Plasticity Mediate Alpine Plant Species Response to Climate Change

In a rapidly changing climate, alpine plants may persist by adapting to new conditions. However, the rate at which the climate is changing might exceed the rate of adaptation through evolutionary processes in long-lived plants. Persistence may depend on phenotypic plasticity in morphology and physiology. Here we investigated patterns of leaf trait variation including leaf area, leaf thickness, specific leaf area, leaf dry matter content, leaf nutrients (C, N, P) and isotopes (δ13C and δ15N) across an elevation gradient on Gongga Mountain, Sichuan Province, China. We quantified inter- and intra-specific trait variation and the plasticity in leaf traits of selected species to experimental warming and cooling by using a reciprocal transplantation approach. We found substantial phenotypic plasticity in most functional traits where δ15N, leaf area, and leaf P showed greatest plasticity. These traits did not correspond with traits with the largest amount of intraspecific variation. Plasticity in leaf functional traits tended to enable plant populations to shift their trait values toward the mean values of a transplanted plants’ destination community, but only if that population started with very different trait values. These results suggest that leaf trait plasticity is an important mechanism for enabling plants to persist within communities and to better tolerate changing environmental conditions under climate change

The matrix metalloproteinase 9 (mmp-9) hemopexin domain is a novel gelatin binding domain and acts as an antagonist

Matrix metalloproteinases (MMPs) are involved in the remodeling processes of the extracellular matrix and the basement membrane. Most MMPs are composed of a regulatory, a catalytic, and a hemopexin subunit. In many tumors the expression of MMP-9 correlates with local tumor growth, invasion, and metastasis. To analyze the role of the hemopexin domain in these processes, the MMP-9 hemopexin domain (MMP-9-PEX) was expressed as a glutathione S-transferase fusion protein in Escherichia coli. After proteolytic cleavage, the isolated PEX domain was purified by size exclusion chromatography. In a zymography assay, MMP-9-PEX was able to inhibit MMP-9 activity. The association and dissociation rates for the interaction of MMP-9-PEX with gelatin were determined by plasmon resonance. From the measured rate constants, the dissociation constant was calculated to be K(d) = 2,4 x 10(-8) m, demonstrating a high affinity between MMP-9-PEX and gelatin. In Boyden chamber experiments the recombinant MMP-9-PEX was able to inhibit the invasion of melanoma cells secreting high amounts of MMP-9 in a dose-dependent manner. These data demonstrate for the first time that the hemopexin domain of MMP-9 has a high affinity binding site for gelatin, and the particular recombinant domain is able to block MMP-9 activity and tumor cell invasion. Because MMP-9 plays an important role in metastasis, this antagonistic effect may be utilized to design MMP inhibition-based cancer therapy

Combined chemotherapy and pembrolizumab salvages multi-chemotherapy agent and avelumab resistant choriocarcinoma: A case report

Introduction: Gestational trophoblastic neoplasia (GTN) including choriocarcinoma (CC) frequently requires multi-agent chemotherapy to achieve cure. In chemotherapy-resistant GTN, immunotherapy with the checkpoint inhibitors pembrolizumab, avelumab and camrelizumab are potential new treatment options previously described in small case series, phase 2 trials and case reports. Case description: A 32-year-old woman was diagnosed with gestational choriocarcinoma (FIGO score 5). Prior administered therapy regimes included methotrexate, actinomycin-D followed by open hysterectomy with bilateral salpingectomy (histology without GTN) as well as multi-agent chemotherapy and avelumab single-agent. After detection of a suspicious pulmonary mass video- assisted thoracoscopic left lung segmentectomy was performed confirming CC. The patient experienced an intracerebral haemorrhage and was treated with an emergency decompressive craniotomy. The cerebrospinal fluid showed an increased ratio of hCG compared to serum. Therapy with combined escalated etoposide and cisplatin with pembrolizumab was commenced followed by maintenance pembrolizumab achieving a complete hCG response and negative PET CT. Discussion: In the management of multi drug- resistant GTN, application of checkpoint inhibitor pembrolizumab is a new therapeutic strategy. In this heavily pre-treated patient incorporation of pembrolizumab resulted in complete long-term response in a patient who had also failed avelumab therapy

Electronic structure of neutral tryptophan radicals in ribonucleotide reductase studied by epr and endor spectroscopy

New transient protein-linked radicals have been analyzed by EPR and ENDOR spectroscopy in the radical enzyme ribonucteotide reductase of E coK, particularly in the mutant Y122F of the protein R2, during the reconstitution of the diiron center. Two different tryptophan radicals (Wa° and W0°) with life-times of several minutes are formed at room temperature. Wa° is freeze-trapped and investigated by EPR and ENDOR in normal and selectively deuterated proteins at 20K Two hyperfine couplings from the βmethylene protons, hyperfine tensors of two a-protons and the complete nitrogen hyperfine tensor are determined. Based on the absence of a large hyperfine coupling from the N-H proton, which could be expected for a cation radical, and on comparison of the experimental data with theoretical spin densities from density functional calculations, WV is assigned to an oxidized neutral tryptophan radical. A small anisotropic hyperfine coupling detected in selectively deuterated W." is tentatively assigned to a proton which is hydrogen bonded to the nitrogen of VW. A similar spin density distribution was obtained also for the second tryptophan radical. WV observed at room temperature by stopped-flow EPR is also assigned to an oxidized neutral radical. The site of Wa° and WtT in protein R2 has been determined from the comparison of the conformation of the βprotons (from EPR data) with X-ray structure data to W111 and W107, respectively, in close neighborhood to the iron center. For the first time, detailed hyperfine parameters are determined for protein-linked oxidized neutral tryptophan radicals. Using the same technique of iron reconstitution, in the mutant R2-Y122H, where the site of the catalytic essential stable tyrosyl radical has been replaced by a histidine, a new stable radical exhibiting a strong magnetic metal interaction is observed by EPR and ENDOR