Low field mobility in bulk GaN and its ternary AlGaN/GaN compounds (quantum kinetic approach).

Analytical expressions for the low-field mobility of charge carrier gases with three-(3D), two-(2D) and one-(1D) dimensionalities are obtained. Multi-ion ionized impurities scattering, acoustic and polar optic phonons are considered as scattering mechanisms. The calculated values of mobility are compared to known experimental data for bulk (3D) n-and p-type wurtzite, n-type zinc-blende GaN crystals and low dimensional (2D and 1D) ternary GaAlN compounds. The resulting analytical expressions give the dependences of mobility on dimensionality of charge carrier gas, its density, effective mass, temperature and confining dimensions. A comparison of the experimental and calculated temperature dependences of the mobility in bulk GaN crystals (3D) and in AlGaN/GaN nanowires (1D) shows that the mobility atT>100Kis determined by the scattering of charge carriers by polar optical phonons with an energy of 91.2 meV. The temperature dependences of mobility in Al0.25Ga0.75N/GaN heterostructures (2D) atT>100Kare in consistent with experiment for electron scattering by polar optical phonons with a noticeably higher energy of 160 meV. We associate this fact with the heterointerface, which according to well-known theoretical studies can change both the strength of electron polar optical phonons scattering and the energy of the phonons.

Azotriptycenes: Photoswitchable Molecular Brakes.

The control of molecular motions is a central topic of molecular machine research. Molecular brakes are fundamental building blocks towards such goal as they allow deliberately decelerating specific motions after an outside stimulus is applied. Here we present azotriptycenes as structural framework for light-controlled molecular brakes. The intrinsic kinetics and their changes upon azotriptycene isomerization are scrutinized comprehensively by a mixed theoretical and variable temperature NMR approach. With azotriptycenes C-N bond rotation rates can be decelerated or accelerated reversibly by up to five orders of magnitude. Rate change effects are highly localized and are strongest for the C-N bond connecting a triptycene rotor fragment to the central diazo group. The detailed mechanistic insights provide a solid basis for further conscious design and applications in the future.

Bulk plasmon-limited mobility in semiconductors: from bulk to nanowires.

Analytical expressions are obtained for the low-field mobility in semiconductors for scattering of three-dimensional (3D), two-dimensional (2D), and one-dimensional (1D) charged carriers by bulk plasmons. The consideration is based on the quantum kinetic equation and model distribution function in form of a shifted Fermi distribution and includes calculations of the dielectric function of 3D, 2D and 1D carriers in the random phase approximation. The resulting analytical expressions give dependences of the plasmon limited mobility on the dimensionality of charge carrier system, their density, effective mass, temperature and confining dimensions. The plasmon limited mobility decreases as the dimensionality of the electron gas D decreases. The physical reason for this is an increase in the absolute value of the cutoff vector with a decrease in D. Comparison of our calculations with known experimental data shows that relative contribution of the electron-plasmon scattering to total mobility reaches a maximum in the temperature range 10-100 K and can be a few percent in bulk crystals, ten of percent in quantum wells, and is close to the experimental values in nanowires. A noticeable effect of the scattering 3D, 2D and 1D electrons by bulk plasmons on mobility is expected in semiconductors with a sufficiently high mobility of more than 105cm2V-1s.

Plasma Profile of Immune Determinants Predicts Pathological Complete Response in Locally Advanced Breast Cancer Patients: A Pilot Study.

BACKGROUND: Complex interactions between cancer and the immune system have an impact on disease progression and therapeutic response. Our objective was to evaluate whether circulating immune-related determinants are associated with pathological complete response (pCR) in patients with locally advanced breast cancer (LABC) subjected to neoadjuvant chemotherapy (NACT). PATIENTS AND METHODS: Luminex technology was used to profile 22 cytokines, 10 chemokines, FGF2, PDGF-BB, VEGF, and Ca15-3/Ca125 glycoforms. Measurements were performed alongside standard hematological determinations on pretreatment plasma samples from 151 patients including 41 cases with pCR assessed following RECIST criteria. RESULTS: Random Forest model analysis selected platelets, eotaxin, IFN-γ, IP10, and TGFß2 as significant predictors of pCR. These immune-related features were combined into a quantitative score predictive of pCR. In patients who scored 0 or 1, none had pCR; the pCR frequency increased in relation to the score value (23.5%, 41.2%, and 78.6%, in score groups 2, 3, and 4, respectively). At multivariable logistic analysis, the pCR score was highly significant (odds ratio = 3.15 per unit increment; CI: 1.85-5.38; P < .0001); among clinical covariates (age, menopausal status, tumor stage, IHC subtype, Ki-67, CA15.3, and CA125), only Ki-67 was statistically significant (P = .013). CONCLUSION: This explorative study aimed to lay the conceptual and practical foundation that a distinctive pattern of the immune determinant blood signature at diagnosis of LABC significantly correlates with the patient's response to NACT and provides the groundwork for larger studies that could lead to a minimally invasive tool for personalized medicine.

Active Mechanical Threading by a Molecular Motor.

Molecular motors transform external energy input into directional motions and offer exquisite precision for nano-scale manipulations. To make full use of molecular motor capacities, their directional motions need to be transmitted and used for powering downstream molecular events. Here we present a macrocyclic molecular motor structure able to perform repetitive molecular threading of a flexible tetraethylene glycol chain through the macrocycle. This mechanical threading event is actively powered by the motor and leads to a direct translation of the unidirectional motor rotation into unidirectional translation motion (chain versus ring). The mechanism of the active mechanical threading is elucidated and the actual threading step is identified as a combined helix inversion and threading event. The established molecular machine function resembles the crucial step of macroscopic weaving or sewing processes and therefore offers a first entry point to a "molecular knitting" counterpart.

Kinetic proofreading of lipochitooligosaccharides determines signal activation of symbiotic plant receptors.

Plants and animals use cell surface receptors to sense and interpret environmental signals. In legume symbiosis with nitrogen-fixing bacteria, the specific recognition of bacterial lipochitooligosaccharide (LCO) signals by single-pass transmembrane receptor kinases determines compatibility. Here, we determine the structural basis for LCO perception from the crystal structures of two lysin motif receptor ectodomains and identify a hydrophobic patch in the binding site essential for LCO recognition and symbiotic function. We show that the receptor monitors the composition of the amphiphilic LCO molecules and uses kinetic proofreading to control receptor activation and signaling specificity. We demonstrate engineering of the LCO binding site to fine-tune ligand selectivity and correct binding kinetics required for activation of symbiotic signaling in plants. Finally, the hydrophobic patch is found to be a conserved structural signature in this class of LCO receptors across legumes that can be used for in silico predictions. Our results provide insights into the mechanism of cell-surface receptor activation by kinetic proofreading of ligands and highlight the potential in receptor engineering to capture benefits in plant-microbe interactions.

Steric Effects on the Thermal Processes of Hemithioindigo Based Molecular Motor Rotation.

Tuning the thermal behavior of light driven molecular motors is fundamentally important for their future rational design. In many molecular motors thermal ratcheting steps are comprised of helicity inversions, energetically stabilizing the initial photoproducts. In this work we investigated a series of five hemithioindigo (HTI) based molecular motors to reveal the influence of steric hindrance in close proximity to the rotation axle on this process. Applying a high yielding synthetic procedure, we synthesized constitutional isomeric derivatives to distinguish between substitution effects at the aromatic and aliphatic position on the rotor fragment. The kinetics of thermal helix inversions were elucidated using low temperature 1 H NMR spectroscopy and an in situ irradiation technique. In combination with a detailed theoretical description, a comparative analysis of substituent effects on the thermal helix inversions of the rotation cycle is now possible. Such deeper understanding of the rotational cycle of HTI molecular motors is essential for speed regulation and future applications of visible light triggered nanomachines.

Dibenzochrysene enables tightly controlled docking and stabilizes photoexcited states in dual-pore covalent organic frameworks.

Covalent organic frameworks (COFs), consisting of covalently connected organic building units, combine attractive features such as crystallinity, open porosity and widely tunable physical properties. For optoelectronic applications, the incorporation of heteroatoms into a 2D COF has the potential to yield desired photophysical properties such as lower band gaps, but can also cause lateral offsets of adjacent layers. Here, we introduce dibenzo[g,p]chrysene (DBC) as a novel building block for the synthesis of highly crystalline and porous 2D dual-pore COFs showing interesting properties for optoelectronic applications. The newly synthesized terephthalaldehyde (TA), biphenyl (Biph), and thienothiophene (TT) DBC-COFs combine conjugation in the a,b-plane with a tight packing of adjacent layers guided through the molecular DBC node serving as specific docking site for successive layers. The resulting DBC-COFs exhibit a hexagonal dual-pore kagome geometry, which is comparable to COFs containing another molecular docking site, namely 4,4',4'',4'''-(ethylene-1,1,2,2-tetrayl)-tetraaniline (ETTA). In this context, the respective interlayer distances decrease from about 4.6 Å in ETTA-COFs to about 3.6 Å in DBC-COFs, leading to well-defined hexagonally faceted single crystals sized about 50-100 nm. The TT DBC-COF features broad light absorption covering large parts of the visible spectrum, while Biph DBC-COF shows extraordinary excited state lifetimes exceeding 10 ns. In combination with the large number of recently developed linear conjugated building blocks, the new DBC tetra-connected node is expected to enable the synthesis of a large family of highly correlated and ordered 2D COFs with promising optoelectronic properties.

Switching on and off Interlayer Correlations and Porosity in 2D Covalent Organic Frameworks.

Two-dimensional covalent organic frameworks (2D COFs) attract great interest owing to their well-defined pore structure, thermal stability, high surface area, and permanent porosity. In combination with a tunable chemical pore environment, COFs are intriguing candidates for molecular sieving based on selective host-guest interactions. Herein, we report on 2D COF structures capable of reversibly switching between a highly correlated crystalline, porous and a poorly correlated, nonporous state by exposure to external stimuli. To identify COF structures with such dynamic response, we systematically studied the structural properties of a family of two-dimensional imine COFs comprising tris(4-aminophenyl)benzene (TAPB) and a variety of dialdehyde linear building blocks including terephthalaldehyde (TA) and dialdehydes of thienothiophene (TT), benzodithiophene (BDT), dimethoxybenzodithiophene (BDT-OMe), diethoxybenzodithiophene (BDT-OEt), dipropoxybenzodithiophene (BDT-OPr), and pyrene (Pyrene-2,7). TAPB-COFs consisting of linear building blocks with enlarged π-systems or alkoxy functionalities showed significant stability toward exposure to external stimuli such as solvents or solvent vapors. In contrast, TAPB-COFs containing unsubstituted linear building blocks instantly responded to exposure to these external stimuli by a drastic reduction in COF layer correlation, long-range order, and porosity. To reverse the process we developed an activation procedure in supercritical carbon dioxide (scCO2) as a highly efficient means to revert fragile nonporous and amorphous COF polymers into highly crystalline and open porous frameworks. Strikingly, the framework structure of TAPB-COFs responds dynamically to such chemical stimuli, demonstrating that their porosity and crystallinity can be reversibly controlled by alternating steps of solvent stimuli and scCO2 activation.

ESMO Consensus Conference on testicular germ cell cancer: diagnosis, treatment and follow-up.

The European Society for Medical Oncology (ESMO) consensus conference on testicular cancer was held on 3-5 November 2016 in Paris, France. The conference included a multidisciplinary panel of 36 leading experts in the diagnosis and treatment of testicular cancer (34 panel members attended the conference; an additional two panel members [CB and K-PD] participated in all preparatory work and subsequent manuscript development). The aim of the conference was to develop detailed recommendations on topics relating to testicular cancer that are not covered in detail in the current ESMO Clinical Practice Guidelines (CPGs) and where the available level of evidence is insufficient. The main topics identified for discussion related to: (1) diagnostic work-up and patient assessment; (2) stage I disease; (3) stage II-III disease; (4) post-chemotherapy surgery, salvage chemotherapy, salvage and desperation surgery and special topics; and (5) survivorship and follow-up schemes. The experts addressed questions relating to one of the five topics within five working groups. Relevant scientific literature was reviewed in advance. Recommendations were developed by the working groups and then presented to the entire panel. A consensus vote was obtained following whole-panel discussions, and the consensus recommendations were then further developed in post-meeting discussions in written form. This manuscript presents the results of the expert panel discussions, including the consensus recommendations and a summary of evidence supporting each recommendation. All participants approved the final manuscript.

Preparation of glycoconjugates from unprotected carbohydrates for protein-binding studies.

Glycobiology, in particular the study of carbohydrate-protein interactions and the events that follow, has become an important research focus in recent decades. To study these interactions, many assays require homogeneous glycoconjugates in suitable amounts. Their synthesis is one of the methodological challenges of glycobiology. Here, we describe a versatile, three-stage protocol for the formation of glycoconjugates from unprotected carbohydrates, including those purified from natural sources, as exemplified here by rhizobial Nod factors and exopolysaccharide fragments. The first stage is to add an oligo(ethylene glycol) linker (OEG-linker) that has a terminal triphenylmethanethiol group to the reducing end of the oligosaccharide by oxime formation catalyzed by aniline. The triphenylmethyl (trityl) tag is then removed from the linker to expose a thiol (stage 2) to allow a conjugation reaction at the thiol group (stage 3). There are many possible conjugation reactions, depending on the desired application. Examples shown in this protocol are as follows: (i) coupling of the oligosaccharide to a support for surface plasmon resonance (SPR) studies, (ii) fluorescence labeling for microscale thermophoresis (MST) or bioimaging, and (iii) biotinylation for biolayer interferometry (BLI) studies. This protocol starts from unprotected carbohydrates and provides glycoconjugates in milligram amounts in just 2 d.

Pazopanib in advanced germ cell tumors after chemotherapy failure: results of the open-label, single-arm, phase 2 Pazotest trial.

Background: Therapeutic options for patients with chemoresistant germ cell tumors (GCTs) are limited. Pazopanib is a selective tyrosine kinase inhibitor with distinct antiangiogenic activity. We aimed to evaluate pazopanib activity in patients with refractory GCT. Patients and methods: In the open-label, single-arm, phase 2 Pazotest study (NCT01743482), patient eligibility included failure of ≥2 platinum-based regimens, and allowed prior high-dose chemotherapy administration. Patients were given pazopanib 800 mg/day until disease progression (PD) or onset of unacceptable toxicity. Measurements of serum tumor markers (STM), computed tomography and FDG-PET were carried out at baseline, after 4 weeks of pazopanib treatment, and every 8 weeks thereafter. PD was defined as increasing levels of STM, increasing size of non-teratomatous masses, or appearance of new lesions. The study primary endpoint was progression-free survival (PFS, H0: 3-month PFS ≤ 10%, H1: ≥25%, α = 5%, ß = 20%). Results: Forty-three patients were enrolled from May 2013 to July 2016. The number of prior chemotherapy regimens was: 2 (11.6%), 3 (51.2%), >3 (37.2%). Grade 3 adverse events were observed in six patients (13.9%). Overall, 70.3% of patients had reduced levels of STM after 4 weeks. There were 2 partial responses (4.7%), 19 cases of stable disease, and 16 cases of PD (6 not evaluable by RECIST). The median follow-up duration was 29.6 months. The 3-month PFS probability was 12.8% [95% confidence interval (CI): 5.7%-28.9%]. The 24-month OS probability was 14.2% (95% CI: 6.0%-33.7%). In patients with a >50% decline in STM, the 24-month OS probability was 24.1% (95% CI: 8.3%-69.6%). The small sample size was the major limitation. Conclusions: Despite pazopanib showed potent but short-lived activity in refractory GCT, long-term survival was obtained in a proportion of treated patients. According to the kinetics of pazopanib activity, this drug may be investigated in less pre-treated patients as an optimal bridging therapy preceding and/or combined with salvage chemotherapy.

Estimates of prostate cancer burden in Italy.

Age-standardized incidence rates of prostate cancer (PC) sharply increased during the period 1990-2005 in Italian areas covered by cancer registries, while corresponding mortality rates remained nearly constant. The latest observations have reported on a reversal of the incidence trend with decreasing values after 2005. We provided incidence, mortality, and prevalence estimates at national and geographical area levels, together with time projections up to the year 2020. We applied the MIAMOD method, using as input national mortality data for the years 1970-2010 and population-based survival data for the period of diagnosis (1985-2002). We assumed relative survival of prostate cancer remained constant after the year of diagnosis (2005). The age-standardized incidence rates of PC were estimated to increase during the period 1984-2005, from 31 per 100,000 in 1984 to 93 per 100,000 in 2005. From 2005 onwards, the estimated rates declined to 71 in 2015 and to 62 in 2020. Age-standardized mortality rates slightly increased from 1970 up to about 19 per 100,000 in 1999 and then started to decrease with an estimated reduction of about 2.3% per year. Mortality projections indicated a continuing reduction, with a predicted age-standardized rate of about 12 per 100,000 in 2020. Prevalence was estimated to continuously increase up to a crude prevalence value of 1.2% in the year 2020. The results indicate that the epidemic peak of PC was reached around the year 2005 followed by declining incidence rates, while a substantial decrease in mortality, starting during the early 2000s, is expected to continue during the 2010s.

Radiotherapy or chemotherapy for clinical stage IIA and IIB seminoma: a systematic review and meta-analysis of patient outcomes.

BACKGROUND: Outcomes of radiotherapy (RT) compared with chemotherapy (CT) remain poorly defined for clinical stage (CS) IIA and IIB seminoma. We aimed to evaluate the current role of the two treatment modalities in this setting of testicular seminoma. PATIENTS AND METHODS: A systematic review and meta-analysis (MA) was carried out to identify all evaluable studies. Search was limited to studies published after 1990 and included the Medline, Embase databases, and abstracts from ASCO (GU), ESMO, AUA, and ASTRO meetings up to April 2014. Sensitivity analyses were applied including the following: CSIIA and CSIIB, paraortic + iliac RT only in both stages, RT dose (≥30 versus <30 Gy), and PEB/EP regimens only. RESULTS: Thirteen studies have been selected for MA on relapse outcome. No randomized trials compared RT and CT. There were 4 prospective and 9 retrospective studies, with a total of 607 patients receiving RT and 283 patients CT. The pooled relapse rate (RR) was similar between the RT [0.11, 95% confidence interval (CI) 0.08-0.14, P for heterogeneity = 0.096, I(2) = 38%] and CT groups (0.08, 95% CI 0.01-0.15, P for heterogeneity <0.001, I(2) = 82.5%). However, in the sensitivity analysis, the pooled RR for RT in CSIIB was 0.12 (95% CI 0.06-0.17) while it was 0.05 (95% CI 0-0.11) for CT. Long-term side-effects and incidence of second cancers were more frequently reported following RT. The overall incidence of nontesticular second malignancies was 0.04 (95% CI 0.01-0.02) in the RT group and 0.02 (95% CI 0.003-0.04) in the CT group. CONCLUSIONS: Although RT and CT appeared to be equal options in CSIIA and IIB seminoma, a trend in favor of CT for a lower incidence of side-effects and RR in CSIIB was found. This evidence is limited by the retrospective quality of studies and their small sample size.

High-dose sequential chemotherapy (HDS) versus PEB chemotherapy as first-line treatment of patients with poor prognosis germ-cell tumors: mature results of an Italian randomized phase II study.

BACKGROUND: In the late 1990s, the use of high-dose chemotherapy (HDCT) and stem-cell rescue held promise for patients with advanced and poor prognosis germ-cell tumors (GCT). We started a randomized phase II trial to assess the efficacy of sequential HDCT compared with cisplatin, etoposide, and bleomycin (PEB). PATIENTS AND METHODS: Patients were randomly assigned to receive four cycles of PEB every 3 weeks or two cycles of PEB followed by a high-dose sequence (HDS) comprising HD-cyclophosphamide (7.0 g/m(2)), 2 courses of cisplatin and HD-etoposide (2.4 g/m(2)) with stem-cell support, and a single course of HD-carboplatin [area under the curve (AUC) 27 mg/ml × min] with autologous stem-cell transplant. Postchemotherapy surgery was planned on responding residual disease in both arms. The primary end point was progression-free survival (PFS). The study was designed to detect a 30% improvement of 5-year PFS (from 40% to 70%), with 80% power and two-sided α at 5%. RESULTS: From December 1996 to March 2007, 85 patients were randomized: 43 in PEB and 42 in HDS arm. Median follow-up was 114.2 months [interquartile range (IQR): 87.7-165.8]. Complete or partial response with normal markers (PRm-) were obtained in 28 (65.1%) and 29 (69.1%) patients, respectively. Five-year PFS was 55.8% [95% confidence interval (CI) 42.8-72.8] and 54.8% (95% CI 41.6%-72.1%) in PEB and HDS arm, respectively (log-rank test P = 0.726). Five-year overall survival was 62.8% (95% CI 49.9-79.0) and 59.3% (95% CI 46.1-76.3). One toxic death (PEB arm) was recorded. CONCLUSIONS: The study failed to meet the primary end point. Furthermore, survival estimates of conventional-dose chemotherapy higher than expected should be accounted for and will likely limit further improvements in the first-line setting. CLINICALTRIALS.GOV: NCT02161692.

Chemically synthesized 58-mer LysM domain binds lipochitin oligosaccharide.

Recognition of carbohydrates by proteins is a ubiquitous biochemical process. In legume-rhizobium symbiosis, lipochitin oligosaccharides, also referred to as nodulation (nod) factors, function as primary rhizobial signal molecules to trigger root nodule development. Perception of these signal molecules is receptor mediated, and nod factor receptor 5 (NFR5) from the model legume Lotus japonicus is predicted to contain three LysM domain binding sites. Here we studied the interactions between nod factor and each of the three NFR5 LysM domains, which were chemically synthesized. LysM domain variants (up to 58 amino acids) designed to optimize solubility were chemically assembled by solid-phase peptide synthesis (SPPS) with microwave heating. Their interaction with nod factors and chitin oligosaccharides was studied by isothermal titration calorimetry and circular dichroism (CD) spectroscopy. LysM2 showed a change in folding upon nod factor binding, thus providing direct evidence that the LysM domain of NFR5 recognizes lipochitin oligosaccharides. These results clearly show that the L. japonicus LysM2 domain binds to the nod factor from Mesorhizobium loti, thereby causing a conformational change in the LysM2 domain. The preferential affinity for nod factors over chitin oligosaccharides was demonstrated by a newly developed glycan microarray. Besides the biological implications, our approach shows that carbohydrate binding to a small protein domain can be detected by CD spectroscopy.

PF-03446962, a fully-human monoclonal antibody against transforming growth-factor ß (TGFß) receptor ALK1, in pre-treated patients with urothelial cancer: an open label, single-group, phase 2 trial.

Despite a compelling preclinical rationale for the use of anti-angiogenic drugs in urothelial cancer (UC), short-living responses have been observed in clinical trials. PF-03446962 is a novel monoclonal antibody against Activin Receptor-Like Kinase-1 (ALK1), a type I subclass of the TGFß receptor, with dose-dependent anti-angiogenic activity. An open label, single-group, phase 2 trial of PF-03446962 was conducted in salvage setting. Patients failing at least one chemotherapy regimen were eligible. Design provided PF-03446962 10 mg/Kg intravenously fortnightly until disease progression (PD) or unacceptable toxicity. Two-month progression-free survival (PFS) was the primary endpoint. The trial was registered with ClinicalTrials.gov, number NCT01620970. Fourteen patients were enrolled from October 2012 to July 2013. Median age was 64 years (interquartile range [IQR]: 58.2-69.5), 9 patients had a Bellmunt score of 1-2, median number of prior drugs was 3. One stable disease and 13 PD were recorded and the study met the futility stopping rule of interim analysis. Median PFS was 1.8 months (95 %CI, 1.4-2.0). After a median follow up of 7.4 months (IQR 4.5-10.9), 8 patients are alive. Median overall survival (OS) was 8 months (95 %CI, 2.9-not estimable). Most common toxicities were thrombocytopenia (G1-2 in 5 cases, persistent G3 in one, with 3 dose delays and 1 dose interruption), fatigue and abdominal pain (G1-2 in 4 cases each). Impairment of quality of life (ESAS score) was observed as well as an increase from baseline to +2 month median levels of vascular endothelial growth factor (VEGF) and interleukin-8. PF-03446962 had no activity as single drug in refractory UC and we do not recommend further investigation outside of the combination with agents targeting the VEGF receptor axis.

Lipochitin oligosaccharides immobilized through oximes in glycan microarrays bind LysM proteins.

Glycan microarrays have emerged as novel tools to study carbohydrate-protein interactions. Here we describe the preparation of a covalent microarray with lipochitin oligosaccharides and its use in studying proteins containing LysM domains. The glycan microarray was assembled from glycoconjugates that were synthesized by using recently developed bifunctional chemoselective aminooxy reagents without the need for transient carbohydrate protecting groups. We describe for the first time the preparation of a covalent microarray with lipochitin oligosaccharides and its use for studying proteins containing LysM domains. Lipochitin oligosaccharides (also referred to as Nod factors) were isolated from bacterial strains or chemoenzymatically synthesized. The glycan microarray also included peptidoglycan-related compounds, as well as chitin oligosaccharides of different lengths. In total, 30 ligands were treated with the aminooxy linker molecule. The identity of the glycoconjugates was verified by mass spectrometry, and they were then immobilized on the array. The presence of the glycoconjugates on the array surface was confirmed by use of lectins and human sera (IgG binding). The functionality of our array was tested with a bacterial LysM domain-containing protein, autolysin p60, which is known to act on the bacterial cell wall peptidoglycan. P60 showed specific binding to Nod factors and to chitin oligosaccharides. Increasing affinity was observed with increasing chitin oligomer length.

Analysis of plasma cytokines and angiogenic factors in patients with pretreated urothelial cancer receiving Pazopanib: the role of circulating interleukin-8 to enhance the prognostic accuracy.

BACKGROUND: Pazopanib achieved the end point of clinical activity in pretreated patients with urothelial cancer in a single-group, phase 2 trial. The objective was to identify biological predictors of clinical benefit to pazopanib in these patients. METHODS: EDTA blood samples were collected at baseline (T0) and after 4 weeks (T1) of treatment, together with radiological imaging in all 41 patients to analyse plasma circulating angiogenic factor levels by multiplex ELISA plates. Changes from T0 to T1 in marker levels were matched with response with the covariance analysis. Univariable and multivariable analyses evaluated the association with overall survival (OS), adjusted for prespecified clinical variables. Net reclassification improvement (NRI) tested the performance of the recognised Cox model. RESULTS: Increasing IL8(T1) level associated with lower response probability at covariance analysis (P=0.010). Both IL8(T0) (P=0.019) and IL8(T1) (P=0.004) associated with OS and the prognostic model, including clinical variables and IL8(T1) best-predicted OS after backward selection. The NRI for this model was 39%.When analysed as a time-varying covariate, IL8(T1) level<80 pg ml(-1) portended significantly greater response (∼80%) and 6-month OS (∼60%) probability than level ≥ 80. CONCLUSION: IL8-level changes during pazopanib allowed for a prognostic improvement and were associated with response probability.

Modified cisplatin, etoposide, and ifosfamide (PEI) salvage therapy for male germ cell tumors: long-term efficacy and safety outcomes.

BACKGROUND: Since 1985, we introduced a modified combination of etoposide, ifosfamide, and cisplatin (PEI) as second-line therapy of adult male germ cell tumors with the aim to reduce toxic effect while maintaining efficacy over the original regimen. PATIENTS AND METHODS: Patients received four cycles of ifosfamide at 2.5 g/m(2) on days 1-2, etoposide, and cisplatin at 100 and 33 mg/m(2), respectively, on days 3-5 every 21 days, followed by surgery. Results were stratified according to the International Germ Cell Consensus Classification Group-2 (IGCCCG-2). RESULTS: From February 1985 to January 2012, 189 patients were treated. 72.6% were IGCCCG-2 intermediate-to-very high risk. Thirty-five patients (18.5%) had a complete response, 67 (35.4%) a marker normalization (PRm-). Median follow-up was 122.1 months (inter-quartile range [IQR]: 71.4-232.0). Two-year progression-free and 5-year overall survival were 34.3% [95% confidence interval (CI) 28.1% to 41.9%] and 42.1% (95% CI 35.3% to 50.2%), respectively. Survival estimates compared favorably with those obtained by conventional dose chemotherapy (CDCT) regimens in each prognostic category. 70.4% of grade 3-4 neutropenia (25.5% febrile neutropenia), 48.1% thrombocytopenia, 21.2% anemia, 3.2% neurotoxic effect, and no severe renal toxic effect were recorded. CONCLUSION: Dose-modified Italian PEI should be considered as an appropriate benchmark for CDCT in the first salvage setting.