Summary Background Phosphatidylinositol 3-kinase (PI3K) pathway activation in squamous cell carcinoma of the head and neck contributes to treatment resistance and disease progression. Buparlisib, a ...pan-PI3K inhibitor, has shown preclinical antitumour activity and objective responses in patients with epithelial malignancies. We assessed whether the addition of buparlisib to paclitaxel improves clinical outcomes compared with paclitaxel and placebo in patients with recurrent or metastatic squamous cell carcinoma of the head and neck. Methods In this multicentre, randomised, double-blind, placebo-controlled phase 2 study (BERIL-1), we recruited patients aged 18 years and older with histologically or cytologically confirmed recurrent and metastatic squamous cell carcinoma of the head and neck after disease progression on or after one previous platinum-based chemotherapy regimen in the metastatic setting. Eligible patients were enrolled from 58 centres across 18 countries and randomly assigned (1:1) to receive second-line oral buparlisib (100 mg once daily) or placebo, plus intravenous paclitaxel (80 mg/m2 on days 1, 8, 15, and 22) in 28 day treatment cycles. Randomisation was done via a central patient screening and randomisation system with an interactive (voice and web) response system and stratification by number of previous lines of therapy in the recurrent and metastatic setting and study site. Patients and investigators (including local radiologists) were masked to treatment assignment from randomisation until the final overall survival analysis. The primary endpoint was progression-free survival by local investigator assessment per Response Evaluation Criteria In Solid Tumors (version 1.1) in all randomly assigned patients. Efficacy analyses were done on the intention-to-treat population, whereas safety was analysed in all patients who received at least one dose of study drug and had at least one post-baseline safety assessment according to the treatment they received. This trial is registered with ClinicalTrials.gov , number NCT01852292 , and is ongoing but no longer enrolling patients. Findings Between Nov 5, 2013, and May 5, 2015, 158 patients were enrolled and randomly assigned to receive either buparlisib plus paclitaxel (n=79) or placebo plus paclitaxel (n=79). Median progression-free survival was 4·6 months (95% CI 3·5–5·3) in the buparlisib group and 3·5 months (2·2–3·7) in the placebo group (hazard ratio 0·65 95% CI 0·45–0·95, nominal one-sided p=0·011). Grade 3–4 adverse events were reported in 62 (82%) of 76 patients in the buparlisib group and 56 (72%) of 78 patients in the placebo group. The most common grade 3–4 adverse events (occurring in ≥10% of patients in the buparlisib group vs the placebo group) were hyperglycaemia (17 22% of 76 vs two 3% of 78), anaemia (14 18% vs nine 12%), neutropenia (13 17% vs four 5%), and fatigue (six 8% vs eight 10%). Serious adverse events (regardless of relation to study treatment) were reported for 43 (57%) of 76 patients in the buparlisib group and 37 (47%) of 78 in the placebo group. On-treatment deaths occurred in 15 (20%) of 76 patients in the buparlisib group and 17 (22%) of 78 patients in the placebo group; most were caused by disease progression and none were judged to be related to study treatment. Interpretation On the basis of the improved clinical efficacy with a manageable safety profile, the results of this randomised phase 2 study suggest that buparlisib in combination with paclitaxel could be an effective second-line treatment for patients with platinum-pretreated recurrent or metastatic squamous cell carcinoma of the head and neck. Further phase 3 studies are warranted to confirm this phase 2 finding. Funding Novartis Pharmaceuticals Corporation.
Dark septate endophytes (DSE) are a form-group of root endophytic fungi with elusive functions. Here, the genomes of two common DSE of semiarid areas, Cadophora sp. and Periconia macrospinosa were ...sequenced and analyzed with another 32 ascomycetes of different lifestyles. Cadophora sp. (Helotiales) and P. macrospinosa (Pleosporales) have genomes of 70.46 Mb and 54.99 Mb with 22,766 and 18,750 gene models, respectively. The majority of DSE-specific protein clusters lack functional annotation with no similarity to characterized proteins, implying that they have evolved unique genetic innovations. Both DSE possess an expanded number of carbohydrate active enzymes (CAZymes), including plant cell wall degrading enzymes (PCWDEs). Those were similar in three other DSE, and contributed a signal for the separation of root endophytes in principal component analyses of CAZymes, indicating shared genomic traits of DSE fungi. Number of secreted proteases and lipases, aquaporins, and genes linked to melanin synthesis were also relatively high in our fungi. In spite of certain similarities between our two DSE, we observed low levels of convergence in their gene family evolution. This suggests that, despite originating from the same habitat, these two fungi evolved along different evolutionary trajectories and display considerable functional differences within the endophytic lifestyle.
Sex hormones influence circulation, periodontitis, and wound healing. The aim of the study was to compare the endothelium-dependent and independent vasodilation in human gingiva in men and women.
...Gingival blood flow was evaluated in twelve male and twelve female subjects with healthy gingiva and no systemic conditions after acetylcholine or nitric oxide donor (NitroPOHL). Agonists were administered into the gingival sulcus at the right secondary incisor (test site). Regional gingival blood flow (GBF) was imaged by Laser Speckle Contrast Imager from the marginal gingiva to the mucogingival junction in four consecutive regions (coronal, midway1, midway2 and apical). Blood flow was expressed in Laser Speckle Perfusion Unit (LSPU). The absolute maximal blood flow change (Dmax), the area under the blood flow curve (AUC), and the time to peak (TTP) were calculated.
Males had higher baseline GBF than females (257 ± 18.2 vs. 225 ± 18.8 LSPU, p < 0.001). Acetylcholine and NitroPOHL significantly increased the GBF in all test regions. The Dmax after the acetylcholine was reduced apically compared to the coronal (90 ± 13 LSPU vs. 117 ± 7 LSPU, p < 0.01), but it was similar after NitroPOHL (78 ± 9 LSPU vs. 86 ± 6 LSPU, p = 0.398) in both sexes. The Dmax and AUC were higher, and the TTP was smaller in men in most regions after acetylcholine but not after NitroPOHL.
In the human gingiva, the endothelium-independent vasodilation propagates without attenuation in the line of the vascular supply in both sexes. At the same time, the endothelium-dependent ascending vasodilation attenuates similarly in men and women. However, men had more pronounced endothelium-dependent vasodilation than women. Therefore, it might contribute to the increased severity of periodontal disease in men.
The study was registered with ClinicalTrials.gov on 09.06.2021 (NCT04918563).
An affinity chromatographic approach was used to investigate the plasmin activity observed in bovine acid whey. Plasminogen-removal gel with tranexamic acid as a ligand was used for selective binding ...of plasminogen and plasmin through their kringle domains. Subsequently, ε-aminocaproic acid was used for elution. Plasmin activity was separated into a bound and non-bound fraction. Surprisingly, only 25% of the total activity in the acid whey was bound to the column, while 50% of the total activity was in the non-bound fraction, and a further 25% of the total activity was unaccounted for. Proteins in the bound fraction were analysed using SDS-PAGE and MALDI-MS/MS fingerprinting analysis, with plasminogen identified. Plasmin activity was purified by a factor of 4313 from the acid whey. The non-bound fraction was subjected to cation-exchange chromatography and zymogram gel analysis and showed the presence of plasminogen-derived proteolytic products such as midi-plasmin, mini-plasmin, and micro-plasmin.
Non-echo planar diffusion weighted magnetic resonance imaging is a reliable surveillance tool of residual cholesteatoma nowadays. It is not known whether the material of the ossicular chain ...prosthesis modifies the sensitivity and specificity of MRI in these cases. The aim of the study was to compare the sensitivity, specificity and a localization-specific accuracy of non-EPI DW MRI sequences for residual cholesteatoma in the following 3 subgroups: patients with titanium ossicular prosthesis (group T), with autologous cortical bone columella (group A) or without any reconstruction (group WR) of hearing bones.
This prospective study covered 28 cases with cholesteatoma of the middle ear undergone second-look surgery, who had preoperative PROPELLER DW-MRI. Surgical findings were compared to the results of the DWI-MRI.
The overall sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were: 0.76-0.8-0.76-0.8. Group T, group A and group WR sensitivity was 0.83-0.6-1, specificity: 0.75-0.75-0.85, PPV: 0.83-0.75-0.66, NPV: 0.75-0.6-1. Overall accuracy was 0.78. Size of missed cholesteatoma was 2-4 mm (mean: 2.66±1.15).
Various materials are suitable for ossicular chain reconstruction. The poor detectability of residual or recurrent cholesteatoma in the middle ears reconstructed with autologous bony prosthesis may still claim second-look surgery instead of the usage of non- EPI DWI sequences independently in these patients.
•The paper is a guide for both researchers and practitioners in risk capital allocation.•We analyze seven risk capital allocation methods applying coherent measures of risk.•We prove how the seven ...methods perform in terms of ten fairness properties.•We simulate Core Compatibility in 24 treatments up to nine subunits.•We conclude that some of the ten properties should be given up in practice.
If a financial unit (a bank, an insurance company, a portfolio, the financial system of a country, etc.) consists of subunits (divisions, subportfolios, etc.), then the risk of the main unit should be allocated to the subunits using a risk capital allocation method in a fair way.
We analyze seven methods widely discussed in the literature or used in practice (Activity based, Beta, Incremental, Cost gap, Marginal Risk Contribution, Shapley, and Nucleolus) in terms of ten reasonable fairness properties (Full Domain, Core Compatibility, Diversification, Strong Monotonicity, Incentive Compatibility Efficiency, Equal Treatment Property, Riskless Portfolio, Covariance, and Decomposition Invariance). We provide proofs or counterexamples for each method and the ten properties that we consider.
We also computed how often on average Core Compatibility is satisfied in randomly generated risk capital allocation situations up to nine subunits in 24 treatments for all methods that do not satisfy Core Compatibility.
We believe that through the descriptions of the examined methods our paper can serve as a useful guide for both practitioners and researchers.
Pituitary adenylate cyclase activating polypeptide (PACAP) is a regulatory and cytoprotective neuropeptide, its deficiency implies accelerated aging in mice. It is present in the auditory system ...having antiapoptotic effects. Expression of Ca
-binding proteins and its PAC1 receptor differs in the inner ear of PACAP-deficient (KO) and wild-type (WT) mice. Our aim was to elucidate the functional role of PACAP in the auditory system. Auditory brainstem response (ABR) tests found higher hearing thresholds in KO mice at click and low frequency burst stimuli. Hearing impairment at higher frequencies showed as reduced ABR wave amplitudes and latencies in KO animals. Increase in neuronal activity, demonstrated by c-Fos immunolabeling, was lower in KO mice after noise exposure in the ventral and dorsal cochlear nuclei. Noise induced neuronal activation was similar in further relay nuclei of the auditory pathway of WT and KO mice. Based on the similar inflammatory and angiogenic protein profile data from cochlear duct lysates, neither inflammation nor disturbed angiogenesis, as potential pathological components in sensorineural hearing losses, seem to be involved in the pathomechanism of the presented functional and morphological changes in PACAP KO mice. The hearing impairment is probably concomitant with the markedly accelerated aging processes in these animals.
Giant cell tumor of bone (GCTB) is a frequently recurring locally aggressive osteolytic lesion, where pathological osteoclastogenesis and bone destruction are driven by neoplastic stromal cells. ...Here, we studied if cell cycle fractions within the mononuclear cell compartment of GCTB can predict its progression-free survival (PFS).
154 cases (100 primaries and 54 recurrent) from 139 patients of 40 progression events, was studied using tissue microarrays. Ploidy and in situ cell cycle progression related proteins including Ki67 and those linked with replication licensing (mcm2), G1-phase (cyclin D1, Cdk4), and S-G2-M-phase (cyclin A; Cdk2) fractions; cell cycle control (p21waf1) and repression (geminin), were tested. The Prentice-Williams-Peterson (PWP) gap-time models with the Akaike information criterion (AIC) were used for PFS analysis.
Cluster analysis showed good correlation between functionally related marker positive cell fractions indicating no major cell cycle arrested cell populations in GCTB. Increasing hazard of progression was statistically associated with the elevated post-G1/S-phase cell fractions. Univariate analysis revealed significant negative association of poly-/aneuploidy (p < 0.0001), and elevated cyclin A (p < 0.001), geminin (p = 0.015), mcm2 (p = 0.016), cyclin D1 (p = 0.022) and Ki67 (B56: p = 0.0543; and Mib1: p = 0.0564 –strong trend) positive cell fractions with PFS. The highest-ranked multivariate interaction model (AIC = 269.5) also included ploidy (HR 5.68, 95%CI: 2.62–12.31, p < 0.0001), mcm2 (p = 0.609), cyclin D1 (HR 1.89, 95%CI: 0.88–4.09, p = 0.105) and cyclin A (p < 0.0001). The first and second best prognostic models without interaction (AIC = 271.6) and the sensitivity analysis (AIC = 265.7) further confirmed the prognostic relevance of combining these markers.
Ploidy and elevated replication licensing (mcm2), G1-phase (cyclin D1) and post-G1 phase (cyclin A) marker positive cell fractions, indicating enhanced cell cycle progression, can assist in identifying GCTB patients with increased risk for a reduced PFS.
•In GCTB, neoplastic stromal cells drive pathological osteoclastogenesis, thus their replication affects tumor progression.•Detection of cell cycle regulation proteins can identify cell cycle fractions in GCTB neoplastic stromal cells.•Unsupervised hierarchical cluster analysis revealed no major defect of cell cycle regulation in GCTB mononuclear cells.•An inverse correlation was found between PFS and elevated post-G1/S-phase mononuclear cell fractions in GCTB.•Ploidy and elevated cyclin D1, mcm2 and cyclin A positive mononuclear cell fractions indicated aggressive GCTB behavior.
We investigated the movement of interstitially infused macromolecules within the central nervous system (CNS) in rats with high and low blood pressure (BP)/heart rate and in rats euthanized ...immediately before infusion (no heart action). Adeno-associated virus 2 (AAV2), fluorescent liposomes, or bovine serum albumin was infused into rat striatum (six hemispheres per group) by convection-enhanced delivery (CED). After infusion, distribution volumes were evaluated. The rats with high BP/heart rate displayed a significantly larger distribution of the infused molecules within the injected site and more extensive transport of those molecules to the globus pallidus. This difference was particularly apparent for AAV2, for which a 16.5-fold greater distribution of viral capsids was observed in the rats with high BP/heart rate than in the rats with no heartbeat. Similar results were observed for liposomes, despite their larger diameter. The distribution of all infused molecules in all rats that had low or no blood flow was confined to the space around brain blood vessels. These findings show that fluid circulation within the CNS through the perivascular space is the primary mechanism by which viral particles and other therapeutic agents administered by CED are spread within the brain and that cardiac contractions power this process.
Transcriptional regulation of LMW glutenin genes were investigated in-silico, using publicly available gene sequences and expression data. Genes were grouped into different LMW glutenin types and ...their promoter profiles were determined using cis-acting regulatory elements databases and published results. The various cis-acting elements belong to some conserved non-coding regulatory regions (CREs) and might act in two different ways. There are elements, such as GCN4 motifs found in the long endosperm box that could serve as key factors in tissue-specific expression. Some other elements, such as the AACA/TA motifs or the individual prolamin box variants, might modulate the level of expression. Based on the promoter sequences and expression characteristic LMW glutenin genes might be transcribed following two different mechanisms. Most of the s- and i-type genes show a continuously increasing expression pattern. The m-type genes, however, demonstrate normal distribution in their expression profiles. Differences observed in their expression could be related to the differences found in their promoter sequences. Polymorphisms in the number and combination of cis-acting elements in their promoter regions can be of crucial importance in the diverse levels of production of single LMW glutenin gene types.
PDF
