Size of nodal domains of the eigenvectors of a G(n,p) graph

Consider an eigenvector of the adjacency matrix of a G(n, p) graph. A nodal domain is a connected component of the set of vertices where this eigenvector has a constant sign. It is known that with high probability, there are exactly two nodal domains for each eigenvector corresponding to a non-leading eigenvalue. We prove that with high probability, the sizes of these nodal domains are approximately equal to each other

Discovery of an aborted reversal (geomagnetic excursion) in the Late Pleistocene sediments of Pinjor Dun, NW Himalaya

We report here the occurrence of an aborted reversal (geomagnetic excursion) in the Late Pleistocene sediments of Pinjor Dun near Chandigarh, NW Himalaya. The event discovered at ~697.5 cm level from the base of Kiratpur section corresponds to the OSL date of 40±5 Ka coinciding with the Laschamp excursion and palaeointensity minima elsewhere. The Pinjor Dun sediments are deposited at a high rate of sedimentation that enables quite enlarged records of remanent geomagnetic field, hence suitable for further high resolution study of the excursion (under progress) to extend its utility as a stratigraphic marker in the Quaternary sediments at the foothills of the Himalaya

The in vivo phosphorylation sites of bovine αB-crystallin

AbstractPhosphate content determinations established that in αB-crystallin two phosphate groups can be present in vivo in bovine lenses. Comparison of tryptic digests of phosphorylated and unphosphorylated αB chains, revealed the location of the two phosphorylation sites in tryptic peptides T2 and T3. Thermolytic digestion and gas-phase sequencing demonstrated that Ser-19 and Ser-45 are the in vivo phosphorylation sites of bovine αB-crystallin. This pattern of phosphorylation differs from the previously reported in vitro obtained results

Large deviations of the maximal eigenvalue of random matrices

We present detailed computations of the 'at least finite' terms (three dominant orders) of the free energy in a one-cut matrix model with a hard edge a, in beta-ensembles, with any polynomial potential. beta is a positive number, so not restricted to the standard values beta = 1 (hermitian matrices), beta = 1/2 (symmetric matrices), beta = 2 (quaternionic self-dual matrices). This model allows to study the statistic of the maximum eigenvalue of random matrices. We compute the large deviation function to the left of the expected maximum. We specialize our results to the gaussian beta-ensembles and check them numerically. Our method is based on general results and procedures already developed in the literature to solve the Pastur equations (also called "loop equations"). It allows to compute the left tail of the analog of Tracy-Widom laws for any beta, including the constant term.Comment: 62 pages, 4 figures, pdflatex ; v2 bibliography corrected ; v3 typos corrected and preprint added ; v4 few more numbers adde

Retinal pigment epithelium is protected against apoptosis by

PURPOSE. The degeneration of retinal pigment epithelial (RPE) cells is considered to be a crucial event in the pathophysiology of age-related macular degeneration (AMD). Cumulative oxidative damage has been implicated in the development of the changes seen in AMD. The present study was undertaken to evaluate the expression of the small heat shock protein ␣B-crystallin in the RPE in response to oxidative stress and to explore whether ␣B-crystallin expression confers an antiapoptotic cytoprotective effect on RPE cells. METHODS. Native human RPE cells from the macula and retinal periphery were analyzed by RT-PCR and Western blot analysis for expression of ␣B-crystallin. Monolayer cultures of human RPE cells were stressed by heat shock (42°C for 20 minutes) or oxidant-mediated injury (50 -300 M H 2 O 2 for 1 hour). Induction of ␣B-crystallin and the corresponding mRNA was assessed by Western and Northern blot analyses. To study the cytoprotective effect of ␣B-crystallin, human RPE cells were transfected with either a neomycin-selectable expression vector containing ␣B-crystallin cDNA or a control vector without ␣B-crystallin cDNA. Caspase-3 activity was determined by observing the cleavage of a colorimetric peptide substrate. Cell viability was quantified by combined propidium iodide and Hoechst 33342 staining. RESULTS. ␣B-crystallin is constitutively expressed in RPE under in vivo and in vitro conditions. Western blot analysis of freshly isolated RPE showed greater baseline expression levels in RPE derived from the macular area than in that from the more peripheral regions. Heat shock treatment and oxidative stress caused a significant increase in ␣B-crystallin mRNA and protein. Oxidant-mediated injury in RPE cells with baseline expression levels of ␣B-crystallin resulted in apoptotic cell death, as measured by caspase-3 activity, whereas RPE cells that had been stably transfected with ␣B-crystallin were more resistant to H 2 O 2 -induced cellular injury. CONCLUSIONS. ␣B-crystallin may function as a stress-inducible antiapoptotic protein in human RPE and is inducible by oxidative stress, a condition implicated in the pathogenesis of AMD. Overexpression of ␣B-crystallin may be an important mechanism for the RPE to prevent apoptotic cell death in response to cellular stress. (Invest Ophthalmol Vis Sci. 2002;43:3575-3582) A ge-related macular degeneration (AMD) is the leading cause of severe visual impairment in elderly individuals

Pharmacokinetic boosting of olaparib:A randomised, cross-over study (PROACTIVE-study)

Background: Pharmacokinetic (PK) boosting is the intentional use of a drug-drug interaction to enhance systemic drug exposure. PK boosting of olaparib, a CYP3A-substrate, has the potential to reduce PK variability and financial burden. The aim of this study was to investigate equivalence of a boosted, reduced dose of olaparib compared to the non-boosted standard dose. Methods: This cross-over, multicentre trial compared olaparib 300 mg twice daily (BID) with olaparib 100 mg BID boosted with the strong CYP3A-inhibitor cobicistat 150 mg BID. Patients were randomised to the standard therapy followed by the boosted therapy, or vice versa. After seven days of each therapy, dense PK sampling was performed for noncompartmental PK analysis. Equivalence was defined as a 90% Confidence Interval (CI) of the geometric mean ratio (GMR) of the boosted versus standard therapy area under the plasma concentration-time curve (AUC0–12 h) within no-effect boundaries. These boundaries were set at 0.57–1.25, based on previous pharmacokinetic studies with olaparib capsules and tablets. Results: Of 15 included patients, 12 were eligible for PK analysis. The GMR of the AUC0–12 h was 1.45 (90% CI 1.27–1.65). No grade ≥3 adverse events were reported during the study. Conclusions: Boosting a 100 mg BID olaparib dose with cobicistat increases olaparib exposure 1.45-fold, compared to the standard dose of 300 mg BID. Equivalence of the boosted olaparib was thus not established. Boosting remains a promising strategy to reduce the olaparib dose as cobicistat increases olaparib exposure Adequate tolerability of the boosted therapy with higher exposure should be established.</p

Localized surface plasmon modes in a system of two interacting metallic cylinders

We study an optical response of a system of two parallel close metallic cylinders having nanoscale dimensions. Surface plasmon excitation in the gap between the cylinders are specifically analyzed. In particular, resonance frequencies and field enhancement were investigated as functions of geometrical characteristics of the system and Ohmic losses in the metal. The results of numerical simulations were systematically compared with the analytical theory, obtained in the quasi-static limit. The analytical method was generalized in order to take into account the retardation effects. We also present the physical qualitative picture of the plasmon modes, which is validated by numerical simulations and analytical theory

The tumour microenvironment shapes dendritic cell plasticity in a human organotypic melanoma culture

Contains fulltext : 220729.pdf (publisher's version ) (Open Access)The tumour microenvironment (TME) forms a major obstacle in effective cancer treatment and for clinical success of immunotherapy. Conventional co-cultures have shed light onto multiple aspects of cancer immunobiology, but they are limited by the lack of physiological complexity. We develop a human organotypic skin melanoma culture (OMC) that allows real-time study of host-malignant cell interactions within a multicellular tissue architecture. By co-culturing decellularized dermis with keratinocytes, fibroblasts and immune cells in the presence of melanoma cells, we generate a reconstructed TME that closely resembles tumour growth as observed in human lesions and supports cell survival and function. We demonstrate that the OMC is suitable and outperforms conventional 2D co-cultures for the study of TME-imprinting mechanisms. Within the OMC, we observe the tumour-driven conversion of cDC2s into CD14(+) DCs, characterized by an immunosuppressive phenotype. The OMC provides a valuable approach to study how a TME affects the immune system

Cemiplimab in locally advanced or metastatic cutaneous squamous cell carcinoma:prospective real-world data from the DRUG Access Protocol

Background: The DRUG Access Protocol provides patients with cancer access to registered anti-cancer drugs that are awaiting reimbursement in the Netherlands and simultaneously collects prospective real-world data (RWD). Here, we present RWD from PD-1 blocker cemiplimab in patients with locally advanced or metastatic cutaneous squamous cell carcinoma (laCSCC; mCSCC). Methods: Patients with laCSCC or mCSCC received cemiplimab 350 mg fixed dose every three weeks. Primary endpoints were objective clinical benefit rate (CBR), defined as objective response (OR) or stable disease (SD) at 16 weeks, physician-assessed CBR, defined as clinician's documentation of improved disease or SD based on evaluation of all available clinical parameters at 16 weeks, objective response rate (ORR), and safety, defined as grade ≥ 3 treatment related adverse events (TRAEs) occurring up to 30 days after last drug administration. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Findings: Between February 2021 and December 2022, 151 patients started treatment. Objective and physician-assessed CBR were 54.3% (95% CI, 46.0–62.4) and 59.6% (95% CI, 51.3–67.5), respectively. ORR was 35.1% (95% CI, 27.5–43.3). After a median follow-up of 15.2 months, median DoR was not reached. Median PFS and OS were 12.2 (95% CI, 7.0-not reached) and 24.2 months (95% CI, 18.8-not reached), respectively. Sixty-eight TRAEs occurred in 29.8% of patients. Most commonly reported TRAE was a kidney transplant rejection (9.5%). Interpretation: Cemiplimab proved highly effective and safe in this real-world cohort of patients with laCSCC or mCSCC, confirming its therapeutic value in the treatment of advanced CSCC in daily clinical practice. Funding: The DRUG Access Protocol is supported by all participating pharmaceutical companies: Bayer, Janssen, Lilly, Merck, Novartis, Roche, and Sanofi.</p

Cemiplimab in locally advanced or metastatic cutaneous squamous cell carcinoma:prospective real-world data from the DRUG Access Protocol

Background: The DRUG Access Protocol provides patients with cancer access to registered anti-cancer drugs that are awaiting reimbursement in the Netherlands and simultaneously collects prospective real-world data (RWD). Here, we present RWD from PD-1 blocker cemiplimab in patients with locally advanced or metastatic cutaneous squamous cell carcinoma (laCSCC; mCSCC). Methods: Patients with laCSCC or mCSCC received cemiplimab 350 mg fixed dose every three weeks. Primary endpoints were objective clinical benefit rate (CBR), defined as objective response (OR) or stable disease (SD) at 16 weeks, physician-assessed CBR, defined as clinician's documentation of improved disease or SD based on evaluation of all available clinical parameters at 16 weeks, objective response rate (ORR), and safety, defined as grade ≥ 3 treatment related adverse events (TRAEs) occurring up to 30 days after last drug administration. Secondary endpoints included duration of response (DoR), progression-free survival (PFS), and overall survival (OS). Findings: Between February 2021 and December 2022, 151 patients started treatment. Objective and physician-assessed CBR were 54.3% (95% CI, 46.0–62.4) and 59.6% (95% CI, 51.3–67.5), respectively. ORR was 35.1% (95% CI, 27.5–43.3). After a median follow-up of 15.2 months, median DoR was not reached. Median PFS and OS were 12.2 (95% CI, 7.0-not reached) and 24.2 months (95% CI, 18.8-not reached), respectively. Sixty-eight TRAEs occurred in 29.8% of patients. Most commonly reported TRAE was a kidney transplant rejection (9.5%). Interpretation: Cemiplimab proved highly effective and safe in this real-world cohort of patients with laCSCC or mCSCC, confirming its therapeutic value in the treatment of advanced CSCC in daily clinical practice. Funding: The DRUG Access Protocol is supported by all participating pharmaceutical companies: Bayer, Janssen, Lilly, Merck, Novartis, Roche, and Sanofi.</p