A comprehensive regulatory and industry review of modeling and simulation practices in oncology clinical drug development.

Exposure-response (E-R) analyses are an integral component in the development of oncology products. Characterizing the relationship between drug exposure metrics and response allows the sponsor to use modeling and simulation to address both internal and external drug development questions (e.g.

A unique series of chromium(iii) mono-alkynyl complexes supported by tetraazamacrocycles.

Described herein is the synthesis and characterization of macrocyclic Cr mono-alkynyl complexes. By using the meso-form of the tetraazamacrocycle HMC (HMC = 5,5,7,12,12,14-hexamethyl-1,4,8,11-tetraazacyclotetradecane), trans-[Cr(HMC)(CPh)Cl]OTf (1a), trans-[Cr(HMC)(CNp)Cl]OTf (2a), trans-[Cr(HMC)(CCHBu)Cl]OTf (3a), and trans-[Cr(HMC)(C(3,5-ClCH))Cl]OTf (4a) complexes have been realized. These complexes were synthesized in high yield through the reaction of trans-[Cr(meso-HMC)(CAr)]OTf (1b-4b) with stoichiometric amounts of methanolic HCl.

Immunogenicity of pembrolizumab in patients with advanced tumors.

Background: Pembrolizumab is a potent, humanized, monoclonal anti-programmed death 1 antibody that has demonstrated effective antitumor activity and acceptable safety in multiple tumor types. Therapeutic biologics can result in the development of antidrug antibodies (ADAs), which may alter drug clearance and neutralize target binding, potentially reducing drug efficacy; such immunogenicity may also result in infusion reactions, anaphylaxis, and immune complex disorders. Pembrolizumab immunogenicity and its impact on exposure, safety, and efficacy was assessed in this study.

Pembrolizumab Plus Pegylated Interferon alfa-2b or Ipilimumab for Advanced Melanoma or Renal Cell Carcinoma: Dose-Finding Results from the Phase Ib KEYNOTE-029 Study.

Pembrolizumab monotherapy, ipilimumab monotherapy, and pegylated interferon alfa-2b (PEG-IFN) monotherapy are active against melanoma and renal cell carcinoma (RCC). We explored the safety and preliminary antitumor activity of pembrolizumab combined with either ipilimumab or PEG-IFN in patients with advanced melanoma or RCC. The phase Ib KEYNOTE-029 study (ClinicalTrials.

Electronic properties and structure of single crystal perylene.

The transport properties of electronic devices made from single crystalline molecular semiconductors typically outperform those composed of thin-films of the same material. To further understand the superiority of these extrinsic device properties, an understanding of the intrinsic electronic structure and properties of the organic semiconductor is necessary. An investigation of the electronic structure and properties of single crystal α-phase perylene (CH), a five-ringed aromatic molecule, is presented using angle-resolved ultraviolet photoemission, x-ray photoelectron spectroscopy (XPS), and field-effect transistor measurements.

Molecular Pathophysiology of Congenital Long QT Syndrome.

Ion channels represent the molecular entities that give rise to the cardiac action potential, the fundamental cellular electrical event in the heart. The concerted function of these channels leads to normal cyclical excitation and resultant contraction of cardiac muscle. Research into cardiac ion channel regulation and mutations that underlie disease pathogenesis has greatly enhanced our knowledge of the causes and clinical management of cardiac arrhythmia.

Non-fullerene acceptors: exciton dissociation with PTCDA versus C60.

Extensive development of new polymer and small molecule donors has helped produce a steady increase in the efficiency of organic photovoltaic (OPV) devices. However, OPV technology would also benefit from the introduction of non-fullerene acceptors. Unfortunately, efforts to replace fullerenes have typically led to significantly reduced efficiencies.

Allosteric gating mechanism underlies the flexible gating of KCNQ1 potassium channels.

KCNQ1 (Kv7.1) is a unique member of the superfamily of voltage-gated K(+) channels in that it displays a remarkable range of gating behaviors tuned by coassembly with different β subunits of the KCNE family of proteins. To better understand the basis for the biophysical diversity of KCNQ1 channels, we here investigate the basis of KCNQ1 gating in the absence of β subunits using voltage-clamp fluorometry (VCF).

Reaction of platinum(II) diamine and triamine complexes with selenomethionine.

We have reacted [Pt(dien)Cl]Cl, [Pt(en)(D(2)O)(2)](2+), and [Pt(Me(4)en)(D(2)O)(2)](2+) [Me(4)en = N,N,N',N'-tetramethylethylenediamine] with selenomethionine (SeMet). When [Pt(dien)Cl]Cl is reacted with SeMet, [Pt(dien)(SeMet-Se)](2+) is formed; two Se-CH(3) resonances are observed due to the different chiralities at the Se atom upon platination. In a reaction of [Pt(dien)Cl]Cl with an equimolar mixture of SeMet and Met, the SeMet product forms more quickly though a slow equilibrium with approximately equal amounts of both products is reached.

TiOPc molecular dislocation networks as nanotemplates for C60 cluster arrays.

By controlled deposition, TiOPc, a molecular semiconductor with anisotropic interactions can generate a molecular film with a characteristic pattern repeat size of 15 nm. This structure then served as a nanotemplate for a superlattice of C(60) clusters with characteristic diameters of 7 nm. As a result, C(60) deposition on the TiOPc film template forms a pattern of nanophase-separated C(60) and TiOPc domains with a characteristic domain size of 7 nm.

Medial artery calcification as an indicator of diabetic peripheral vascular disease.

Background: Mönckeberg sclerosis or medial artery calcification (MAC) is a well-known phenomenon associated with diabetic and other arterial disease. However, its consequence within the foot, and specifically the first dorsal metatarsal artery, has not previously been studied.

Materials And Methods: Nearly 1,000 foot x-rays were studied over a 9-month period in a busy hospital to identify the prevalence of first dorsal metatarsal artery calcification.

Fermi level alignment in self-assembled molecular layers: the effect of coupling chemistry.

Photoelectron spectroscopy was used to explore changes in Fermi level alignment, within the pi-pi* gap, arising from modifications to the coupling chemistry of conjugated phenylene ethynylene oligomers to the Au surface. Self-assembled monolayers were formed employing either thiol (4,4'-ethynylphenyl-1-benzenethiol or OPE-T) or isocyanide (4,4'-ethynylphenyl-1-benzeneisocyanide or OPE-NC) coupling. The electronic density of states in the valence region of the two systems are nearly identical with the exception of a shift to higher binding energy by about 0.

Valence electron orbitals of an oligo(p-phenylene-ethynylene)thiol on gold.

This communication reports measurement of one-photon (21.2 eV) and one-color, two-photon (3.2-4.

Transitional cell carcinoma in high-grade high-stage ovarian carcinoma. An indicator of favorable response to chemotherapy.

We reviewed 53 high-grade carcinomas of the ovary in order to define pathologic features that correlate with prognosis. All tumors were Stage III with comparable amounts of residual tumor left after the primary resection. Similar postoperative chemotherapeutic regimens were given to each patient, and there was a clinical followup of at least four years in each case.