Low-Frequency Oscillations in Mid-rostral Dorsolateral Prefrontal Cortex Support Response Inhibition.

Executive control of movement enables inhibiting impulsive responses critical for successful navigation of the environment. Circuits mediating stop commands involve prefrontal and basal ganglia structures with fMRI evidence demonstrating increased activity during response inhibition in the dorsolateral prefrontal cortex (dlPFC)-often ascribed to maintaining task attentional demands. Using direct intraoperative cortical recordings in male and female human subjects, we investigated oscillatory dynamics along the rostral-caudal axis of dlPFC during a modified Go/No-go task, probing components of both proactive and reactive motor control.

Tumor-agnostic transcriptome-based classifier identifies spatial infiltration patterns of CD8+T cells in the tumor microenvironment and predicts clinical outcome in early-phase and late-phase clinical trials.

Background: The immune status of a patient's tumor microenvironment (TME) may guide therapeutic interventions with cancer immunotherapy and help identify potential resistance mechanisms. Currently, patients' immune status is mostly classified based on CD8+tumor-infiltrating lymphocytes. An unmet need exists for comparable and reliable precision immunophenotyping tools that would facilitate clinical treatment-relevant decision-making and the understanding of how to overcome resistance mechanisms.

Matching by OS Prognostic Score to Construct External Controls in Lung Cancer Clinical Trials.

External controls (eControls) leverage historical data to create non-randomized control arms. The lack of randomization can result in confounding between the experimental and eControl cohorts. To balance potentially confounding variables between the cohorts, one of the proposed methods is to match on prognostic scores.

Circulating tumor DNA: Opportunities and challenges for pharmacometric approaches.

To support further development of model-informed drug development approaches leveraging circulating tumor DNA (ctDNA), we performed an exploratory analysis of the relationships between treatment-induced changes to ctDNA levels, clinical response and tumor size dynamics in patients with cancer treated with checkpoint inhibitors and targeted therapies. This analysis highlights opportunities for pharmacometrics approaches such as for optimizing sampling design strategies. It also highlights challenges related to the nature of the data and associated variability overall emphasizing the importance of mechanistic modeling studies of the underlying biology of ctDNA processes such as shedding, release and clearance and their relationships with tumor size dynamic and treatment effects.

Unexpected scaffold rearrangement product of pirenzepine found in commercial samples.

Pharmacovigilance aims at a better understanding of the molecular events triggered by medications to prevent adverse effects, which despite significant advances in our analytical repertoire plague the use of drugs until today. In this study, we find that clinically prescribed and commercially available pirenzepine may not be the correct compound. Pirenzepine can undergo an unexpected scaffold rearrangement from the pharmaceutical active ingredient (API) to a previously uncharacterized benzimidazole.

Reinstatement of synaptic plasticity in the aging brain through specific dopamine transporter inhibition.

Aging-related neurological deficits negatively impact mental health, productivity, and social interactions leading to a pronounced socioeconomic burden. Since declining brain dopamine signaling during aging is associated with the onset of neurological impairments, we produced a selective dopamine transporter (DAT) inhibitor to restore endogenous dopamine levels and improve cognitive function. We describe the synthesis and pharmacological profile of (S,S)-CE-158, a highly specific DAT inhibitor, which increases dopamine levels in brain regions associated with cognition.

Synthesis and characterization of enantiopure planar-chiral phosphorus-linked diferrocenes.

In the course of an ongoing synthetic project on cyclic diferrocenylphosphines, we obtained a group of planar-chiral diferrocenyl compounds useful as precursors for subsequent cyclization. Here we report the crystal structures of two symmetric compounds [(Fc)(Ph)P], one of which contains four stereogenic centres (two C chiral and two planar chiral centres), i.e.

Corrigendum: Combination of T-Cell Bispecific Antibodies With PD-L1 Checkpoint Inhibition Elicits Superior Anti-Tumor Activity.

[This corrects the article .].

Halogen-Imparted Reactivity in Lithium Carbenoid Mediated Homologations of Imine Surrogates: Direct Assembly of bis-Trifluoromethyl-β-Diketiminates and the Dual Role of LiCHI.

The selective formal insertion (homologation) of a carbon unit bridging the two trifluoroacetamidoyl chlorides (TFAICs) units is reported. The tactic is levered on a highly chemoselective homologation-metalation-acyl nucleophilic substitution sequence which precisely enables to assemble novel trifluoromethylated β-diketiminates within a single synthetic operation. Unlike previous homologations conducted with LiCHCl furnishing aziridines, herein we exploit the unique capability of iodomethyllithium to act contemporaneously as a C1 source (homologating effect) and metalating agent.

Cancer Cell Resistance Against the Clinically Investigated Thiosemicarbazone COTI-2 Is Based on Formation of Intracellular Copper Complex Glutathione Adducts and ABCC1-Mediated Efflux.

COTI-2 is a novel anticancer thiosemicarbazone in phase I clinical trial. However, the effects of metal complexation (a main characteristic of thiosemicarbazones) and acquired resistance mechanisms are widely unknown. Therefore, in this study, the copper and iron complexes of COTI-2 were synthesized and evaluated for their anticancer activity and impact on drug resistance in comparison to metal-free thiosemicarbazones.

Synthesis, Characterization, and Phosphoesterase Activity of a Series of 4f- and 4d-Sandwich-Type Germanotungstates [(-CH)N]H[(M(HO))(γ-GeWO)] (M = Ce, Nd, Gd, Er, = 7; Zr, = 6).

We report on a family of five new 4f- and 4d-doped sandwich-type germanotungstates with the general formula [(-CH)N]H[(M(HO))(γ-GeWO)]·3(CH)CO (M = Ce, Nd, Gd, Er, = 7; Zr, = 6), which have been synthesized at room temperature in an acetone-water mixture. Among the compound series, , which has been obtained in the presence of 30% HO, represents the first example of a 4d-substituted germanotungstate incorporating the intact dilacunary [γ-GeWO] building block. All compounds were characterized thoroughly in the solid state by single-crystal and powder X-ray diffraction (XRD), IR spectroscopy, thermogravimetric analysis (TGA), and elemental analysis and in solution by NMR and UV-vis spectroscopy.

Improving the Stability of Maleimide-Thiol Conjugation for Drug Targeting.

Maleimides are essential compounds for drug conjugation reactions via thiols to antibodies, peptides and other targeting units. However, one main drawback is the occurrence of thiol exchange reactions with, for example, glutathione resulting in loss of the targeting ability. A new strategy to overcome such retro-Michael exchange processes of maleimide-thiol conjugates by stabilization of the thiosuccinimide via a transcyclization reaction is presented.

Enhanced arecoline derivatives as muscarinic acetylcholine receptor M1 ligands for potential application as PET radiotracers.

Supported by their involvement in many neurodegenerative disorders, muscarinic acetylcholine receptors (mAChRs) are an interesting target for PET imaging. Nevertheless, no radiotracer is established in clinical routine. Within this work we aim to develop novel PET tracers based on the structure of arecoline.

Synthesis, characterization, antimicrobial and cytotoxic activity of novel half-sandwich Ru(II) arene complexes with benzoylthiourea derivatives.

Three new ruthenium(II)-arene complexes, [Ru(η-p-cymene)(L)Cl] (C1) where L is N-((4 methoxyphenyl)carbamothioyl)benzamide; [Ru(η-p-cymene)(L)Cl] (C2) where L is 4-(3-benzoylthioureido)benzoic acid and [Ru(η-p-cymene)(L)Cl] (C3) where L is methyl 4-(3- benzoylthioureido)benzoate have been synthetized, characterized and evaluated for their antimicrobial and anticancer activity. Characterization was performed using H and C NMR, IR spectroscopy, mass spectrometry, electrical conductivity measurements and X-Ray diffraction analysis. X-Ray diffraction analysis of C1 showed typical expected "piano-stool" geometry with ruthenium coordinated to ligand via nitrogen and sulfur atoms of benzoylthiourea derivatives.

Cation-Directed Synthetic Strategy Using 4f Tungstoantimonates as Nonlacunary Precursors for the Generation of 3d-4f Clusters.

The first synthetic pathway using a series of four nonlacunary 4f-heterometal-substituted polyoxotungstate clusters Na[(Ln(HO)(OH)(CHCOO))(WO)(SbWO)]·HO (; Ln = Tb, Dy, Ho, Er, Y) as precursors for the directed preparation of nine new 3d-4f heterometallic tungstoantimonates KNaH[TM(HO)Ln(HO)(WO)(SbWO)]·HO (; TM = Co, Ni; Ln = Tb, Dy, Ho, Er, Y) has been developed. Systematic studies revealed an increased K content in the aqueous acidic reaction mixture to be the key step in the cation-directed preparation of 3d-4f compounds; among those, the Co-containing members represent the first examples of (Ln = Tb, Dy, Ho, Er, Y) heterometallic tungstoantimonates exhibiting the building block. All 13 compounds have been characterized thoroughly in the solid state by powder and single-crystal X-ray diffraction (XRD), revealing a cyclic trimeric polyoxometalate architecture with three units encapsulating a planar triangle of Ln ions in the case of and a heterometallic core of one TM and three Ln for (TM = Co, Ni; Ln = Tb, Dy, Ho, Er, Y).

Investigations on the Anticancer Potential of Benzothiazole-Based Metallacycles.

A series of 2-phenylbenzothiazole derivatives and their corresponding organometallic ruthenium(II) and osmium(II) complexes were synthesized, designed to exploit both, the attributes of the half-sandwich transition metal scaffold and the bioactivity spectrum of the applied 2-phenylbenzothiazoles. All synthesized compounds were characterized via standard analytical methods. The obtained organometallics showed antiproliferative activity in the low μM range and are thus at least an order of magnitude more potent than the free ligands.

Binding of a Fatty Acid-Functionalized Anderson-Type Polyoxometalate to Human Serum Albumin.

The Anderson-type hexamolybdoaluminate functionalized with lauric acid (LA), (TBA)[Al(OH)MoO{(OCH)CNHCOCH}]·9HO (TBA-AlMo-LA, where TBA = tetrabutylammonium), was prepared via two synthetic routes and characterized by thermogravimetric and elemental analyses, mass spectrometry, IR and H NMR spectroscopy, and powder and single-crystal X-ray diffraction. The interaction of TBA-AlMo-LA with human serum albumin (HSA) was investigated via fluorescence and circular dichroism spectroscopy. The results revealed that TBA-AlMo-LA binds strongly to HSA (63% quenching at an HSA/TBA-AlMo-LA ratio of 1:1), exhibiting static quenching.

Synthesis of Novel Heterocycles by Amide Activation and Umpolung Cyclization.

Herein, we report a metal-free synthesis of cyclic amidines, oxazines, and an oxazinone under mild conditions by electrophilic amide activation. This strategy features an unusual Umpolung cyclization mode and enables the smooth union of α-aryl amides and diverse alkylazides, effectively rerouting our previously reported α-amination transform.

A Many-Faced Alkaloid: Polymorphism of (-)-Monophyllidin.

The synthesis of the alkaloid (-)-monophyllidin is described. The molecule is a hybrid of xanthoxyline and (S)-proline, accessible in one-step through a Mannich reaction. In the solid-state, defined structural arrangements with different physical properties are formed.

Incorporation of Cr into a Keggin Polyoxometalate as a Chemical Strategy to Stabilize a Labile {CrO} Tetrahedral Conformation and Promote Unattended Single-Ion Magnet Properties.

Polyoxometalates (POMs) provide rigid and highly symmetric coordination sites and can be used as a strategy for the stabilization of magnetic ions. Herein, we report a new member of the Keggin archetype, the Cr-centered Keggin anion [α-CrWO] (CrW), with the unusual tetrahedral coordination of Cr reported for the first time in POMs conferring unattended magnetic properties. POM chemistry has recently presented excellent examples of single-molecule and single-ion magnets (SMMs and SIMs) as well as molecular spin qubits; however, the majority of POM-based SIMs reported to date contain lanthanoid ions.

Synthesis, Modification, and Biological Evaluation of a Library of Novel Water-Soluble Thiopyridone-Based Organometallic Complexes and Their Unexpected (Biological) Behavior.

A series of 16 dinuclear thiopyridone-based organometallics with excellent water solubility, increased stability and remarkable cytotoxicity were synthesized and characterized. The complexes of this work formed dimeric species featuring a double positive charge in polar protic solvents, accounting for their outstanding solubility in aqueous solution. Most of them displayed higher antiproliferative activity than their parental thiomaltol complex, with unexpected cytotoxicity trends depending on the employed metal center, ligand modification, and cell line.

Structure-Activity Relationships of Novel Thiazole-Based Modafinil Analogues Acting at Monoamine Transporters.

Atypical dopamine reuptake inhibitors, such as modafinil, are used for the treatment of sleeping disorders and investigated as potential therapeutics against cocaine addiction and for cognitive enhancement. Our continuous effort to find modafinil analogues with higher inhibitory activity on and selectivity toward the dopamine transporter (DAT) has previously led to the promising thiazole-containing derivatives CE-103, CE-111, CE-123, and CE-125. Here, we describe the synthesis and activity of a series of compounds based on these scaffolds, which resulted in several new selective DAT inhibitors and gave valuable insights into the structure-activity relationships.