Metachronous isolated penile metastasis from sigmoid colon adenocarcinoma: A case report.

Background: Sigmoid colon adenocarcinoma has a high incidence among gastrointestinal tumors, and it very rarely metastasizes to the penis. The literature reports that the prognosis after penile metastasis is generally poor, with a median survival of about 9 mo. Metachronous isolated metastasis to the penis originating from sigmoid colon adenocarcinoma has not been reported so far.

Monoamine oxidase binding not expected to significantly affect [F]flortaucipir PET interpretation.

Purpose: [F]-labeled positron emission tomography (PET) radioligands permit in vivo assessment of Alzheimer's disease biomarkers, including aggregated neurofibrillary tau (NFT) with [F]flortaucipir. Due to structural similarities of flortaucipir with some monoamine oxidase A (MAO-A) inhibitors, this study aimed to evaluate flortaucipir binding to MAO-A and MAO-B and any potential impact on PET interpretation.

Methods: [F]Flortaucipir autoradiography was performed on frozen human brain tissue slices, and PET imaging was conducted in rats.

Use of the PET ligand florbetapir for in vivo imaging of pancreatic islet amyloid deposits in hIAPP transgenic mice.

Aims/hypothesis: Islet amyloid deposits contribute to beta cell dysfunction and death in most individuals with type 2 diabetes but non-invasive methods to determine the presence of these pathological protein aggregates are currently not available. Therefore, we examined whether florbetapir, a radiopharmaceutical agent used for detection of amyloid-β deposits in the brain, also allows identification of islet amyloid in the pancreas.

Methods: Saturation binding assays were used to determine the affinity of florbetapir for human islet amyloid polypeptide (hIAPP) aggregates in vitro.

A rapid gene delivery-based mouse model for early-stage Alzheimer disease-type tauopathy.

The perforant pathway projection from the entorhinal cortex (EC) to the hippocampal dentate gyrus is critically important for long-term memory and develops tau and amyloid pathologies and progressive degeneration starting in the early stages of Alzheimer disease (AD). However, perforant pathway function has not been assessed in experimental models of AD, and a therapeutic agent that protects its structure and function has not yet been identified. Therefore, we developed a new adeno-associated virus-based mouse model for perforant pathway tauopathy.

Wake-promoting agents: search for next generation modafinil: part IV.

In search of a next generation molecule to the novel wake promoting agent modafinil, a series of diphenyl ether derived wakefulness enhancing agents (in rat) was developed. From this work, racemic compound 16 was separated into its chiral enantiomers to profile them individually.

Amyloid deposition and advanced age fails to induce Alzheimer's type progression in a double knock-in mouse model.

It has been challenging to develop transgenic and gene-targeted mouse models that recapitulate all of the neuropathological features of Alzheimer's disease (AD). For example, in the APP/PS-1 double knock-in mutant mouse (DKI), frank neurodegeneration is not observed at middle age and synapse loss is pronounced only within amyloid plaques. Here, we investigated whether continued amyloid deposition and advanced age of 24-27 months lead to loss of neurons and synapses, tau hyperphosphorylation, and other pathological features of AD.

Wake promoting agents: search for next generation modafinil, lessons learned: part III.

In searching for a next generation molecule to the novel wake promoting agent modafinil (compound 1), a series of fluorene-derived wakefulness enhancing agents were developed and evaluated in rat. Extensive pharmacokinetic studies of a potent member of the series (compound 15) revealed that the wake promotion activity of the analog was likely due to an active metabolite (compound 3).

Wake-promoting agents: search for next generation modafinil: part II.

In search of a next generation molecule to modafinil, a novel wake promoting agent, we previously disclosed bi-phenyl derived racemate compound (±)-2 as a new generation of wake-promoting agent. Here we describe the profiles of the individual enantiomers (-)-2 and (+)-2, respectively.

Wake-promoting agents: search for next generation modafinil: part I.

In search of a next generation molecule to the novel wake promoting agent modafinil, a series of bi-phenyl derived wakefulness enhancing agents (in rat) was developed. From this work, compound 17 has been selected for additional studies.

Identification of pyridazin-3-one derivatives as potent, selective histamine H₃ receptor inverse agonists with robust wake activity.

H(3)R structure-activity relationships on a novel class of pyridazin-3-one H(3)R antagonists/inverse agonists are disclosed. Modifications of the pyridazinone core, central phenyl ring and linker led to the identification of molecules with excellent target potency, selectivity and pharmacokinetic properties. Compounds 13 and 21 displayed potent functional H(3)R antagonism in vivo in the rat dipsogenia model and demonstrated robust wake activity in the rat EEG/EMG model.

The roles of dopamine transport inhibition and dopamine release facilitation in wake enhancement and rebound hypersomnolence induced by dopaminergic agents.

Study Objective: Rebound hypersomnolence (RHS: increased sleep following increased wake) is a limiting side-effect of many wake-promoting agents. In particular, RHS in the first few hours following wake appears to be associated with dopamine (DA)-releasing agents, e.g.

Armodafinil promotes wakefulness and activates Fos in rat brain.

Modafinil increases waking and labeling of Fos, a marker of neuronal activation. In the present study, armodafinil, the R-enantiomer of racemic modafinil, was administered to rats at 30 or 100 mg/kg i.p.

A transgenic rat model of Alzheimer's disease with extracellular Abeta deposition.

Many transgenic mouse models of Alzheimer's disease (AD) that deposit amyloid (Abeta) have been produced, but development of an Abeta-depositing rat model has not been successful. Here, we describe a rat model with extracellular fibrillar Abeta deposition. Two lines of Sprague Dawley rats with transgenes expressing human amyloid precursor protein (APP) with the familial AD (FAD) mutations K670N/M671L and K670N/M671L/V717I were crossed.

Activation of c-Jun N-terminal kinase and p38 in an Alzheimer's disease model is associated with amyloid deposition.

The mechanisms by which neurons and synapses are lost in Alzheimer's disease (AD) are not completely understood. To characterize potential signaling events linked to AD pathogenesis, activation-specific antibodies were used to examine mitogen-activated protein kinase (MAPK) kinase pathways at various ages in mice transgenic for human amyloid precursor protein-695 with the Swedish familial AD mutations (Tg2576) and homozygous for a P264L familial AD mutation introduced by targeting of the presenilin-1 gene (PS1(P264L)). Although the c-Jun N-terminal kinase (JNK) and p38 pathways were significantly activated in the cortex at both 7 and 12 months of age, there was no significant activation of the extracellular signal-regulated kinase pathway.

FAD mutant PS-1 gene-targeted mice: increased A beta 42 and A beta deposition without APP overproduction.

To investigate the consequences of mutant presenilin-1 (PS-1) expression under the control of the normal PS-1 gene, a gene-targeted mouse bearing the FAD mutation P264L was made. Gene-targeted models are distinct from transgenic models because the mutant gene is expressed at normal levels, in the absence of the wild-type protein. PS-1(P264L/P264L) mice had normal expression of PS-1 mRNA, but levels of the N- and C-terminal protein fragments of PS-1 were reduced while levels of the holoprotein were increased.