Surgical Lymph Node Biopsy for the Diagnosis of Lymphoma: A Case Report.

We report the diagnosis, treatment, and outcomes of a 52-year-old woman who originally presented to her primary care provider with adenopathy. Core needle biopsy (CNB) was inconclusive as it could not distinguish between follicular and diffuse large B-cell lymphomas (DLBCLs). A left axillary surgical lymph node biopsy was performed and demonstrated that the patient had a DLBCL arising from grade 3 follicular lymphoma.

Development of allosteric and selective CDK2 inhibitors for contraception with negative cooperativity to cyclin binding.

Compared to most ATP-site kinase inhibitors, small molecules that target an allosteric pocket have the potential for improved selectivity due to the often observed lower structural similarity at these distal sites. Despite their promise, relatively few examples of structurally confirmed, high-affinity allosteric kinase inhibitors exist. Cyclin-dependent kinase 2 (CDK2) is a target for many therapeutic indications, including non-hormonal contraception.

Screening through Lead Optimization of High Affinity, Allosteric Cyclin-Dependent Kinase 2 (CDK2) Inhibitors as Male Contraceptives That Reduce Sperm Counts in Mice.

Although cyclin-dependent kinase 2 (CDK2) is a validated target for both cancer and contraception, developing a CDK2 inhibitor with exquisite selectivity has been challenging due to the structural similarity of the ATP-binding site, where most kinase inhibitors bind. We previously discovered an allosteric pocket in CDK2 with the potential to bind a selective compound and then discovered and structurally confirmed an anthranilic acid scaffold that binds this pocket with high affinity. These allosteric inhibitors are selective for CDK2 over structurally similar CDK1 and show contraceptive potential.

DFG-1 Binding: A New Residue for Developing Selective Kinase Inhibitors.

Only 15% of human kinases carry a bulky residue at the DFG-1 position, providing an opportunity for the design of selective ATP-site inhibitors without the typical hinge-binding interactions. The low sequence homology among unrelated kinases with bulky DFG-1 residues provides a new paradigm for selective kinase inhibitor development.

Defining and Characterizing Frequent Attenders: Systematic Literature Review and Recommendations.

Purpose: To decrease cost and improve efficiency, health care organizations have focused on frequent attenders - patients with high health care utilization. Prior studies have investigated singular health care settings, used varying definitions of frequent attendance, and inconsistently identified factors correlated with frequent attendance. The purpose of this article is to suggest a uniform definition of frequent attenders for different health care settings and to determine factors correlated with frequent attendance.

Review of rationale and progress toward targeting cyclin-dependent kinase 2 (CDK2) for male contraception†.

Cyclin-dependent kinase 2 (CDK2) is a member of the larger cell cycle regulating CDK family of kinases, activated by binding partner cyclins as its name suggests. Despite its canonical role in mitosis, CDK2 knockout mice are viable but sterile, suggesting compensatory mechanisms for loss of CDK2 in mitosis but not meiosis. Here, we review the literature surrounding the role of CDK2 in meiosis, particularly a cyclin-independent role in complex with another activator, Speedy 1 (SPY1).

Cooperativity Between Orthosteric Inhibitors and Allosteric Inhibitor 8-Anilino-1-Naphthalene Sulfonic Acid (ANS) in Cyclin-Dependent Kinase 2.

While kinases have been attractive targets to combat many diseases, including cancer, selective kinase inhibition has been challenging, because of the high degree of structural homology in the active site, where many kinase inhibitors bind. We have previously discovered that 8-anilino-1-naphthalene sulfonic acid (ANS) binds an allosteric pocket in cyclin-dependent kinase 2 (Cdk2). Here, we detail the positive cooperativity between ANS and orthosteric Cdk2 inhibitors dinaciclib and roscovitine, which increase the affinity of ANS toward Cdk2 5-fold to 10-fold, and the relatively noncooperative effects of ATP.

Synthesis and Spectral Properties of 8-Anilinonaphthalene-1-sulfonic Acid (ANS) Derivatives Prepared by Microwave-Assisted Copper(0)-Catalyzed Ullmann Reaction.

For decades, the dye 8-anilino-1-naphthalenesulfonic acid (ANS) has been used to study biological systems due to its environmentally sensitive fluorescent nature and propensity to bind to hydrophobic pockets of proteins. However, the syntheses of ANS and its derivatives have been low yielding, requiring harsh reaction conditions and long reaction times. We have developed efficient, mild microwave-assisted copper(0)-catalyzed Ullmann coupling conditions to synthesize ANS derivatives with yields of up to 74%.

Quantitative conformational profiling of kinase inhibitors reveals origins of selectivity for Aurora kinase activation states.

Protein kinases undergo large-scale structural changes that tightly regulate function and control recognition by small-molecule inhibitors. Methods for quantifying the conformational effects of inhibitors and linking them to an understanding of selectivity patterns have long been elusive. We have developed an ultrafast time-resolved fluorescence methodology that tracks structural movements of the kinase activation loop in solution with angstrom-level precision, and can resolve multiple structural states and quantify conformational shifts between states.

PTEN recruitment controls synaptic and cognitive function in Alzheimer's models.

Dyshomeostasis of amyloid-β peptide (Aβ) is responsible for synaptic malfunctions leading to cognitive deficits ranging from mild impairment to full-blown dementia in Alzheimer's disease. Aβ appears to skew synaptic plasticity events toward depression. We found that inhibition of PTEN, a lipid phosphatase that is essential to long-term depression, rescued normal synaptic function and cognition in cellular and animal models of Alzheimer's disease.

Inhibition of colon cancer growth by methylselenocysteine-induced angiogenic chemomodulation is influenced by histologic characteristics of the tumor.

Despite an armamentarium that is wide in range, scope of action, and target, chemotherapy has limited success in colorectal cancer (CRC). Novel approaches are needed to overcome tumor barriers to chemotherapy that includes an abnormal tumor vasculature constituting a poor drug delivery system. We have previously shown that 5-methylselenocysteine (MSC) enhances therapeutic efficacy of irinotecan in various human tumor xenografts.

pH sensitivity of Si--C linked organic monolayers on crystalline silicon surfaces.

The electrochemical behavior of Si--C linked organic monolayers is studied in electrolyte-insulator-Si devices, under conditions normally encountered in potentiometric biosensors, to gain fundamental knowledge on the behavior of such Si electrodes under practical conditions. This is done via titration experiments, Mott-Schottky data analysis, and data fitting using a site-binding model. The results are compared with those of native SiO(2) layers and native SiO(2) layers modified with hexamethyldisilazane.

Si-C linked organic monolayers on crystalline silicon surfaces as alternative gate insulators.

Herein, the influence of silicon surface modification via Si-C(n)H(2n+1) (n=10,12,16,22) monolayer-based devices on p-type 100 and n-type 100 silicon is studied by forming MIS (metal-insulator-semiconductor) diodes using a mercury probe. From current density-voltage (J-V) and capacitance-voltage (C-V) measurements, the relevant parameters describing the electrical behavior of these diodes are derived, such as the diode ideality factor, the effective barrier height, the flatband voltage, the barrier height, the monolayer dielectric constant, the tunneling attenuation factor, and the fixed charge density (Nf). It is shown that the J-V behavior of our MIS structures could be precisely tuned via the monolayer thickness.