New ZW4864 Derivatives as Small-Molecule Inhibitors for the β-Catenin/BCL9 Protein-Protein Interaction.

A series of 1-(3-(2-amino-2-oxoethoxy)phenyl)piperidine-3-carboxamide derivatives was reported as new small-molecule β-catenin/B-cell lymphoma 9 (BCL9) protein-protein interaction (PPI) inhibitors. Compounds - were discovered to inhibit the β-catenin/BCL9 PPI with = 0.85-2.

Characterization of Hydrophilic α-Helical Hot Spots on the Protein-Protein Interaction Interfaces for the Design of α-Helix Mimetics.

The cooperativity index, , was developed to examine the binding synergy between hot spots of the ligand-protein. For the first time, the convergence of the side-chain spatial arrangements of hydrophilic α-helical hot spots Thr, Tyr, Asp, Asn, Ser, Cys, and His in protein-protein interaction (PPI) complex structures was disclosed and quantified by developing novel clustering models. In-depth analyses revealed the driving force for the protein-protein binding conformation convergence of hydrophilic α-helical hot spots.

Discovery of an Orally Bioavailable Small-Molecule Inhibitor for the β-Catenin/B-Cell Lymphoma 9 Protein-Protein Interaction.

Aberrant activation of Wnt/β-catenin signaling is strongly associated with many diseases including cancer invasion and metastasis. Small-molecule targeting of the central signaling node of this pathway, β-catenin, is a biologically rational approach to abolish hyperactivation of β-catenin signaling but has been demonstrated to be a difficult task. Herein, we report a drug-like small molecule, , that binds with β-catenin and selectively disrupts the protein-protein interaction (PPI) between B-cell lymphoma 9 (BCL9) and β-catenin while sparing the β-catenin/E-cadherin PPI.

Discovery of 1-Benzoyl 4-Phenoxypiperidines as Small-Molecule Inhibitors of the β-Catenin/B-Cell Lymphoma 9 Protein-Protein Interaction.

Structure-based design and optimization were performed to develop small-molecule β-catenin/B-cell lymphoma 9 (BCL9) inhibitors and improve their inhibitory activities. Compound with a novel 1-benzoyl 4-phenoxypiperidine scaffold was discovered to disrupt the β-catenin/BCL9 protein-protein interaction (PPI) with a of 0.96 μM in AlphaScreen competitive inhibition assays and displayed good selectivity for β-catenin/BCL9 over β-catenin/E-cadherin PPIs.

Discovery of 2-(3-(3-Carbamoylpiperidin-1-yl)phenoxy)acetic Acid Derivatives as Novel Small-Molecule Inhibitors of the β-Catenin/B-Cell Lymphoma 9 Protein-Protein Interaction.

The β-catenin/B-cell lymphoma 9 (BCL9) protein-protein interaction (PPI) is a potential target for the suppression of hyperactive Wnt/β-catenin signaling that is vigorously involved in cancer initiation and development. Herein, we describe the medicinal chemistry optimization of a screening hit to yield novel small-molecule inhibitors of the β-catenin/BCL9 interaction. The best compound can disrupt the β-catenin/BCL9 interaction with a of 3.

Engineered Three-Dimensional Tumor Models to Study Natural Killer Cell Suppression.

A critical hurdle associated with natural killer (NK) cell immunotherapies is inadequate infiltration and function in the solid tumor microenvironment. Well-controlled 3D culture systems could advance our understanding of the role of various biophysical and biochemical cues that impact NK cell migration in solid tumors. The objectives of this study were to establish a biomaterial which (i) supports NK cell migration and (ii) recapitulates features of the in vivo solid tumor microenvironment, to study NK infiltration and function in a 3D system.

Noncoding RNAs in cancer immunity: functions, regulatory mechanisms, and clinical application.

It is well acknowledged that immune system is deeply involved in cancer initiation and progression, and can exert both pro-tumorigenic and anti-tumorigenic effects, depending on specific microenvironment. With the better understanding of cancer-associated immune cells, especially T cells, immunotherapy was developed and applied in multiple cancers and exhibits remarkable efficacy. However, currently only a subset of patients have responses to immunotherapy, suggesting that a boarder view of cancer immunity is required.

Targeting the Side-Chain Convergence of Hydrophobic α-Helical Hot Spots To Design Small-Molecule Mimetics: Key Binding Features for , + 3, and + 7.

The conformational convergence of hydrophobic α-helical hot spots was revealed by analyzing α-helix-mediated protein-protein interaction (PPI) complex structures. The pharmacophore models were derived for hydrophobic α-helical hot spots at positions , + 3, and + 7. These provide the foundation for designing generalizable scaffolds that can directly mimic the binding mode of the side chains of α-helical hot spots, offering a new class of small-molecule α-helix mimetics.

Optimization of Peptidomimetics as Selective Inhibitors for the β-Catenin/T-Cell Factor Protein-Protein Interaction.

The β-catenin/T-cell factor (Tcf) protein-protein interaction (PPI) plays a critical role in the β-catenin signaling pathway which is hyperactivated in many cancers and fibroses. Based on compound 1, which was designed to target the Tcf4 GANDE binding site of β-catenin, extensive structure-activity relationship studies have been conducted. As a result, compounds 53 and 57 were found to disrupt the β-catenin/Tcf PPI with the K values of 0.

Treatment of Enteropathogenic Diarrhea in Cancer Patients: A Series of Three Cases.

Enteropathogenic (EPEC) is a common cause of watery diarrhea in children in the developing world and an infrequent cause of significant diarrhea in adult patients. EPEC diarrhea, while not commonly seen in cancer patients, can cause significant distress to patients, and antimicrobial choice for this condition in this patient population is not clearly delineated in the literature. We report 3 cases of EPEC diarrhea in cancer patients and discuss the use of azithromycin for successful treatment of these patients.

Two cases of disseminated infection following live organism anti-cancer vaccine administration in cancer patients.

Vaccines containing live attenuated bacterial or viral organisms are currently being investigated as potential therapy for locally advanced or metastatic cancers. However, the use of such live organisms in an immunocompromised population, such as patients who recently or are currently receiving chemotherapy, raises the concern that these organisms can themselves disseminate and cause frank infection. We report a hereunto unreported phenomenon of anti-cancer vaccines (containing live attenuated organisms) leading to frank, disseminated infection.

Comparison of Quantitative Mass Spectrometry Platforms for Monitoring Kinase ATP Probe Uptake in Lung Cancer.

Recent developments in instrumentation and bioinformatics have led to new quantitative mass spectrometry platforms including LC-MS/MS with data-independent acquisition (DIA) and targeted analysis using parallel reaction monitoring mass spectrometry (LC-PRM), which provide alternatives to well-established methods, such as LC-MS/MS with data-dependent acquisition (DDA) and targeted analysis using multiple reaction monitoring mass spectrometry (LC-MRM). These tools have been used to identify signaling perturbations in lung cancers and other malignancies, supporting the development of effective kinase inhibitors and, more recently, providing insights into therapeutic resistance mechanisms and drug repurposing opportunities. However, detection of kinases in biological matrices can be challenging; therefore, activity-based protein profiling enrichment of ATP-utilizing proteins was selected as a test case for exploring the limits of detection of low-abundance analytes in complex biological samples.

Randomized, placebo-controlled trial evaluating the safety of one-year administration of green tea catechins.

Purpose: Although preclinical, epidemiological and prior clinical trial data suggest that green tea catechins (GTCs) may reduce prostate cancer (PCa) risk, several preclinical studies and case reports have reported liver toxicities and acute gastrointestinal bleeding. Based on these observations, regulatory bodies have required stringent inclusion criteria with frequent, excessive toxicity monitoring and early stopping rules in clinical trials. These requirements have impeded recruitment and retention of subjects in chemoprevention trials and subsequent progress in agent development efforts.

APOSTL: An Interactive Galaxy Pipeline for Reproducible Analysis of Affinity Proteomics Data.

With continuously increasing scale and depth of coverage in affinity proteomics (AP-MS) data, the analysis and visualization is becoming more challenging. A number of tools have been developed to identify high-confidence interactions; however, a cohesive and intuitive pipeline for analysis and visualization is still needed. Here we present Automated Processing of SAINT Templated Layouts (APOSTL), a freely available Galaxy-integrated software suite and analysis pipeline for reproducible, interactive analysis of AP-MS data.

Chemoproteomics Reveals Novel Protein and Lipid Kinase Targets of Clinical CDK4/6 Inhibitors in Lung Cancer.

Several selective CDK4/6 inhibitors are in clinical trials for non-small cell lung cancer (NSCLC). Palbociclib (PD0332991) is included in the phase II/III Lung-MAP trial for squamous cell lung carcinoma (LUSQ). We noted differential cellular activity between palbociclib and the structurally related ribociclib (LEE011) in LUSQ cells.

Nutritionally variant streptococci bacteremia in cancer patients: a retrospective study, 1999-2014.

Background: Nutritionally variant Streptococci (NVS), Abiotrophia and Granulicatella are implicated in causing endocarditis and blood stream infections more frequently than other sites of infection. Neutropenia and mucositis are the most common predisposing factors for infection with other pathogens in cancer patients. In this study, we investigated the clinical characteristics of NVS bacteremia in cancer patients and identified risk factors and outcomes associated with these infections.

A case of rupioid syphilis masquerading as aggressive cutaneous lymphoma.

Secondary syphilis has been known since the late 19th century as the great imitator; however, some experts now regard cutaneous lymphoma as the great imitator of skin disease. Either disease, at times an equally fastidious diagnosis, has reported to mimic each other even. It is thus vital to consider these possibilities when presented with a patient demonstrating peculiar skin lesions.

Diagnostic value of bronchoalveolar lavage in leukemic and bone marrow transplant patients: the impact of antimicrobial therapy.

There is significant morbidity and mortality from pneumonia in leukemic and bone marrow transplant patients. We sought to explore the diagnostic yield of bronchoalveolar lavage (BAL) in these patients with new pulmonary infiltrates. A retrospective chart review of approximately 200 Non- human immunodeficiency virus (HIV) leukemic and Hematopoietic stem cell transplantation (HSCT) patients who underwent bronchoscopy at a single academic cancer center was performed.

Escherichia coli: an important pathogen in patients with hematologic malignancies.

Background: Escherichia coli (E. coli) is a pathogen of great concern in immunosuppressed patients. While antimicrobial prophylactic therapy has become the standard, the emergence of resistant pathogens has some questioning its use.

The Role of Corticosteroids in Adult Respiratory Distress Syndrome caused by Viridans Group Streptococci Bacteremia in Neutropenic Patients.

In the past decades, viridans group Streptococci (VGS) have emerged as an important cause of bacteremia in neutropenic patients with cancer. The clinical course of VGS bacteremia can be devastating including septic shock and adult respiratory distress syndrome (ARDS). It has been suggested that septicemia with VGS triggers the development of noncardiogenic pulmonary edema in patients with pre-existing damage of the lungs due to aggressive cytotoxic treatment.

Bordetella bronchiseptica in the immunosuppressed population - a case series and review.

Organisms that are not known to cause serious infection in the immunocompetent population can, in fact, cause devastating illness in immunosuppressed neutropenic populations especially those who are undergoing hematopoietic stem cell transplantation (HSCT), and solid organ transplantation or a history of malignancy. One organism of interest isolated from immunosuppressed patients at our institution was Bordetella bronchiseptica. It is known to cause respiratory tract disease in the animal population which includes dogs, cats, and rabbits.

Tacrolimus associated posterior reversible encephalopathy syndrome - a case series and review.

Tacrolimus is an immunosuppressive drug mainly used to lower the risk of transplant rejection in individuals who are post solid organ or hematopoietic transplantation. It is a macrolide which reduces peptidyl-propyl isomerase activity and inhibits calcineurin, thus inhibiting T-lymphocyte signal transduction and interleukin-2 (IL-2) transcription. It has been associated with Posterior Reversible Encephalopathy Syndrome (PRES), a disease of sudden onset that can present as a host of different symptoms, depending on the affected area of the brain.

Stemness of B-cell progenitors in multiple myeloma bone marrow.

Purpose: In myeloma, B cells and plasma cells show a clonal relationship. Clonotypic B cells may represent a tumor-initiating compartment or cancer stem cell responsible for minimal residual disease in myeloma.

Experimental Design: We report a study of 58 patients with myeloma at time of diagnosis or relapse.

Correlation between COX-2 and APC expression in left versus right-sided human colon cancer.

Background: Because of clinicopathologic and genetic differences between left-sided colorectal cancer (LSCRC) and right-sided colon cancer (RSCC), cyclooxygenase-2(COX-2) and adenomatous polyposis coli (APC) expression may be of clinical relevance.

Materials And Methods: Clinicopathologic information for 72 primary colon tumors, 44 left and 28 right, from 72 patients (34 F, 38 M) were analyzed. COX-2 and wild-type APC (W-APC) immunohistochemical expressions were determined for each case.