Clinical Significance of Nephrogenic Adenoma of the Urinary Bladder: Implications for Differential Diagnosis and Potential for Malignant Transformation.

Nephrogenic adenoma of the urinary bladder is a rare, benign lesion associated with prior inflammation or irritation of the urothelium. Although typically benign, nephrogenic adenoma can present diagnostic challenges due to its potential to mimic malignant tumors of the urinary tract. In this report, we present a case of an elderly woman with a history of recurrent urinary tract infections and bladder stone surgery who developed nephrogenic adenoma.

Timely Surgical Resection Achieved Prolonged Remission in Patients With Malignant Mesothelioma of the Tunica Vaginalis Testis and Retroperitoneal Recurrence.

Malignant mesothelioma of the tunica vaginalis testis (MMTVT) is a rare tumor of the testicular sheath. More than 50% of cases initially present as recurrent hydrocele, but there have also been documented cases with hematocele, inguinal hernia, or epididymitis. Due to the non-specific symptoms and signs of the disease, it is almost always diagnosed intra- or postoperatively.

Efficacy and Safety of Autologous Dendritic Cell-Based Immunotherapy, Docetaxel, and Prednisone vs Placebo in Patients With Metastatic Castration-Resistant Prostate Cancer: The VIABLE Phase 3 Randomized Clinical Trial.

Importance: DCVAC/PCa is an active cellular immunotherapy designed to initiate an immune response against prostate cancer.

Objective: To evaluate the efficacy and safety of DCVAC/PCa plus chemotherapy followed by DCVAC/PCa maintenance treatment in patients with metastatic castration-resistant prostate cancer (mCRPC).

Design, Setting, And Participants: The VIABLE double-blind, parallel-group, placebo-controlled, phase 3 randomized clinical trial enrolled patients with mCRPC among 177 hospital clinics in the US and Europe between June 2014 and November 2017.

AC105 Increases Extracellular Magnesium Delivery and Reduces Excitotoxic Glutamate Exposure within Injured Spinal Cords in Rats.

Magnesium (Mg) homeostasis is impaired following spinal cord injury (SCI) and the loss of extracellular Mg contributes to secondary injury by various mechanisms, including glutamate neurotoxicity. The neuroprotective effects of high dose Mg supplementation have been reported in many animal models. Recent studies found that lower Mg doses also improved neurologic outcomes when Mg was formulated with polyethylene glycol (PEG), suggesting that a PEG/ Mg formulation might increase Mg delivery to the injured spinal cord, compared with that of MgSO alone.

Discovery of potent and selective spiroindolinone MDM2 inhibitor, RO8994, for cancer therapy.

The field of small-molecule inhibitors of protein-protein interactions is rapidly advancing and the specific area of inhibitors of the p53/MDM2 interaction is a prime example. Several groups have published on this topic and multiple compounds are in various stages of clinical development. Building on the strength of the discovery of RG7112, a Nutlin imidazoline-based compound, and RG7388, a pyrrolidine-based compound, we have developed additional scaffolds that provide opportunities for future development.

Discovery of Potent and Orally Active p53-MDM2 Inhibitors RO5353 and RO2468 for Potential Clinical Development.

The development of small-molecule MDM2 inhibitors to restore dysfunctional p53 activities represents a novel approach for cancer treatment. In a previous communication, the efforts leading to the identification of a non-imidazoline MDM2 inhibitor, RG7388, was disclosed and revealed the desirable in vitro and in vivo pharmacological properties that this class of pyrrolidine-based inhibitors possesses. Given this richness and the critical need for a wide variety of chemical structures to ensure success in the clinic, research was expanded to evaluate additional derivatives.

Preclinical optimization of MDM2 antagonist scheduling for cancer treatment by using a model-based approach.

Purpose: Antitumor clinical activity has been demonstrated for the MDM2 antagonist RG7112, but patient tolerability for the necessary daily dosing was poor. Here, utilizing RG7388, a second-generation nutlin with superior selectivity and potency, we determine the feasibility of intermittent dosing to guide the selection of initial phase I scheduling regimens.

Experimental Design: A pharmacokinetic-pharmacodynamic (PKPD) model was developed on the basis of preclinical data to determine alternative dosing schedule requirements for optimal RG7388-induced antitumor activity.

Stapled α-helical peptide drug development: a potent dual inhibitor of MDM2 and MDMX for p53-dependent cancer therapy.

Stapled α-helical peptides have emerged as a promising new modality for a wide range of therapeutic targets. Here, we report a potent and selective dual inhibitor of MDM2 and MDMX, ATSP-7041, which effectively activates the p53 pathway in tumors in vitro and in vivo. Specifically, ATSP-7041 binds both MDM2 and MDMX with nanomolar affinities, shows submicromolar cellular activities in cancer cell lines in the presence of serum, and demonstrates highly specific, on-target mechanism of action.

Discovery of RG7388, a potent and selective p53-MDM2 inhibitor in clinical development.

Restoration of p53 activity by inhibition of the p53-MDM2 interaction has been considered an attractive approach for cancer treatment. However, the hydrophobic protein-protein interaction surface represents a significant challenge for the development of small-molecule inhibitors with desirable pharmacological profiles. RG7112 was the first small-molecule p53-MDM2 inhibitor in clinical development.

MDM2 small-molecule antagonist RG7112 activates p53 signaling and regresses human tumors in preclinical cancer models.

MDM2 negatively regulates p53 stability and many human tumors overproduce MDM2 as a mechanism to restrict p53 function. Thus, inhibitors of p53-MDM2 binding that can reactivate p53 in cancer cells may offer an effective approach for cancer therapy. RG7112 is a potent and selective member of the nutlin family of MDM2 antagonists currently in phase I clinical studies.

Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: implications for therapy.

The p53 tumor suppressor retains its wild-type conformation and transcriptional activity in half of all human tumors, and its activation may offer a therapeutic benefit. However, p53 function could be compromised by defective signaling in the p53 pathway. Using a small-molecule MDM2 antagonist, nutlin-3, to probe downstream p53 signaling we find that the cell-cycle arrest function of the p53 pathway is preserved in multiple tumor-derived cell lines expressing wild-type p53, but many have a reduced ability to undergo p53-dependent apoptosis.

In vivo activation of the p53 pathway by small-molecule antagonists of MDM2.

MDM2 binds the p53 tumor suppressor protein with high affinity and negatively modulates its transcriptional activity and stability. Overexpression of MDM2, found in many human tumors, effectively impairs p53 function. Inhibition of MDM2-p53 interaction can stabilize p53 and may offer a novel strategy for cancer therapy.

Macrophage inhibitory cytokine-1: a novel biomarker for p53 pathway activation.

The p53 tumor suppressor protein plays a key function in the cellular response to stress by activating a subset of genes responsible for cell cycle arrest and apoptosis. Activation of the p53 pathway in tumor cells has been proposed as a novel approach to cancer therapy and substantial efforts have been dedicated to the discovery of pharmacological p53 activators. Here, we show that the transforming growth factor-beta superfamily cytokine, macrophage inhibitory cytokine-1 (MIC-1), can serve as a secreted biomarker for activation of p53 in both cellular and xenograft models of human cancer.

Short-term cardiovascular effects of plasmapheresis in norepinephrine-refractory septic shock.

Objective: To examine the short-term cardiovascular effects of plasmapheresis in seven patients (six surgical, one medical) with norepinephrine-refractory septic shock.

Design And Setting: Retrospective observational study in a secondary community hospital.

Interventions: Plasmapheresis was performed as follows: blood flow, 120 ml/min; exchange volume, 10 fresh frozen plasma (ca.