Perioperative management of patients with glioblastoma copresenting with pheochromocytoma: illustrative case.

Background: Undiagnosed pheochromocytoma can present with hemodynamic instability during surgical procedures. Here, the authors discuss a 69-year-old male with isocitrate dehydrogenase (IDH)-wildtype glioblastoma copresenting with undiagnosed pheochromocytoma, which, to the authors' knowledge, is the second reported case in the literature.

Observations: The patient presented to the emergency department with a 1-month history of coordination difficulties, progressive morning headache, and mild left-side weakness.

Glucocorticoids disrupt longitudinal advance of cortical bone basic multicellular units in the rabbit distal tibia.

Glucocorticoids (GCs) are the leading cause of secondary osteoporosis. The emerging perspective, derived primarily from 2D histological study of trabecular bone, is that GC-induced bone loss arises through the uncoupling of bone formation and resorption at the level of the basic multicellular unit (BMU), which carries out bone remodeling. Here we explore the impact of GCs on cortical bone remodeling in the rabbit model.

Activation of the Anaphase Promoting Complex Restores Impaired Mitotic Progression and Chemosensitivity in Multiple Drug-Resistant Human Breast Cancer.

The development of multiple-drug-resistant (MDR) cancer all too often signals the need for toxic alternative therapy or palliative care. Our recent in vivo and in vitro studies using canine MDR lymphoma cancer cells demonstrate that the Anaphase Promoting Complex (APC) is impaired in MDR cells compared to normal canine control and drug-sensitive cancer cells. Here, we sought to establish whether this phenomena is a generalizable mechanism independent of species, malignancy type, or chemotherapy regime.

Daily administration of parathyroid hormone slows the progression of basic multicellular units in the cortical bone of the rabbit distal tibia.

Basic Multicellular Units (BMUs) conduct bone remodeling, a critical process of tissue turnover which, if imbalanced, can lead to disease, including osteoporosis. Parathyroid hormone (PTH 1-34; Teriparatide) is an osteoanabolic treatment for osteoporosis; however, it elevates the rate of intra-cortical remodeling (activation frequency) leading, at least transiently, to increased porosity. The purpose of this study was to test the hypothesis that PTH not only increases the rate at which cortical BMUs are initiated but also increases their progression (Longitudinal Erosion Rate; LER).

Association Between Insulin Resistance and the Inflammatory Marker C-reactive Protein in a Representative Healthy Adult Canadian Population: Results From the Canadian Health Measures Survey.

Objectives: Insulin resistance (IR) leads to type 2 diabetes mellitus. Multiple IR causes have been identified, including inflammation. This study determines the association between IR and the inflammatory marker C-reactive protein (CRP) in a healthy Canadian population and examines potential differences by sex and age.

Activation of the Anaphase Promoting Complex Reverses Multiple Drug Resistant Cancer in a Canine Model of Multiple Drug Resistant Lymphoma.

Like humans, canine lymphomas are treated by chemotherapy cocktails and frequently develop multiple drug resistance (MDR). Their shortened clinical timelines and tumor accessibility make canines excellent models to study MDR mechanisms. Insulin-sensitizers have been shown to reduce the incidence of cancer in humans prescribed them, and we previously demonstrated that they also reverse and delay MDR development in vitro.

Direct Assessment of Rabbit Cortical Bone Basic Multicellular Unit Longitudinal Erosion Rate: A 4D Synchrotron-Based Approach.

Cortical bone remodeling is carried out by basic multicellular units (BMUs), which couple resorption to formation. Although fluorochrome labeling has facilitated study of BMU formative parameters since the 1960s, some resorptive parameters, including the longitudinal erosion rate (LER), have remained beyond reach of direct measurement. Indeed, our only insights into this spatiotemporal parameter of BMU behavior come from classical studies that indirectly inferred LER.

Current cancer therapies and their influence on glucose control.

This review focuses on the development of hyperglycemia arising from widely used cancer therapies spanning four drug classes. These groups of medications were selected due to their significant association with new onset hyperglycemia, or of potentially severe clinical consequences when present. These classes include glucocorticoids that are frequently used in addition to chemotherapy treatments, and the antimetabolite class of 5-fluorouracil-related drugs.

Capecitabine-induced hyperosmolar hyperglycaemic state.

An elderly woman with metastatic breast cancer was admitted with hyperglycaemic hyperosmolar state (HHS) and an elevated haemoglobin A1C. For 1 week, she had experienced confusion, nausea and frequent urination. Preceding this, she had completed seven cycles of capecitabine chemotherapy for her breast cancer.

The role of Anaphase Promoting Complex activation, inhibition and substrates in cancer development and progression.

The Anaphase Promoting Complex (APC), a multi-subunit ubiquitin ligase, facilitates mitotic and G1 progression, and is now recognized to play a role in maintaining genomic stability. Many APC substrates have been observed overexpressed in multiple cancer types, such as CDC20, the Aurora A and B kinases, and Forkhead box M1 (FOXM1), suggesting APC activity is important for cell health. We performed BioGRID analyses of the APC coactivators CDC20 and CDH1, which revealed that at least 69 proteins serve as APC substrates, with 60 of them identified as playing a role in tumor promotion and 9 involved in tumor suppression.

Cortical Bone Porosity in Rabbit Models of Osteoporosis.

Cortical bone porosity is intimately linked with remodeling, is of growing clinical interest, and is increasingly accessible by imaging. Thus, the potential of animal models of osteoporosis (OP) to provide a platform for studying how porosity develops and responds to interventions is tremendous. To date, rabbit models of OP have largely focused on trabecular microarchitecture or bone density; some such as ovariectomy (OVX) have uncertain efficacy and cortical porosity has not been extensively reported.

Bilateral osteonecrosis of the hip in panhypopituitarism.

Osteonecrosis, also known as avascular necrosis, is a condition that causes significant morbidity and loss of function. It is a common complication seen with supraphysiological steroid use. Early diagnosis is critical as it impacts prognosis.

Unsuspected Von Hippel-Lindau syndrome in acute-onset resistant hypertension.

The discovery of adrenal lesions during routine testing for hypertension requires focused consideration for adrenal overproduction of cortisol, aldosterone or metanephrines. An otherwise healthy 25-year-old woman presented with headaches, diaphoresis and hot flushes with grossly elevated urine catecholamines, normetanephrines and norepinephrine levels, yet normal metanephrines, epinephrine/epinephrine, cortisol and aldosterone levels. Subsequent functional uptake studies and scans identified bilateral adrenal adenomas consistent with phaeochromocytomas.

Metformin inhibits the development, and promotes the resensitization, of treatment-resistant breast cancer.

Multiple drug resistant (MDR) malignancy remains a predictable and often terminal event in cancer therapy, and affects individuals with many cancer types, regardless of the stage at which they were originally diagnosed or the interval from last treatment. Protein biomarkers of MDR are not globally used for clinical decision-making, but include the overexpression of drug-efflux pumps (ABC transporter family) such as MDR-1 and BCRP, as well as HIF1α, a stress responsive transcription factor found elevated within many MDR tumors. Here, we present the important in vitro discovery that the development of MDR (in breast cancer cells) can be prevented, and that established MDR could be resensitized to therapy, by adjunct treatment with metformin.

Effects of intermittent fasting on health markers in those with type 2 diabetes: A pilot study.

Aim: To determine the short-term biochemical effects and clinical tolerability of intermittent fasting (IF) in adults with type 2 diabetes mellitus (T2DM).

Methods: We describe a three-phase observational study (baseline 2 wk, intervention 2 wk, follow-up 2 wk) designed to determine the clinical, biochemical, and tolerability of IF in community-dwelling volunteer adults with T2DM. Biochemical, anthropometric, and physical activity measurements (using the Yale Physical Activity Survey) were taken at the end of each phase.

Male Hypogonadism and Osteoporosis: The Effects, Clinical Consequences, and Treatment of Testosterone Deficiency in Bone Health.

It is well recognized that bone loss accelerates in hypogonadal states, with female menopause being the classic example of sex hormones affecting the regulation of bone metabolism. Underrepresented is our knowledge of the clinical and metabolic consequences of overt male hypogonadism, as well as the more subtle age-related decline in testosterone on bone quality. While menopause and estrogen deficiency are well-known risk factors for osteoporosis in women, the effects of age-related testosterone decline in men on bone health are less well known.

The ubiquitin-conjugating enzyme, Ubc1, indirectly regulates SNF1 kinase activity via Forkhead-dependent transcription.

The SNF1 kinase in is an excellent model to study the regulation and function of the AMP-dependent protein kinase (AMPK) family of serine-threonine protein kinases. Yeast discoveries regarding the regulation of this non-hormonal sensor of metabolic/environmental stress are conserved in higher eukaryotes, including poly-ubiquitination of the α-subunit of yeast (Snf1) and human (AMPKα) that ultimately effects subunit stability and enzyme activity. The ubiquitin-cascade enzymes responsible for targeting Snf1 remain unknown, leading us to screen for those that impact SNF1 kinase function.

Mitotic degradation of yeast Fkh1 by the Anaphase Promoting Complex is required for normal longevity, genomic stability and stress resistance.

The Saccharomyces cerevisiae Forkhead Box (Fox) orthologs, Forkheads (Fkh) 1 and 2, are conserved transcription factors required for stress response, cell cycle progression and longevity. These yeast proteins play a key role in mitotic progression through activation of the ubiquitin E3 ligase Anaphase Promoting Complex (APC) via transcriptional control. Here, we used genetic and molecular analyses to demonstrate that the APC E3 activity is necessary for mitotic Fkh1 protein degradation and subsequent cell cycle progression.

Development, Maintenance, and Reversal of Multiple Drug Resistance: At the Crossroads of TFPI1, ABC Transporters, and HIF1.

Early detection and improved therapies for many cancers are enhancing survival rates. Although many cytotoxic therapies are approved for aggressive or metastatic cancer; response rates are low and acquisition of de novo resistance is virtually universal. For decades; chemotherapeutic treatments for cancer have included anthracyclines such as Doxorubicin (DOX); and its use in aggressive tumors appears to remain a viable option; but drug resistance arises against DOX; as for all other classes of compounds.

A Genome Scale Screen for Mutants with Delayed Exit from Mitosis: Ire1-Independent Induction of Autophagy Integrates ER Homeostasis into Mitotic Lifespan.

Proliferating eukaryotic cells undergo a finite number of cell divisions before irreversibly exiting mitosis. Yet pathways that normally limit the number of cell divisions remain poorly characterized. Here we describe a screen of a collection of 3762 single gene mutants in the yeast Saccharomyces cerevisiae, accounting for 2/3 of annotated yeast ORFs, to search for mutants that undergo an atypically high number of cell divisions.

The SNF1 Kinase Ubiquitin-associated Domain Restrains Its Activation, Activity, and the Yeast Life Span.

The enzyme family of heterotrimeric AMP-dependent protein kinases is activated upon low energy states, conferring a switch toward energy-conserving metabolic pathways through immediate kinase actions on enzyme targets and delayed alterations in gene expression through its nuclear relocalization. This family is evolutionarily conserved, including the presence of a ubiquitin-associated (UBA) motif in most catalytic subunits. The potential for the UBA domain to promote protein associations or direct subcellular location, as seen in other UBA-containing proteins, led us to query whether the UBA domain within the yeast AMP-dependent protein kinase ortholog, SNF1 kinase, was important in these aspects of its regulation.

Development and validation of fast and simple flow injection analysis-tandem mass spectrometry (FIA-MS/MS) for the determination of metformin in dog serum.

A simple, fast and sensitive quantification method for the drug metformin in dog serum was developed using flow injection analysis (FIA)-tandem mass spectrometry (MS/MS). The method was fully validated according to industry standards. It is the first time that FIA-MS/MS for metformin was developed surpassing all existing methods in terms of time of analysis.

Mechanisms of disease: role of neurotrophins in diabetes and diabetic neuropathy.

Neuropathy is an insidious and devastating consequence of diabetes. Early studies provided a strong rationale for deficient neurotrophin support in the pathogenesis of diabetic neuropathy in a number of critical tissues and organs. It has now been over a decade since the first failed human neurotrophin supplementation clinical trials, but mounting evidence still implicates these trophic factors in diabetic neuropathy.

TFPI1 mediates resistance to doxorubicin in breast cancer cells by inducing a hypoxic-like response.

Thrombin and hypoxia are important players in breast cancer progression. Breast cancers often develop drug resistance, but mechanisms linking thrombin and hypoxia to drug resistance remain unresolved. Our studies using Doxorubicin (DOX) resistant MCF7 breast cancer cells reveals a mechanism linking DOX exposure with hypoxic induction of DOX resistance.