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The oncogenic Pim kinase proteins (Pim-1/2/3) regulate tumorigenesis through phosphorylating essential proteins that control cell cycle and proliferation. Pim kinase is a potential chemotherapeutic target in cancer and its inhibition is currently the focus of intensive drug design and development efforts. The distinctive presence of proline amino acids in the hinge region provides an opportunity to inhibit Pim kinase while conserving the physiological functions of other kinases and reducing the toxicity profiles of the inhibitors. selleck chemicals llc Various Pim kinase inhibitors have been clinically evaluated for the treatment of hematological cancers, yet none has reached the clinic. In this review, we discuss the design and development of selective and potent Pim inhibitors with novel chemotypes focusing on structural features essential for high potency and selectivity.Adrenergic systems regulate both cognitive function and immune function. The primary source of adrenergic signaling in the brain is norepinephrine (NE) neurons of the locus coeruleus (LC), which are vulnerable to age-related degeneration and are one of the earliest sites of pathology and degeneration in neurodegenerative disorders such as Alzheimer’s Disease (AD). Loss of adrenergic tone may potentiate neuroinflammation both in aging and neurodegenerative conditions. Importantly, beta-blockers (beta-adrenergic antagonists) are a common treatment for hypertension, co-morbid with aging, and may further exacerbate neuroinflammation associated with loss of adrenergic tone in the central nervous system (CNS). The present studies were designed to both examine proinflammatory consequences of beta-blocker administration in an acute lipopolysaccharide (LPS) model as well as to examine chronic effects of beta-blocker administration on neuroinflammation and behavior in an amyloid-beta protein precursor (APP) mouse modelAdditionally, beta-blockers impaired learning and memory and modulated synaptic phagocytosis with implications for synaptic degeneration. These findings warrant further consideration of the proinflammatory consequences of chronic beta-blocker administration, which are not restricted to the periphery in patients with neurodegenerative disorders.Increasing evidence suggests that alpha-synuclein (α-syn) oligomers are obligate intermediates in the pathway involved in α-syn fibrillization and Lewy body (LB) formation, and may also accumulate within LBs in Parkinson’s disease (PD) and other synucleinopathies. Therefore, the development of tools and methods to detect and quantify α-syn oligomers has become increasingly crucial for mechanistic studies to understand their role in PD, and to develop new diagnostic methods and therapies for PD and other synucleinopathies. The majority of these tools and methods rely primarily on the use of aggregation state-specific or conformation-specific antibodies. Given the impact of the data and knowledge generated using these antibodies on shaping the foundation and directions of α-syn and PD research, it is crucial that these antibodies are thoroughly characterized, and their specificity or ability to capture diverse α-syn species is tested and validated. Herein, we describe an antibody characterization and validationest that the great majority of α-syn aggregate-specific antibodies do not differentiate between oligomers and fibrils, thus highlighting the importance of exercising caution when interpreting results obtained using these antibodies. Our results also underscore the critical importance of the characterization and validation of antibodies before their use in mechanistic studies and as diagnostic tools or therapeutic agents. This will not only improve the quality and reproducibility of research and reduce costs but will also reduce the number of therapeutic antibody failures in the clinic.

Whether gastric emptying tests predict longitudinal outcomes in patients with symptoms of gastroparesis is unclear. We aimed to determine whether baseline gastric emptying tests and gut motility parameters could impact longitudinal symptom(s) and quality of life (QOL) in a prospective, observational cohort study of patients with symptoms of gastroparesis.

One hundred fifty patients with gastroparesis symptoms underwent simultaneous scintigraphy (GES) and wireless motility capsule (WMC) measurement of gastric emptying and other motility parameters. Patient Assessment of Upper Gastrointestinal Symptoms and Quality of Life were administered at baseline, and 3 and 6 months after testing. Multivariable generalized linear marginal models were fit to determine which baseline parameters predict longitudinal changes in symptoms and QOL.

Overall upper GI symptoms and QOL scores were moderate in severity at baseline and significantly improved over 6 months. Clinical variables, including female gender, harder stoolof life outcomes. These factors may help to risk stratify patients and guide treatment decisions. ClinicalTrials.gov no NCT02022826.

Studies have suggested marked increases in transplant delisting due to clinical improvement for patients with hepatitis C virus (HCV) associated cirrhosis in the era of direct acting antivirals (DAAs). This study provides a ‘real world’ assessment of waitlist dynamics for HCV transplant candidates in the current era.

This was a retrospective cohort study of adults waitlisted for liver transplant (LT) alone between 1/1/2005-12/31/2018 using national US data. The post-DAA era included all listings occurring after 1/1/2013. Temporal trends in waitlisting, patient characteristics and outcomes with decompensated cirrhosis were evaluated. Adjusted competing risks models assessed the interaction of DAA-era and HCV history on (i) waitlist mortality, and (ii) delisting due to clinical improvement.

Overall listing rates for HCV patients have decreased in the DAA era and particularly with Model for End-stage Liver Disease score ≥15 and ≥30. Rates of refractory ascites and severe encephalopathy at listing have increased. Delisting due to clinical improvement remains low (6.1% for 2013-2017 versus 5.2% for 2009-2012 versus 4% for 2005-2008; p < .001) and, for many, ascites (46.5%) and encephalopathy (30.5%) persist at delisting. Waitlist recovery is more frequent for HCV patients post-DAA (adjusted SHR 1.78 vs pre-DAA, 95% CI 1.58-2.02; p<.001), while improvements in waitlist mortality by era are similar to non-HCV candidates (adjusted SHR 0.74 [95% CI 0.7-0.78; p < .001] and 0.77 [95% CI 0.74-0.8; p < .001], respectively).

Listing rates for decompensated HCV cirrhosis have decreased in the DAA era. Delisting of HCV patients for clinical improvement has increased, but remains infrequent and many continue to experience considerable morbidity.

Listing rates for decompensated HCV cirrhosis have decreased in the DAA era. Delisting of HCV patients for clinical improvement has increased, but remains infrequent and many continue to experience considerable morbidity.