Back to the drawing board: Overview of the next generation of combination therapy for inflammatory bowel disease.

Inflammatory bowel disease (IBD) is entering a potentially new era of combined therapeutics. Triantafillidis provide an insightful review of the current state of combination therapy, with a focus on the use of a combined biologic and immunomodulator, as well as emerging data on the future potential of dual-biologic therapy (DBT). While current evidence for DBT is limited, encouraging safety profiles and ongoing trials suggest a brighter future for this approach.

Reactive Immunomodulator Addition to Infliximab Monotherapy Restores Clinical Response in Inflammatory Bowel Disease: A Meta-Analysis.

Background And Aims: Patients with inflammatory bowel disease (IBD) receiving infliximab (IFX) commonly experience immunogenic loss of response (LOR) by formation of anti-drug antibodies (ADAs). An immunomodulator (IMM) used in combination with initial IFX induction is known to reduce ADA development and improve clinical outcomes. We aimed to assess the impact of reactively adding an IMM to patients on IFX monotherapy.

Pharmacologic Anticoagulation Is Associated With a Lower Risk of Recurrent Venous Thromboembolic Events During Janus Kinase Inhibitor Use for Patients With a Prior Thrombosis.

Background: Janus kinase (JAK) inhibitors tofacitinib and upadacitinib are effective therapies for inflammatory bowel disease and rheumatologic disorders but currently possess a warning for increased venous thromboembolism (VTE) risk. Some patients with a history of VTE may benefit from a JAK inhibitor, but the risk of recurrent VTE with JAK inhibitor use is unclear. Our goal was to observe rates of new VTE events after starting JAK inhibitor therapy in patients with a prior VTE, and observe whether concurrent anticoagulation (AC) reduces this risk.

Stress promotes the infiltration of peripheral immune cells to the brain.

Immune cells and the brain have a privileged interaction. Here, we report changes in the hippocampal immune microenvironment at the single cell level after stress, uncovering the tight orchestration of immune cell infiltration into the hippocampus after stress to maintain homeostasis. We show the distribution of several immune cell types in the hippocampus associated with their susceptibility or resilience to the learned helplessness paradigm in a sex- and microbiota-dependent manner using single-cell RNA sequencing and bioinformatic tools, flow cytometry, and immunofluorescence.

Phenotypic Screening Following Transcriptomic Deconvolution to Identify Transcription Factors Mediating Axon Growth Induced by a Kinase Inhibitor.

After injury to the central nervous system (CNS), both neuron-intrinsic limitations on regenerative responses and inhibitory factors in the injured CNS environment restrict regenerative axon growth. Instances of successful axon regrowth offer opportunities to identify features that differentiate these situations from that of the normal adult CNS. One such opportunity is provided by the kinase inhibitor RO48, which dramatically enhances neurite outgrowth of neurons in vitro and substantially increased contralateral sprouting of corticospinal tract neurons when infused intraventricularly following unilateral pyramidotomy.

AAV8 transduction capacity is reduced by prior exposure to endosome-like pH conditions.

Adeno-associated virus (AAV) is an essential instrument in the neuroscientist's toolkit, which allows delivery of DNA to provide labeling with fluorescent proteins or genetic instructions to regulate gene expression. In the field of neural regeneration, the transduction of neurons enables the observation and regulation of axon growth and regeneration, and in the future will likely be a mechanism for delivering molecular therapies to promote sprouting and regeneration after central nervous system injury. Traditional formulations of AAV preparations permit efficient viral transduction under physiologic conditions, but an improved understanding of the mechanistic limitations of AAV transduction may facilitate production of more resilient AAV strains for investigative and therapeutic purposes.

Vaccination against cocaine using a modifiable dendrimer nanoparticle platform.

Pharmacological therapies for the treatment of cocaine addiction have had disappointing efficacy, and the lack of recent developments in the clinical care of cocaine-addicted patients indicates a need for novel treatment strategies. Recent studies have shown that vaccination against cocaine to elicit production of antibodies that reduce concentrations of free drug in the blood is a promising method to protect against the effects of cocaine and reduce rates of relapse. However, the poorly immunogenic nature of cocaine remains a major hurdle to active immunization.

Glycogen synthase kinase-3 promotes T helper type 17 differentiation by promoting interleukin-9 production.

T helper type 17 (Th17) cells are recognized as important contributors to the deleterious effects of several neurological and psychiatric diseases. Clarifying mechanisms that control the production of Th17 cells may therefore provide new strategies for developing novel interventions in a broad spectrum of disorders. Th17 cell differentiation is promoted by glycogen synthase kinase-3 (GSK3), but the mechanisms for this are only beginning to be understood.

Involvement of Innate and Adaptive Immune Systems Alterations in the Pathophysiology and Treatment of Depression.

Major depressive disorder (MDD) is a prevalent and debilitating disorder, often fatal. Treatment options are few and often do not provide immediate relief to the patients. The increasing involvement of inflammation in the pathology of MDD has provided new potential therapeutic avenues.

Defective Inflammatory Pathways in Never-Treated Depressed Patients Are Associated with Poor Treatment Response.

Inflammation has been involved in the pathophysiology and treatment response of major depressive disorder (MDD). Plasma cytokine profiles of 171 treatment-naive MDD patients (none of the MDD patients received an adequate trial of antidepressants or evidence-based psychotherapy) and 64 healthy controls (HCs) were obtained. MDD patients exhibited elevated concentrations of 18 anti- and proinflammatory markers and decreased concentrations of 6 cytokines.

Distinct characteristics of hippocampal pathogenic T17 cells in a mouse model of depression.

Increasing evidence indicates that multiple actions of the immune system are closely intertwined with the development of depression and subsequent recovery processes. One of these interactions is substantial evidence that the T17 subtype of CD4 T cells promotes susceptibility to depression-like behaviors in mice. Comparing subtypes of CD4 T cells, we found that administration of T17 cells, but not T1 cells or T, promoted susceptibility to learned-helplessness depressive-like behavior and accumulated in the hippocampus of learned helpless mice.

Th17 cells in depression.

T helper 17 (Th17) cells have recently been implicated in depression, which adds to the list of several other diseases of the central nervous system (CNS) that are already known to involve Th17 cells. In CNS diseases, it is thought that the signature cytokine produced by Th17 cells, interleukin-17A (IL-17A), mediates the detrimental effects of Th17 cells. In depression, although Th17 cells increase, the lack of a consistent correlation between depression severity and blood IL-17A levels suggests that Th17 cells promote depressive symptoms, which may not be entirely dependent on IL-17.

Stressed and Inflamed, Can GSK3 Be Blamed?

Psychological stress has a pervasive influence on our lives. In many cases adapting to stress strengthens organisms, but chronic or severe stress is usually harmful. One surprising outcome of psychological stress is the activation of an inflammatory response that resembles inflammation caused by infection or trauma.

Outcomes Using Grafts from Donors after Cardiac Death.

Background: Previous reports suggest that donation after cardiac death (DCD) liver grafts have increased primary nonfunction (PNF) and cholangiopathy thought to be due to the graft warm ischemia before cold flushing.

Study Design: In this single-center, retrospective study, 866 adult liver transplantations were performed at our institution from January 2005 to August 2014. Forty-nine (5.

Donor Age-Based Analysis of Liver Transplantation Outcomes: Short- and Long-Term Outcomes Are Similar Regardless of Donor Age.

Background: The shortage of donor organs has led to increasing use of extended criteria donors, including older donors. The upper limit of donor age that produces acceptable outcomes continues to be explored. In liver transplantation, with appropriate selection, graft survival and patient outcomes would be comparable regardless of age.

Morbid obesity in liver transplant recipients adversely affects longterm graft and patient survival in a single-institution analysis.

Objective: The effects of obesity in liver transplantation remain controversial. Earlier institutional data demonstrated no significant difference in postoperative complications or 1-year mortality. This study was conducted to test the hypothesis that obesity alone has minimal effect on longterm graft and overall survival.

Organ allocation in pediatric renal transplants: is there an optimal donor?

The 2005 revised allocation scheme for pediatric renal transplantation made the decision of whether to transplant an available living-donor (LD) kidney or use a deceased-donor (DD) kidney controversial. The aim of this study was to examine kidney allograft utilization, sensitization, and outcomes of pediatric transplant recipients. Between January 2000 and December 2009, 91 consecutive pediatric kidney recipients (<20 yr) were transplanted.

Outcomes with split liver transplantation are equivalent to those with whole organ transplantation.

Background: Split liver transplantation is an excellent option for expansion of the donor organ pool. However, reports of increased morbidity in split liver recipients may limit use of this technique.

Study Design: This was a single center retrospective analysis investigating split liver transplantation.

Liver transplantation for hepatocellular carcinoma: long-term results suggest excellent outcomes.

Background: Selected 5-year survival results after liver transplantation for hepatocellular carcinoma (HCC) have been reported to be 70%. Our hypothesis was that liver transplantation is effective for long-term cancer control for HCC.

Study Design: A 20-year retrospective review of a prospectively collected database was carried out.

Utilization of hepatitis B core antibody-positive donor liver grafts.

Background: The inclusion of hepatitis B core antibody-positive (HBcAb+) liver donors is a strategy utilized to increase organ availability. This study examined HBcAb+ transplantation practices to identify specific factors influencing outcomes.

Methods: Twenty-five HBcAb+ liver transplants were identified retrospectively among 868 adult transplants performed between 1 January 1997 and 31 December 2009.

Management of excluded bile ducts in paediatric orthotopic liver transplant recipients of technical variant allografts.

Background: A strategy to increase the number of size- and weight-appropriate organs and decrease the paediatric waiting list mortality is wider application of sectional orthotopic liver transplantation (OLT). These technical variants consist of living donor, deceased donor reduced and split allografts. However, these grafts have an increased risk of biliary complications.

Increased consistency and efficiency in routine potency testing by bioassay with direct use of cryopreserved (ready-to-plate) cells.

The use of cells as a cryopreserved, readily available reagent has facilitated high-throughput screening of new drug candidates by bioassay. This practice is considerably less labor intensive and allows more flexibility in laboratory testing than traditional continuous cell culture. We have shown that this practice can be adapted to cell proliferation and reporter gene assay formats used in routine sample testing for determination of relative potency of commercial product in a Quality Control Laboratory.