Publications

Colorectal cancer (CRC) is the third most common cancer type, and third highest in mortality rates among cancer-related deaths in the United States. Originating from intestinal epithelial cells in the colon and rectum, that are impacted by numerous factors including genetics, environment and chronic, lingering inflammation, CRC can be a problematic malignancy to treat when detected at advanced stages. Chemotherapeutic agents serve as the historical first line of defense in the treatment of metastatic CRC. In recent years, however, combinational treatment with targeted therapies, such as vascular endothelial growth factor, or epidermal growth factor receptor inhibitors, has proven to be quite effective in patients with specific CRC subtypes. While scientific and clinical advances have uncovered promising new treatment options, the five-year survival rate for metastatic CRC is still low at about 14%. Current research into the efficacy of immunotherapy, particularly immune checkpoint inhibitor therapy (ICI) in mismatch repair deficient and microsatellite instability high (dMMR-MSI-H) CRC tumors have shown promising results, but its use in other CRC subtypes has been either unsuccessful, or not extensively explored. This Review will focus on the current status of immunotherapies, including ICI, vaccination and adoptive T cell therapy (ATC) in the treatment of CRC and its potential use, not only in dMMR-MSI-H CRC, but also in mismatch repair proficient and microsatellite instability low (pMMR-MSI-L).

JNK is a stress-activated protein kinase that modulates pathways implicated in a variety of disease states. JNK-interacting protein-1 (JIP1) is a scaffolding protein that enhances JNK signaling by creating a proximity effect between JNK and upstream kinases. A minimal peptide region derived from JIP1 is able to inhibit JNK activity both in vitro and in cell. We report here a series of small molecules JIP1 mimics that function as substrate competitive inhibitors of JNK. One such compound, BI-78D3, dose-dependently inhibits the phosphorylation of JNK substrates both in vitro and in cell. In animal studies, BI-78D3 not only blocks JNK dependent Con A-induced liver damage but also restores insulin sensitivity in mouse models of type 2 diabetes. Our findings open the way for the development of protein kinase inhibitors targeting substrate specific docking sites, rather than the highly conserved ATP binding sites. In view of its favorable inhibition profile, selectivity, and ability to function in the cellular milieu and in vivo, BI-78D3 represents not only a JNK inhibitor, but also a promising stepping stone toward the development of an innovative class of therapeutics.

The nuclear factor kappaB (NF-kappaB) pathway plays a central role in inflammation and immunity. In response to proinflammatory cytokines and pathogen-associated molecular patterns, NF-kappaB activation is controlled by IkappaB kinase (IKK)beta. Using Cre/lox-mediated gene targeting of IKKbeta, we have uncovered a tissue-specific role for IKKbeta during infection with group B streptococcus. Although deletion of IKKbeta in airway epithelial cells had the predicted effect of inhibiting inflammation and reducing innate immunity, deletion of IKKbeta in the myeloid lineage unexpectedly conferred resistance to infection that was associated with increased expression of interleukin (IL)-12, inducible nitric oxide synthase (NOS2), and major histocompatibility complex (MHC) class II by macrophages. We also describe a previously unknown role for IKKbeta in the inhibition of signal transducer and activator of transcription (Stat)1 signaling in macrophages, which is critical for IL-12, NOS2, and MHC class II expression. These studies suggest that IKKbeta inhibits the "classically" activated or M1 macrophage phenotype during infection through negative cross talk with the Stat1 pathway. This may represent a mechanism to prevent the over-exuberant activation of macrophages during infection and contribute to the resolution of inflammation. This establishes a new role for IKKbeta in the regulation of macrophage activation with important implications in chronic inflammatory disease, infection, and cancer.

Rheumatoid arthritis (RA) is a chronic inflammatory disease marked by bone and cartilage destruction. Current biologic therapies are beneficial in only a portion of patients; hence small molecules targeting key pathogenic signaling cascades represent alternative therapeutic strategies. Here we show that c-Jun N-terminal kinase (JNK) 1, but not JNK2, is critical for joint swelling and destruction in a serum transfer model of arthritis. The proinflammatory function of JNK1 requires bone marrow-derived cells, particularly mast cells. Without JNK1, mast cells fail to degranulate efficiently and release less IL-1β after stimulation via Fcγ receptors (FcγRs). Pharmacologic JNK inhibition effectively prevents arthritis onset and abrogates joint swelling in established disease. Hence, JNK1 controls mast cell degranulation and FcγR-triggered IL-1β production, in addition to regulating cytokine and matrix metalloproteinase biosynthesis, and is an attractive therapeutic target in inflammatory arthritis.

Supplementary Figures 1-4 from Macrophage Expression of Hypoxia-Inducible Factor-1α Suppresses T-Cell Function and Promotes Tumor Progression

Purpose: Older adults are less likely to meet physical activity guidelines and spend more time sitting than younger adults. Aging adults have elevated cardiometabolic disease and cancer risk, which can be exacerbated in postmenopausal women due to hormonal shifts and increased adiposity. The postural change of standing increases muscle contractions and arterial blood flow and induces compensatory changes in heart rate and blood pressure. Thus, interrupting prolonged sitting with brief standing breaks may be a feasible approach to improve aging-associated metabolic and vascular health outcomes. Methods: Postmenopausal women with overweight or obesity (n = 79; age 67 ± 7y) were enrolled in a three-condition, randomized crossover trial. Participants completed three supervised, 5-h experimental conditions: Prolonged sitting (Control), frequent Sit-to-Stands (STS - 2 min stand every 15 min), and Hourly Standing Breaks (HSB - 8 min stand every hour). Each standing break condition included 40 min of total standing time but varied in number and duration of breaks. Standardized liquid meals were consumed at 0 min (M1) and 180 min (M2). Blood samples were collected across the condition periods to determine the incremental area under the curve (iAUC) for glucose and insulin during the total and post-meal periods: 0-300 min, 0-120 min, and 180-300 min. Condition impact on superficial femoral artery endothelial function was assessed using flow-mediated dilation (FMD). Linear mixed models compared iAUC and FMD ratio (5 h-to-baseline) values between experimental and control conditions. Results: There was no evidence of between-condition differences (p > 0.05) for insulin and glucose iAUCs from 0-300 min. However, STS significantly lowered 2-hr postprandial blood glucose excursion after M2 compared to after M1 by -13.4% (p = 0.04). Control and HSB had significantly higher 2-hr postprandial insulin excursions after M2 compared to after M1 (+10.9%, p = 0.03; +11.5%, p = 0.02, respectively). Both STS and HSB significantly mitigated the negative effect of prolonged sitting on FMD-measured endothelial function observed in the control (+17.9%, p < 0.001 and + 22.5%, p < 0.001, respectively). Conclusion: Brief, low-intensity interruptions of sitting time with standing acutely improves endothelial functioning in older women. Supported by: National Institute of Aging (P01 AG052352) and National Center for Advancing Translational Sciences (UL1TR001442)

To develop an epidemiological profile of children that work in the streets of Tijuana, Mexico, and to determine the prevalence of cigarette smoking in this group, as well as the prevalence of those factors associated with tobacco experimentation.cross-sectional.Children aged 8 through 15, who work in the streets of Tijuana were included. Demographic, socioeconomic, and smoking related variables were analyzed.The study included 110 children, with a mean age of 11.43 years. Of these 91.7% live with one or both of their parents; 60% attend school and an additional 30% did so in the past. Only 6.4% of these children are the principal economic support of the household, and 51.8% reported an average daily income of $US 10 or less. Only 9.1% reported experimentation with tobacco, and 31% of them tobacco prompting (in the form of lighting up a cigarette) by an adult of the family; this is significantly more frequent on behalf of the father than of the mother (21.8% vs 4.5% p < 0.001).Most of the children under 15 years of age who work in the streets of Tijuana live with their parents and maintain close relationships with their family. Most of them attend school and work in the streets only to complement the family income. Their tobacco experimentation is not greater than that of other children of the same age group.