Izencitinib (TD-1473), an oral, gut-selective pan-Janus kinase (JAK) inhibitor under investigation for treatment of inflammatory bowel diseases, was designed for optimal efficacy in the gastrointestinal tract while minimizing systemic exposures and JAK-related safety findings. The nonclinical safety of izencitinib was evaluated in rat and dog repeat-dose and rat and rabbit reproductive and developmental toxicity studies. Systemic exposures were compared with JAK inhibitory potency to determine effects at or above pharmacologic plasma concentrations (≥1× plasma average plasma concentration [Cave]:JAK 50% inhibitory concentration [IC50] ratio). In rats and dogs, 1000 and 30 mg/kg/day izencitinib, respectively, produced minimal systemic findings (ie, red/white cell changes) and low systemic concentrations (approximately 1× plasma Cave:JAK IC50 ratio) with an 8× nonclinical:clinical systemic area under the curve (AUC) margin compared with exposures at the highest clinically tested dose (300 mg, quaque die, once daily, phase 1 study in healthy volunteers). In dogs, it was possible to attain sufficient systemic exposures to result in immunosuppression characteristic of systemic JAK inhibition, but at high AUC margins (43×) compared with systemic exposures observed at the highest tested dose in humans. No adverse findings were observed in the gastrointestinal tract or systemic tissues. Izencitinib did not affect male or female fertility. Izencitinib did not affect embryonic development in rats and rabbits as commonly reported with systemic JAK inhibition, consistent with low maternal systemic concentrations (2-6× plasma Cave:JAK IC50 ratio, 10-33× nonclinical:clinical AUC margin) and negligible fetal exposures. In conclusion, the izencitinib gut-selective approach resulted in minimal systemic findings in nonclinical species at pharmacologic, clinically relevant systemic exposures, highlighting the impact of organ-selectivity in reducing systemic safety findings.

Dietary factors have not as yet had their roles clearly defined with respect to the development of human cancer. The complexities of studying nutrition and its relation to tumor development are significant; overt human cancers usually take many years to develop, often with a lag time of 20 to 40 years. Experimental animal models evolve through a multistage process, and there is reason to believe that this is the case with human cancer. Some groups of rats were allowed to consume a balanced diet ad libitum and others were given 75% of the amount consumed by the ad libitum groups. Cancer of the kidney, pancreas, colorectum, prostate, endometrium, and breast in human populations have been associated with above-average levels of dietary protein intake. The rats used in the studies of Ross et al. developed so many different types of tumors that one cannot easily delineate the effect of diet on specific types.

After 15 years of existence, the ACVP/STP Coalition for Veterinary Pathology Fellows will dissolve, primarily due to lack of renewed financial sponsorship. While in operation, the Coalition organized 32 new training position for veterinary pathologists, supported by $7.4 M from sponsors, including pharmaceutical and biotechnology companies, contract research organizations, private individuals and allied veterinary pathology support groups. All residual funds will be donated to ACVP and STP with the understanding that the two organizations will use these funds to enhance training by collaborating on outreach efforts, thus maintaining the legacy and spirit of the Coalition.

Background: Colorectal cancer (CRC) is the third most commonly diagnosed cancer worldwide. Screening is linked to significant reductions in CRC incidence and mortality, however, uptake rates remain alarmingly low. Methods: We conducted a systematic review, meta-analysis and meta-regression to examine the effectiveness of interventions aimed at increasing CRC screening uptake. We conducted a sensitivity analysis of studies that recruited vulnerable populations (minority, underserved, poor). Meta-regression examined whether intervention type, duration, gender, age, number of behaviour change techniques (BCTs) and other components of the intervention or methodology modified the overall intervention effect. Findings: A total of 102 RCTs involving 1.94 million participants were included. Meta-analysis showed significant benefit of all interventions combined (g= 0.26; OR 1.60; 95% CI 1.49-1.71, p<0.001); sensitivity analysis showed that interventions were significantly more beneficial when restricted to vulnerable population studies (k= 36, g=0.43, OR 2.18; 95% CI 1.78-2.67, P<0.001). Meta-regression showed that age, duration, number of BCTs and type of intervention did not modify intervention effects. Interventions that incorporated the BCTs ‘prompts/cues’ and techniques from the categories of ‘Social Support’, ‘Goals and Planning’ and ‘Shaping Knowledge’ were more effective than other interventions. Quality of the majority of the studies was unclear or poor (k = 86, 84.3%). Discussion: Techniques reducing structural barriers to screening were effective in increasing uptake, especially among vulnerable populations. The meta-analysis and meta-regression led to the identification of specific intervention components and BCTs potentially effective in increasing CRC screening uptake for different populations. A lack of psychosocial and theory-driven interventions was observed.

Toxicologic pathologists contribute significantly to the development of new biopharmaceuticals, yet there is often a lack of awareness of this specialized role. As the members of multidisciplinary teams, toxicologic pathologists participate in all aspects of the drug development process. This review is part of an initiative by the Society of Toxicologic Pathology to educate scientists about toxicologic pathology and to attract junior scientists, veterinary students, and veterinarians into the field. We describe the role of toxicologic pathologists in identifying candidate agents, elucidating bioactive pathways, and evaluating efficacy and toxicity in preclinical animal models. Educational and specialized training requirements and the challenges of working in a global environment are discussed. The biopharmaceutical industry provides diverse, challenging, and rewarding career opportunities in toxicologic pathology. We hope that this review promotes understanding of the important role the toxicologic pathologist plays in drug development and encourages exploration of an important career option.

SummaryThe role of lymphocytes in the pathogenesis of lung fibrosis is not clear, but the weight of the evidence supports a pro‐fibrotic effect for lymphocytes. The high‐affinity interleukin‐2 receptor (haIL‐2R) is expressed on activated, but not quiescent, T lymphocytes. This selective expression of haIL‐2R provides the basis for therapeutic strategies that target IL‐2R‐expressing cells. We hypothesized that elimination of activated lymphocytes by IL‐2R‐targeted chimeric proteins might ameliorate lung fibrosis. We investigated the effects of IL‐2‐Bax, a novel apoptosis‐inducing IL‐2R‐targeted chimeric protein, on bleomycin‐induced lung injury in mice. Treatment groups included (i) a single intratracheal instillation of bleomycin and twice‐daily intraperitoneal injections of IL‐2‐Bax; (ii) intratracheal bleomycin and intraperitoneal IL‐2‐PE664Glu, an older‐generation chimeric protein; (iii) intratracheal bleomycin/intraperitoneal PBS; (iv) intratracheal saline/intraperitoneal PBS. Lung injury was evaluated 14 days after intratracheal instillation by cell count in bronchoalveolar lavage (BAL) fluid, semi‐quantitative and quantitative histomorphological measurements and by biochemical analysis of lung hydroxyproline. Bleomycin induced a BAL lymphocytosis that was significantly attenuated by IL‐2‐Bax and IL‐2‐PE664Glu. However, morphometric parameters and lung hydroxyproline were unaffected by the chimeric proteins. These results show that IL‐2‐Bax reduces the lymphocytic infiltration of the lungs in response to bleomycin, but this effect is not accompanied by a decrease in lung fibrosis.

The role of lymphocytes in the pathogenesis of lung fibrosis is not clear, but the weight of the evidence supports a pro-fibrotic effect for lymphocytes. The high-affinity interleukin-2 receptor (haIL-2R) is expressed on activated, but not quiescent, T lymphocytes. This selective expression of haIL-2R provides the basis for therapeutic strategies that target IL-2R-expressing cells. We hypothesized that elimination of activated lymphocytes by IL-2R-targeted chimeric proteins might ameliorate lung fibrosis. We investigated the effects of IL-2-Bax, a novel apoptosis-inducing IL-2R-targeted chimeric protein, on bleomycin-induced lung injury in mice. Treatment groups included (i) a single intratracheal instillation of bleomycin and twice-daily intraperitoneal injections of IL-2-Bax; (ii) intratracheal bleomycin and intraperitoneal IL-2-PE66(4Glu), an older-generation chimeric protein; (iii) intratracheal bleomycin/intraperitoneal PBS; (iv) intratracheal saline/intraperitoneal PBS. Lung injury was evaluated 14 days after intratracheal instillation by cell count in bronchoalveolar lavage (BAL) fluid, semi-quantitative and quantitative histomorphological measurements and by biochemical analysis of lung hydroxyproline. Bleomycin induced a BAL lymphocytosis that was significantly attenuated by IL-2-Bax and IL-2-PE66(4Glu). However, morphometric parameters and lung hydroxyproline were unaffected by the chimeric proteins. These results show that IL-2-Bax reduces the lymphocytic infiltration of the lungs in response to bleomycin, but this effect is not accompanied by a decrease in lung fibrosis.

Intratracheal instillation (IT) of bleomycin is a widely used experimental model for lung fibrosis. In this study we describe the time-course of bleomycin-induced lung fibrosis in mice using computer-assisted morphometry. C57Bl/6J mice were treated with a single IT dose of bleomycin or control saline. Animals were killed 3, 6, 14 and 21 days post-IT. Lung injury was evaluated by analysis of bronchoalveolar lavage (BAL) fluid, hydroxyproline concentration in the lung, routine light microscopic examination resulting in a semiquantitative morphological index (SMI) of lung injury, and quantitative morphological measurements (fibrosis fraction and alveolar wall area fraction) aided by optimas image analysis software. Changes in BAL fluid attributed to bleomycin treatment include increased total cell count (days 14 and 21), and increased percentage of neutrophils (days 3 and 6) followed by a sustained increase in lymphocytes (days 6, 14 and 21). Hydroxyproline levels increased in bleomycin-treated mice on days 14 and 21. Median SMI grades were significantly elevated on days 3, 14 and 21. Computer-assisted morphometry demonstrated a 3-fold increase in fibrosis fraction and a 1.3-fold increase in wall area fraction in bleomycin-treated mice on day 14, with no further increase on day 21. These data also demonstrate that the most suitable time point for assessing lung fibrosis in this model is 14 days after IT instillation of bleomycin, based on the observation that at 14 days the animals developed extensive fibrosis, but had less variability in the fibrotic response and lower mortality than later at 21 days. Computer-assisted morphometry provides objective and quantitative measurements that are a useful tool for the evaluation of bleomycin-induced lung injury.