IDO1 scavenges reactive oxygen species in myeloid-derived suppressor cells to prevent graft-versus-host disease.

Tryptophan-catabolizing enzyme indoleamine 2,3-dioxygenase 1 (IDO1) also has an immunological function to suppress T cell activation in inflammatory circumstances, including graft-versus-host disease (GVHD), a fatal complication after allogeneic bone marrow transplantation (allo-BMT). Although the mononuclear cell expression of IDO1 has been associated with improved outcomes in GVHD, the underlying mechanisms remain unclear. Herein, we used IDO-deficient (Ido1-/-) BMT to understand why myeloid IDO limits the severity of GVHD. Hosts with Ido1-/- BM exhibited increased lethality, with enhanced proinflammatory and reduced regulatory T cell responses compared with wild type (WT) allo-BMT controls. Despite the comparable expression of the myeloid-derived suppressor cell (MDSC) mediators, arginase-1, inducible nitric oxide synthase, and interleukin 10, Ido1-/- Gr-1+CD11b+ cells from allo-BMT or in vitro BM culture showed compromised immune-suppressive functions and were skewed toward the Ly6ClowLy6Ghi subset, compared with the WT counterparts. Importantly, Ido1-/-Gr-1+CD11b+ cells exhibited elevated levels of reactive oxygen species (ROS) and neutrophil numbers. These characteristics were rescued by human IDO1 with intact heme-binding and catalytic activities and were recapitulated by the treatment of WT cells with the IDO1 inhibitor L1-methyl tryptophan. ROS scavenging by N-acetylcysteine reverted the Ido1-/-Gr-1+CD11b+ composition and function to an MDSC state, as well as improved the survival of GVHD hosts with Ido1-/- BM. In summary, myeloid-derived IDO1 enhances GVHD survival by regulating ROS levels and limiting the ability of Gr-1+CD11b+ MDSCs to differentiate into proinflammatory neutrophils. Our findings provide a mechanistic insight into the immune-regulatory roles of the metabolic enzyme IDO1.

Clinical and radiological diagnosis of gallstone ileus: a mini review.

Gallstone ileus is a rare cause of bowel obstruction, which mainly affects the elderly population. The associated mortality is estimated to be up to 30%. The presentation of gallstone ileus is notoriously non-specific, and this often contributes to the delay in diagnosis. The diagnosis of gallstone ileus relies on a radiological approach, and herein we discuss the benefits and drawbacks of the use of different modalities of radiological imaging: plain abdominal films, computed tomography, magnetic resonance imaging, and ultrasound scanning. Based on our case experience and review of the literature, the authors conclude that although an effective first-line tool, plain abdominal films are not adequate for diagnosing gallstone ileus. In fact, the gold standard in an acutely unwell patient is computed tomography.

East Asian adolescents' ethnic identity development and cultural integration: A qualitative investigation.

Drawing on the current conceptualization of acculturation/enculturation as bilinear, multidimensional processes proceeding in interaction with surrounding contexts, this study examined ethnic identity development and cultural integration of 13 adolescents from East Asian immigrant families. Five domains emerged via the Consensual Qualitative Research method: ethnic/cultural identity and socialization; bicultural living; racial context-racism and stereotypes; family context-parental expectation; and peer context-friendship/dating. Overall, the participants experienced a cultural split and discontinuity between the 2 worlds of home and ethnic community versus school and society in general. They received strong ethnic socialization messages from family and ethnic community. Although most participants experienced hurtful racial discrimination, they used passive coping (e.g., dismiss, minimize, defend perpetrators). The model minority stereotype was prevalent and deeply engrained in many aspects of their lives including ethnic identity development, cultural socialization messages from mainstream society, discrimination experiences, and academic/occupational demands imposed by self, parents, peers, and society. Although they appreciated parents' high expectations of academic/occupational success, they felt pressured and desired to have space and independence. Friendship/dating patterns reflected ethnic identity development as well as contextual influence. Implications for research and practice are discussed. (PsycINFO Database Record

Experimental analysis of PM2.5 reduction characteristics between Korean red pine (Pinus densiflora) and sawtooth oak (Quercus acutissima) saplings under different densities and arrangement structures.

As global air pollution, particularly fine particulate matter (PM2.5), has become a major environmental problem, various PM2.5 mitigation technologies including green infrastructure have received significant attention. However, owing to spatial constraints on urban greening, there is a lack of management plans for urban forests to efficiently mitigate PM2.5. In this study, we assessed the PM2.5 reduction capabilities of Pinus densiflora (Korean red pine) and Quercus acutissima (sawtooth oak) by measuring the changes of PM2.5 concentrations using an experimental chamber system. In addition, the PM2.5 reduction efficiency in 90 min (PMRE90) and the amount of PM2.5 reduction per leaf area (PMRLA) were compared based on arrangement structures and density levels. The results showed that the PM2.5 reduction by plants was significantly greater than that of the control experiment without any plants, and an additional reduction effect of approximately 1.38 times was induced by a 1.5 m s-1 air flow. The PMRE90 of Korean red pine was the highest at medium density. In contrast, the PMRE90 of sawtooth oak was the highest at high density. The PMRLA of both species was highest at low densities. The different responses of the species to total reduction were well explained by total leaf area (TLA). The PMRE90 of both species was positively correlated with TLA. The PMRLA of sawtooth oak was approximately 2.3 times greater than that of Korean red pine. However, there were no significant differences in both PMRE90 and PMRLA between the arrangement structures. Our findings reveal the potential mechanisms of vegetation in reducing PM2.5 according to arrangement structure and density. This highlights the importance of efficiently using urban green spaces with spatial constraints on PM2.5 mitigation in the future.

Altered hippocampal gene expression, glial cell population, and neuronal excitability in aminopeptidase P1 deficiency.

Inborn errors of metabolism are often associated with neurodevelopmental disorders and brain injury. A deficiency of aminopeptidase P1, a proline-specific endopeptidase encoded by the Xpnpep1 gene, causes neurological complications in both humans and mice. In addition, aminopeptidase P1-deficient mice exhibit hippocampal neurodegeneration and impaired hippocampus-dependent learning and memory. However, the molecular and cellular changes associated with hippocampal pathology in aminopeptidase P1 deficiency are unclear. We show here that a deficiency of aminopeptidase P1 modifies the glial population and neuronal excitability in the hippocampus. Microarray and real-time quantitative reverse transcription-polymerase chain reaction analyses identified 14 differentially expressed genes (Casp1, Ccnd1, Myoc, Opalin, Aldh1a2, Aspa, Spp1, Gstm6, Serpinb1a, Pdlim1, Dsp, Tnfaip6, Slc6a20a, Slc22a2) in the Xpnpep1-/- hippocampus. In the hippocampus, aminopeptidase P1-expression signals were mainly detected in neurons. However, deficiency of aminopeptidase P1 resulted in fewer hippocampal astrocytes and increased density of microglia in the hippocampal CA3 area. In addition, Xpnpep1-/- CA3b pyramidal neurons were more excitable than wild-type neurons. These results indicate that insufficient astrocytic neuroprotection and enhanced neuronal excitability may underlie neurodegeneration and hippocampal dysfunction in aminopeptidase P1 deficiency.

Threshold Concepts in a Literary Magazine Produced by Health Care Students.

This article was migrated. The article was marked as recommended. Introduction: Progress Notes is a literary magazine featuring works from health care students in the USA. It is edited by medical students at the Uniformed Services University of the Health Sciences (USUHS) to provide a space for their creative works. Since the magazine's inception in 2016, four volumes have been published, containing 130 works of poetry, fiction, reflection, and artwork. Goal: To understand the themes and perspectives of the published works. Methods: After Institutional Review Board approval, two researchers used qualitative thematic analysis to examine the texts, coding independently and resolving differences by discussion. They arranged the codes into themes which were discussed until consensus. A third researcher read the texts, codes and themes and verified that they were an accurate reflection of the published works. Artwork was assigned themes by the same two researchers who analyzed the written works, and a sample selection was verified by the third researcher. Results: Researchers identified eight themes across poetry, fiction, and reflective essays: vocation, death, failure/resilience, emotional restraint, personhood of the patient, approach to the patient, military physicians, and moments of personal realization. Four themes were identified in the artwork: death; comradeship/aloneness; vocation/quest; and competence. Discussion: Students submitted creative works in which they grapple with what it means to be a physician. Analyzed through the lens of the threshold concepts, researchers identified: "I am a healer;" "I can deal with ambiguity;" "The patient is the focus;" "As a military medical officer, I serve two masters;" and "As a physician, I have a unique and complex relationship with death." These threshold concepts represent an ontological shift in the students' professional identity. Conclusion: A literary magazine edited, and featuring works by, health care students provides a forum in which health care students wrestle with the elusive and enigmatic fundamental principles of being a physician.

Microsatellite Instability: A Predictive Biomarker for Cancer Immunotherapy.

Immunotherapy has shown promising results in various types of cancers. Checkpoint inhibitor drugs developed for cancer immunotherapy have been approved by the US Food and Drug Administration (FDA) for patients with advanced melanoma, non-small cell lung cancer, renal cell carcinoma, bladder cancers, and refractory Hodgkin lymphoma. In the latest announcement, the FDA has granted accelerated approval to pembrolizumab for pediatric and adult patients with microsatellite instability-high (MSI-H) or mismatch repair-deficient solid tumors. This is the first time the agency has approved a cancer treatment based on a common biomarker rather than organ-based approach. MSI-H, either due to inherited germline mutations of mismatch repair genes or epigenetic inactivation of these genes, is found in a subset of colorectal and noncolorectal carcinomas. It is known that MSI-H causes a build up of somatic mutations in tumor cells and leads to a spectrum of molecular and biological changes including high tumor mutational burden, increased expression of neoantigens and abundant tumor-infiltrating lymphocytes. These changes have been linked to increased sensitivity to checkpoint inhibitor drugs. In this mini review, we provide an update on MSI-related solid tumors with special focus on the predictive role of MSI for checkpoint immunotherapy.

Intestinal and Extraintestinal Cancers Associated With Inflammatory Bowel Disease.

Inflammatory bowel disease (IBD) with its 2 most common entities, ulcerative colitis and Crohn's disease, causes an increased risk of developing intestinal cancers. In fact, malignancies are the second most common cause of death after cardiovascular diseases in both sexes of patients with IBD. Risk factors for colorectal cancer in IBD correlate with the duration of the disease, extent of disease, the association with primary sclerosing cholangitis, family history, and early age at onset. Patients with IBD also have an increased risk for developing a variety of extraintestinal malignancies. In particular, lymphomas, mostly non-Hodgkin lymphomas and skin cancers, are more frequently observed in IBD patients. Longstanding inflammation and the degree of immunosuppression as a result of IBD treatment appear to be the main driving factors for IBD-related carcinogenesis. This review provides an update on the clinical and pathological features of IBD-related intestinal and extraintestinal malignancies.

Intestinal Stem Cells Exhibit Conditional Circadian Clock Function.

The circadian clock is a molecular pacemaker that produces 24-hr physiological cycles known as circadian rhythms. How the clock regulates stem cells is an emerging area of research with many outstanding questions. We tested clock function in vivo at the single cell resolution in the Drosophila intestine, a tissue that is exquisitely sensitive to environmental cues and has circadian rhythms in regeneration. Our results indicate that circadian clocks function in intestinal stem cells and enterocytes but are downregulated during enteroendocrine cell differentiation. Drosophila intestinal cells are principally synchronized by the photoperiod, but intestinal stem cell clocks are highly responsive to signaling pathways that comprise their niche, and we find that the Wnt and Hippo signaling pathways positively regulate stem cell circadian clock function. These data reveal that intestinal stem cell circadian rhythms are regulated by cellular signaling and provide insight as to how clocks may be altered during physiological changes such as regeneration and aging.

Tissue specific increase of the catalytic subunits of the 26S proteasome by indirect antioxidant dithiolethione in mice: enhanced activity for degradation of abnormal protein.

Decreases in the 26S proteasome are related to the toxicities of abnormal protein aggregates and may contribute to pathogenesis of degenerative diseases. Therefore, maintenance of proteasome function can be a novel strategy to protect cells against abnormal protein-mediated toxicity. In the present study, we have demonstrated the tissue specific increase of the catalytic subunits of the proteasome in mice following oral administration of 3H-1,2-dithiole-3-thione (D3T, 0.5 mmol/kg), which functions as a cancer preventive agent in animal and human studies. Expression of the 20S catalytic core subunits PSMB5, PSMB6, and PSMB7 were increased in liver, lung, small intestine, and colon of mice at 24 h after D3T treatment. Elevated expression of proteasome catalytic subunits led to increases in proteasomal peptidase activities in these tissues. Oral administration of D3T also exerted a pharmacodynamic action in some brain regions of these mice and proteasomal peptidase activities were significantly elevated in the cerebral cortex-hippocampus. Moreover, tissue extracts from D3T-treated mice and cell lysates obtained from D3T-incubated murine neuroblastoma cells exhibited the enhanced capacity to degrade mutant human SOD1G93A protein. These results indicate that the catalytic subunits of the 26S proteasome are inducible in multiple tissues of mouse including brain by exogenous chemical treatment. Increased proteasome expression by inducers may have a role in protection/attenuation of protein aggregate-mediated disorders.

Expending Role of Microsatellite Instability in Diagnosis and Treatment of Colorectal Cancers.

BACKGROUND: Colorectal carcinomas with high-frequency microsatellite instability (MSI-H) account for 15% of all colorectal cancers, including 12% of sporadic cases and 3% of cancers associated with Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer syndrome, HNPCC). Lynch syndrome is an autosomal dominant hereditary cancer syndrome, caused by germline mutations in mismatch repair genes, including MLH1, MSH2, MSH6 and PMS2. METHODS: Published articles from peer-reviewed journals were obtained from PubMed, Google Scholar and Clinicaltrials.gov . Based on the recent research data, we provide an update on the MSI testing, along with the evolving role of MSI in diagnosis, prognosis and treatment of colorectal cancers. RESULTS: Studies have led to significant advances in the molecular pathogenesis and clinicopathological characteristics of MSI-H colorectal cancers. Emerging evidence suggests that colorectal cancers with MSI-H show different outcome and treatment response from those with microsatellite stable (MSS) tumors. Therefore, MSI testing is essential not only in the genetic context, but it may also have important prognostic and predictive value of response to chemotherapy and immunotherapy. CONCLUSIONS: Many experts and professional authorities have recommended a universal MSI testing in all individuals newly diagnosed with colorectal cancers.

The Circadian Clock Gene BMAL1 Coordinates Intestinal Regeneration.

BACKGROUND & AIMS: The gastrointestinal syndrome is an illness of the intestine caused by high levels of radiation. It is characterized by extensive loss of epithelial tissue integrity, which initiates a regenerative response by intestinal stem and precursor cells. The intestine has 24-hour rhythms in many physiological functions that are believed to be outputs of the circadian clock: a molecular system that produces 24-hour rhythms in transcription/translation. Certain gastrointestinal illnesses are worsened when the circadian rhythms are disrupted, but the role of the circadian clock in gastrointestinal regeneration has not been studied. METHODS: We tested the timing of regeneration in the mouse intestine during the gastrointestinal syndrome. The role of the circadian clock was tested genetically using the BMAL1 loss of function mouse mutant in vivo, and in vitro using intestinal organoid culture. RESULTS: The proliferation of the intestinal epithelium follows a 24-hour rhythm during the gastrointestinal syndrome. The circadian clock runs in the intestinal epithelium during this pathologic state, and the loss of the core clock gene, BMAL1, disrupts both the circadian clock and rhythmic proliferation. Circadian activity in the intestine involves a rhythmic production of inflammatory cytokines and subsequent rhythmic activation of the JNK stress response pathway. CONCLUSIONS: Our results show that a circadian rhythm in inflammation and regeneration occurs during the gastrointestinal syndrome. The study and treatment of radiation-induced illnesses, and other gastrointestinal illnesses, should consider 24-hour timing in physiology and pathology.

Standardized Herbal Formula PM014 Inhibits Radiation-Induced Pulmonary Inflammation in Mice.

Radiation therapy is widely used for thoracic cancers. However, it occasionally causes radiation-induced lung injuries, including pneumonitis and fibrosis. Chung-Sang-Bo-Ha-Tang (CSBHT) has been traditionally used to treat chronic pulmonary disease in Korea. PM014, a modified herbal formula derived from CSBHT, contains medicinal herbs of seven species. In our previous studies, PM014 exhibited anti-inflammatory effects in a chronic obstructive pulmonary disease model. In this study, we have evaluated the effects of PM014 on radiation-induced lung inflammation. Mice in the treatment group were orally administered PM014 six times for 2 weeks. Effects of PM014 on radiation pneumonitis were evaluated based on histological findings and differential cell count in bronchoalveolar lavage fluid. PM014 treatment significantly inhibited immune cell recruitment and collagen deposition in lung tissue. Normal lung volume, evaluated by radiological analysis, in PM014-treated mice was higher compared to that in irradiated control mice. PM014-treated mice exhibited significant changes in inspiratory capacity, compliance and tissue damping and elastance. Additionally, PM014 treatment resulted in the downregulation of inflammatory cytokines, chemokines, and fibrosis-related genes and a reduction in the transforming growth factor-ß1-positive cell population in lung tissue. Thus, PM014 is a potent therapeutic agent for radiation-induced lung fibrosis and inflammation.