Unique DUOX2+ACE2+ small cholangiocytes are pathogenic targets for primary biliary cholangitis.

Cholangiocytes play a crucial role in bile formation. Cholangiocyte injury causes cholestasis, including primary biliary cholangitis (PBC). However, the etiology of PBC remains unclear despite being characterized as an autoimmune disease. Using single-cell RNA sequencing (scRNA-seq), fluorescence-activated-cell-sorting, multiplex immunofluorescence (IF) and RNAscope analyses, we identified unique DUOX2+ACE2+ small cholangiocytes in human and mouse livers. Their selective decrease in PBC patients was associated with the severity of disease. Moreover, proteomics, scRNA-seq, and qPCR analyses indicated that polymeric immunoglobulin receptor (pIgR) was highly expressed in DUOX2+ACE2+ cholangiocytes. Serum anti-pIgR autoantibody levels were significantly increased in PBC patients, regardless of positive and negative AMA-M2. Spatial transcriptomics and multiplex IF revealed that CD27+ memory B and plasma cells accumulated in the hepatic portal tracts of PBC patients. Collectively, DUOX2+ACE2+ small cholangiocytes are pathogenic targets in PBC, and preservation of DUOX2+ACE2+ cholangiocytes and targeting anti-pIgR autoantibodies may be valuable strategies for therapeutic interventions in PBC.

Building Programs to Eradicate Toxoplasmosis Part IV: Understanding and Development of Public Health Strategies and Advances "Take a Village".

Purpose of Review: Review international efforts to build a global public health initiative focused on toxoplasmosis with spillover benefits to save lives, sight, cognition and motor function benefiting maternal and child health. Recent Findings: Multiple countries' efforts to eliminate toxoplasmosis demonstrate progress and context for this review and new work. Summary: Problems with potential solutions proposed include accessibility of accurate, inexpensive diagnostic testing, pre-natal screening and facilitating tools, missed and delayed neonatal diagnosis, restricted access, high costs, delays in obtaining medicines emergently, delayed insurance pre-approvals and high medicare copays taking considerable physician time and effort, harmful shortcuts being taken in methods to prepare medicines in settings where access is restricted, reluctance to perform ventriculoperitoneal shunts promptly when needed without recognition of potential benefit, access to resources for care, especially for marginalized populations, and limited use of recent advances in management of neurologic and retinal disease which can lead to good outcomes. Supplementary Information: The online version contains supplementary material available at 10.1007/s40124-022-00268-x.

Building Programs to Eradicate Toxoplasmosis Part III: Epidemiology and Risk Factors.

Purpose of Review: Review comprehensive data on rates of toxoplasmosis in Panama and Colombia. Recent Findings: Samples and data sets from Panama and Colombia, that facilitated estimates regarding seroprevalence of antibodies to Toxoplasma and risk factors, were reviewed. Summary: Screening maps, seroprevalence maps, and risk factor mathematical models were devised based on these data. Studies in Ciudad de Panamá estimated seroprevalence at between 22 and 44%. Consistent relationships were found between higher prevalence rates and factors such as poverty and proximity to water sources. Prenatal screening rates for anti-Toxoplasma antibodies were variable, despite existence of a screening law. Heat maps showed a correlation between proximity to bodies of water and overall Toxoplasma seroprevalence. Spatial epidemiological maps and mathematical models identify specific regions that could most benefit from comprehensive, preventive healthcare campaigns related to congenital toxoplasmosis and Toxoplasma infection.

Building Programs to Eradicate Toxoplasmosis Part II: Education.

Purpose of Review: Review work to create and evaluate educational materials that could serve as a primary prevention strategy to help both providers and patients in Panama, Colombia, and the USA reduce disease burden of Toxoplasma infections. Recent Findings: Educational programs had not been evaluated for efficacy in Panama, USA, or Colombia. Summary: Educational programs for high school students, pregnant women, medical students and professionals, scientists, and lay personnel were created. In most settings, short-term effects were evaluated. In Panama, Colombia, and USA, all materials showed short-term utility in transmitting information to learners. These educational materials can serve as a component of larger public health programs to lower disease burden from congenital toxoplasmosis. Future priorities include conducting robust longitudinal studies of whether education correlates with reduced adverse disease outcomes, modifying educational materials as new information regarding region-specific risk factors is discovered, and ensuring materials are widely accessible.

Effects of CpG oligodeoxynucleotide 1826 on acute radiation-induced lung injury in mice.

BACKGROUND: The radiation-induced lung injury is a common complication from radiotherapy in lung cancer. CpG ODN is TLR9 activator with potential immune modulatory effects and sensitization of radiotherapy in lung cancer. This study aimed to examine the effect of CpG ODN on acute radiation-induced lung injury in mice. METHODS AND RESULTS: The mouse model of radiation-induced lung injury was established by a single dose of 20 Gy X-rays exposure to the left lung. The results showed that the pneumonia score was lower in RT+CpG group than in RT group on 15th and 30th days. Compared with RT group, CpG ODN reduced the serum concentrations of MDA (P < 0.05) and increased the serum concentrations of SOD, GSH (P < 0.05). The serum concentration of TNF-α in RT+CpG group was lower on 15th and 30th days post-irradiation (P < 0.05). CONCLUSION: The study demonstrated that CpG ODN has preventive effects of acute radiation-induced lung injury in mice. Lung inflammatory reaction and oxidative stress are promoted in the initiation of radiation-induced pneumonia. CpG ODN may reduce the injury of reactive oxygen species and adjust the serum TNF-α concentration in the mice after irradiation, which reduces the generation of the inflammatory cytokines.

Effects of CpG oligodeoxynucleotide 1826 on acute radiation-induced lung injury in mice

BACKGROUND: The radiation-induced lung injury is a common complication from radiotherapy in lung cancer. CpG ODN is TLR9 activator with potential immune modulatory effects and sensitization of radiotherapy in lung cancer. This study aimed to examine the effect of CpG ODN on acute radiation-induced lung injury in mice. METHODS AND RESULTS: The mouse model of radiation-induced lung injury was established by a single dose of 20 Gy X-rays exposure to the left lung. The results showed that the pneumonia score was lower in RT+CpG group than in RT group on 15th and 30th days. Compared with RT group, CpG ODN reduced the serum concentrations of MDA (P < 0.05) and increased the serum concentrations of SOD, GSH (P < 0.05). The serum concentration of TNF-α in RT+CpG group was lower on 15th and 30th days post-irradiation (P < 0.05). CONCLUSION: The study demonstrated that CpG ODN has preventive effects of acute radiation-induced lung injury in mice. Lung inflammatory reaction and oxidative stress are promoted in the initiation of radiation-induced pneumonia. CpG ODN may reduce the injury of reactive oxygen species and adjust the serum TNF-α concentration in the mice after irradiation, which reduces the generation of the inflammatory cytokines.

Gene expression profiling of lobular carcinoma in situ reveals candidate precursor genes for invasion.

PURPOSE: Lobular carcinoma in situ (LCIS) is both a risk indicator and non-obligate precursor of invasive lobular carcinoma (ILC). We sought to characterize the transcriptomic features of LCIS and ILC, with a focus on the identification of intrinsic molecular subtypes of LCIS and the changes involved in the progression from normal breast epithelium to LCIS and ILC. METHODS: Fresh-frozen classic LCIS, classic ILC, and normal breast epithelium (N) from women undergoing prophylactic or therapeutic mastectomy were prospectively collected, laser-capture microdissected, and subjected to gene expression profiling using Affymetrix HG-U133A 2.0 microarrays. RESULTS: Unsupervised hierarchical clustering of 40 LCIS samples identified 2 clusters of LCIS distinguished by 6431 probe sets (p < 0.001). Genes identifying the clusters included proliferation genes and other genes related to cancer canonical pathways such as TGF beta signaling, p53 signaling, actin cytoskeleton, apoptosis and Wnt-Signaling pathway. A supervised analysis to identify differentially expressed genes (p < 0.001) between normal epithelium, LCIS, and ILC, using 23 patient-matched triplets of N, LCIS, and ILC, identified 169 candidate precursor genes, which likely play a role in LCIS progression, including PIK3R1, GOLM1, and GPR137B. These potential precursor genes map significantly more frequently to 1q and 16q, regions frequently targeted by gene copy number alterations in LCIS and ILC. CONCLUSION: Here we demonstrate that classic LCIS is a heterogeneous disease at the transcriptomic level and identify potential precursor genes in lobular carcinogenesis. Understanding the molecular heterogeneity of LCIS and the potential role of these potential precursor genes may help personalize the therapy of patients with LCIS.