Clinical Characteristics, Genetic Features, and Long-Term Outcome of Wilson's Disease in a Taiwanese Population: An 11-Year Follow-Up Study.

OBJECTIVE: aaWilson's disease (WD) is a rare genetic disorder of copper metabolism, and longitudinal follow-up studies are limited. We performed a retrospective analysis to determine the clinical characteristics and long-term outcomes in a large WD cohort. METHODS: aaMedical records of WD patients diagnosed from 2006-2021 at National Taiwan University Hospital were retrospectively evaluated for clinical presentations, neuroimages, genetic information, and follow-up outcomes. RESULTS: aaThe present study enrolled 123 WD patients (mean follow-up: 11.12 ± 7.41 years), including 74 patients (60.2%) with hepatic features and 49 patients (39.8%) with predominantly neuropsychiatric symptoms. Compared to the hepatic group, the neuropsychiatric group exhibited more Kayser-Fleischer rings (77.6% vs. 41.9%, p < 0.01), lower serum ceruloplasmin levels (4.9 ± 3.9 vs. 6.3 ± 3.9 mg/dL, p < 0.01), smaller total brain and subcortical gray matter volumes (p < 0.0001), and worse functional outcomes during follow-up (p = 0.0003). Among patients with available DNA samples (n = 59), the most common mutations were p.R778L (allelic frequency of 22.03%) followed by p.P992L (11.86%) and p.T935M (9.32%). Patients with at least one allele of p.R778L had a younger onset age (p = 0.04), lower ceruloplasmin levels (p < 0.01), lower serum copper levels (p = 0.03), higher percentage of the hepatic form (p = 0.03), and a better functional outcome during follow-up (p = 0.0012) compared to patients with other genetic variations. CONCLUSION: aaThe distinct clinical characteristics and long-term outcomes of patients in our cohort support the ethnic differences regarding the mutational spectrum and clinical presentations in WD.

Comparison of the Diagnostic Accuracies of Monocyte Distribution Width, Procalcitonin, and C-Reactive Protein for Sepsis: A Systematic Review and Meta-Analysis.

OBJECTIVES: We performed a systemic review and meta-analysis to evaluate the diagnostic accuracy of monocyte distribution width (MDW) and to compare with procalcitonin and C-reactive protein (CRP), in adult patients with sepsis. DATA SOURCES: A systematic literature search was performed in PubMed, Embase, and the Cochrane Library to identify all relevant diagnostic accuracy studies published before October 1, 2022. STUDY SELECTION: Original articles reporting the diagnostic accuracy of MDW for sepsis detection with the Sepsis-2 or Sepsis-3 criteria were included. DATA EXTRACTION: Study data were abstracted by two independent reviewers using a standardized data extraction form. DATA SYNTHESIS: Eighteen studies were included in the meta-analysis. The pooled sensitivity and specificity of MDW were 84% (95% CI [79-88%]) and 68% (95% CI [60-75%]). The estimated diagnostic odds ratio and the area under the summary receiver operating characteristic curve (SROC) were 11.11 (95% CI [7.36-16.77]) and 0.85 (95% CI [0.81-0.89]). Significant heterogeneity was observed among the included studies. Eight studies compared the diagnostic accuracies of MDW and procalcitonin, and five studies compared the diagnostic accuracies of MDW and CRP. For MDW versus procalcitonin, the area under the SROC was similar (0.88, CI = 0.84-0.93 vs 0.82, CI = 0.76-0.88). For MDW versus CRP, the area under the SROC was similar (0.88, CI = 0.83-0.93 vs 0.86, CI = 0.78-0.95). CONCLUSIONS: The results of the meta-analysis indicate that MDW is a reliable diagnostic biomarker for sepsis as procalcitonin and CRP. Further studies investigating the combination of MDW and other biomarkers are advisable to increase the accuracy in sepsis detection.

Tumor-derived GCSF Alters Tumor and Systemic Immune System Cell Subset Composition and Signaling.

While immunotherapies such as immune checkpoint blockade and adoptive T-cell therapy improve survival for a subset of human malignancies, many patients fail to respond. Phagocytes including dendritic cells (DC), monocytes, and macrophages (MF) orchestrate innate and adaptive immune responses against tumors. However, tumor-derived factors may limit immunotherapy effectiveness by altering phagocyte signal transduction, development, and activity. Using Cytometry by Time-of-Flight, we found that tumor-derived GCSF altered myeloid cell distribution both locally and systemically. We distinguished a large number of GCSF-induced immune cell subset and signal transduction pathway perturbations in tumor-bearing mice, including a prominent increase in immature neutrophil/myeloid-derived suppressor cell (Neut/MDSC) subsets and tumor-resident PD-L1+ Neut/MDSCs. GCSF expression was also linked to distinct tumor-associated MF populations, decreased conventional DCs, and splenomegaly characterized by increased splenic progenitors with diminished DC differentiation potential. GCSF-dependent dysregulation of DC development was recapitulated in bone marrow cultures in vitro, using medium derived from GCSF-expressing tumor cell cultures. Importantly, tumor-derived GCSF impaired T-cell adoptive cell therapy effectiveness and was associated with increased tumor volume and diminished survival of mice with mammary cancer. Treatment with neutralizing anti-GCSF antibodies reduced colonic and circulatory Neut/MDSCs, normalized colonic immune cell composition and diminished tumor burden in a spontaneous model of mouse colon cancer. Analysis of human colorectal cancer patient gene expression data revealed a significant correlation between survival and low GCSF and Neut/MDSC gene expression. Our data suggest that normalizing GCSF bioactivity may improve immunotherapy in cancers associated with GCSF overexpression. Significance: Tumor-derived GCSF leads to systemic immune population changes. GCSF blockade restores immune populations, improves immunotherapy, and reduces tumor size, paralleling human colorectal cancer data. GCSF inhibition may synergize with current immunotherapies to treat GCSF-secreting tumors.

Metabolic Changes Associated With Cardiomyocyte Dedifferentiation Enable Adult Mammalian Cardiac Regeneration.

BACKGROUND: Cardiac regeneration after injury is limited by the low proliferative capacity of adult mammalian cardiomyocytes (CMs). However, certain animals readily regenerate lost myocardium through a process involving dedifferentiation, which unlocks their proliferative capacities. METHODS: We bred mice with inducible, CM-specific expression of the Yamanaka factors, enabling adult CM reprogramming and dedifferentiation in vivo. RESULTS: Two days after induction, adult CMs presented a dedifferentiated phenotype and increased proliferation in vivo. Microarray analysis revealed that upregulation of ketogenesis was central to this process. Adeno-associated virus-driven HMGCS2 overexpression induced ketogenesis in adult CMs and recapitulated CM dedifferentiation and proliferation observed during partial reprogramming. This same phenomenon was found to occur after myocardial infarction, specifically in the border zone tissue, and HMGCS2 knockout mice showed impaired cardiac function and response to injury. Finally, we showed that exogenous HMGCS2 rescues cardiac function after ischemic injury. CONCLUSIONS: Our data demonstrate the importance of HMGCS2-induced ketogenesis as a means to regulate metabolic response to CM injury, thus allowing cell dedifferentiation and proliferation as a regenerative response.

Duchenne muscular dystrophy newborn screening: the first 50,000 newborns screened in Taiwan.

BACKGROUND: Duchenne muscular dystrophy (DMD/Duchenne) is a progressive X-linked muscular disease with an overall incidence of 1:5,000 live male births. Recent availability in treatment for DMD raised the need of early diagnosis, and DMD became as a selective item of newborn screening (NBS) since Feb. 2021 in our center. MATERIALS AND METHODS: Dried blood spots (DBS) muscle-type creatine kinase (CK) isoform was measured with a commercialized kit with age-adjusted cutoffs. Subjects with an elevation of CK in the first screen were requested for a re-screen 2 weeks later. A DBS whole-exome sequencing (WES) panel for dystrophin and other neuromuscular-related genes was applied to confirm the diagnosis for subjects with persistent hyperCKemia. RESULTS: During a 1-year period, 50,572 newborns (male 26,130) received DMD screening at a mean age of 2 days (SD 1 day). Among them, 632 (1.2%) had an elevated CK value. A re-screen at a mean age of 14 days (SD 8 days) revealed 14 subjects with persistent hyperCKemia, and DMD was confirmed in 3 of them. The incidence of DMD in Taiwan was 1:8,710 (95% CI 1 in 2,963 to 1 in 25,610) live birth males. Results of DMD DBS also assisted in Pompe newborn screening. CONCLUSIONS: NBS for DMD enables earlier management of the disease. The high re-screening rate could potentially be waived by moving the DBS WES assay to a second-tier test. The long-term benefit and the impact of newborn screening on the prognosis of DMD, however, remain further elucidated.

Drug-Drug Interactions With Cyclosporine in the Anti-Hepatitis C Viral PrOD Combination Regimen of Paritaprevir/Ritonavir-Ombitasvir and Dasabuvir in Organ Transplant Recipients With Severe Hepatic Fibrosis or Cirrhosis.

BACKGROUND: The clinical guidelines suggest that the dosing of cyclosporine (CsA), during combination therapy with paritaprevir/ritonavir-ombitasvir and dasabuvir (PrOD), would be only one-fifth of the pre-PrOD total daily dose to be administered once daily. However, this dosing may not be applicable to all patients depending on their clinical condition. This study focuses on the pharmacokinetic dynamics of PrOD with CsA in Asian organ transplant recipients with severe liver fibrosis or cirrhosis who undergo concurrent treatment with PrOD treatment and CsA. The efficacy and safety of PrOD treatment was also evaluated. METHODS: Data from 7 patients obtained between January 2017 and September 2017 were retrospectively analyzed. Determinations of the blood concentrations of CsA were made, whether used as a single treatment or in combination therapy with PrOD. RESULTS: The combination regimen compared with CsA administered alone resulted in a 4.53-fold and 5.52-fold increase in the area under the concentration-time curve from time 0-12 hours (AUC0-12 h) of CsA on days 1 and 15, respectively. In addition, the maximal concentration, time to maximum concentration, and terminal phase elimination half-life (t1/2) of CsA were increased during the combined treatment of PrOD and CsA. The authors proposed reducing the CsA dosage during PrOD treatment to one-seventh of that of the pre-PrOD treatment of the total daily dose to maintain target CsA levels. All patients achieved sustained virologic responses at week 12. There were no episodes of serious adverse events or graft rejections observed. CONCLUSIONS: Although the combination with PrOD significantly affects the pharmacokinetics of CsA, it is effective and safe with regular monitoring of the CsA blood concentrations and appropriate CsA dose adjustment.

Incisor liability and its effects among East Asian children.

BACKGROUND/PURPOSE: Incisor liability is the discrepancy in the sum of the mesiodistal crown width between the primary and permanent incisors. Incisor liability affects the integrity and eruption of the permanent incisors during the transition from the primary to permanent dentition. This study investigated the incisor liability in the primary dentition of Taiwanese children. METHODS: The digital periapical films of 203 upper arches of 105 boys and 98 girls and 195 lower arches of 119 boys and 76 girls aged between 3 and 6 years were selected in this retrospective study. The mesiodistal crown widths of the primary and permanent incisors were measured using the medical imaging software for both arches. Differences in incisor liability values were statistically analyzed. RESULTS: The mean ± standard deviation of the incisor liability values were 8.32 ± 1.88 and 6.91 ± 1.13 mm for the upper and lower arches, respectively, in all children. The incisor liability was closely related with the total crown widths of the permanent incisors for upper and lower arches. The incisor liability values were higher among boys than girls for the upper but not lower arch. CONCLUSION: Incisor liability differs depending on ethnicity. In Taiwanese children, incisor liability was closely related with the crown widths of the permanent incisors. The incisor liability values of boys were higher than those of girls in the upper arch but not the lower arch.

A novel deep intronic variant strongly associates with Alkaptonuria.

Alkaptonuria is a rare autosomal recessive inherited disorder of tyrosine metabolism, which causes ochronosis, arthropathy, cardiac valvular calcification, and urolithiasis. The epidemiology of alkaptonuria in East Asia is not clear. In this study, patients diagnosed with alkaptonuria from January 2010 to June 2020 were reviewed. Their clinical and molecular features were further compared with those of patients from other countries. Three patients were found to have alkaptonuria. Mutation analyses of the homogentisate 1,2-dioxygenase gene (HGD) showed four novel variants c.16-2063 A > C, p.(Thr196Ile), p.(Gly344AspfsTer25), and p.(Gly362Arg) in six mutated alleles (83.3%). RNA sequencing revealed that c.16-2063 A > C activates a cryptic exon, causing protein truncation p.(Tyr5_Ile6insValTer17). A literature search identified another 6 patients with alkaptonuria in East Asia; including our cases, 13 of the 18 mutated alleles have not been reported elsewhere in the world. Alkaptonuria is rare in Taiwan and East Asia, with HGD variants being mostly novel and private.

Inflammation-Induced Metastatic Colonization of the Lung Is Facilitated by Hepatocyte Growth Factor-Secreting Monocyte-Derived Macrophages.

A rate-limiting step for circulating tumor cells to colonize distant organ sites is their ability to locate a microenvironmental niche that supports their survival and growth. This can be achieved by features intrinsic to the tumor cells and/or by the conditioning of a "premetastatic" niche. To determine if pulmonary inflammation promotes the latter, we initiated models for inflammatory asthma, hypersensitivity pneumonitis, or bleomycin-induced sterile inflammation before introducing tumor cells with low metastatic potential into the circulation. All types of inflammation increased the end-stage metastatic burden of the lungs 14 days after tumor cell inoculation without overtly affecting tumor extravasation. Instead, the number and size of early micrometastatic lesions found within the interstitial tissues 96 hours after tumor cell inoculation were increased in the inflamed lungs, coincident with increased tumor cell survival and the presence of nearby inflammation-induced monocyte-derived macrophages (MoDM; CD11b+CD11c+). Remarkably, the adoptive transfer of these MoDM was sufficient to increase lung metastasis in the absence of inflammation. These inflammation-induced MoDM secrete a number of growth factors and cytokines, one of which is hepatocyte growth factor (HGF), that augmented tumor cell survival under conditions of stress in vitro. Importantly, blocking HGF signaling with the cMET inhibitor capmatinib abolished inflammation-induced early micrometastatic lesion formation in vivo. These findings indicate that inflammation-induced MoDM and HGF in particular increase the efficiency of early metastatic colonization in the lung by locally preconditioning the microenvironment. IMPLICATIONS: Inflammation preconditions the distant site microenvironment to increase the metastatic potential of tumor cells that arrive there.

Importance of prey size on investigating prey availability of larval fishes.

Prey availability plays an important role in determining larval fish survival. Numerous studies have found close relationships between the density of mesozooplankton and larval fishes; however, emerging studies suggest that small-size zooplankton are more important prey for some larval fish species. One arising question is whether the size of zooplankton determines the relationship between zooplankton and larval fish community in natural environments. To address this question, we collected small-size (50-200 µm) zooplankton, mesozooplankton (> 330 µm), and larval fish using three different mesh-size (50, 330, 1000 µm, respectively) nets in the East China Sea, and examined their relationships in density. Both meso- and small-size zooplankton densities showed positive relationships with larval fish density, while the relationship is much stronger for the small-size zooplankton. Specifically, the smallest size classes (50-75 and 75-100 µm) of small-size zooplankton showed the highest positive relationships with larval fish density. Temperature, salinity, and chlorophyll-a concentration did not significantly explain larval fish density. Based on these findings, we demonstrate the importance of considering prey size when investigating prey availability for larval fishes.

Folinate Supplementation Ameliorates Methotrexate Induced Mitochondrial Formate Depletion In Vitro and In Vivo.

(1) Background: Antifolate methotrexate (MTX) is the most common disease-modifying antirheumatic drug (DMARD) for treating human rheumatoid arthritis (RA). The mitochondrial-produced formate is essential for folate-mediated one carbon (1C) metabolism. The impacts of MTX on formate homeostasis in unknown, and rigorously controlled kinetic studies can greatly help in this regard. (2) Methods: Combining animal model (8-week old female C57BL/6JNarl mice, n = 18), cell models, stable isotopic tracer studies with gas chromatography/mass spectrometry (GC/MS) platforms, we systematically investigated how MTX interferes with the partitioning of mitochondrial and cytosolic formate metabolism. (3) Results: MTX significantly reduced de novo deoxythymidylate (dTMP) and methionine biosyntheses from mitochondrial-derived formate in cells, mouse liver, and bone marrow, supporting our postulation that MTX depletes mitochondrial 1C supply. Furthermore, MTX inhibited formate generation from mitochondria glycine cleavage system (GCS) both in vitro and in vivo. Folinate selectively rescued 1C metabolic pathways in a tissue-, cellular compartment-, and pathway-specific manner: folinate effectively reversed the inhibition of mitochondrial formate-dependent 1C metabolism in mouse bone marrow (dTMP, methionine, and GCS) and cells (dTMP and GCS) but not methionine synthesis in liver/liver-derived cells. Folinate failed to fully recover hepatic mitochondrial-formate utilization for methionine synthesis, suggesting that the efficacy of clinical folinate rescue in MTX therapy on hepatic methionine metabolism is poor. (4) Conclusion: Conducting studies in mouse and cell models, we demonstrate novel findings that MTX specifically depletes mitochondrial 1C supply that can be ameliorated by folinate supplementation except for hepatic transmethylation. These results imply that clinical use of low-dose MTX may particularly impede 1C metabolism via depletion of mitochondrial formate. The MTX induced systematic and tissue-specific formate depletion needs to be addressed more carefully, and the efficacy of folinate with respect to protecting against such depletion deserves to be evaluated in medical practice.

Modified Balloon-in-Stent Technique for Circumferential Vertebral Artery Dissecting Aneurysm.

BACKGROUND: Treatment for circumferential vertebral artery dissecting aneurysms (VADAs) remains challenging. Stent-assisted coil embolization is the most common treatment technique. However, this approach presents high rates of incomplete occlusion and recurrence, often requiring the addition of second or third stents for reconstruction. A flow diverter may achieve favorable clinical outcomes, but it cannot result in immediate aneurysm occlusion and is limited by strict antiplatelets and expensive price. We report excellent results of a 1-stage modified balloon-in-stent technique for circumferential VADA. METHODS: A total of 12 patients were treated with the modified balloon-in-stent technique for VADAs. A homogeneous coil was used to fill the aneurysm sac, followed by deployment of 1 self-expandable stent and in-stent Scepter balloon angioplasty. Clinical presentations, outcomes, and imaging results were evaluated over at least 2 years of follow-up. RESULTS: Our 12 patients were examined during a mean follow-up period of 36.2 months (range, 2-5 years). The initial symptoms presented included subarachnoid hemorrhage (5 of 12; 41.7%), ischemia (3 of 12; 25.0%), and nonischemia (4 of 12; 33.3%). The modified BIS technique and coil embolization were successful in all patients. No technique-related complications or recanalization occurred during follow-up. CONCLUSIONS: We demonstrated an innovative modified BIS technique to treat circumferential VADA by using a coiling basket followed by the deployment of a self-expandable stent and in-stent Scepter balloon angioplasty. This strategy is safe, feasible, and cost effective and was not associated with recurrence or complications over at least 2 years of follow-up.

Diversity in the Taiwanese Swimming Crabs (Crustacea: Brachyura: Portunidae) Estimated through DNA Barcodes, with Descriptions of 14 New Records.

The swimming crabs (family Portunidae) are distributed worldwide and commonly inhabit estuaries, mangroves, reefs, shallow and the deep sea. Previously, 75 species and 19 genera in this family were known to Taiwan. Our study examined specimens in Taiwanese waters, including the islands, collected between 2016 and 2020 or deposited in museums. Through the cytochrome oxidase subunit I DNA barcode marker and morphological examination, 71 species were identified. The minimum interspecific distances were greater than 4.09%, except in two unresolved groups: Charybdis miles (De Haan, 1835) and Ch. sagamiensis Parisi, 1916, as well as Thranita pelsarti (Montgomery, 1931) and Thr. prymna (Herbst, 1803). In addition, 14 species belonging to nine genera were confirmed as new records to Taiwan, viz. Carupa ohashii Takeda, 1993, Lupocyclus inaequalis (Walker, 1887), Luu. tugelae Barnard, 1950, Lupocycloporus minutus (Shen, 1937), Monomia gladiator (Fabricius, 1798), M. lucida Koch & Duris, 2018, Podophthalmus minabensis Sakai, 1961, Thalamita gatavakensis Nobili, 1906, Tha. spinifera Borradaile, 1902, Thalamitoides quadridens A. Milne-Edwards, 1869, Tho. tridens A. Milne-Edwards, 1869, Thr. cerasma (Wee & Ng, 1995), Thr. coeruleipes (Hombron & Jacquinot, 1846) and Xiphonectes tuberculosus (A. Milne-Edwards, 1861). This study thus raises the total number of Portunidae species in Taiwan to 89.

Parafoveal atrophy after human amniotic membrane graft for macular hole in patients with high myopia.

PURPOSE: To report the surgical outcome and postoperative hypopigmented change around fovea among patients with high myopia who received human amniotic membrane (hAM) graft transplantation for macular hole (MH). METHOD: This retrospective, interventional case series included 10 eyes of 10 consecutive patients (5 (50%) male) with high myopia (axial length over 26.5 mm) who received hAM graft to treat persisted or chronic MH with or without retinal detachment in two hospitals. Postoperative parafoveal atrophy was identified with colour fundus picture and structure optical coherent tomography. Baseline characteristics and short-term visual outcome were analysed. RESULTS: The preoperative mean (±SD) axial length and MH diameter were 29.9 (±1.8) mm and 881.8 (±438.5) µm, respectively. After hAM transplantation, seven (70%) eyes had complete MH closure and the mean best-corrected visual acuity (BCVA) improved from 1.26 (±0.48) logarithm of minimal angle of resolution (logMAR) before operation to 1.11 (±0.44) logMAR on the last visit (p=0.074). Patchy atrophy-like depigmentation developed around the MH lesion in four (40.0%) eyes as early as in the first month after surgery. None of them had visual worsening. In terms of demographics, axial length, MH size, ocular history, preoperative BCVA and postoperative BCVA, there was no significant difference between those with and without the parafoveal atrophy. No graft rejection and inflammation happened during the follow-up. CONCLUSION: Parafovea atrophy, a rare complication in the conventional MH surgery, was observed in 40% of eyes with highly myopic MH after hAM graft transplantation. The pathogenesis and long-term consequence need further investigations.

Comparison between Cryopreserved and Dehydrated Human Amniotic Membrane Graft in Treating Challenging Cases with Macular Hole and Macular Hole Retinal Detachment.

PURPOSE: To evaluate the surgical outcomes of cryopreserved and dehydrated human amniotic membrane (hAM) graft transplantation for macular hole (MH) and macular hole retinal detachment (MHRD) repair. MATERIALS AND METHODS: This retrospective, interventional case series was conducted in two hospitals. Two types of hAM grafts, namely, the dehydrated form (AmnioGen, HCT Regenerative, Taiwan) and the cryopreserved form (AmnioGraft, Bio-Tissue, Miami, FL), were consecutively used in MH surgeries. Anatomical and functional outcomes between the 2 types of hAM grafts were compared. RESULTS: Seventeen patients (mean age: 62.1 ± 10.0 years, 9 (52.9%) males) were enrolled. Of them, 11 patients had persistent MH, 3 had MH without prior surgery, and 3 had MHRD. A cryopreserved hAM graft was used in 10 patients, and a dehydrated hAM graft was used in 8 patients. One patient used a cryopreserved hAM in the first MH surgery and a dehydrated hAM in the second surgery for extramacular hole with retinal detachment. After a 6-month follow-up, 13 (76.5%) patients had sealed MHs. The average visual acuity (VA) of cases with sealed MHs improved from 1.38 ± 0.62 to 1.12 ± 0.47 logMAR (p=0.03). In the other 4 cases with persistent MH, 3 had graft dislocation and 1 had a reopened MH with graft contraction. There were no significant differences in closure rate (80.00% vs. 71.43%, p=0.68) or VA improvement (0.19 ± 0.37 logMAR vs. 0.15 ± 0.41 logMAR, p=0.85) between the 2 kinds of hAM graft. CONCLUSION: This preliminary case series showed that both cryopreserved hAM and dehydrated hAM are feasible alternative grafts for either persistent or recurrent MH. Both approaches have similar anatomical and functional outcomes.

Cutting Edge: Intestinal Mucus Limits the Clonal Deletion of Developing T Cells Specific for an Oral Antigen.

A layer of mucus functions to segregate contents of the intestinal lumen from the intestinal epithelium. The MUC2 mucin is the primary constituent of intestinal mucus and plays critical protective roles against luminal microbes and other noxious agents. In this study, we investigated whether MUC2 helps maintain CD8 T cell tolerance toward intestinal luminal Ags by gavaging wild-type and Muc2-/- mice with a model Ag and monitoring immune responses posttreatment. We report that orally delivered OVA rapidly disseminates through the blood of Muc2-/- (but not control) mice and causes immune activation of Ag-specific CD8 T cells at both local and distal sites. Further, the administration of oral OVA to Muc2-/- mice led to its presentation by thymic dendritic cells and the deletion of Ag-specific thymocytes. Collectively, our findings suggest that intestinal mucus helps limit the shaping of the TCR repertoire of developing thymocytes by intestinal luminal Ags.

A global phylogeny of Stegnogramma ferns (Thelypteridaceae): generic and sectional revision, historical biogeography and evolution of leaf architecture.

The thelypteroid fern genus Stegnogramma s.l. contains around 18-35 species and has a global, cross-continental distribution ranging from tropical to temperate regions. Several genera and infrageneric sections have been recognized previously in Stegnogramma s.l., but their phylogenetic relationships are still unclear. In this study, we present a global phylogeny of Stegnogramma s.l. with the most comprehensive sampling to date and aim to pinpoint the phylogenetic positions of biogeographically and taxonomically important taxa. Based on the reconstructed historical biogeography and character evolution, we propose a new (infra)generic classification and discuss the diversification of Stegnogramma s.l. in a biogeographical context. New names or combinations are made for 12 (infra)species, including transferring the monotypic species of Craspedosorus to Leptogramma. Finally, we discuss a possible link between leaf architecture and ecological adaptation, and hypothesize that the increase in leaf dissection and free-vein proportion is an adaptive feature to cool climates in Stegnogramma s.l.

Correlation of Morphology and In-Vitro Degradation Behavior of Spray Pyrolyzed Bioactive Glasses.

Bioactive glass (BG) is considered to be one of the most remarkable materials in the field of bone tissue regeneration due to its superior bioactivity. In this study, both un-treated and polyethylene glycols (PEG)-treated BG particles were prepared using a spray pyrolysis process to study the correlation between particle morphology and degradation behavior. The phase compositions, surface morphologies, inner structures, and specific surface areas of all BG specimens were examined by X-ray diffraction, scanning electron microscopy, transmission electron microscopy, and nitrogen adsorption/desorption, respectively. Simulated body fluid (SBF) immersion evaluated the assessments of bioactivity and degradation behavior. The results demonstrate three particle morphologies of solid, porous, and hollow factors. The correlation between porosity, bioactivity, and degradation behavior was discussed.

Cancer-associated fibroblast-derived interleukin-1ß activates protumor C-C motif chemokine ligand 22 signaling in head and neck cancer.

Oral cancer, a subtype of head and neck cancer, is characterized by increased infiltrating regulatory T cells (Treg); however, the pathological significance of the increase in Tregs in disease prognosis and progression and their underlying mechanism remain unestablished. C-C motif chemokine ligand 22 (CCL22) has been implicated in the recruitment of Tregs. We used RT-qPCR to determine CCL22 mRNA expression in clinical specimens and cultured cells. Loss-of-function and gain-of-function studies were carried out to analyze the effects of CCL22 modulations on cell proliferation, migration, invasion, and tumorigenesis and the mechanism involved in the deregulation of CCL22. In oral cancer specimens, CCL22 mRNA was upregulated. The increase was not only associated with reduced disease-free survival but also strongly correlated with an increase in FOXP3 mRNA, a master regulator of Treg development and functions. Silencing CCL22 expression reduced cell proliferation, migration, and invasion, whereas ectopic overexpression showed opposite effects. Manipulation of CCL22 expression in cancer cells altered tumorigenesis in both immune-compromised and -competent mice, supporting both autonomous and non-autonomous actions of CCL22. Release of interleukin 1ß (IL-1ß) from cancer-associated fibroblasts (CAF) induces CCL22 mRNA expression in oral cancer cells by activating transcription factor nuclear factor kappa B (NF-κB). Our data support a model in which CAF-derived IL-1ß, CCL22, and its receptor CCR4 foster a protumor environment by promoting cell transformation and Treg infiltration. Intervention of the IL-1ß-CCL22-CCR4 signaling axis may offer a novel therapeutic strategy for oral cancer treatment.