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This study aimed to investigate the effectiveness of neoadjuvant chemotherapy in patients with breast cancer in different age groups and evaluate the impact of age group on survival outcome according to different treatment responses. Data were retrospectively collected from the cancer registry database of Kaohsiung Medical University Hospital in Taiwan under an approved protocol. Overall, 96 elder patients (aged >50 years) and 96 younger controls (aged ≤50 years) who received neoadjuvant chemotherapy and breast surgical treatment were examined after 1:1 matching. Logistic regression analysis was used to investigate the effectiveness of treatment response in patients of different age groups. Additionally, the Kaplan-Meier estimator and log-rank test were performed to evaluate the effect of age group and treatment response on disease-free and overall survival (OS). Although no direct significant association was found between age group and treatment response, several significant results were found in treatment response stratification analysis. Among 16 pathological complete response (pCR) patients, elder patients showed significantly greater 5-year disease-free survival (DFS) than younger patients (DFS rate, 85.7% vs. 0%, p = 0.041). However, in 176 non-pCR patients, elder patients showed poor DFS compared to younger patients (DFS rate, 16.6% vs. 32.3%; log-rank test, p = 0.031). With limited sample size and study design, our study results demonstrate that patients aged >50 years who achieved pCR after neoadjuvant chemotherapy could obtain better survival outcome than younger patients. However, the younger patients showed no survival benefits regardless of pCR status.

Introduction: Invasive ductal carcinoma (IDC) of the breast is a heterogeneous disease characterized by multiple subtypes. IDC survival is highly impacted by tumor burden, molecular subtypes, and gene profiles. Gene mutation is a type of genomic instability regarded as having a considerable effect on IDC prognosis. Using integrated survival analysis, this study identified candidate genes and a high-risk group of patients with early-stage IDC to provide further understanding of the genetic characteristics associated with poor survival. Methods: The gene mutation profiles, baseline demographics, clinicopathologic variables, and treatment characteristics of the early-stage IDC subpopulation were downloaded from an open access data platform. These data were analyzed for a total of 444 patients. In total, 40 genes commonly involved in IDC were listed, and the genes exhibiting significant differences (as estimated using the log-rank test) were selected as the candidate genes. Results: The patients were divided into control, low-risk, and high-risk groups according to their gene mutation profiles. The 5-year overall survival rates of low-risk, control, and high-risk patients were 97.4%, 96.1%, and 73.0%, respectively. The high-risk group had a significantly higher risk of poor overall ­survival (adjusted hazard ratio = 6.57, 95% confidence interval = 1.51–28.7, p = 0.012) than that of the control group, and the low-risk group did not have a significant survival difference compared with control group. Conclusions: This study proposed an integrative approach for the identification of candidate genes for risk assessment of overall survival in these patients through typical survival analysis methods. The 14 candidate genes selected are particularly involved in cell-cycle processes, deoxyribonucleic acid repair, and drug resistance; their mutations were found to be generally associated with disease progression or therapeutic resistance, which is commonly associated with poor overall survival outcomes in IDC.

From April 23 to November 2021, a wave of COVID-19 infections caused by a new Alpha variant swept across Taiwan, resulting in 14,458 positive cases and 830 deaths among over 3.8 million people tested. To cope with the sudden increase in sample volume, as of December 14, 2021, a network of 249 laboratories with a total diagnostic capacity of 158,492 real-time reverse transcription polymerase chain reaction tests per day was established in 22 administrative regions. As of April 2022, over 9.5 million specimens were tested. Fully automated high-throughput and point-of-care nucleic acid testing, and rapid antigen testing, were simultaneously implemented to expand the country's daily diagnostic capacity. Saliva testing and sample pooling were also introduced to increase screening efficiency in certain situations. Antibody testing and genomic sequencing were also adopted for more precise epidemic investigation. Other challenges encountered and overcome include a lack of resources and interfacing of laboratory information management systems for case reporting, limited specimen allocation and delivery, and limited staff for diagnostic processing.

Through early and proactive laboratory testing of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes novel coronavirus 2019, Taiwan has demonstrated an efficient and rapid control response to contain the outbreak. Two days after the World Health Organization announced the complete viral genome sequence, the national laboratory of the Taiwan Centers for Disease Control developed a specific real-time reverse transcription polymerase chain reaction (real-time RT-PCR) test for SARS-CoV-2. The national laboratory network was further strengthened through the recruitment of medical centers and regional hospitals distributed throughout most geographical regions of the country. Ultimately, a network of 60 laboratories with a capacity of 7,342 real-time RT-PCR tests per day was established. Between January 14 and August 5, 2020, a total of 158,772 tests were conducted, corresponding to 120,487 cases. Test results were obtained within 24 hours, enabling an efficient and rapid control response.

A polyphasic taxonomic approach was used to characterize a nitrogen-fixing bacterium, designated strain CC-HIH110T, isolated from paddy soil in Taiwan. Cells of strain CC-HIH110T were Gram-stain-negative, rod-shaped, motile with polar flagella, catalase-positive and oxidase-positive. Optimal growth occurred at 30 °С, pH 7 and 1 % NaCl. Phylogenetic analyses based on 16S rRNA genes revealed a distinct taxonomic position attained by strain CC-HIH110T associated with Rhizobium oryziradicis (98.4 % sequence identity), Allorhizobium vitis (97.8 %), Allorhizobium taibaishanense (97.7 %) and Allorhizobium undicola (96.0 %), and lower sequence similarity to other species. Average nucleotide identity (ANI) and digital DNA-DNA hybridization (dDDH) values between strain CC-HIH110T and the type strains of other closely related species were 71.5-88.6 % and 19.6-35.5 %, respectively. Strain CC-HIH110T contained C16 : 0 3-OH, C14 : 0 3-OH/iso C16 : 1 I and C18 : 1 ω7c/C18 : 1 ω6c as the predominant fatty acids. The polar lipid profile consisted of diphosphatidylglycerol, phosphatidylglycerol, phosphatidylethanolamine, phosphatidylmonomethylethanolamine, phosphatidyldimethylethanolamine, phosphatidylcholine, three unknown aminophospholipids, two unknown phospholipids and an unknown lipid. The major polyamine was homospermidine. The DNA G+C content was 55.0 mol% and the predominant quinone was ubiquinone (Q-10). Based on its distinct phylogenetic, phenotypic and chemotaxonomic traits together with results of comparative 16S rRNA gene sequence, ANI and dDDH analyses, strain CC-HIH110T is proposed to represent a novel Allorhizobium species, for which the name Allorhizobium terrae sp. nov. (type strain CC-HIH110T=BCRC 80932T=JCM 31228T). In addition, Rhizobium oryziradicis is reclassified as Allorhizobium oryziradicis (type strain N19T=ACCC 19962T=KCTC 52413T) comb. nov.

BACKGROUND The associations between malignant transformation of oral potentially malignant disorders (OPMDs), oral cancer development and prognosis, and apurinic/apyrimidinic endonuclease 1 (APE1) functional polymorphisms are unclear. METHODS Patients with OPMDs, patients with oral cancer, and healthy controls from the community were recruited to determine the effects of APE1 polymorphisms on malignant transformation, overall survival, and genetic susceptibility, respectively. RESULTS The APE1 Asp148Glu polymorphisms significantly correlated with a high hazard ratio for OPMD malignant transformation (adjusted hazard ratio [AHR] = 2.29; 95% confidence interval [CI] = 1.44-3.74) and low overall survival in oral cancer patients (AHR = 1.71, 95% CI = 1.11-2.56) according to follow-up and survival analysis. However, APE1 polymorphisms did not significantly correlate with development of oral cancer in the case-control study and logistic regression analysis. CONCLUSIONS These results indicate that APE1 Asp148Glu polymorphisms may have indirect roles in increasing the OPMD malignant transformation rate and in decreasing overall survival in oral cancer patients.

Intestinal immunity is coordinated by specialized mononuclear phagocyte populations, constituted by a diversity of cell subsets. Although the cell subsets constituting the mononuclear phagocyte network are thought to be similar in both small and large intestine, these organs have distinct anatomy, microbial composition, and immunological demands. Whether these distinctions demand organ-specific mononuclear phagocyte populations with dedicated organ-specific roles in immunity are unknown. Here we implement a new strategy to subset murine intestinal mononuclear phagocytes and identify two novel subsets which are colon-specific: a macrophage subset and a Th17-inducing dendritic cell (DC) subset. Colon-specific DCs and macrophages co-expressed CD24 and CD14, and surprisingly, both were dependent on the transcription factor IRF4. Novel IRF4-dependent CD14+CD24+ macrophages were markedly distinct from conventional macrophages and failed to express classical markers including CX3CR1, CD64 and CD88, and surprisingly expressed little IL-10, which was otherwise robustly expressed by all other intestinal macrophages. We further found that colon-specific CD14+CD24+ mononuclear phagocytes were essential for Th17 immunity in the colon, and provide definitive evidence that colon and small intestine have distinct antigen presenting cell requirements for Th17 immunity. Our findings reveal unappreciated organ-specific diversity of intestine-resident mononuclear phagocytes and organ-specific requirements for Th17 immunity.

Background We developed a porous Ti alloy/PEEK composite interbody cage by utilizing the advantages of polyetheretherketone (PEEK) and titanium alloy (Ti alloy) in combination with additive manufacturing technology. Methods Porous Ti alloy/PEEK composite cages were manufactured using various controlled porosities. Anterior intervertebral lumbar fusion and posterior augmentation were performed at three vertebral levels on 20 female pigs. Each level was randomly implanted with one of the five cages that were tested: a commercialized pure PEEK cage, a Ti alloy/PEEK composite cage with nonporous Ti alloy endplates, and three composite cages with porosities of 40, 60, and 80%, respectively. Micro-computed tomography (CT), backscattered-electron SEM (BSE-SEM), and histological analyses were performed. Results Micro-CT and histological analyses revealed improved bone growth in high-porosity groups. Micro-CT and BSE-SEM demonstrated that structures with high porosities, especially 60 and 80%, facilitated more bone formation inside the implant but not outside the implant. Histological analysis also showed that bone formation was higher in Ti alloy groups than in the PEEK group. Conclusion The composite cage presents the biological advantages of Ti alloy porous endplates and the mechanical and radiographic advantages of the PEEK central core, which makes it suitable for use as a single implant for intervertebral fusion.

Intestinal immunity is coordinated by specialized mononuclear phagocyte populations, constituted by a diversity of cell subsets. Although the cell subsets constituting the mononuclear phagocyte network are thought to be similar in both small and large intestine, these organs have distinct anatomy, microbial composition, and immunological demands. Whether these distinctions demand organ-specific mononuclear phagocyte populations with dedicated organ-specific roles in immunity are unknown. Here we implement a new strategy to subset murine intestinal mononuclear phagocytes and identify two novel subsets which are colon-specific: a macrophage subset and a Th17-inducing dendritic cell (DC) subset. Colon-specific DCs and macrophages co-expressed CD24 and CD14, and surprisingly, both were dependent on the transcription factor IRF4. Novel IRF4-dependent CD14+CD24+ macrophages were markedly distinct from conventional macrophages and failed to express classical markers including CX3CR1, CD64 and CD88, and surprisingly expressed little IL-10, which was otherwise robustly expressed by all other intestinal macrophages. We further found that colon-specific CD14+CD24+ mononuclear phagocytes were essential for Th17 immunity in the colon, and provide definitive evidence that colon and small intestine have distinct antigen presenting cell requirements for Th17 immunity. Our findings reveal unappreciated organ-specific diversity of intestine-resident mononuclear phagocytes and organ-specific requirements for Th17 immunity.

While developmental programming of innate-like γδT cells generates dedicated IFN-γ-producing (γδIFN-γ) or IL-17-producing (γδ17) subsets, emerging evidence suggests these are further shaped by environmental cues. Such cues include the intestinal microbiota, although the nature of microbiota-dependent regulation is poorly understood since some reports hold that microbiota exert strictly activating signals, while other reports show microbiota are strictly suppressive. Whether the impact of microbiota on γδT cells is indeed exclusively binary, and whether regulatory modules stemming from the microbiota can be dynamic in response to changing physiologic conditions remains unknown. Here we identify a microbiota-dependent regulatory module for γδ17 cells in which microbiota concomitantly upregulate IL-17-production and the inhibitory receptor programmed cell death protein 1 (PD-1). Concomitant expression of these two modules, the requirements for microbiota, and preferential upregulation of a PD-1high phenotype is conserved for γδ17 cells resident within multiple mucosal barriers. Importantly, microbiota-driven PD-1 inhibits IL-17 production by endogenous γδ17 effectors. We further show that these two microbiota-dependent modules are dynamic, wherein both PD-1 and IL-17 producing functions are downregulated upon depletion of microbiota, and concomitantly upregulated in response to intestinal inflammation. We also identify enhanced capacity for lipid uptake as an inflammation-associated metabolic response specific to the γδ17 subset, thus linking augmented γδ17 effector functions to dynamic subset-specific metabolic remodeling within the intestine. Supported by NIH R01-AI088100 awarded to MLS

In light of recent studies identifying gain-of-function variants of spleen tyrosine kinase (Syk) as a cause of multi-organ inflammatory disease, Syk inhibition has become an attractive pharmacological target. Therapeutic potential of Syk inhibition may extend beyond that of gain-of-function mutations, since Syk activity initiates downstream responses to several pattern-recognition receptors, which are collectively thought to trigger pathology in several inflammatory diseases, including inflammatory bowel disease (IBD). We previously identified the IBD-linked gene Tnfaip3 (A20) as a suppressor of Syk-dependent inflammatory signals in dendritic cells (DCs) and report here that small molecule inhibition of Syk with FDA-approved drug Fostamatinib mitigates the small intestinal inflammation that develops spontaneously in mice with DC-specific loss of A20 (A20cko mice). In our investigation of IBD in these mice we surprisingly found that A20cko mice also had striking inflammation of the liver that shared many biochemical and histological features characteristic of IBD-associated liver disease, including extensive bridging fibrosis. Importantly, Syk inhibition normalized liver biochemistries and significantly reduced intrahepatic inflammation and fibrosis. Mechanistically, plasma proteomics and liver immunophenotyping pinpointed the key impact of Syk inhibition on restricting chemokine expression linked to recruitment of pro-inflammatory monocytes into in the liver. Collectively this work identifies the interplay of Syk and A20 signaling as drivers of inflammation along the gut-liver axis and suggests Syk is a valid target for pharmacological intervention for IBD and IBD-associated liver disease. Supported by R01AI145930-01A1

C-type lectin receptors (CLRs) play key roles in antifungal defense. CLR-induced NF-κB is central to CLR functions in immunity, and thus, molecules that control the amplitude of CLR-induced NF-κB could profoundly influence host defense against fungal pathogens. However, little is known about the mechanisms that negatively regulate CLR-induced NF-κB, and molecules which act on the CLR family broadly and which directly regulate acute CLR-signaling cascades remain unidentified. Here, we identify the ubiquitin-editing enzyme A20 as a negative regulator of acute NF-κB activation downstream of multiple CLR pathways. Absence of A20 suppression results in exaggerated CLR responses in cells which are A20 deficient and also cells which are A20 haplosufficient, including multiple primary immune cells. Loss of a single allele of A20 results in enhanced defense against systemic Candida albicans infection and prolonged host survival. Thus, A20 restricts CLR-induced innate immune responses in vivo and is a suppressor of host defense against systemic fungal infection.

Background: Invasive ductal carcinoma (IDC) breast cancer is a heterogeneous disease characterized by multiple subtypes. Breast cancer survival is highly impacted by tumor burden, molecular subtypes, and gene profiles. Gene mutation is a type of genomic instability regarded as having a considerable effect on breast cancer prognosis. Using integrated survival analysis, this study identified candidate genes and a high-risk group of patients with early-stage IDC breast cancer to provide further understanding of the genetic characteristics associated with poor survival. Methods: The gene mutation profiles, baseline demographics, clinicopathological variables, and treatment characteristics of the early-stage breast cancer subpopulation were downloaded from an open access data platform. These data were analyzed for a total of 444 patients. In total, 32 genes commonly involved in breast cancer were listed, and the genes exhibiting significant differences (as estimated using the log-rank test) were selected as the candidate genes. Results: The patients were divided into control, low-risk, and high-risk groups according to their gene mutation profiles. The 5-year overall survival rates were 97.6%, 96.0%, and 68.2%, respectively. The high-risk group had a significantly higher risk of poor overall survival (adjusted hazard ratio = 9.94, 95% confidence interval = 2.24–44.20, P = 0.003) than the other groups and the low-risk group did not have a significantly higher risk of poor overall survival compared with controls. Conclusions: This study proposed an integrative approach for the identification of candidate genes for risk assessment of overall survival in these patients through typical survival analysis methods. The 10 candidate genes selected are particularly involved in cell-cycle processes, DNA repair, and drug resistance; their mutations were found to be generally associated with disease progression or therapeutic resistance, which is commonly associated with poor survival outcomes.

IRGM and its mouse orthologue Irgm1 are dynamin-like proteins that regulate vesicular remodeling, intracellular microbial killing, and pathogen immunity. IRGM dysfunction is linked to inflammatory bowel disease (IBD), and while it is thought that defective intracellular killing of microbes underscores IBD susceptibility, studies have yet to address how IRGM/Irgm1 regulates immunity to microbes relevant to intestinal inflammation. Here we find that loss of Irgm1 confers marked susceptibility to Citrobacter rodentium, a noninvasive intestinal pathogen that models inflammatory responses to intestinal bacteria. Irgm1-deficient mice fail to control C. rodentium outgrowth in the intestine, leading to systemic pathogen spread and host mortality. Surprisingly, susceptibility due to loss of Irgm1 function was not linked to defective intracellular killing of C. rodentium or exaggerated inflammation, but was instead linked to failure to remodel specific colon lamina propria (C-LP) myeloid cells that expand in response to C. rodentium infection and are essential for C. rodentium immunity. Defective immune remodeling was most striking in C-LP monocytes, which were successfully recruited to the infected C-LP, but subsequently underwent apoptosis. Apoptotic susceptibility was induced by C. rodentium infection and was specific to this setting of pathogen infection, and was not apparent in other settings of intestinal inflammation. These studies reveal a novel role for Irgm1 in host defense and suggest that deficiencies in survival and remodeling of C-LP myeloid cells that control inflammatory intestinal bacteria may underpin IBD pathogenesis linked to IRGM dysfunction., Author summary Intestinal macrophages are seeded by peripheral monocytes that enter the intestine and mature into an essential component of immune defense. While this process is shaped by intestinal bacteria, the mechanisms that regulate the process, and their roles in host defense to enteric pathogens are poorly defined. We find that Irgm1 –the orthologue of the human Crohn’s disease resistance gene, IRGM–is required for monocyte/macrophage remodeling in response to the gram-negative enteric pathogen Citrobacter rodentium, with absence of Irgm1 leading to systemic spread of the bacterium and host mortality. Failure to remodel colonic monocytes/macrophages was due to a key requirement for Irgm1 in colon-infiltrating monocytes, which underwent dramatically high rates of cell death, specifically during the setting of enteric bacterial infection. While Irgm1/IRGM proteins are well appreciated for their role in regulating intracellular bacterial killing, our results expand the paradigm for Irgm1/IRGM-mediated host defense by demonstrating an essential function for Irgm1/IRGM to control the survival and population remodeling of monocytes and macrophages that expand during enteric infection and defend against pathogenic bacteria. These findings have significant implications for the genesis of Crohn’s disease in individuals that carry IRGM variants.

During March–April 2018, an infectious measles index case traveling from Thailand led to two successive generations of measles transmission in Taiwan, with 21 cases confirmed. The median patient age was 30.5 years (range 22–47 years); six (27%) had documented receipt of one (n = 3) or more (n = 3) previous measles-containing vaccine doses at age ≥12 months. Epidemiological investigation and sequence analysis found that most (n = 16, 76%) measles transmissions had occurred in airport and flight settings; secondary and tertiary cases included cabin crew (n = 7), airport staff (n = 2), and passengers who had been at the same airport or on the same flight (n = 7). This investigation serves as a reminder that an international airport can be a hotspot for measles transmission. International travelers, airline cabin crew, and airport employees are recommended to check their vaccination status and ensure that they are fully vaccinated against measles. Furthermore, it is recommended that airline and airport employers have an occupational health vaccination program in place to ensure appropriate pre-employment assessment of measles immunity and vaccination. Keywords: Measles, Outbreak, Airport, Air travel, Vaccination

Objective Transoral laser microsurgery (TLM) is an alternative method for organ preservation in squamous cell carcinoma of hypopharynx (HPSCC). The purpose of this study was to analyze the oncologic results and quality of life (QOL) in HPSCC patients after TLM. Methods Forty-six patients who underwent TLM were included, 34 of them had QOL evaluations. The QOL analyses were measured with EORTC QLQ-C-30, QLQ-H&N35, VHI-30, and MDADI at least 6 months postoperatively. Results Most patients were male (96%) with a median age of 60 years. Four patients (9%) were at the T1 category, 24 (52%) at T2, 15 (33%) at T3, and 3 (7%) at T4. Twenty-nine patients (63%) had cervical lymph node metastases and 26 (57%) received postoperative radiotherapy. With a median follow-up of 61 months for all patients, 18 (39%) had tumor recurrence, including 4 local, 7 regional, and 7 distant. The 5-year overall and disease-specific survival (DSS) rates were 59% and 77%, respectively. The 5-year laryngeal preservation rate was 89%. Most patients had satisfactory QOLs. Conclusion In early and selective moderately advanced HPSCC, TLM can achieve optimal oncologic results and satisfactory QOL. Lasers Surg. Med. 50:117-124, 2018. © 2017 Wiley Periodicals, Inc.

Objective This paper aims to comprehensively document a rare case of thyroid carcinoma with rhabdoid phenotype and literature review of this disease. Methods A 59-year-old man presented with a rapidly enlarging, painful left lateral cervical mass. CT scan revealed a tumor over the left the thyroid gland with multiple left cervical lymphadenopathy over left level II–IV and level VI. Fine-needle aspiration cytology reported carcinoma, type undetermined. Total thyroidectomy with central compartment and left neck dissection was performed. Results Pathology report showed rhabdoid phenotype of thyroid carcinoma. Final staging was pT4N1M1. Conclusions Although WHO classification of thyroid tumor histology does not define this disease entity, few cases were reported. In the last 20 years, English literature review revealed only 12 cases about thyroid carcinoma with rhabdoid phenotype. Major treatment of thyroid carcinoma with rhabdoid phenotype is surgery, and the benefit of adjuvant therapies as radiotherapy or systemic chemotherapy is not clear. The prognosis of thyroid carcinoma with rhabdoid phenotype is extremely poor, with mean survival of only 6 months.

IRGMand its mouse orthologueIrgm1are dynamin-like proteins that regulate vesicular remodeling, intracellular microbial killing, and pathogen immunity.IRGMdysfunction is linked to inflammatory bowel disease (IBD), and while it is thought that defective intracellular killing of microbes underscores IBD susceptibility, studies have yet to address how IRGM/Irgm1 regulates immunity to microbes relevant to intestinal inflammation. Here we find that loss of Irgm1 confers marked susceptibility toCitrobacter rodentium, a noninvasive intestinal pathogen that models inflammatory responses to intestinal bacteria. Irgm1-deficient mice fail to controlC. rodentiumoutgrowth in the intestine, leading to systemic pathogen spread and host mortality. Surprisingly, susceptibility due to loss of Irgm1 function was not linked to defective intracellular killing ofC. rodentiumor exaggerated inflammation, but was instead linked to failure to remodel specific colon lamina propria (C-LP) myeloid cells that expand in response toC. rodentiuminfection and are essential forC. rodentiumimmunity. Defective immune remodeling was most striking in C-LP monocytes, which were successfully recruited to the infected C-LP, but subsequently underwent apoptosis. Apoptotic susceptibility was induced byC. rodentiuminfection and was specific to this setting of pathogen infection, and was not apparent in other settings of intestinal inflammation. These studies reveal a novel role for Irgm1 in host defense and suggest that deficiencies in survival and remodeling of C-LP myeloid cells that control inflammatory intestinal bacteria may underpin IBD pathogenesis linked to IRGM dysfunction.Author SummaryIntestinal macrophages are seeded by peripheral monocytes that enter the intestine and mature into an essential component of immune defense. While this process is shaped by intestinal bacteria, the mechanisms that regulate the process, and their roles in host defense to enteric pathogens are poorly defined. We find thatIrgm1– the orthologue of the human Crohn’s disease resistance gene,IRGM– is required for monocyte/macrophage remodeling in response to the gram-negative enteric pathogenCitrobacter rodentium, with absence of Irgm1 leading to systemic spread of the bacterium and host mortality. Failure to remodel colonic monocytes/macrophages was due to a key requirement for Irgm1 in colon-infiltrating monocytes, which underwent dramatically high rates of cell death, specifically during the setting of enteric bacterial infection. While Irgm1/IRGM proteins are well appreciated for their role in regulating intracellular bacterial killing, our results expand the paradigm for Irgm1/IRGM-mediated host defense by demonstrating an essential function for Irgm1/IRGM to control the survival and population remodeling of monocytes and macrophages that expand during enteric infection and defend against pathogenic bacteria. These findings have significant implications for the genesis of Crohn’s disease in individuals that carryIRGMvariants.

Intestinal immunity is coordinated by specialized populations of mononuclear phagocytes. Although the cell subsets that constitute these populations are thought uniform throughout the intestine, small and large intestine have distinct anatomy, microbial composition, and immunological demands. Whether these distinctions demand organ-specific mononuclear phagocyte populations with dedicated organ-specific roles in immunity is unknown. Here we implement a new strategy to subset murine intestinal mononuclear phagocytes and identify two novel subsets which are colon-specific: a macrophage subset and a Th17-inducing dendritic cell (DC) subset. Colon-specific DCs and macrophages co-expressed CD24 and CD14, and surprisingly, both were dependent on the transcription factor IRF4. Novel IRF4-dependent CD14+CD24+ macrophages were markedly distinct from conventional macrophages and failed to express classical markers including CX3CR1, CD64 and CD88, and surprisingly expressed little IL-10, which was otherwise robustly expressed by all other intestinal macrophages. We further found that colon-specific CD14+CD24+ mononuclear phagocytes were essential for Th17 immunity in the colon, and provide definitive evidence that colon and small intestine have distinct antigen presenting cell requirements for Th17 immunity. Our findings reveal unappreciated organ-specific diversity of intestine-resident mononuclear phagocytes and organ-specific requirements for Th17 immunity.

Made available in DSpace on 2018-11-26T17:10:26Z (GMT). No. of bitstreams: 0 Previous issue date: 2016-10-25 Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) Center of Gastrointestinal Biology and Disease PSC partners seeking a cure American Gastroenterological Association Research Foundation Gut Microbiome Pilot Research Award Pew Charitable Trusts Normal dynamics between microbiota and dendritic cells (DCs) support modest numbers of T cells, yet these do not cause inflammation. The DCs that induce inflammatory T cells and the signals that drive this process remain unclear. Here, we demonstrate that small intestine DCs lacking the signaling attenuator A20 induce inflammatory T cells and that the signals perceived and antigen-presenting cell (APC) functions are unique for different DC subsets. Thus, although CD103(+)CD11b(+) DCs exclusively instruct IFN gamma(+) T cells, CD103(+)CD11b(+) DCs exclusively instruct IL-17(+) T cells. Surprisingly, APC functions of both DC subsets are upregulated in a MyD88-independent fashion. In contrast, CD103(-)CD11b(+) DCs instruct both IFN gamma(+) and IL-17(+) T cells, and only the IL-17-inducing APC functions require MyD88. In disease pathogenesis, both CD103(-)CD11b(+) and CD103(+)CD11b(+) DCs expand pathologic Th17 cells. Thus, in disease pathogenesis, specific DCs instruct specific inflammatory T cells. Duke Univ, Dept Immunol, Sch Med, Durham, NC 27710 USA Univ Estadual Paulista, Dept Phys, BR-15054000 Sao Jose Do Rio Preto, SP, Brazil Univ Erlangen Nurnberg, Dept Biol, D-91058 Erlangen, Germany Univ Calif San Francisco, Dept Med, San Francisco, CA 94143 USA Duke Univ, Sch Med, Dept Pathol, Durham, NC 27710 USA Univ Estadual Paulista, Dept Phys, BR-15054000 Sao Jose Do Rio Preto, SP, Brazil CAPES: 9693/14-09 Center of Gastrointestinal Biology and Disease: P30 DK034987

A polyphasic approach was used to characterize a novel nitrogen-fixing bacterial strain, designated CC-HIH038T, isolated from cultivated soil in Taiwan. Cells of strain CC-HIH038T were Gram-stain-negative, facultatively aerobic and spiral-shaped, with motility provided by a single polar flagellum. The 16S rRNA gene sequence analysis of strain CC-HIH038T showed highest sequence similarity to Azospirillum doebereinerae (98.0 %), Azospirillum thiophilum (97.5 %), Azospirillum rugosum (97.4 %) and Azospirillum zeae (97.2 %) and lower sequence similarity (

Immune responses in the intestine are coordinated by specialized populations of mononuclear phagocytes. Although the functions of intestine-resident mononuclear phagocytes and the different cell subsets that constitute these populations are thought uniform across the entire intestine, it is clear that the anatomy, microbes, and immunological demands are distinct for small and large intestine. Whether these distinctions also include organ-specific mononuclear phagocyte populations, or that these have organ-specific roles in immunity are unknown. Here we identify two novel subsets of colon-specific mononuclear phagocytes, a dendritic cell (DC) subset and a macrophage subset, both of which are exclusive to the colon and are not found in small intestine. These colon-specific DCs and macrophages co-expressed CD14 and CD24, markers which are generally singularly expressed by intestinal DCs and macrophages and commonly used to distinguish between these two cell types. Colon-specific CD14+CD24+ DCs and macrophages failed to express macrophage markers CX3CR1, F4/80, CD64 and CD88, and surprisingly, both the DC and macrophage subset were dependent on the transcription factor IRF4. We further find that colon and small intestine have distinct antigen presenting cell (APC) requirements for Th17 immunity and that while colon-specific CD14+CD24+ APCs were essential for Th17 immunity in the colon, this role in small intestine was mediated by different APC subsets. Our findings reveal unappreciated organ-specific diversity of intestine-resident mononuclear phagocytes and organ-specific requirements for Th17 immunity.

Advanced electrode designs have made single-unit neural recordings commonplace in modern neuroscience research. However, single-unit resolution remains out of reach for the intrinsic neurons of the gastrointestinal system. Single-unit recordings of the enteric (gut) nervous system have been conducted in anesthetized animal models and excised tissue, but there is a large physiological gap between awake and anesthetized animals, particularly for the enteric nervous system. Here, we describe the opportunity for advancing enteric neuroscience offered by single-unit recording capabilities in awake animals. We highlight the primary challenges to microelectrodes in the gastrointestinal system including structural, physiological, and signal quality challenges, and we provide design criteria recommendations for enteric microelectrodes.

Aim To evaluate, compare and improve quality of care for patients with breast cancer at the institution and population level requires a standard set of core measures. We performed a population-based cohort study to examine the association between hospital volume and breast cancer core measures compliance in Taiwan. Methods Data were obtained from the Health Promotion Administration, Ministry of Health and Welfare, Taiwan. All women with a diagnosis of breast cancer between 2007 and 2011 were selected. Hospitals were divided into quartiles of hospital volume based on the total number of breast cancer surgery performed from 2007 to 2011. The core measure set that evaluates the quality of care for breast cancer included one preoperation and nine treatment-related indicators. Results Our final study population included 38 943 patients from 74 hospitals. An increase in hospital volume was associated with better core measures compliance as indicated by higher adherence rates. As compared with the lower quartiles (quartiles 1/2/3) of hospital volume, quartile 4 (high volume) showed significantly higher adherence rate in two indicators measured (“percentage of breast cancer patients whose diagnoses were histologically and cytologically confirmed before surgery” and “percentage of stage 1 and 2 patients with sentinel node sampling performed,” P = 0.011 and 0.016, respectively). An increasing trend in compliance for “percentage of stage 1 patients who underwent breast conserving surgery” was observed in high-volume but not low-volume hospitals (P

An aerobic, Gram-stain-negative, rod-shaped, DDT-resistant bacterium, designated strain CC-ALB-2T, was isolated from the Arabidopsis thaliana rhizosphere. Strain CC-ALB-2T was able to grow at 25–37 °C, at pH 5.0–8.0, with 1.0 % (w/v) NaCl and tolerate up to 200 mg l−1 DDT. 16S rRNA gene sequence analysis of strain CC-ALB-2T showed highest sequence similarity to Novosphingobium stygium KCTC 2891T (97.1 %) and Novosphingobium soli DSM 22821T (96.8 %), and lower levels of similarity ( Novosphingobium . The major fatty acid profile consisted of C14 : 0 2-OH (13.1 %), C16 : 0 (10.0 %), C15 : 0 iso 3-OH (5.8 %), C16 : 1ω7c/C16 : 1ω6c (summed feature 3, 24.7 %) and C18 : 1ω7c/C18 : 1ω6c (summed feature 8, 42.4 %). The polar lipid profile constitutes sphingoglycolipid, glycolipid, diphosphatidylglycerol, phosphatidylethanolamine, phosphatidyldimethylethanolamine, phosphatidylglycerol and phosphatidylcholine. The polyamine pattern showed a predominance of spermidine as the major polyamine. The predominant quinone system was ubiquinone (Q-10). The DNA G+C content was 68.9±0.1 mol%. Based on the phylogenetic, phenotypic and chemotaxonomic features, strain CC-ALB-2T is proposed to represent a novel species of the genus Novosphingobium for which the name Novosphingobium arabidopsis sp. nov. is proposed. The type strain is CC-ALB-2T ( = BCRC 80571T = JCM 18896T).

The immune system’s ability to eradicate cancer requires coordination between innate and adaptive immune cells. No other cell type bridges innate and adaptive immunity better than the dendritic cell (DC). For this reason, DCs, specifically the Batf3-dependent DC subset, are thought to be key to anti-tumor immunity. Although the anti-tumor functions of Batf3-dependent DCs have been well described in skin cancer, whether these DCs have similar anti-tumor functions in other cancers is unknown. Here we investigated the roles of Batf3-dependent DCs in colon cancer and paradoxically found that these DCs actually promote colon tumorigenesis. Thus, in a spontaneous colorectal cancer mouse model, loss of Batf3-dependent DCs resulted in decreased colon tumor number. Although Batf3-dependent DCs are best known for expanding IFNγ-producing T cells, in colon tumors, we surprisingly found that Batf3-dependent DCs were required to expand tumor-infiltrating γδT cells producing IL-17. IL-17 is known to promote colon tumorigenesis and our findings pinpoint IL-17-producing γδT cells as a key source of IL-17 for tumor growth, and surprisingly describe a requirement for Batf3-dependent DCs to expand an IL-17-producing T cell population. In addition, we identified tumor-infiltrating Batf3-dependent DCs uniquely upregulate high levels of PD-L1as a second mode of action to promote colon cancer. PD-L1 upregulation and high PD-L1 expression on Batf3-dependent DCs was specific within the tumor microenvironment. Collectively, these paradoxical pro-tumorigenic functions of Batf3-dependent DCs suggest that these DCs are not universally anti-tumor and that targeted therapies that modulate Batf3-dependent DCs could benefit colon cancer patients.

IRGM and its mouse orthologue Irgm1 are dynamin-like proteins that regulate vesicular remodeling, intracellular microbial killing and pathogen immunity. IRGM dysfunction is also linked to inflammatory bowel disease (IBD), and while it is thought that defective intracellular killing of microbes underscores IBD susceptibility, studies have yet to address how IRGM/Irgm1 regulates immunity to microbes relevant to intestinal inflammation. Here we find that loss of Irgm1 confers marked susceptibility to Citrobacter rodentium, a noninvasive intestinal pathogen that models inflammatory responses to intestinal bacteria similar to that of IBD. Irgm1-deficient mice fail to control C. rodentium outgrowth in the intestine, leading to systemic pathogen spread and host mortality. Surprisingly, susceptibility due to loss of Irgm1 function was not linked to defective intracellular killing of C. rodentium or exaggerated inflammation, but was instead linked to failure to remodel specific colon lamina propria (C-LP) myeloid cells that expand in response to C. rodentium infection and are essential for C. rodentium immunity. Defective immune remodeling was most striking in C-LP monocytes, which were successfully recruited to the infected C-LP, but subsequently underwent apoptosis. Apoptotic susceptibility was induced by C. rodentium infection and was specific to this setting of pathogen infection, and was not apparent in other settings of intestinal inflammation. These studies reveal a novel role for Irgm1 in host defense and suggest that deficiencies in survival and remodeling of C-LP myeloid cells that control inflammatory intestinal bacteria may underpin IBD pathogenesis linked to IRGM dysfunction.