Sepsis-trained macrophages promote antitumoral tissue-resident T cells.

Sepsis induces immune alterations, which last for months after the resolution of illness. The effect of this immunological reprogramming on the risk of developing cancer is unclear. Here we use a national claims database to show that sepsis survivors had a lower cumulative incidence of cancers than matched nonsevere infection survivors. We identify a chemokine network released from sepsis-trained resident macrophages that triggers tissue residency of T cells via CCR2 and CXCR6 stimulations as the immune mechanism responsible for this decreased risk of de novo tumor development after sepsis cure. While nonseptic inflammation does not provoke this network, laminarin injection could therapeutically reproduce the protective sepsis effect. This chemokine network and CXCR6 tissue-resident T cell accumulation were detected in humans with sepsis and were associated with prolonged survival in humans with cancer. These findings identify a therapeutically relevant antitumor consequence of sepsis-induced trained immunity.

Myeloid cell influx into the colonic epithelium is associated with disease severity and non-response to anti-Tumor Necrosis Factor Therapy in patients with Ulcerative Colitis.

Ulcerative colitis (UC) is an idiopathic chronic inflammatory disease of the colon with sharply rising global prevalence. Dysfunctional epithelial compartment (EC) dynamics are implicated in UC pathogenesis although EC-specific studies are sparse. Applying orthogonal high-dimensional EC profiling to a Primary Cohort (PC; n=222), we detail major epithelial and immune cell perturbations in active UC. Prominently, reduced frequencies of mature BEST4+OTOP2+ absorptive and BEST2+WFDC2+ secretory epithelial enterocytes were associated with the replacement of homeostatic, resident TRDC+KLRD1+HOPX+ γδ+ T cells with RORA+CCL20+S100A4+ TH17 cells and the influx of inflammatory myeloid cells. The EC transcriptome (exemplified by S100A8, HIF1A, TREM1, CXCR1) correlated with clinical, endoscopic, and histological severity of UC in an independent validation cohort (n=649). Furthermore, therapeutic relevance of the observed cellular and transcriptomic changes was investigated in 3 additional published UC cohorts (n=23, 48 and 204 respectively) to reveal that non-response to anti-Tumor Necrosis Factor (anti-TNF) therapy was associated with EC related myeloid cell perturbations. Altogether, these data provide high resolution mapping of the EC to facilitate therapeutic decision-making and personalization of therapy in patients with UC.

IL-22BP production is heterogeneously distributed in Crohn's disease.

Crohn's disease (CD), a form of inflammatory bowel disease (IBD), is characterized by impaired epithelial barrier functions and dysregulated mucosal immune responses. IL-22 binding protein (IL-22BP) is a soluble inhibitor regulating IL-22 bioactivity, a cytokine proposed to play protective roles during CD. We and others have shown that IL-22BP is produced in IBD inflamed tissues, hence suggesting a role in CD. In this work, we extended the characterization of IL-22BP production and distribution in CD tissues by applying enzyme-linked immunosorbent assays to supernatants obtained from the culture of endoscopic biopsies of patients, and reverse transcription-quantitative polymerase chain reaction on sorted immune cell subsets. We reveal that IL-22BP levels are higher in inflamed ileums than colons. We observe that in a cell-intrinsic fashion, populations of mononuclear phagocytes and eosinophils express IL-22BP at the highest levels in comparison to other sources of T cells. We suggest the enrichment of intestinal eosinophils could explain higher IL-22BP levels in the ileum. In inflamed colon, we reveal the presence of increased IL-22/IL22BP ratios compared to controls, and a strong correlation between IL-22BP and CCL24. We identify monocyte-derived dendritic cells (moDC) as a cellular subtype co-expressing both cytokines and validate our finding using in vitro culture systems. We also show that retinoic acid induces the secretion of both IL-22BP and CCL24 by moDC. Finally, we report on higher IL-22BP levels in active smokers. In conclusion, our work provides new information relevant to therapeutic strategies modulating IL-22 bioactivity in CD, especially in the context of disease location.

Real-world treatment patterns of palbociclib and blood count monitoring in patients with advanced breast cancer in Japan.

Aim: To reveal the treatment patterns of palbociclib and complete blood count (CBC) monitoring in a Japanese real-world setting. Materials & methods: Deidentified data of patients with advanced breast cancer who received palbociclib from 2017 to 2020 were examined from a Japanese claims database. Results & conclusion: We identified 1074 patients. Palbociclib was commonly prescribed as second- or later-line treatment in 2017/2018; thereafter its first-line treatment increased. Regardless of treatment lines, fulvestrant was most commonly prescribed in combination with palbociclib (57-66% in the first-third-line), and this finding differed from that in the USA. Most patients initiated palbociclib at 125 mg/day; however, over a half of patients reduced doses within the first 8 weeks. Although CBC was regularly monitored, some patients did not undergo blood tests. Early dose reduction and CBC monitoring should be performed cautiously to minimize safety concern and prevent early treatment discontinuation.

Recent Trends in the Practice of Procedural Sedation Under Local Anesthesia for Catheter Ablation, Gastrointestinal Endoscopy, and Endoscopic Surgery in Japan: A Retrospective Database Study in Clinical Practice from 2012 to 2015.

OBJECTIVES: To investigate changes in sedation practice during 2012-2015, using a large health claims database, for catheter ablation (CA), gastrointestinal endoscopic examination (EE), and surgery (ES) after dexmedetomidine (DEX) was approved for procedural sedation in 2013. We assessed the trends of sedative utilization, sedative-analgesic combinations, and, additionally, incidence of complications from 2012 to 2015. METHODS: Using the database provided by Medical Data Vision Co., Ltd. (Tokyo, Japan), annual utilization proportions of the sedatives and sedative-analgesic combinations and occurrence of complications were calculated in patients with a record of local anesthesia and CA, EE, and/or ES but without general anesthesia used on the same day. The sedatives studied were DEX, propofol (PF), midazolam (MDZ), diazepam, flunitrazepam, thiamylal (TIA), thiopental (TIO), and ketamine. RESULTS: DEX was used most often for CA, followed by PF. From 2012 to 2015, the proportion of DEX increased from 30 to 36%, and that of PF slightly decreased from 29 to 27%. The order of utilization proportions did not change for EE or ES. The use of benzodiazepines, particularly MDZ, predominated. The top five sedative-analgesic combination patterns changed during the study period for CA, but not for EE or ES. The most common complications with CA, EE, and ES were bradycardia, nausea and vomiting, and respiratory depression, respectively. There were no changes in the complications' trends for the procedures. CONCLUSION: The approved use of DEX for procedural sedation resulted in changes for CA, but not for EE or ES. The complication trends did not change.

Development of the Japanese Core Outcome Measures Index (COMI): cross-cultural adaptation and psychometric validation.

BACKGROUND: The patient-rated Core Outcome Measures Index (COMI) assesses the multidimensional impact of back problems on the sufferer. The brevity and comprehensibility of the tool make it practical for use in clinical and research settings. Although the COMI has been cross-culturally adapted in various languages worldwide, there is currently no Japanese version. The aim of this study was to develop a Japanese version of the COMI by: (1) performing a cross-cultural adaptation of the English version and (2) evaluating the psychometric properties of the Japanese version of the COMI in Japanese volunteers with chronic back problems. METHODS: The English version of the COMI was cross-culturally adapted for the Japanese language using established guidelines. The pre-final version was pilot-tested in five Japanese-speaking patients with low back pain (LBP) and a history of spine surgery. The psychometric properties of the Japanese COMI were tested in a group of 1052 individuals with chronic LBP (LBP ≥3 months), aged 20-69 years, who were recruited through a web-based survey. The psychometric properties that were evaluated included convergent and known-group validity, using the following reference questionnaires: EuroQol 5 Dimension, Roland Morris Disability Questionnaire, Short Form 8™ Health Survey, and the Keele STarT Back Screening Tool. RESULTS: The pre-final version of the cross-culturally adapted Japanese COMI was completed without any major problems of understanding or acceptability. For the evaluation of its psychometric properties, tests for convergent validity showed moderate correlations between COMI items and the respective reference questionnaires for symptom-specific well-being [- 0.33--0.48] and disability domains [0.48] and strong correlations (> 0.5) for the other domains and the COMI summary score. The analysis of known-group validity showed a linear trend for the COMI score in relation to prognostic risk (P < 0.001). CONCLUSIONS: The Japanese COMI retained conceptual equivalence to the original using comprehensible and acceptable Japanese expressions. We developed a Japanese version of the COMI that displayed qualities that support its convergent and known-group validity. The availability of a Japanese version of the COMI should allow for improved documentation of the care provided to patients with back problems.

Poly-cyclodextrin functionalized porous bioceramics for local chemotherapy and anticancer bone reconstruction.

The progress in bone cancer surgery and multimodal treatment concept achieve only modest improvement in the overall survival, due to failure in clearing out residual cancer cells at the surgical margin and extreme side-effects of adjuvant postoperative treatments. Our study aims to propose a new method based on cyclodextrin polymer (polyCD) functionalized hydroxyapatite (HA) for achieving a high local drug concentration with a sustained release profile and a better control of residual malignant cells via local drug delivery and promotion of the reconstruction of bone defects. PolyCD, a versatile carrier for therapeutic molecules, can be incorporated into HA (bone regeneration scaffold) through thermal treatment. The parameters of polyCD treatment on the macroporous HA (porosity 65%) were characterized via thermogravimetric analysis. Good cytocompatibility of polyCD functionalized bioceramics was demonstrated on osteoblast cells by cell vitality assay. An antibiotic (gentamicin) and an anticancer agent (cisplatin) were respectively loaded on polyCD functionalized bioceramics for drug release test. The results show that polyCD functionalization leads to significantly improved drug loading quantity (30% more concerning gentamicin and twice more for cisplatin) and drug release duration (7 days longer concerning gentamicin and 3 days longer for cisplatin). Conclusively, this study offers a safe and reliable drug delivery system for bioceramic matrices, which can load anticancer agents (or/and antibiotics) to reduce local recurrence (or/and infection).

Spherical cell shape of FLC-4 cell, a human hepatoma cell, enhances hepatocyte-specific function and suppresses tumor phenotype through the integration of mRNA-microRNA interaction.

The induction mechanism of HNF-4α by spherical cell shape in human hepatoma cells, FLC-4, was investigated. To get insight into the induction mechanism of HNF-4α in three-dimensional FLC-4 cells, mRNA microarray analysis was performed. The gene expression related to drug metabolism and nuclear receptors, such as LXRα, was elevated in spherical FLC-4 cells. We found the first time that the expressions of genes related to malignancy of hepatoma cells, such as HIF-1α, c-Myc and VEGFC, were downregulated by spherical cell shape. Network analysis revealed that HNF-4α would elicit both the enhancement of hepatocyte-specific gene expression and suppression of malignancy. Since HNF-4α gene expression was known to be regulated by microRNA, we inferred that spherical cell shape would induce HNF-4α gene expression through microRNA. To investigate the possibility of such a mechanism, mRNA-microRNA interactions were examined using microRNA microarray and bioinformatics analysis. The level of miR-24, a microRNA targeting HNF-4α, was reduced in spherical FLC-4 cells. On the other hand, spherical cell shape-induced miR-194 and miR-320c would directly downregulate SLC7A5 and E2F1 gene expression, respectively, which are both related to malignancy. Our study suggested that spherical cell shape would induce HNF-4α gene expression and consequent enhancement hepatocyte-specific functions. Spherical cell shape itself would suppress malignancy in FLC-4 cells through microRNA, such as miR-194 and miR-320c.

A novel human hepatoma cell line, FLC-4, exhibits highly enhanced liver differentiation functions through the three-dimensional cell shape.

We characterized three-dimensional human hepatoma cell lines, functional liver cell (FLC) cell lines, to establish a highly differentiated hepatoma cell line. We investigated the effect of extracellular matrix and cell morphology on liver-specific gene expression in FLC cells. The hepatocyte nuclear factor-4α (HNF-4α) and other liver-specific gene expressions were enhanced in spherical FLC-4 cells on EHS-gel, but other human hepatoma cells such as HepG2 did not show the enhancement. Importantly, the liver-specific gene expression levels in spherical FLC-4 cells cultured on EHS-gel were comparable to those of human liver and were much higher than those of other human hepatoma cell lines. The major matrix components and growth factors in EHS-gel did not affect cell shape and liver functions. To exclude any effect of the extracellular matrix, we made spherical FLC-4 cells by actin filament disruption. The actin-disrupted spherical cells also showed an enhanced liver-specific gene expression. We concluded that three-dimensional cell shape per se is one of the most important determinants of liver differentiation functions in FLC-4 cells. Cell morphology-dependent induction of liver-specific gene expression was mediated through microtubule organization. In conclusion, differentiation of FLC-4 human hepatoma cell line can be enhanced to a human liver-like level through the three-dimensional cell shape in a microtubule-dependent manner.

Effect of an isocaloric carbohydrate-protein-antioxidant drink on cycling performance.

PURPOSE: Fourteen male cyclists were studied to compare the effect of carbohydrate-protein-antioxidant beverage (CHOPA) to an isocaloric carbohydrate-only (CHO) beverage on time to fatigue and muscle damage. METHODS: Subjects performed two sets of rides to exhaustion on a cycle ergometer. In each set, the first ride was performed at 70% VO2peak, and the second was performed 24 h later at 80%. CHO or CHOPA was consumed every 15 min during exercise and immediately afterward. Plasma CK and LDH and muscle soreness were measured pre- and postexercise. RESULTS: Time to fatigue was not different between CHO and CHOPA at 70% VO2peak (95.8 +/- 29.7 vs 98.1 +/- 28.7 min), 80% VO2peak (42.3 +/- 18.6 vs 42.9 +/- 21.8 min), or total performance time (138.1 +/- 39.3 vs 140.9 +/- 43.7 min). Postexercise CK was increased (P < 0.05) from baseline in CHO (203 +/- 120 vs 582 +/- 475 U.L(-1)) but not with CHOPA (188 +/- 119 vs 273 +/- 169 U.L(-1)). Similarly, LDH values increased over baseline in CHO (437 +/- 46 vs 495 +/- 64 U.L(-1)) but not with CHOPA (432 +/- 40 vs 451 +/- 43 U.L(-1)). Postexercise CPK and LDH were higher after the CHO trial than after the CHOPA trial. Median postexercise muscle soreness was higher in CHO (3.0 +/- 5.0) than with CHOPA (1.0 +/- 3.0). CONCLUSION: No differences in time to fatigue were observed between the beverages, despite lower total carbohydrate content in the CHOPA beverage. The CHOPA beverage attenuated postexercise muscle damage, as evidenced by CK and LDH values, compared with an isocaloric CHO beverage.