► We examined role of myofibroblasts in activating myeloid cells in tumor microenvironment. ► S100A8/A9 in myeloid cells is upregulated by IL-6 and IL-8 released from myofibroblasts. ► Myofibroblasts ...induce differentiation of myeloid cells into MDSCs or M2 macrophages.
S100A8/A9 and myeloid cells in the tumor microenvironment play an important role in cancer invasion and progression, and the effect of tumor-infiltrated myofibroblasts on myeloid cells in the tumor microenvironment is relatively unknown. Accordingly, we investigated the role of myofibroblasts in the upregulation of S100A8/A9 as well as in the differentiation of myeloid cells in the colorectal cancer (CRC) microenvironment.
To investigate the interactions among cancer cells, myofibroblasts, and inflammatory cells in the microenvironment of CRC, we used 10 CRC cell lines, 18CO cells and THP-1 cells, which were co-cultured with each other or cultured in conditioned media (CM) of other cells. Expression of S100A8/A9 was evaluated via Western blot, immunohistochemical staining and immunofluorescence. The secreted factors from the cell lines were analyzed using cytokine antibody array. Flow cytometry analysis was performed to analyze the differentiation markers of myeloid cells.
18CO CM induced increased expression of S100A8/A9 in THP-1 cells. Increased expression of S100A8/A9 was noted in inflammatory cells of the peri- and intra-tumoral areas, along with myofibroblasts in colon cancer tissue. S100A8/A9-expressing inflammatory cells also exhibited CD68 expression in colon cancer tissue, and 18CO CM induced differentiation of THP-1 cells into myeloid-derived suppressor cells (MDSCs) or M2 macrophages expressing S100A8/A9. Significant amounts of IL-6 and IL-8 were detected in 18CO CM, compared to those in both controls and THP-1 CM, and tumor-infiltrated myofibroblasts expressed IL-8 in colon cancer tissue. Finally, neutralizing antibodies to IL-6 and IL-8 attenuated 18CO CM-induced increased expression of S100A8/A9.
The upregulation of S100A8/A9 in tumor-infiltrated myeloid cells could be triggered by IL-6 and IL-8 released from myofibroblasts, and myofibroblasts might induce the differentiation of myeloid cells into S100A8/9-expressing MDSCs or M2 macrophages in the CRC microenvironment.
SARS-CoV-2 mRNA vaccines induce robust anti-spike (S) antibody and CD4+ T cell responses. It is not yet clear whether vaccine-induced follicular helper CD4+ T (TFH) cell responses contribute to this ...outstanding immunogenicity. Using fine-needle aspiration of draining axillary lymph nodes from individuals who received the BNT162b2 mRNA vaccine, we evaluated the T cell receptor sequences and phenotype of lymph node TFH. Mining of the responding TFH T cell receptor repertoire revealed a strikingly immunodominant HLA-DPB1∗04-restricted response to S167–180 in individuals with this allele, which is among the most common HLA alleles in humans. Paired blood and lymph node specimens show that while circulating S-specific TFH cells peak one week after the second immunization, S-specific TFH persist at nearly constant frequencies for at least six months. Collectively, our results underscore the key role that robust TFH cell responses play in establishing long-term immunity by this efficacious human vaccine.
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•SARS-CoV-2 vaccines induce robust human TFH cell responses in draining lymph nodes•HLA-DPB1∗04 restricts the immunodominant SARS-CoV-2 S167–180 epitope•S167–180 is recognized by T cell receptors with a public α-chain motif•S-specific TFH cells are maintained in draining lymph nodes 6 months after vaccination
Analysis of draining lymph nodes of individuals vaccinated with BNT162b2 mRNA vaccine against SARS-CoV-2 identifies viral-spike-specific follicular helper CD4+ T cells that persist for months and contribute to long-term immunity.
We search for lepton-flavor-violating τ→ℓV0 decays, where ℓ is an electron or muon and V0 is one of the vector mesons ρ0, ϕ, ω, K⁎0 and K¯⁎0. We use 854 fb−1 of data collected with the Belle detector ...at the KEKB asymmetric-energy e+e− collider. No evidence for a signal is found in any decay mode, and we obtain 90% confidence level upper limits on the individual branching fractions in the range (1.2–8.4)×10−8.
Inflammatory bowel disease (IBD) is multifactorial and involves immunological, environmental and genetic factors. Although there are no animal models that effectively mimic human IBD, experimental ...models allow us to analyze the mechanisms of chronic intestinal inflammation. IBD can be induced in mice by dextran sulfate sodium (DSS) or by a 2,4,6-trinitrobenzene sulfonic acid (TNBS)‑ethanol enema, which evoke immune responses and colitis. In this study, in order to compare the mechanisms of inflammatory response in mice, 3 distinct models of IBD were established: 2% TNBS-induced acute colitis, 4% DSS-induced acute colitis and 2% DSS-induced chronic colitis. In addition, to evaluate the effects of TNBS on inflammasome activation, we used caspase-1 knockout (KO) mice. Changes in both body weight and survival became prominent after day 1 in the 2% TNBS‑induced colitis model, and after day 5 in the 4% DSS-induced colitis model. The TNBS- and DSS-treated mice, but not the caspase-1 KO mice, showed a massive bowel edema and disruption of epithelial cells. The level of CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSCs) was increased in all tested tissues of the TNBS- and DSS-treated groups, apart from the basal membrane (BM) in the DSS-induced colitis groups and the lamina propria (LP) in the DSS-induced chronic colitis group. We further analyzed different subsets of CD4(+) T cells in LP and found that the levels of interferon (IFN)γ‑secreting (IFNγ(+)), IL-17‑secreting (IL-17(+)), but not those of IL-4-secreting (IL-4(+)) T cells increased upon treatment with TNBS or DSS. In addition, discrepancies between the histopathologies of wild-type and caspase-1 KO mice indicated that the pathogenesis of IBD may be associated with the inflammasome pathway responses mediated by caspase‑1 in TNBS‑induced colitis.
To evaluate the enhancement patterns, prevalence of secondary signs, and histopathologic features of 20-mm-diameter or smaller pancreatic cancers seen on multiphasic multidetector computed ...tomographic (CT) images.
This retrospective study was approved by the institutional review board; the requirement for informed consent was waived. From January 2002 through September 2009, the authors reviewed the clinical and imaging data of 130 consecutive patients (76 men, 54 women; mean age, 64.1 years; age range, 28-82 years) who had surgically proven 30-mm-diameter or smaller pancreatic cancers and underwent preoperative multidetector CT and 33 consecutive patients (17 men, 16 women; mean age, 65.1 years; age range, 48-84 years) who had histopathologically proven pancreatic cancer and underwent incidental multidetector CT before the diagnosis was rendered. Only pancreatic phase CT was performed in two patients, and only hepatic venous phase CT was performed in nine patients. Two radiologists in consensus classified the tumor attenuation as hyper-, iso-, or hypoattenuation during the pancreatic and hepatic venous phases. Accompanying secondary signs, temporal changes in tumor attenuation, and histopathologic findings also were analyzed. The Fisher exact test, χ(2) test, generalized estimating equation, and Student t test were used to compare the variables.
Seventy tumors were 20 mm or smaller, and 93 were 21-30 mm. Isoattenuating pancreatic cancers were more commonly observed among the 20-mm or smaller tumors (16 of 59, 27%) than among the 21-30-mm tumors (12 of 93, 13%) (P = .033). They were also more common among well-differentiated tumors (seven of 12, 58%) than among moderately differentiated (20 of 124, 16%) and poorly differentiated (one of 10, 10%) tumors (P = .001). The prevalence of secondary signs differed significantly according to tumor size (53 76% of 70 ≤20-mm tumors vs 92 99% of 93 21-30-mm tumors) (P < .001). The prevalence of secondary signs was high among isoattenuating pancreatic cancers (14 88% of 16 ≤20-mm tumors vs all 12 100% 21-30-mm tumors). Most of the isoattenuating tumors seen at prediagnostic CT were hypoattenuating after 6 months (100% four of four during pancreatic phase, 71% five of seven during hepatic venous phase).
The prevalence of isoattenuating pancreatic cancers differed significantly according to tumor size and cellular differentiation. Most small isoattenuating pancreatic cancers showed secondary signs.
http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.11101133/-/DC1.
The relativistic magnetron is one of the most attractive high-power microwave sources, due to its compactness with high efficiency. It can generate hundreds of megawatts of microwave power in the L- ...and S-bands. However, the efficiency of the magnetron is often limited due to the mode stability. In this Letter, three-dimensional particle-in-cell simulation suggests even further increase of total efficiency of the magnetron can be realised via mode stabilisation using a self-excited extended interaction in a collector region. A six-vaned radial relativistic magnetron with a single radial output port powered by 400 kV, <10 kA electron beam with a 70 ns pulse demonstrates >900 MW with an efficiency of ∼48%. This improvement is attributed to the mode locking of operating π-mode by a power-boosted TE315 mode excited in the extended cavity.
Background Limited data exist regarding the long-term outcomes of EMR compared with gastrectomy. Objective To compare the long-term outcomes after EMR and surgery. Design Retrospective analysis with ...propensity-score matching. Setting Tertiary care center. Patients This study involved 215 patients with intramucosal gastric cancer completely removed by EMR and 843 patients who underwent curative surgical resection between January 1997 and August 2002. Propensity-score matching yielded 551 matched patients. Interventions EMR versus surgery. Main Outcome Measurements Death and recurrence. Results In the matched cohort, there were no significant between-group differences in the risk of death (hazard ratio HR for the EMR group 1.39; 95% CI, 0.87-2.23) or recurrence (HR 1.18; 95% CI, 0.22-6.35). Although patients who underwent EMR had higher risk of metachronous gastric cancers (HR 6.72; 95% CI, 2.00-22.58), all recurrent or metachronous gastric cancers after EMR were successfully re-treated without affecting overall survival. Although complication rates were similar (odds ratio 0.84; 95% CI, 0.41-1.70), there were no mortalities in the EMR group compared with 2 in the surgery group. The EMR group had a significantly shorter hospital stay (median 8 days, interquartile range IQR 6-11 days vs 15 days, IQR 12-19 days; P < .001) and lower cost of care ($2049, IQR $1586-2425 vs $4042, IQR $3458-4959; P < .001). Limitations Retrospective, nonrandomized study. Conclusions EMR was comparable to surgery in terms of risk of death and recurrence. Because of its lower medical costs and shorter duration of hospital stay, EMR has advantages over surgery.
Aim: Autophagy is a cellular process of degradation of damaged cytoplasmic components and regulates cell death or proliferation. Unilateral ureteral obstruction (UUO) is a model of progressive renal ...fibrosis in the obstructed kidney. And UUO is followed by compensatory cellular proliferation in the contralateral kidney. We investigate the role of autophagy in the obstructed kidney and contralateral kidney after UUO.
Methods: To obtain the evidence and the patterns of autophagy during UUO, the rats were sacrificed 3, 7 and 14 days after UUO. To examine the efficacy of the autophagy inhibitors, 3‐methyladenine (3‐MA), the rats were treated daily with intraperitoneal injection of 3‐MA (30 mg/kg per day) for 7 days.
Results: After UUO, autophagy was induced in the obstructed kidney in a time‐dependent manner. Inhibition of autophagy by 3‐MA enhanced tubular cell apoptosis and tubulointerstitial fibrosis in the obstructed kidney after UUO. In the contralateral kidney, autophagy was also induced and prolonged during UUO. Inhibition of autophagy by 3‐MA increased the protein expression of proliferating cell nuclear antigen significantly in the contralateral kidney after UUO. The Akt‐mammalian target of rapamycin (mTOR) signalling pathway was involved in the induction of autophagy after UUO in both kidneys.
Conclusion: Our present results support that autophagy induced by UUO has a renoprotective role in the obstructed kidney and regulatory role of compensatory cellular proliferation in the contralateral kidney through Akt‐mTOR signalling pathway.
Autophagy is a mechanism of limited destruction of cellular organelles which protects cells against major stresses. This study provides functional evidence that autophagy protects against tubular damage and interstitial fibrosis in the obstructed kidney. Furthermore, it is proposed that autophagy suppresses cell proliferation in the contralateral kidney, providing a link between autophagy and compensatory hypertrophy.
The aim of this randomized single-blinded active-controlled clinical study was to evaluate the early efficacy of low-dose Escherichia coli–derived recombinant human bone morphogenetic protein 2 ...(rhBMP-2) soaked with hydroxyapatite granules (BMP-2/H) as compared with an inorganic bovine bone xenograft (ABX) in maxillary sinus floor augmentation. In a total of 127 subjects who were enrolled at 6 centers, maxillary sinus floors were augmented with 1 mg/mL of rhBMP-2 (0.5 to 2.0 mg per sinus) and BMP-2/H (0.5 to 2.0 g; n = 65) or with ABX alone (0.5 to 2.0 g; n = 62). Core biopsies were obtained 3 mo after the augmentation surgery and were analyzed histomorphometrically. The mean new bone formation with BMP-2/H and ABX augmentation was 16.10% ± 10.52% and 8.25% ± 9.47%, respectively. The BMP-2/H group was noninferior to the ABX group; the lower limit of the 1-sided 97.5% confidence interval for the difference between the 2 groups was calculated as 4.33%, which was greater than the prespecified noninferiority margin of −3.75%. An additional test with the Wilcoxon rank-sum test with a 2-sided 5% significance level showed that bone formation between the 2 groups was significantly different (P < 0.0001). The soft tissue and residual graft areas showed no significant differences between the groups. With regard to safety, no significant difference between the 2 groups was observed; there was no significant increase in the amount of rhBMP-2 antibody in the serum after BMP-2/H grafting. Our study suggested that low-dose Escherichia coli–derived rhBMP-2 with hydroxyapatite was effective in early stages for enhanced bone formation after maxillary sinus floor augmentation without harmful adverse events (Clinicaltrials.gov NCT01634308).
Chromosomal rearrangements of the human KMT2A/MLL gene are associated with de novo as well as therapy-induced infant, pediatric, and adult acute leukemias. Here, we present the data obtained from ...3401 acute leukemia patients that have been analyzed between 2003 and 2022. Genomic breakpoints within the KMT2A gene and the involved translocation partner genes (TPGs) and KMT2A-partial tandem duplications (PTDs) were determined. Including the published data from the literature, a total of 107 in-frame KMT2A gene fusions have been identified so far. Further 16 rearrangements were out-of-frame fusions, 18 patients had no partner gene fused to 5'-KMT2A, two patients had a 5'-KMT2A deletion, and one ETV6::RUNX1 patient had an KMT2A insertion at the breakpoint. The seven most frequent TPGs and PTDs account for more than 90% of all recombinations of the KMT2A, 37 occur recurrently and 63 were identified so far only once. This study provides a comprehensive analysis of the KMT2A recombinome in acute leukemia patients. Besides the scientific gain of information, genomic breakpoint sequences of these patients were used to monitor minimal residual disease (MRD). Thus, this work may be directly translated from the bench to the bedside of patients and meet the clinical needs to improve patient survival.
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