Interleukin (IL)-10, a cytokine with anti-inflammatory effects, is produced by blood cells and cells of various organs. Ischemia–reperfusion injury (IRI) is a systemic inflammatory disease caused by ...a systemic circulation of pro-inflammatory cytokines and chemokines produced from blood cells or organs damaged by ischemia. Apoptosis, a key event after IRI, is correlated with the degree of injury. Here we investigated the effects and mechanism of IL-10 in renal IRI. Compared to wild-type (WT) mice with a renal IRI, IL-10 knockout (IL-10 KO) mice with IRI demonstrated decreased renal function as represented by blood urea nitrogen and serum creatinine, upregulated early acute kidney injury (AKI) biomarkers such as kidney injury molecule-1 (Kim-1), increased mRNA expression of the pro-inflammatory cytokines IL-1β, IL-6, and IL-18 and a chemokine (regulated on activation, normal T cell expressed and secreted; RANTES), and increased expression of the pro-apoptosis factors Bax and cleaved caspase-3. When tubular epithelial cells (TECs) from IL-10 KO mice were put in a hypoxic state and added with recombinant IL-10, their expression of Bax decreased. Our findings demonstrated that IL-10 suppressed the production of pro-inflammatory cytokines, renal dysfunction, and the expression of pro-apoptosis factors after IRI.
The complex diversity of nonpathogenic microbes that colonize the human body, known as microbiota, exert considerable effects on physiological homeostasis, and immune regulation. Helicobacter pylori ...(H. pylori) is a bacterium that frequently colonizes human stomach and is a major pathogenic agent for peptic ulcer diseases, gastric cancer, and mucosa-associated lymphoid tissue (MALT) lymphoma. Due to its acidic pH and peristaltic movements, the stomach has been considered a hostile environment for most microorganisms, however various commensal microorganisms are capable of colonizing the stomach to form a stomach niche. Recent pieces of evidence indicate that commensal gastric microbes or their metabolites influence the capability of H. pylori to colonize the stomach and directly modulate its pathogenicity and carcinogenic potential. In this article, we present an overview of recent advances in the understanding of H. pylori-commensal interactions in the pathogenesis and clinical evolution of H. pylori-associated gastric malignancies.
•H. pylori causes gastric cancer and MALT-lymphoma.•A core of commensal microbes (microbiota) resides in human stomach.•Gastric microbiota fluctuates in response to various factors.•Gastric microbiota interacts with H. pylori.•Gastric microbiota-H. pylori interplay has a role in carcinogenesis.
Abstract
Mutated receptor tyrosine kinases (MT-RTKs) such as internal tandem duplication of FMS-like tyrosine kinase 3 (FLT3 ITD) and a point mutation KIT D816V are driver mutations for acute myeloid ...leukemia (AML). Clathrin assembly lymphoid myeloid leukemia protein (CALM) regulates intracellular transport of RTKs, however, the precise role for MT-RTKs remains elusive. We here show that CALM knock down leads to severely impaired FLT3 ITD- or KIT D814V-dependent cell growth compared to marginal influence on wild-type FLT3- or KIT-mediated cell growth. An antipsychotic drug chlorpromazine (CPZ) suppresses the growth of primary AML samples, and human CD34
+
CD38
-
AML cells including AML initiating cells with MT-RTKs
in vitro
and
in vivo
. Mechanistically, CPZ reduces CALM protein at post transcriptional level and perturbs the intracellular localization of MT-RTKs, thereby blocking their signaling. Our study presents a therapeutic strategy for AML with MT-RTKs by altering the intracellular localization of MT-RTKs using CPZ.
Most B cell precursor acute lymphoblastic leukemia (BCP ALL) can be classified into known major genetic subtypes, while a substantial proportion of BCP ALL remains poorly characterized in relation to ...its underlying genomic abnormalities. We therefore initiated a large-scale international study to reanalyze and delineate the transcriptome landscape of 1,223 BCP ALL cases using RNA sequencing. Fourteen BCP ALL gene expression subgroups (G1 to G14) were identified. Apart from extending eight previously described subgroups (G1 to G8 associated with MEF2D fusions, TCF3–PBX1 fusions, ETV6–RUNX1–positive/ETV6–RUNX1–like, DUX4 fusions, ZNF384 fusions, BCR–ABL1/Ph–like, high hyperdiploidy, and KMT2A fusions), we defined six additional gene expression subgroups: G9 was associated with both PAX5 and CRLF2 fusions; G10 and G11 with mutations in PAX5 (p.P80R) and IKZF1 (p.N159Y), respectively; G12 with IGH–CEBPE fusion and mutations in ZEB2 (p.H1038R); and G13 and G14 with TCF3/4–HLF and NUTM1 fusions, respectively. In pediatric BCP ALL, subgroups G2 to G5 and G7 (51 to 65/67 chromosomes) were associated with low-risk, G7 (with ≤50 chromosomes) and G9 were intermediate-risk, whereas G1, G6, and G8 were defined as high-risk subgroups. In adult BCP ALL, G1, G2, G6, and G8 were associated with high risk, while G4, G5, and G7 had relatively favorable outcomes. This large-scale transcriptome sequence analysis of BCP ALL revealed distinct molecular subgroups that reflect discrete pathways of BCP ALL, informing disease classification and prognostic stratification. The combined results strongly advocate that RNA sequencing be introduced into the clinical diagnostic workup of BCP ALL.
CEBPA‐IGH, a fusion gene of the immunoglobulin heavy‐chain locus (IGH) and the CCAAT enhancer‐binding protein α (C/EBPα) gene, is recurrently found in B‐ALL cases and causes aberrant expression of ...C/EBPα, a master regulator of granulocyte differentiation, in B cells. Forced expression of C/EBPα in B cells was reported to cause loss of B‐cell identity due to the inhibition of Pax5, a master regulator of B‐cell differentiation; however, it is not known whether the same mechanism is applicable for B‐ALL development by CEBPA‐IGH. It is known that a full‐length isoform of C/EBPα, p42, promotes myeloid differentiation, whereas its N‐terminal truncated isoform, p30, inhibits myeloid differentiation through the inhibition of p42; however, the differential role between p42 and p30 in ALL development has not been clarified. In the present study, we examined the effect of the expression of p42 and p30 in B cells by performing RNA‐seq of mRNA from LCL stably transfected with p42 or p30. Unexpectedly, suppression of PAX5 target genes was barely observed. Instead, both isoforms suppressed the target genes of MEF2 family members (MEF2s), other regulators of B‐cell differentiation. Similarly, MEF2s target genes rather than PAX5 target genes were suppressed in CEBP‐IGH‐positive ALL (n = 8) compared with other B‐ALL (n = 315). Furthermore, binding of both isoforms to MEF2s target genes and the reduction of surrounding histone acetylation were observed in ChIP‐qPCR. Our data suggest that the inhibition of MEF2s by C/EBPα plays a role in the development of CEBPA‐IGH‐positive ALL and that both isoforms work co‐operatively to achieve it.
In the present study, we found that C/EBPα aberrantly expressed in B cells inhibited the function of MEF2 family members by performing RNA‐seq of mRNA of C/EBPα‐transfectants and analyzing RNA‐seq data of 323 clinical samples of ALL. Two isoforms of C/EBPα, p42 and p30, co‐operatively worked for MEF2 inhibition, although it was reported that they worked competitively in AML development.
Background
To promote precision oncology in clinical practice, the Japanese Society of Medical Oncology, the Japanese Society of Clinical Oncology, and the Japanese Cancer Association, jointly ...published “Clinical practice guidance for next-generation sequencing in cancer diagnosis and treatment” in 2017. Since new information on cancer genomic medicine has emerged since the 1st edition of the guidance was released, including reimbursement for NGS-based multiplex gene panel tests in 2019, the guidance revision was made.
Methods
A working group was organized with 33 researchers from cancer genomic medicine designated core hospitals and other academic institutions. For an impartial evaluation of the draft version, eight committee members from each society conducted an external evaluation. Public comments were also made on the draft. The finalized Japanese version was published on the websites of the three societies in March 2020.
Results
The revised edition consists of two parts: an explanation of the cancer genomic profiling test (General Discussion) and clinical questions (CQs) that are of concern in clinical practice. Particularly, patient selection should be based on the expectation that the patient's post-test general condition and organ function will be able to tolerate drug therapy, and the optimal timing of test should be considered in consideration of subsequent treatment plans, not limited to treatment lines.
Conclusion
We expect that the revised version will be used by healthcare professionals and will also need to be continually reviewed in line with future developments in cancer genome medicine.
We conducted a nationwide questionnaire-based survey in 2019 following 2001, 2007 and 2013 surveys to clarify the real-world management of infection during chemotherapy for acute leukemia in Japan. ...An online questionnaire was sent through SurveyMonkey
®
to member institutions of the Japan Adult Leukemia Study Group in June 2019. The questionnaire consisted of 52 multiple-choice questions covering prophylactic measures, screening and diagnostic tests, empirical antibiotic therapy, antifungal management, the usage of granulocyte-colony stimulating factor, and vaccinations against influenza and pneumococcus during intensive chemotherapy for acute leukemia. Questions associated with antimicrobial stewardship were also included. Usable responses were received from 163 of 218 (74.8%) institutions. Approximately, half (52.2%) of the institutes did not have infectious disease department. As antibiotic prophylaxis, fluoroquinolones (62%) were most commonly used in induction chemotherapy for acute myeloid leukemia. No prophylaxis accounted for 19% of the institutions, which has gradually increased compared to previous surveys. In empirical antibiotic therapy for febrile neutropenia, monotherapy with β-lactam antibiotics was the most commonly used first-line therapy. De-escalation was not considered in 42.2% of the institutions. In conclusion, this study clarified the real-world management of infection during intensive chemotherapy for acute leukemia in 2019 and raised future issues in Japan.
Age and comorbidities are important factors to be considered in the selection of tyrosine kinase inhibitors (TKIs) for first‐line treatment in patients with chronic myeloid leukemia in chronic phase ...(CML‐CP). However, it is yet unclear whether TKI selection, particularly, imatinib versus second‐generation TKIs (2GTKIs), impacts treatment outcomes in the clinical practice. To address this, we compared the clinical outcomes of prospectively registered 452 patients with CML‐CP treated with imatinib and 2GTKIs, taking into consideration their age and/or comorbidities. A total of 136 patients (30.1%) were classified into an older cohort (≥65 years) and 316 (69.9%) into a younger cohort (18‐64 years). The TKI selection did not vary based on age (70.6% received 2GTKIs in the younger cohort and 66.2% in the older cohort). The median follow‐up period was 5.4 years. Treatment responses including the cumulative incidence of deep molecular response (BCR‐ABL1 international scale ≤0.0032%) at any time were similar between the two age cohorts regardless of the type of TKI. The 5‐year overall survival (OS) in the older cohort was lower than that in the younger cohort (95.9% vs 83.8%; p < 0.0001), whereas the 5‐year OS in patients treated with 2GTKIs was not influenced by age factors and comorbidities. Therefore, our results suggest that the selection of 2GTKIs as first‐line treatment is an effective option for both younger and older CML‐CP patients with or without comorbidities. This trial was registered at UMIN‐CTR as 00003581.
The overall survival in patients with chronic myeloid leukemia in chronic phase (CML‐CP) who treated with second‐generation tyrosine kinase inhibitors (2GTKIs) was not influenced by age factors, which was not observed in patients on imatinib. 2GTKI as first‐line treatment is a considerable option for both elderly and younger patients with CML‐CP.
Although azacitidine is the first‐line drug for higher‐risk myelodysplastic syndrome (MDS) patients, its efficacy for lower‐risk MDS remains unestablished. Therefore, we conducted a prospective study ...to examine the efficacy and safety of a 5‐day regimen of azacitidine (AZA‐5) for lower‐risk MDS. The primary endpoint was hematological improvement (HI) after 4 courses of therapy. A total of 51 patients with lower‐risk MDS based on the French‐American‐British (FAB) classification (44 patients with refractory anemia RA and 7 patients with refractory anemia with ringed sideroblasts RARS) were enrolled from 6 centers in Japan. The median age was 75 years (range: 51‐88). These patients received AZA‐5 (75 mg/m2; once daily for 5 sequential days). The median number of AZA‐5 courses was 8 (range: 1‐57), and 45 patients (88.2%) received more than 4 courses. HI and transfusion independency were seen in 24 patients (47.1%) and 11 patients (39.2%), respectively. A total of 11 patients (21.6%) achieved complete remission or marrow remission. WT1 mRNA levels were not significantly correlated with therapy response. Grade 3 or 4 neutropenia and thrombocytopenia occurred in 26 (51.0%) and 11 (21.5%) patients, respectively. Nonhematological grade 3 or 4 adverse events were observed in 9 patients (17.6%). Together, these results indicate that AZA‐5 is feasible and effective for lower‐risk MDS patients as well as for higher‐risk MDS patients.
Five‐day regimen of azacitidine for lower‐risk MDS.
Interleukin (IL)-18 is markedly elevated in systemic inflammatory diseases that cause the 'cytokine storm' such as adult-onset Still's disease (AOSD) and hemophagocytic lymphohistiocytosis (HLH). The ...differences in IL-18 between AOSD and HLH, especially in adults, is uncertain. Macrophage activation syndrome (MAS), a form of secondary HLH, is often difficult to differentiate cases of AOSD that include MAS from other secondary HLH. In this case-control study, we investigated whether serum IL-18 levels could be a useful biomarker for the differential diagnosis of AOSD with or without MAS (AOSD group) and other secondary HLH in adults (adult HLH group).
We enrolled 46 patients diagnosed with AOSD including 9 patients with MAS and 31 patients in the adult HLH group, which excluded AOSD-associated MAS. The clinical features and laboratory data were compared between the AOSD and adult HLH groups. In addition, we subdivided the AOSD group (with or without MAS) and the adult HLH group (whether lymphoma-associated or not) and compared the four groups. A logistic regression analysis was used to identify factors with high efficacy in differentiating the two groups, followed by a receiver operating characteristic (ROC) curve analysis to evaluate the differential diagnostic ability of IL-18. We analyzed the correlation between IL-18 and various laboratory parameters in the AOSD group.
Serum IL-18 levels of patients in the AOSD groups were significantly higher than those of the adult HLH groups, and were closely correlated with ferritin, soluble interleukin-2 receptor (sIL-2R), and other laboratory data. Univariate and multivariate logistic regression analyses revealed that IL-18, sIL-2R, and 'arthralgia or arthritis' are independent factors useful in the differential diagnosis of AOSD from adult HLH. In the differential diagnosis of both groups, the area under the curve obtained from the ROC curve of IL-18 with a cutoff value of 18,550 pg/mL was 0.91 (95% confidence interval 0.83-1.00; sensitivity 90.3%, specificity 93.5%), and the differential diagnosis ability of IL-18 was superior to that of other laboratory data.
IL-18 could be a useful biomarker for the differential diagnosis of AOSD and adult HLH.