ABSTRACT
N6-methyladenosine (m6A) is the most prevalent epitranscriptomic modification in mammalian mRNA. Recent studies have revealed m6A is involved in the pathogenesis of various malignant tumors including hematologic neoplasms. Nevertheless, the specific roles of m6A modification and m6A regulators in myelodysplastic neoplasms (MDS) remain poorly understood. Herein, we demonstrated that m6A level and the expression of m6A methyltransferase METTL14 were elevated in MDS patients with bone marrow blasts ≥5%. Additionally, m6A level and METTL14 expression were upregulated as the disease risk increased and significantly associated with adverse clinical outcomes. Knockdown of METTL14 inhibited cell proliferation and colony formation ability of MDS cells. Moreover, in vivo experiments showed METTL14 knockdown remarkably reduced tumor burden and prolonged the survival of mice. Mechanistically, METTL14 facilitated the m6A modification of SETBP1 mRNA by formation of METTL3-METTL14 complex, leading to increased stabilization of SETBP1 mRNA and subsequent activation of the PI3K-AKT signaling pathway. Overall, this study elucidated the involvement of the METTL14/m6A/SETBP1/PI3K-AKT signaling axis in MDS, highlighting the therapeutic potential of targeting METTL3-METTL14 complex-mediated m6A modification for MDS therapy.
ABSTRACT
The monotonicity of color type in naturally colored cottons (NCCs) has become the main limiting factor to their widespread use, simultaneously coexisting with poor fiber quality. The synchronous improvement of fiber quality and color become more urgent and crucial as the demand for sustainable development increases. The homologous gene of wild cotton Gossypium stocksii LAC15 in G. hirsutum, GhLAC15, was also dominantly expressed in the developing fibers of brown cotton XC20 from 5 DPA (day post anthesis) to 25 DPA, especially at the secondary cell wall thickening stage (20 DPA and 25 DPA). In XC20 plants with downregulated GhLAC15 (GhLAC15i), a remarkable reduction in proanthocyanidins (PAs) and lignin contents was observed. Some of the key genes in the phenylpropane and flavonoid biosynthesis pathway were down-regulated in GhLAC15i plants. Notably, the fiber length of GhLAC15i plants showed an obvious increase and the fiber color was lightened. Moreover, we found that the thickness of cotton fiber cell wall was decreased in GhLAC15i plants and the fiber surface became smoother compared to that of WT. Taken together, this study revealed that GhLAC15 played an important role in PAs and lignin biosynthesis in naturally colored cotton fibers. It might mediate fiber color and fiber quality by catalyzing PAs oxidation and lignin polymerization, ultimately regulating fiber colouration and development.
Subject(s)
Cotton Fiber , Gene Expression Regulation, Plant , Gossypium , Laccase , Lignin , Plant Proteins , Cell Wall/metabolism , Color , Gossypium/genetics , Gossypium/metabolism , Gossypium/enzymology , Laccase/metabolism , Laccase/genetics , Lignin/metabolism , Plant Proteins/genetics , Plant Proteins/metabolism , Proanthocyanidins/metabolismABSTRACT
Electromagnetic wave lensing, a common physical phenomenon recognized in visible light for centuries, finds extensive applications in manipulating light in optical systems such as telescopes and cameras. Magnetohydrodynamic wave is a common perturbation phenomenon in the corona. By using high spatio-temporal resolution observations from the Solar Dynamics Observatory, here, we report the observation of a magnetohydrodynamic wave lensing in the highly ionized and magnetized coronal plasma, where quasi-periodic wavefronts emanated from a flare converged at a specific point after traversing a coronal hole. The entire process resembles an electromagnetic wave lensing from the source to the focus. Meanwhile, the magnetohydrodynamic wave lensing is well reproduced through a magnetohydrodynamic numerical simulation with full spatio-temporal resolution. We further investigate potential applications for coronal seismology, as the lensing process encodes information on the Alfvén speed, in conjunction with favorable geometric and density variations.
ABSTRACT
Mutant isocitrate dehydrogenases (IDHs) produce R-2-hydroxyglutarate (R-2HG), which inhibits the growth of most acute myeloid leukemia (AML) cells. Here, we showed that necroptosis, a form of programmed cell death, contributed to the antileukemia activity of R-2HG. Mechanistically, R-2HG competitively inhibited the activity of lysine demethylase 2B (KDM2B), an α-ketoglutarate-dependent dioxygenase. KDM2B inhibition increased histone 3 lysine 4 trimethylation levels and promoted the expression of receptor-interacting protein kinase 1 (RIPK1), which consequently caused necroptosis in AML cells. The expression of RIPK3 was silenced because of DNA methylation in IDH-mutant (mIDH) AML cells, resulting in R-2HG resistance. Decitabine up-regulated RIPK3 expression and repaired endogenous R-2HG-induced necroptosis pathway in mIDH AML cells. Together, R-2HG induced RIPK1-dependent necroptosis via KDM2B inhibition in AML cells. The loss of RIPK3 protected mIDH AML cells from necroptosis. Restoring RIPK3 expression to exert R-2HG's intrinsic antileukemia effect will be a potential therapeutic strategy in patients with AML.
Subject(s)
Glutarates , Leukemia, Myeloid, Acute , Lysine , Humans , Necroptosis , Leukemia, Myeloid, Acute/drug therapy , Apoptosis , Receptor-Interacting Protein Serine-Threonine Kinases/metabolismABSTRACT
BACKGROUND: The outcome of relapsed/refractory (R/R) acute myeloid leukemia (AML) remains extremely poor. Venetoclax (VEN)-based regimens have shown promise in treating R/R AML. OBJECTIVE: This phase 2 study aimed to systematically evaluate the efficacy and safety of the VAA regimen (VEN plus Cytarabine and Azacitidine) in R/R AML patients. METHODS: Thirty R/R AML patients were enrolled. The study adopted a stepwise ramp-up of VEN dosing, starting with 100 mg on day 1, escalating to 200 mg on day 2, and reaching 400 mg from day 3 to day 9. Cytarabine (10 mg/m2, q12h) was administered intravenously twice daily from days 1 to 10, and Azacitidine (75 mg/m2) was administered via subcutaneous injection once daily from days 1-7. The primary efficacy endpoint was the composite complete remission rate (CRc), including complete response (CR) and complete response with incomplete blood count recovery (CRi). Secondary endpoints included overall survival (OS), duration of response (DOR), and safety analysis. RESULTS: The CRc rate was 63.3% (19/30), with CR in 36.7% of patients and CRi in 26.7%. Notably, 14 (73.7%) of 19 patients achieving CRc showed undetectable measurable residual disease by flow cytometry. With a median follow-up of 10.7 months, the median OS had not been reached, and the median DOR was 18.3 months. The most common grade 3-4 adverse events (AEs) were neutropenia (100%), anemia (96.7%), thrombocytopenia (90.0%), and leukopenia (90.0%). Infections, with pneumonia being the most prevalent (43.3%), were observed, including one fatal case of Pseudomonas aeruginosa septicemia. There were no treatment-related deaths. CONCLUSION: The VAA regimen is an effective and safe option for patients with R/R AML, demonstrating a high CRc rate and manageable safety profile.
Subject(s)
Leukemia, Myeloid, Acute , Leukopenia , Sulfonamides , Humans , Cytarabine/adverse effects , Azacitidine , Leukemia, Myeloid, Acute/drug therapy , Bridged Bicyclo Compounds, Heterocyclic/adverse effects , Pathologic Complete Response , Leukopenia/chemically induced , Antineoplastic Combined Chemotherapy Protocols/adverse effectsABSTRACT
Chromosomal instability is a prominent biological feature of myelodysplastic syndromes (MDS), with over 50% of patients with MDS harboring chromosomal abnormalities or a complex karyotype (CK). Despite this observation, the mechanisms underlying mitotic and chromosomal defects in MDS remain elusive. In this study, we identified ectopic expression of the transcription factor ONECUT3, which is associated with CKs and poorer survival outcomes in MDS. ONECUT3-overexpressing cell models exhibited enrichment of several notable pathways, including signatures of sister chromosome exchange separation and mitotic nuclear division with the upregulation of INCENP and CDCA8 genes. Notably, dysregulation of chromosome passenger complex (CPC) accumulation, besides the cell equator and midbody, during mitotic phases consequently caused cytokinesis failure and defective chromosome segregation. Mechanistically, the homeobox (HOX) domain of ONECUT3, serving as the DNA binding domain, occupied the unique genomic regions of INCENP and CDCA8 and transcriptionally activated these 2 genes. We identified a lead compound, C5484617, that functionally targeted the HOX domain of ONECUT3, inhibiting its transcriptional activity on downstream genes, and synergistically resensitized MDS cells to hypomethylating agents. This study revealed that ONECUT3 promoted chromosomal instability by transcriptional activation of INCENP and CDCA8, suggesting potential prognostic and therapeutic roles for targeting high-risk MDS patients with a CK.
Subject(s)
Myelodysplastic Syndromes , Transcription Factors , Humans , Transcription Factors/genetics , Transcription Factors/metabolism , Ectopic Gene Expression , Myelodysplastic Syndromes/genetics , Myelodysplastic Syndromes/metabolism , Chromosomal Instability , KaryotypeABSTRACT
Enhancing the aerodynamic performance of bristled wings is an important topic for small flying robotics. This paper numerically investigates this situation at very low Reynolds numbers by using elliptic cylinders as the bristles instead of circular cylinders. Optimal configuration of the bristled wing with five elliptic cylinders is obtained, which corresponds to the maximum lift. The results show that, compared with the case of circular cylindrical bristles, the aerodynamic performance of the elliptical bristles can be enhanced effectively. The enhancement can be more significant as the aspect ratio of the ellipses increases and the gap width decreases. The bristled wing generates more lift compared to a flat-plate wing with a length five times that of the major axis of an ellipse. For the cases that the attack angleαfor the whole wing is equal to those for the elliptical bristlesθ, the optimal attack angle for ellipses maximizing the total lift force of the five-bristle model is between 40° and 45°. Forα ≠θwith the Reynold numberRe⪠0.1, the optimal ellipse attack angle is between 40° and 45°. Forα ≠θwithReâ¼ 1, the optimal ellipse attack angle deviates heavier from the range between 40° and 45° at someαvalues and reaches approximately 32° atα= 20°. This paper can lay a foundation for optimal design of small flying robotics and enhancement of flow through porous structures in future.
Subject(s)
Flight, Animal , Robotics , Animals , Biomechanical Phenomena , Models, Biological , Wings, AnimalABSTRACT
BACKGROUND: The incidence of gastric cancer remains high, and it is the sixth most common cancer and the fourth leading cause of cancer deaths worldwide. Oral contrast-enhanced ultrasonography is a simple, non-invasive, and painless method for the diagnosis of gastric tumors. AIM: To explore the diagnostic value of oral contrast-enhanced ultrasonography for the detection of gastric tumors. METHODS: The screening results based on oral contrast-enhanced ultrasonography and electronic gastroscopy were compared with those of the postoperative pathological examination. RESULTS: Among 42 patients with gastric tumors enrolled in the study, the diagnostic accordance rate was 95.2% for oral contrast-enhanced ultrasonography (n = 40) and 90.5% for electronic gastroscopy (n = 38) compared with postoperative pathological examination. The Kappa value of consistency test with pathological findings was 0.812 for oral contrast-enhanced ultrasonography and 0.718 for electronic gastroscopy, and there was no significant difference between them (P = 0.397). For the TNM staging of gastric tumors, the accuracy rate of oral contrast-enhanced ultrasonography was 81.9% for the overall T staging and 50%, 77.8%, 100%, and 100% for T1, T2, T3, and T4 staging, respectively. The sensitivity and specificity were both 100% for stages T3 and T4. The diagnostic accuracy rate of oral contrast-enhanced ultrasonography was 93.8%, 80%, 100%, and 100% for stages N0, N1-N3, M0, and M1, respectively. CONCLUSION: The accordance rate of qualitative diagnosis by oral contrast-enhanced ultrasonography is comparable to that of gastroscopy, and it could be used as the preferred method for the early screening of gastric tumors.
Subject(s)
Myelodysplastic Syndromes , Humans , Prognosis , Myelodysplastic Syndromes/genetics , Mutation , KaryotypeABSTRACT
Objectives: Dual specificity phosphatase 1 (DUSP1) is high-expressed in various cancers and plays an important role in the cellular response to agents that damage DNA. We aimed to investigate the expressions and mechanisms of DUSP1 signaling pathway regulating cytarabine (Ara-C) resistance in acute myeloid leukemia (AML). Methods: Immunohistochemistry was performed on bone marrow biopsy specimens from AML and controls to explore the expression of DUSP1. Western blot and Q-PCR were used to detect the protein and mRNA expression levels. MTT assay was used to detect the proliferation of cells. Cell apoptosis was detected by flow cytometry. The immune protein-protein interaction (PPI) network of DUSP1 was analyzed in the platform of Pathway Commons, and immune infiltration analysis was used to study the immune microenvironment of AML. Results: We found that the expression levels of DUSP1 in AML patients exceeded that in controls. Survival analysis in public datasets showed that AML patients with higher levels of DUSP1 had poor clinical outcomes. Further public data analysis indicated that DUSP1 was overexpressed in NRAS mutated AML. DUSP1 knockdown by siRNA could sensitize AML cells to Ara-C treatments. The phosphorylation level of mitogen-activated protein kinase (MAPK) pathway was significantly elevated in DUSP1 down-regulated NRAS G13D mutated AML cells. The PPI analysis showed DUSP1 correlated with immune gene CREB1 and CXCL8 in NRAS mutated AML. We also revealed a correlation between tumor-infiltrating immune cells in RAS mutated AML microenvironment. Conclusion: Our findings suggest that DUSP1 signaling pathways may regulate Ara-C sensitivity in AML.
Subject(s)
Cytarabine , Leukemia, Myeloid, Acute , Humans , Cytarabine/pharmacology , Cytarabine/therapeutic use , Dual Specificity Phosphatase 1/genetics , Dual Specificity Phosphatase 1/metabolism , Dual Specificity Phosphatase 1/pharmacology , Antimetabolites, Antineoplastic/pharmacology , Antimetabolites, Antineoplastic/therapeutic use , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/pathology , Signal Transduction , Apoptosis/genetics , Tumor MicroenvironmentSubject(s)
Febrile Neutropenia , Hematologic Diseases , Hematologic Neoplasms , Humans , Polymyxin B/adverse effects , Prospective Studies , Antifungal Agents/therapeutic use , Fever/drug therapy , Febrile Neutropenia/drug therapy , Anti-Bacterial Agents/therapeutic use , Drug Therapy, Combination , Hematologic Neoplasms/drug therapyABSTRACT
The treatment of patients with refractory and/or relapsed (R/R) high-risk myelodysplastic syndrome (HR-MDS) remains a daunting clinical challenge. Venetoclax is a selective BCL-2 inhibitor, which combined with hypomethylating agents (HMAs), increased responses and prolonged survival in unfit and previously untreated acute myeloid leukemia. We performed a retrospective study of patients with R/R HR-MDS receiving combination azacytidine (AZA) plus 15-days duration of venetoclax (VEN-15d) in order to determine their efficacy and toxicity in this context. We showed that the overall response rate was 57.2% (20/35) and the median over survival was 14 months in R/R MDS. The most common treatment-emergent adverse events were peripheral blood cytopenias and infectious complications. Our retrospective study showed that the real-world experience of treating R/R MDS with AZA plus VEN-15d highlights an encouraging response rate with myelosuppression being the major toxicity. Of note, VEN-15d with AZA may salvage patients failing to respond optimally to HMAs and reduce the disease-burden for subsequent allogeneic stem cell transplantation in our analysis. These data of combination AZA plus VEN-15d in R/R MDS warrant further prospective evaluation in clinical trials.
Subject(s)
Leukemia, Myeloid, Acute , Myelodysplastic Syndromes , Humans , Azacitidine/adverse effects , Retrospective Studies , Bridged Bicyclo Compounds, Heterocyclic/adverse effects , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Leukemia, Myeloid, Acute/therapyABSTRACT
BACKGROUND: Decitabine (DAC) is used as the first-line therapy in patients with higher-risk myelodysplastic syndromes (HR-MDS) and elderly acute myeloid leukaemia (AML) patients unsuitable for intensive chemotherapy. However, the clinical outcomes of patients treated with DAC as a monotherapy are far from satisfactory. Adding all-trans retinoic acid (ATRA) to DAC reportedly benefitted MDS and elderly AML patients. However, the underlying mechanisms remain unclear and need further explorations from laboratory experiments. METHODS: We used MDS and AML cell lines and primary cells to evaluate the combined effects of DAC and ATRA as well as the underlying mechanisms. We used the MOLM-13-luciferase murine xenograft model to verify the enhanced cytotoxic effect of the drug combination. RESULTS: The combination treatment reduced the viability of MDS/AML cells in vitro, delayed leukaemia progress, and extended survival in murine xenograft models compared to non- and mono-drug treated models. DAC application as a single agent induced Nrf2 activation and downstream antioxidative response, and restrained reactive oxygen species (ROS) generation, thus leading to DAC resistance. The addition of ATRA blocked Nrf2 activation by activating the RARα-Nrf2 complex, leading to ROS accumulation and ROS-dependent cytotoxicity. CONCLUSIONS: These results demonstrate that combining DAC and ATRA has potential for the clinical treatment of HR-MDS/AML and merits further exploration.
Subject(s)
Antineoplastic Agents , Leukemia, Myeloid, Acute , Myelodysplastic Syndromes , Humans , Animals , Mice , Aged , Decitabine/pharmacology , NF-E2-Related Factor 2 , Reactive Oxygen Species , Antineoplastic Agents/therapeutic use , Myelodysplastic Syndromes/chemically induced , Myelodysplastic Syndromes/drug therapy , Tretinoin/pharmacology , Leukemia, Myeloid, Acute/drug therapy , AzacitidineABSTRACT
Single gene mutations in the RAS pathway are uncommon and of unknown significance in myelodysplastic syndrome (MDS) patients, RAS pathway-related gene mutations (RASwaymut ) as a whole may be significant and require further elucidation. The clinical and molecular data of 370 MDS patients who were newly diagnosed between 1 November 2016 and 31 August 2020 in our hospital were collected and retrospectively reviewed. RASwaymut were detected in 57 (15.41%) patients. Higher median percentage of marrow blasts (2% vs. 1%, P = 0.00), more co-mutated genes (4, interquartile range [IQR]: 2-5. vs. 2, IQR:1-4, P = 0.00), more higher risk patients according to international prognostic scoring system-revised (IPSS-R) (80.70% vs. 59.11%, P = 0.002) as well as higher acute myeloid leukemia transformation rate (35.09% vs. 14.38%, P = 0.02) were observed in patients with RASwaymut when compared to those with wild type RAS pathway-related genes (RASwaywt ). The most frequent co-mutated genes were ASXL1 (28.6%), TET2 (23.2%), U2AF1, RUNX1, TP53 (14.3%); DNMT3A (12.5%), among which ASXL1 mutation rate were significantly higher than those with RASwaywt (p < 0.05). RASwaymut had no significant effect on response to disease-modifying treatment in MDS patients. However, Overall survivals (OS) of RASwaymut patients were significantly shorter than those with RASwaywt (16.05 m. vs. 92.3 m, P = 0.00), especially in patients with marrow blasts less than 5% (P = 0.002), normal karyotype (P = 0.01) and lower risk (P = 0.00). While multivariate prognostic analysis showed that RASwaymut co-mutated with TET2 was an independent poor prognostic factor for all MDS patients (P = 0.00, hazrad ratio [HR] = 4.77 with 95% confidence interval [CI]: 2.4-9.51) and RASwaymut patients (P = 0.02, HR 2.76, 95% CI 1.21-6.29). In conclusion, RASwaymut was associated with higher IPSS-R risk, higher incidence of leukemic transformation thus shorter OS in MDS patients, it could be viewed as a whole to predict poor prognosis. Co-mutation with TET2 may promote disease progression and was an independent poor prognostic factor in MDS patients.
Subject(s)
Clinical Relevance , Myelodysplastic Syndromes , Humans , Retrospective Studies , Mutation , Prognosis , Myelodysplastic Syndromes/geneticsABSTRACT
Clinical trials have shown that trastuzumab (H) and pertuzumab (P) combined with chemotherapy as neoadjuvant therapy increased pathological complete response (pCR) rate of patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer. However, date in China in the real world are currently limited. Clinical data from patients with HER2-positive breast cancer who received HP combined with chemotherapy as neoadjuvant therapy at 2 institutions from March 2019 to February 2022 were retrospectively analyzed. Adverse reactions were evaluated using CTCAE version 5.0. The primary endpoint was total pathologic complete response (tpCR; ypT0/isypN0), and the secondary endpoints were breast pathologic complete response (bpCR; ypT0/is) and axillary pathologic complete response (apCR; ypN0). Factors influencing tpCR were also analyzed. A total of 302 patients were included in the analysis, of which 145 were treated with H + P + taxane + carboplatin (TcbHP), 94 with H + P + taxane (THP) and 63 with sequential anthracycline and cyclophosphamide, followed by H + P + taxane (AC-THP). The overall tpCR rate was 64.9%, and those of TcbHP, THP, and AC-THP were 73.1%, 52.1%, and 65.1%, respectively. The tpCR rate of the hormone receptor (HR) negative group (80.3%) was higher than that of the HR positive group (52.1%). The overall bpCR rate was 73.5% and the apCR rate was 75.8%. In the univariate analysis, HR, HER2 status and treatment regimen were related factors that affected tpCR. In the multivariate analysis, HR, HER2 status and treatment regimen were independent predictors of tpCR (P < .001, P < .001 and P = .009). The levels 3 and 4 toxicities rates of TcbHP were slightly higher than those of THP and AC-THP. HP combined with chemotherapy has achieved a high pCR rate. The TcbHP regimen had the highest pCR. HR-negative tumors demonstrated a higher pCR. HR, HER2 status and treatment regimen were independent predictors of tpCR. The adverse reactions are controllable.
Subject(s)
Breast Neoplasms , Neoadjuvant Therapy , Anthracyclines/therapeutic use , Antibodies, Monoclonal, Humanized , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/pathology , Bridged-Ring Compounds , Carboplatin/therapeutic use , Cyclophosphamide , Female , Hormones/therapeutic use , Humans , Neoadjuvant Therapy/adverse effects , Receptor, ErbB-2/metabolism , Retrospective Studies , Taxoids/therapeutic use , TrastuzumabABSTRACT
BACKGROUND: The implication of mutational variant allelic frequency (VAF) has been increasingly considered in the prognostic interpretation of molecular data in myeloid malignancies. However, the impact of VAF on outcomes of myelodysplastic syndromes (MDS) has not been extensively explored. METHODS: Targeted next-generation sequencing was performed in 350 newly diagnosed MDS cases. The associations of mutational VAF of each gene with overall survival (OS) and leukemia-free survival (LFS) were examined by multivariate Cox regression after univariate analysis. RESULTS: Shorter OS was independently associated with DNMT3A VAF (HR 1.020 per 1% VAF increase; 95% CI 1.005-1.035; p = 0.011) and TP53 VAF (HR 1.014 per 1% VAF increase; 95% CI 1.006-1.022; p = 0.001). LFS analyses revealed that TET2 VAF (HR 1.013 per 1% VAF increase; 95% CI 1.005-1.022; p = 0.003) and TP53 VAF (HR 1.012 per 1% VAF increase; 95% CI 1.004-1.021; p = 0.005) were independently associated with faster leukemic transformation. Furthermore, we established nomograms to predict OS and LFS, respectively, by integrating independent mutational predictors into the revised International Prognostic Scoring System. CONCLUSION: Our study highlights that VAF of certain genes should be incorporated into routine clinical prognostication of survival and leukemic transformation of MDS.
Subject(s)
Myelodysplastic Syndromes , Tumor Suppressor Protein p53 , Gene Frequency , Humans , Mutation , Myelodysplastic Syndromes/genetics , Prognosis , Tumor Suppressor Protein p53/geneticsABSTRACT
BACKGROUND: Trisomy 8 positivity myelodysplastic syndrome with Behçet's disease is rare. Isolated trisomy 8 is a frequent cytogenetic abnormality in the MDS, but the characteristic of trisomy 8 and the association between trisomy 8 positivity myelodysplastic syndrome and Behçet's disease is unclear. CASE PRESENTATION: Here, we reported a 63-year-old man, who presented with fever, abdominal pain and hematochezia. Imaging studies revealed bowel wall thickening and mural hyperenhancement of terminal ileum and cecum. Colonoscopy found multiple round ulcers in terminal ileum, ileocecal valve and multiple yellow dotted pseudomembranous attachments throughout the colon. Capsule endoscopy also revealed multiple irregular ulcers in lower ileum. Serum C-reactive protein levels and fecal calprotectin were abnormally high. The clostridium difficile toxin A and B was positive. However, the patient's intestinal ulcers did not resolve after two weeks course of vancomycin. Considered that the patient was diagnosed as MDS-RAEB2 with a karyotype of 47 XX, + 8. And detailed inquiry of medical history revealed epifolliculitis and frequently recurrent oral ulcers 2 months before admission. A diagnosis of trisomy 8 positivity MDS with BD was made. Then he received glucocorticoid along with the 5th course of azacytidine. The follow-up endoscopy showed significantly improved intestinal ulcer 2 months after treatment. we report a rare disease and provide the diagnose and treatment ideas. CONCLUSIONS: We highlight the challenges and the process of thinking about of the diagnosis. This may provide a new idea for the diagnosis of intestinal ulcers.
Subject(s)
Intestinal Diseases , Myelodysplastic Syndromes , Colonoscopy , Humans , Male , Middle Aged , Myelodysplastic Syndromes/complications , Trisomy , Ulcer/drug therapyABSTRACT
Common variable immunodeficiency (CVID) was a kind of primary immunodeficiency disorders with heterogeneous phenotype and genotype. Lipopolysaccharide-responsive and beige-like anchor (LRBA) mutation was identified as disease associated in CVID, advanced genetic method will help to detect atypical cases. We report a case of adult patient manifested as hemophagocytic lymphohistiocytosis (HLH), bone marrow examination suggested prosperity to MDS, manifested as increased immature myeloid cells and dysplastic hematopoiesis. Whole exome sequencing (WES) identified a novel heterogeneous c.1876T > C (p.W626R) mutation in LRBA and four somatic mutations: ASXL1 (c.1967dupA); PTPN11 (c.226G > A), U2AF1 (c.101C > T and c.470A > G), among which ASXL1 was a high-risk marker of clonal hematopoiesis. Combined with her recurrent severe infections and immune abnormalities such as hypoimmunoglobulinemia, the patient was diagnosed with CVID. Subsequent hematopoietic stem cell transplantation saved her from severe cytopenia and immune deficiency. This case report highlights the great promise of utilization of WES for diagnosing rare disease with atypical manifestations and guiding further treatment.
ABSTRACT
Purpose: To explore the efficacy and safety of lower-dose decitabine in patients with lower-risk MDS, a prospective multicenter phase II study was conducted to compare decitabine with the best supportive care (BSC). Methods: Patients diagnosed with lower-risk MDS from September 2013 to August 2018 were assigned to the decitabine group or the BSC group. Decitabine (12 mg/m2/day) was administered over 1 hour/day for 5 consecutive days in a 4-week cycle. BSC, including growth factors, transfusion, thalidomide, lenalidomide, and immunosuppressive agents were given consecutively. The endpoints included the proportion of patients who achieved overall response (OR) in the first 2 or 3 courses, event-free survival (EFS), and overall survival (OS). Results: A total of recruited 82 patients were analyzed. In the decitabine group, 65.9% (27/41) achieved OR after 2 or 3 cycles of treatment, compared with 22.0% (9/41) in the BSC group (p <0.01). Besides, 44.0% (11/25) in the decitabine group became independent of RBC/Platelets transfusion, compared with 27.8% (5/18) in the BSC group. Patients with gene mutation and treated with decitabine achieved a higher OR rate, compared with those without gene mutation [72.0% (18/25) vs 11.5% (3/26), p <0.01]. There was no significant difference in the median EFS between the decitabine and BSC groups (20.6 vs 14.3 months respectively, p = 0.665). In the decitabine group, the most significant adverse events were infections of any grades or neutropenic fever (46.3%, 19/41) and one patient (4.2%) died of acute cerebral infarction within 6 weeks of treatment. Conclusion: Lower-dose decitabine demonstrated promising clinical response with acceptable toxicity profiles in patients with low- and intermediate 1-risk MDS. A higher response rate to decitabine was observed in patients with mutated genes. Therefore, lower-dose decitabine can be advocated for patients with low-risk MDS and mutated genes.