Dysregulation of calcium ion homeostasis and abnormal protein aggregation have been proposed as major pathogenic hallmarks underpinning selective degeneration of motor neurons in amyotrophic lateral ...sclerosis (ALS). Recently, mutations in annexin A11 (
), a gene encoding a Ca
-dependent phospholipid-binding protein, have been identified in familial and sporadic ALS. However, the physiological and pathophysiological roles of
remain unknown. Here, we report functions of
related to intracellular Ca
homeostasis and stress granule dynamics. We analyzed the exome sequences of 500 Korean patients with sALS and identified nine
variants in 13 patients. The amino-terminal variants p.G38R and p.D40G within the low-complexity domain of ANXA11 enhanced aggregation propensity, whereas the carboxyl-terminal ANX domain variants p.H390P and p.R456H altered Ca
responses. Furthermore, all four variants in ANXA11 underwent abnormal phase separation to form droplets with aggregates and led to the alteration of the biophysical properties of ANXA11. These functional defects caused by ALS-linked variants induced alterations in both intracellular Ca
homeostasis and stress granule disassembly. We also revealed that p.G228Lfs*29 reduced ANXA11 expression and impaired Ca
homeostasis, as caused by missense variants. Ca
-dependent interaction and coaggregation between ANXA11 and ALS-causative RNA-binding proteins, FUS and hnRNPA1, were observed in motor neuron cells and brain from a patient with ALS-FUS. The expression of ALS-linked
variants in motor neuron cells caused cytoplasmic sequestration of endogenous FUS and triggered neuronal apoptosis. Together, our findings suggest that disease-associated
mutations can contribute to ALS pathogenesis through toxic gain-of-function mechanisms involving abnormal protein aggregation.
Ibrutinib is highly effective in patients with relapsed or refractory mantle cell lymphoma (MCL) in major clinical trials. Although there has been a dramatic improvement in survival outcomes in the ...salvage setting, nonresponders to ibrutinib have a bleak prognosis. Therefore, this retrospective study was conducted to identify the most appropriate therapeutic strategy and prognosis‐related factors to predict the response of patients with relapsed or refractory MCL to ibrutinib monotherapy. Thirty‐three consecutive refractory or relapsed MCL patients treated with ibrutinib were analyzed in this study. The median overall survival (OS) and progression‐free survival (PFS) after initiation of ibrutinib were 35.1 months and 27.4 months, respectively. Risk factor analysis showed that high risk according to the Mantle Cell Lymphoma International Prognostic Index (MIPI) and nonresponse to ibrutinib at the first three cycles were significantly associated with inferior OS. Poor PFS was associated with high‐risk biologic MIPI, prior bendamustine exposure, and nonresponse to ibrutinib during the first three cycles. After ibrutinib failure, primary nonresponders had poorer OS and PFS than inconsistent responders. The overall response rate for the first salvage therapy was only 33%, with a median TTP of 3.2 months. There was no effective therapeutic strategy except for allogeneic hematopoietic stem cell transplantation (allo‐HSCT). Although ibrutinib responders exhibited favorable survival outcomes, nonresponders had a dismal prognosis. To overcome these limitations, it may be necessary to modify therapeutic strategies, such as selecting inconsistent responders for earlier allo‐HSCT.
Although ibrutinib responders exhibited favorable survival outcomes, nonresponders had a dismal prognosis. To overcome these limitations, it may be necessary to modify therapeutic strategies.
The risk of developing tuberculosis (TB) in allogeneic hematopoietic stem cell transplantation (HSCT) recipients is expected to be relatively high in an intermediate TB burden country. This ...single-center retrospective study was conducted to investigate risk factors and the incidence of TB after allogeneic HSCT.
From January 2004 to March 2011, 845 adult patients were enrolled. Starting April 2009, patients were given isoniazid (INH) prophylaxis based on interferon-γ release assay results. The incidence of TB was analyzed before and after April 2009, and compared it with that of the general population in Korea.
TB was diagnosed in 21 (2.49%) of the 845 allogeneic HSCT patients. The median time to the development of TB was 386 days after transplantation (range, 49-886). Compared with the general population, the standardized incidence ratio of TB was 9.10 (95% CI; 5.59-14.79). Extensive chronic graft-versus-host disease (GVHD) was associated with the development of TB (P = 0.003). Acute GVHD, conditioning regimen with total body irradiation and conditioning intensity were not significantly related. INH prophylaxis did not reduce the incidence of TB (P = 0.548). Among 21 TB patients, one patient had INH prophylaxis.
Allogeneic HSCT recipients especially those who suffer from extensive chronic GVHD are at a high risk of developing TB. INH prophylaxis did not statistically change the incidence of TB, however, further well-designed prospective studies are needed.
Renal impairment (RI) is common in patients with multiple myeloma (MM) and new therapies that can improve renal function are needed. The phase III IKEMA study (clinicaltrials gov. Identifier: ...NCT03275285) investigated isatuximab (Isa) with carfilzomib and dexamethasone (Kd) versus Kd in relapsed MM. This subgroup analysis examined results from patients with RI, defined as estimated glomerular filtration rate <60 mL/min/1.73 m². Addition of Isa prolonged progression-free survival (PFS) in patients with RI (hazard ratio: 0.27; 95% confidence interval CI: 0.11-0.66; median PFS not reached for Isa-Kd versus 13.4 months for Kd 20.8-month follow-up). Complete renal responses occurred more frequently with Isa-Kd (52.0%) versus Kd (30.8%) and were durable in 32.0% versus 7.7% of patients, respectively. Treatment exposure was longer with Isa-Kd, with median number of started cycles and median duration of exposure of 20 versus 9 cycles and 81.0 versus 35.7 weeks for Isa-Kd versus Kd, respectively. Among patients with RI, the incidence of patients with grade ≥3 treatment-emergent adverse events was similar between the two arms (79.1% in Isa-Kd vs. 77.8% in Kd). In summary, the addition of Isa to Kd improved clinical outcomes with a manageable safety profile in patients with RI, consistent with the benefit observed in the overall IKEMA study population.
Multi-cancer early detection remains a key challenge in cell-free DNA (cfDNA)-based liquid biopsy. Here, we perform cfDNA whole-genome sequencing to generate two test datasets covering 2125 patient ...samples of 9 cancer types and 1241 normal control samples, and also a reference dataset for background variant filtering based on 20,529 low-depth healthy samples. An external cfDNA dataset consisting of 208 cancer and 214 normal control samples is used for additional evaluation. Accuracy for cancer detection and tissue-of-origin localization is achieved using our algorithm, which incorporates cancer type-specific profiles of mutation distribution and chromatin organization in tumor tissues as model references. Our integrative model detects early-stage cancers, including those of pancreatic origin, with high sensitivity that is comparable to that of late-stage detection. Model interpretation reveals the contribution of cancer type-specific genomic and epigenomic features. Our methodologies may lay the groundwork for accurate cfDNA-based cancer diagnosis, especially at early stages.
Acute promyelocytic leukemia (APL) is generally held to have favorable risk, but we have observed a high incidence of early deaths caused by fatal bleeding and differentiation syndrome (DS). We ...retrospectively analyzed 259 APL patients from 2002 to 2014 who all received all-trans retinoic acid (ATRA) with the support of sufficient transfusions, followed by 4 days of idarubicin. High-risk status was determined as a diagnostic leukocyte count (WBCdx) >10 × 10
/L (Sanz criteria). For patients with hyperleukocytosis, we sometimes conducted leukapheresis and also used hydroxyurea and prophylactic dexamethasone. Because we frequently observed patient fatalities from progressive hyperleukocytosis, we also checked the maximum leukocyte count (WBCmax) and stratified patients by their incremental ratios. The 8-week cumulative incidence of early death and DS was 13.5% and 17.8%, respectively. We found that WBCmax correlated better with early death and DS, even in the low-risk group, than WBCdx. Among the patients with WBCdx <10 × 10
/L, a WBCmax >43 × 10
/L correlated with early death (26.7%) and DS (40.0%). Also, having a WBCdx of 10 to 43 × 10
/La that increased to a WBCmax >43 × 10
/L correlated with increased early death (33.3%). The multivariate analysis revealed that a WBCmax >43 × 10
/L correlated significantly with both early death and DS.
Progranulin (PGRN) haploinsufficiency due to progranulin gene (GRN) variants can cause frontotemporal dementia (FTD) with aberrant TAR DNA-binding protein 43 (TDP-43) accumulation. Despite microglial ...burden with TDP-43-related pathophysiology, direct microglial TDP-43 pathology has not been clarified yet, only emphasized in neuronal pathology. Thus, the objective of this study was to investigate TDP-43 pathology in microglia of patients with PGRN haploinsufficiency.
To design a human microglial cell model with PGRN haploinsufficiency, monocyte-derived microglia (iMGs) were generated from FTD-GRN patients carrying pathogenic or likely pathogenic variants (p.M1? and p.W147*) and three healthy controls.
iMGs from FTD-GRN patients with PGRN deficiency exhibited severe neuroinflammation phenotype and failure to maintain their homeostatic molecular signatures, along with impaired phagocytosis. In FTD-GRN patients-derived iMGs, significant cytoplasmic TDP-43 aggregation and accumulation of lipid droplets with profound lysosomal abnormalities were observed. These pathomechanisms were mediated by complement C1q activation and upregulation of pro-inflammatory cytokines.
Our study provides considerable cellular and molecular evidence that loss-of-function variants of GRN in human microglia can cause microglial dysfunction with abnormal TDP-43 aggregation induced by inflammatory milieu as well as the impaired lysosome. Elucidating the role of microglial TDP-43 pathology in intensifying neuroinflammation in individuals with FTD due to PGRN deficiency and examining consequential effects on microglial dysfunction might yield novel insights into the mechanisms underlying FTD and neurodegenerative disorders.
Isolated extramedullary relapse (EMR) without bone marrow relapse (BMR) after allogeneic hematopoietic cell transplantation (allo-HCT) is a rare condition in patients with acute lymphoblastic ...leukemia (ALL), and the role of immunotherapeutic agents for these patients remains unclear. We analyzed treatment outcomes of blinatumomab or inotuzumab ozogamicin (INO) as first- or second-line salvage therapy in nine patients with Philadelphia chromosome-negative B-cell precursor ALL presenting with isolated EMR after previous allo-HCT. In seven patients receiving blinatumomab as first-line salvage therapy, 4 (57.1%) achieved complete remission (CR). Among the three patients without remission after blinatumomab, two switched to INO and subsequently showed responses {one CR and one partial response PR}, and one switched to multiagent chemotherapy that led to CR. In the two patients receiving first-line salvage therapy with INO, one showed PR and the other achieved CR. Overall, 6 (66.7%) of nine patients achieved CR, and five of them proceeded to allo-HCT in CR. The median overall survival after relapse was 27.8 months. In conclusion, both blinatumomab and INO showed good response rates and a safe bridging role to second allo-HCT in patients with isolated EMR. However, clinical differences between isolated EMR and EMR with BMR remain to be elucidated.
We attempted to identify the incidence and survival outcome of hepatic sinusoidal obstruction syndrome/veno-occlusive disease (VOD/SOS) after hematopoietic cell transplantation (HCT) under strategy ...of prophylactic ursodiol and intravenous heparin or prostaglandin E1 (PGE1). From 2009 to 2018, 2572 consecutive allogeneic-HCT cases were reviewed. We used oral ursodiol for all transplants, and most were administered low-dose heparin, while PGE1 in selected cases with low platelet count at the time of preconditioning. Diagnosis and severity grades were reassessed by revised EBMT criteria. The overall incidence of hepatic VOD/SOS was 3.4% (Mild 0.9%, Moderate 0.6%, Severe 0.7%, Very severe 1.2%) after allogeneic-HCT under strategy of intravenous prophylaxis. The 1-year overall survival of VOD/SOS was 41.4% which was divided into 73.9% for mild, 66.7% for moderate, 38.9% for severe, and 6.5% for very severe grade. Very high disease risk index, male gender, donor other than matched sibling donor, and busulfex > 9 mg/kg were affecting factors for development of VOD/SOS. For severe to very severe VOD/SOS, history of pre-HCT liver dysfunction was an additionally affecting factor. Allogeneic-HCT using ursodiol and intravenous prophylaxis was considered safe without significant bleeding complications and should be evaluated in future clinical trials. For those with high-risk of VOD/SOS, early intervention and management is important.
Objective
The objective of this study was to explore characteristics of bone marrow mesenchymal stromal cells (BM‐MSCs) derived from patients with myelodysplastic syndrome (MDS) and multiple myeloma ...(MM).
Methods
BM‐MSCs were recovered from 17 of MDS patients, 23 of MM patients and 9 healthy donors and were passaged until proliferation stopped. General characteristics and gene expression profiles of MSCs were analysed. In vitro, ex vivo coculture, immunohistochemistry and knockdown experiments were performed to verify gene expression changes.
Results
BM‐MSCs failed to culture in 35.0% of patients and 50.0% of recovered BM‐MSCs stopped to proliferate before passage 6. MDS‐ and MM‐MSCs shared characteristics including decreased osteogenesis, increased angiogenesis and senescence‐associated molecular pathways. In vitro and ex vivo experiments showed disease‐specific changes such as neurogenic tendency in MDS‐MSCs and cardiomyogenic tendency in MM‐MSCs. Although the age of normal control was younger than patients and telomere length was shorter in patient's BM‐MSCs, they were not different according to disease category nor degree of proliferation. Specifically, poorly proliferation BM‐MSCs showed CDKN2A overexpression and CXCL12 downregulation. Immunohistochemistry of BM biopsy demonstrated that CDKN2A was intensely accumulation in perivascular BM‐MSCs failed to culture. Interestingly, patient's BM‐MSCs revealed improved proliferation activity after CDKN2A knockdown.
Conclusion
These results collectively indicate that MDS‐MSCs and MM‐MSCs have common and different alterations at various degrees. Hence, it is necessary to evaluate their alteration status using representative markers such as CDKN2A expression.
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