Efficacy and Mechanisms of Silybum Marianum, Silymarin, and Silibinin on Rheumatoid Arthritis and Osteoarthritis Symptoms: A Systematic Review.

BACKGROUND: Rheumatoid arthritis (RA) and osteoarthritis (OA) are the most common forms of skeletal disease worldwide. OBJECTIVE: The current systematic review investigated the mechanisms of Silybum marianum, silymarin, and silibinin on RA and OA symptoms. METHODS: The PRISMA 2020 statement was used for reporting Items in this systematic review. The result was a list of five databases, including Web of Science, Cochrane Library, Embase, PubMed, and Scopus. After determining the inclusion and exclusion criteria, of 437 records identified, 21 studies were eligible. The data were extracted from the studies and imported into an Excel form, and finally, the effects, outcomes, and associated mechanisms were surveyed. RESULTS: Silybum marianum and its main constituents revealed immunomodulatory, anti-inflammatory, antioxidant, and anti-apoptotic properties in humans and laboratory animals. Moreover, they protect the joints against the cartilage matrix's hypocellularity and fibrillation, reduce synovitis, and inhibit degeneration of aggrecan and collagen-II in human chondrocytes. They also, through reducing inflammatory cytokines, show an analgesic effect. Although silymarin and silibinin have low absorption, their bioavailability can be increased with nanoparticles. CONCLUSION: In experimental studies, Silybum marianum, silymarin, and silibinin revealed promising effects on RA and OA symptoms. However, more clinical studies are needed in this field to obtain reliable results and clinical administration of these compounds.

A familial SAMD9 variant present in pediatric myelodysplastic syndrome.

Myelodysplastic syndrome (MDS) is a rare pediatric diagnosis characterized by ineffective hematopoiesis with potential to evolve into acute myelogenous leukemia (AML). In this report, we describe a unique case of a 17-yr-old female with an aggressive course of MDS with excess blasts who was found to have monosomy 7 and a SAMD9 germline variant, which has not previously been associated with a MDS phenotype. This case of MDS was extremely rapidly progressing, showing resistance to chemotherapy and stem cell transplant, unfortunately resulting in patient death. It is imperative to further investigate this rare variant to aid in the future care of patients with this variant.

Two mutations in the SBDS gene reveal a diagnosis of Shwachman-Diamond syndrome in a patient with atypical symptoms.

We present the case of a 53-yr-old woman with an inherited bone marrow failure coexisting with uncommon extrahematological symptoms, such as cirrhosis and skin abnormalities. Whole-exome sequencing revealed a diagnosis of Shwachman-Diamond syndrome (SDS) with an atypical presentation. Unexpected was the age of disease expression, normally around the pediatric age, with a predominantly median survival age of 36 yr. To our knowledge, she was the first adult patient with a molecular diagnosis of Shwachman-Diamond in Uruguay. The patient was referred to our service when she was 43-yr-old with a history of bone marrow failure with anemia and thrombocytopenia. All secondary causes of pancytopenia were excluded. Bone marrow aspirate and biopsy specimens were hypocellular for the patient's age. Numerous dysplastic features were observed in the three lineages. She had a normal karyotype and normal chromosomal fragility. A diagnosis of low-risk hypoplastic MDS was made. Dermatological examination revealed reticulate skin pigmentation with hypopigmented macules involving the face, neck, and extremities; nail dystrophy; premature graying; and thin hair. Extrahematological manifestations were present (e.g., learning difficulties, short stature). Last, she was diagnosed with cryptogenic liver cirrhosis CHILD C. This rules out all other possible causes of chronic liver disease. This clinical presentation initially oriented the diagnosis toward telomeropathy, so we did a telomeropathy NGS panel that came up negative. Finally, we did an exome sequencing that confirmed the diagnosis of SDS. Using whole-exome sequencing, we were able to find two compound heterozygous mutations in the SBDS gene that were responsible for the phenotype of a patient that was undiagnosed for 10 years. An earlier genetic diagnosis could have influenced our patient's outcome.

SOCS1 Haploinsufficiency Presenting as Severe Enthesitis, Bone Marrow Hypocellularity, and Refractory Thrombocytopenia in a Pediatric Patient with Subsequent Response to JAK Inhibition.

Haploinsufficiency of suppressor of cytokine signaling 1 (SOCS1) is a recently discovered autoinflammatory disorder with significant rheumatologic, immunologic, and hematologic manifestations. Here we report a case of SOCS1 haploinsufficiency in a 5-year-old child with profound arthralgias and immune-mediated thrombocytopenia unmasked by SARS-CoV-2 infection. Her clinical manifestations were accompanied by excessive B cell activity, eosinophilia, and elevated IgE levels. Uniquely, this is the first report of SOCS1 haploinsufficiency in the setting of a chromosomal deletion resulting in complete loss of a single SOCS1 gene with additional clinical findings of bone marrow hypocellularity and radiologic evidence of severe enthesitis. Immunologic profiling showed a prominent interferon signature in the patient's peripheral blood mononuclear cells, which were also hypersensitive to stimulation by type I and type II interferons. The patient showed excellent clinical and functional laboratory response to tofacitinib, a Janus kinase inhibitor that disrupts interferon signaling. Our case highlights the need to utilize a multidisciplinary diagnostic approach and consider a comprehensive genetic evaluation for inborn errors of immunity in patients with an atypical immune-mediated thrombocytopenia phenotype.

[Sternal bone marrow cell morphology evaluation utility for diagnostic categorization in patients with acquired hypocellular bone marrow failure syndromes].

Objective: Diagnostic value assessment of sternal bone marrow cell morphology in patients with acquired hypocellular bone marrow failure syndromes (BMFS) characterized by normal cytogenetics. Methods: A total of 194 eligible patients with an acquired hypocellular BMFS pre-sternum diagnosis in Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College from June 2014 to January 2019 were reviewed. Sternal bone marrow evaluation was performed, and a post-sternum diagnosis was made. Clinical characteristics and overall survival (OS) were then compared among patients with different post-sternum diagnosis. Binary logistic regression was used to develop a predictive scoring system. Results: In 152 patients with pre-sternum AA diagnosis, 29 patients with a pre-sternum idiopathic cytopenia of undetermined significance (ICUS) diagnosis, and 13 patients with a pre-sternum clonal cytopenia of undetermined significance (CCUS) diagnosis, sternal bone marrow evaluation resulted in a change of diagnosis to hypocellular myelodysplastic syndrome (hypo-MDS) in 42.8% (65/152) , 24.1% (7/29) , and 30.8% (4/13) , respectively. Patients with a post-sternum hypo-MDS diagnosis showed a significant difference in OS compared with patients with a post-sternum AA diagnosis (P=0.005) . Patients with ICUS/CCUS showed no difference in OS compared with AA and hypo-MDS (P=0.095 and P=0.480, respectively) . A 4-item predictive scoring system to identify hypocellular BMFS patients that need sternal bone marrow evaluation was developed, including age > 60 years old (OR=6.647, 95% CI 1.954-22.611, P=0.002, 2 points) , neutrophil alkaline phosphatase score ≤ 160 (OR=2.654, 95% CI 1.214-5.804, P=0.014, 1 point) , abnormal erythroid markers evaluated by flow cytometry on iliac bone marrow (OR=6.200, 95% CI 1.165-32.988, P=0.032, 2 points) , and DAT (DNMT3A, ASXL1, TET2) genes mutation (OR=4.809, 95% CI 1.587-14.572, P=0.005, 1 point) . The Akaike information criterin (AIC) was 186.1. Conclusion: Patients with a pre-sternum acquired hypocellular BMFS diagnosis characterized by normal cytogenetics may not reach accurate diagnostic categorization without sternal bone marrow cell morphology evaluation, which could be considered a diagnostic tool for this patient population. A predictive scoring system was developed, and when the total score is ≥ 2 points, sternal bone marrow evaluation should be performed for accurate diagnostic categorization that is critical to optimal patient care.

Bone Marrow Hypocellularity in Patients with End-Stage Kidney Disease.

BACKGROUND: Anemia and pancytopenia are not uncommon in patients with chronic kidney disease (CKD). Nevertheless, there is insufficient literature analyzing bone marrow pathology in patients with CKD or end-stage kidney disease (ESKD) receiving dialysis. METHODS: This observational cohort study included 22 patients with ESKD and 23 patients with CKD that received bone marrow biopsy and aspiration at Chang Gung Memorial Hospital. Demographic, hematological, and biochemical data were collected at the time of bone marrow study for analysis. RESULTS: Bone marrow aspiration demonstrated that patients with ESKD had a lower percentage of blasts than patients with CKD (0.52 ± 0.84 versus 1.06 ± 0.78 %, p = 0.033). Bone marrow biopsy revealed that the overall incidence of hypocellular bone marrow was 55.6%. Furthermore, patients with ESKD had higher proportion of hypocellular bone marrow than patients with CKD (72.7% versus 39.1%, p = 0.023). In a multivariate logistic regression model, it was revealed that ESKD status (odds ratio 9.43, 95% confidence interval 1.66-53.63, p = 0.011) and megakaryocyte count within bone marrow (odds ratio 0.48, 95% confidence interval 0.29-0.79, p = 0.004) were significant predictors for bone marrow hypocellularity. CONCLUSION: Bone marrow hypocellularity is common in patients with kidney dysfunction. Hypocellular marrow occurs more frequently in patients with ESKD than patients with CKD.

Identification and characterization of novel ACD variants: modulation of TPP1 protein level offsets the impact of germline loss-of-function variants on telomere length.

Telomere biology disorders, largely characterized by telomere lengths below the first centile for age, are caused by variants in genes associated with telomere replication, structure, or function. One of these genes, ACD, which encodes the shelterin protein TPP1, is associated with both autosomal dominantly and autosomal recessively inherited telomere biology disorders. TPP1 recruits telomerase to telomeres and stimulates telomerase processivity. Several studies probing the effect of various synthetic or patient-derived variants have mapped specific residues and regions of TPP1 that are important for interaction with TERT, the catalytic component of telomerase. However, these studies have come to differing conclusions regarding ACD haploinsufficiency. Here, we report a proband with compound heterozygous novel variants in ACD (NM_001082486.1)-c.505_507delGAG, p.(Glu169del); and c.619delG, p.(Asp207Thrfs*22)-and a second proband with a heterozygous chromosomal deletion encompassing ACD: arr[hg19] 16q22.1(67,628,846-67,813,408)x1. Clinical data, including symptoms and telomere length within the pedigrees, suggested that loss of one ACD allele was insufficient to induce telomere shortening or confer clinical features. Further analyses of lymphoblastoid cell lines showed decreased nascent ACD RNA and steady-state mRNA, but normal TPP1 protein levels, in cells containing heterozygous ACD c.619delG, p.(Asp207Thrfs*22), or the ACD-encompassing chromosomal deletion compared to controls. Based on our results, we conclude that cells are able to compensate for loss of one ACD allele by activating a mechanism to maintain TPP1 protein levels, thus maintaining normal telomere length.

Aplastic anemia in a patient with CVID due to NFKB1 haploinsufficiency.

Acquired aplastic anemia (AA) is a life-threatening bone marrow failure caused by an autoimmune cytotoxic T lymphocyte attack on hematopoietic stem and progenitor cells. Factors contributing to aberrant autoimmune activation in AA include a deficit of T regulatory cells and high levels of inflammatory cytokines. Several acquired conditions of immune dysregulation and genetic polymorphisms in inflammatory cytokines and human leukocyte antigen genes have been linked to an increased risk of AA. However, AA has not been reported in patients with Mendelian disorders of immune regulation. Here we report a patient with familial common variable immunodeficiency (CVID) caused by a pathogenic variant in NFKB1, who developed AA as an adult. The patient had a difficult clinical course and was unable to tolerate standard AA therapy with cyclosporine A and eltrombopag, with complications attributed in part to the effect of cyclosporine A on NF-κB signaling. Our case suggests a novel link between genetic disorders of immune regulation and AA and highlights the importance of recognizing inherited autoimmunity syndromes in AA patients for the selection of optimal therapy and prognostic counseling.

Bone marrow features in Pearson syndrome with neonatal onset: A case report and review of the literature.

Pearson syndrome (PS) is a rare mitochondrial disorder that usually presents with transfusion-dependent macrocytic anemia, exocrine pancreatic dysfunction, and lactic acidosis. Typical bone marrow (BM) features are vacuolization in hematopoietic progenitors, hypocellularity, and ringed sideroblasts. At the neonatal age, PS may have a variable clinical onset. Moreover, there is little information about BM features at this age and the timing of their presentation. We report a neonatal case of PS that presented with refractory anemia and atypical BM features. We reviewed the BM findings in neonatal-onset PS cases to stress the importance and limitations of BM evaluation at this age.

Distinct mutation profile and prognostic relevance in patients with hypoplastic myelodysplastic syndromes (h-MDS).

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematologic malignancies. Although most MDS patients have normal or increased BM cellularity (NH-MDS), some have hypocellular BM (h-MDS). The reports concerning the differences in genetic alterations between h-MDS and NH-MDS patients are limited. In this study, 369 MDS patients diagnosed according to the WHO 2008 criteria were recruited. h-MDS patients had lower PB white blood cell and blast counts, and lower BM blast percentages, than those with NH-MDS. h-MDS was closely associated with lower-risk MDS, defined by the International Prognostic Scoring System (IPSS) and revised IPSS (IPSS-R). IPSS-R could properly predict the prognosis in h-MDS (P<0.001) as in NH-MDS patients. The h-MDS patients had lower incidences of RUNX1, ASXL1, DNMT3A, EZH2 and TP53 mutations than NH-MDS patients. The cumulated incidence of acute leukemic transformation at 5 years was 19.3% for h-MDS and 40.4% for NH-MDS patients (P= 0.001). Further, the patients with h-MDS had longer overall survival (OS) than those with NH-MDS (P= 0.001), and BM hypocellularity remains an independent favorable prognostic factor for OS irrespective of age, IPSS-R, and gene mutations. Our findings provide evidence that h-MDS indeed represent a distinct clinico-biological subgroup of MDS and can predict better leukemia-free survival and OS.

Enhancement of kinase selectivity in a potent class of arylamide FMS inhibitors.

Structure-activity relationship (SAR) studies on a highly potent series of arylamide FMS inhibitors were carried out with the aim of improving FMS kinase selectivity, particularly over KIT. Potent compound 17r (FMS IC50 0.7 nM, FMS cell IC50 6.1 nM) was discovered that had good PK properties and a greater than fivefold improvement in selectivity for FMS over KIT kinase in a cellular assay relative to the previously reported clinical candidate 4. This improved selectivity was manifested in vivo by no observed decrease in circulating reticulocytes, a measure of bone safety, at the highest studied dose. Compound 17r was highly active in a mouse pharmacodynamic model and demonstrated disease-modifying effects in a dose-dependent manner in a strep cell wall-induced arthritis model of rheumatoid arthritis in rats.

Acute Myeloid Leukemia with t(8;21)(q22;q22) (AML1/ETO) in a Patient with Marked Hypocellularity and Low Blasts Count / 영남의대학술지

According to the World Health Organization (WHO) classification system, cases with t(8;21)(q22;q22) should be diagnosed as acute myeloid leukemia (AML) even with a blast count of less than 20 percent in blood or bone marrow. It is an uncommon manifestation, moreover hypocellularity is rarely observed in this subtype of leukemia. Here, we report a case of t(8;21) in a patient with marked hypocellularity of less than 5 percent and a blast count of less than 20 percent. This patient responded relatively well to chemotherapy. An allogeneic bone marrow transplantation was performed with good engraftment . This case suggests that hypocellular AML with a t(8;21) has as good a prognosis as hypercellular AML with t(8;21).