Notes

miRNAs: Important Players throughout Neurodegenerative Issues and Epilepsy.
03 (95% confidence interval [CI] 4.24 to 5.82) at a 1-month follow-up and 4.61 (95% CI 3.27 to 5.95) at the last reported follow-up (range 24-40 weeks in 3/4 studies). Local tumor control rates ranged widely from 60% to 100% at varying follow-ups. Grade I-II complications were reported in 9/148 [6.1%] patients and grade III-V complications were reported in 3/148 [2.0%]) patients. PCA, as a stand-alone or adjunct modality, may be a viable therapy in appropriately selected patients with painful spinal metastases who were traditionally managed with open surgery and/or radiation therapy.
Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) occasionally undergoes Richter transformation, mostly to diffuse large B-cell lymphoma, but its evolution to other types of B-cell lymphoma is rare. We report a CLL evolved to mantle cell lymphoma by acquiring t(11;14)(q13;q32); CCND1-IGH.

A Retrospective review of clinical and laboratory data.

A 39-year-old male patient was diagnosed with CLL/SLL, and was initially followed without specific treatment, but subsequently received chlorambucil/fludarabine/rituximab due to exacerbated lymphocytosis. While his CLL/SLL waned and waxed, the immunophenotype and genotype of neoplastic B-cells remained unchanged, without cyclin D1 expression and CCND1-IGH fusion. Eleven years after the diagnosis, the patient's disease showed evidence of progression. Bone marrow examination demonstrated "CLL" with the morphology and immunophenotype similar to those seen in the previous biopsies. Unexpectedly, the neoplastic B-cells demonstrated cyclin D1 expression and harbored t(11;14)(q13;q32); CCND1-IGH, suggesting a clonal evolution to mantle cell lymphoma. He subsequently received cytoreductive chemotherapy followed by allogenic bone marrow transplant and remained in remission since then.

The retention of immunophenotype suggests a clonal relationship between CLL/SLL and mantle cell lymphoma. While the acquisition of t(11;14)(q13;q32); CCND1-IGH likely alters the disease course, the pathogenesis of this illegitimate translocation in CLL remains to be studied.
The retention of immunophenotype suggests a clonal relationship between CLL/SLL and mantle cell lymphoma. While the acquisition of t(11;14)(q13;q32); CCND1-IGH likely alters the disease course, the pathogenesis of this illegitimate translocation in CLL remains to be studied.
Unexplained cytopenia (UC) and low-risk myelodysplastic syndrome (MDS) are distinguished mainly by morphologic dysplasia, which sometimes shows inter-observer discrepancy. We hypothesized that gene mutations are strong prognostic factors for these low-risk patients.

We enrolled patients from 4 medical centers with unexplained cytopenia of at least 1 lineage. Diagnosis of low-risk MDS was made according to WHO 2016 classification and a revised international prognostic scoring system (R-IPSS) score of ≤ 3.5. DNA was extracted from bone marrow or blood and sequenced by targeted next generation sequencing (NGS).

One hundred twenty-one patients were recruited 25% with UC and 75% with low-risk MDS. Complete blood counts were similar, but low-risk MDS patients carried higher numbers of mutations (1 vs. 0; P=.04) than UC patients. Overall, the most frequent mutated genes were TET2 (14.6%), SF3B1 (12.2%), and ASXL1 (9.7%). Survival rates of low-risk MDS patients versus UC patients were not significantly different. UC patients and low-risk MDS patients without genetic abnormalities showed superior 5-year progression free survival compared to MDS patients with mutations (100% vs. 76.0%; P=.005). Overall, ASXL1 mutations were associated with decreased 4-year overall survival compared to wild-type (59% vs. 31%; P=.01). In a multivariate analysis, ASXL1 and DNMT3A mutations in low-risk MDS patients were associated with a higher risk of disease progression with hazard ratios of 7.88 (95% CI 1.76-35.32, P=.01) and 7.45 (95% CI 1.61-34.46, P=.01), respectively.

Mutation detection is important for proper risk stratification of patients presenting with idiopathic cytopenia.
Mutation detection is important for proper risk stratification of patients presenting with idiopathic cytopenia.
In the single-arm, phase 1b/2 CARTITUDE-1 study, ciltacabtagene autoleucel (cilta-cel), an anti-B-cell maturation antigen chimeric antigen receptor T-cell (CAR-T) therapy, showed encouraging efficacy in US patients with multiple myeloma (MM) who previously received an immunomodulatory drug, proteasome inhibitor, and anti-CD38 monoclonal antibody (triple-class exposed).

A dataset of US patients refractory to an anti-CD38 monoclonal antibody (MAMMOTH) was used to identify patients who would meet eligibility for CARTITUDE-1 and received subsequent non-CAR-T therapy. The intent-to-treat (ITT) population in CARTITUDE-1 included patients who underwent apheresis (N=113); the modified ITT (mITT) population was the subset who received cilta-cel (n=97). Corresponding populations were identified from the MAMMOTH dataset ITT population (n=190) and mITT population of patients without progression/death within 47 days (median apheresis-to-cilta-cel infusion time) from onset of therapy (n=122). GS 4071 Using 11 nearest neighbor propensity score matching to control for selected baseline covariates, 95 and 69 patients in CARTITUDE-1 ITT and mITT populations, respectively, were matched to MAMMOTH patients.

In ITT cohorts of CARTITUDE-1 vs. MAMMOTH, improved overall response rate (ORR; 84% vs. 28% [P < .001]) and longer progression-free survival (PFS; hazard ratio [HR], 0.11 [95% confidence interval (CI), 0.05-0.22]) and overall survival (OS; HR, 0.20 [95% CI, 0.10-0.39]) were observed. Similar results were seen in mITT cohorts of CARTITUDE-1 vs. MAMMOTH (ORR 96% vs. 30% [P < .001]; PFS HR, 0.02 [95% CI, 0.01-0.14]; OS HR, 0.05 [95% CI, 0.01-0.22]) and with alternative matching methods.

Cilta-cel yielded significantly improved outcomes versus real-world therapies in triple-class exposed patients with relapsed/refractory MM.
Cilta-cel yielded significantly improved outcomes versus real-world therapies in triple-class exposed patients with relapsed/refractory MM.Myeloproliferative neoplasms research has entered a dynamic and exciting era as we witness exponential growth of novel agents in advanced/early phase clinical trials for myelofibrosis (MF). Building on the success and pivotal role of ruxolitinib, many novel agents, spanning a wide range of mechanisms/targets (epigenetic regulation, apoptotic/intracellular signaling pathways, telomerase, bone marrow fibrosis) are in clinical development; several are studied in registrational trials and hold great potential to expand the therapeutic arsenal/shift the treatment paradigm if regulatory approval is granted. Insight into MF pathogenesis and its molecular underpinnings, preclinical studies demonstrating synergism of ruxolitinib with investigational agents, urgent unmet clinical needs (cytopenias, loss of response to JAK inhibitors); and progressive disease fueled the rapid rise of innovative therapeutics. New strategies include pairing ruxolitinib with erythroid maturation agents to manage anemia (luspatercept), desiandard agent monotherapy.
The first-degree relatives of patients with diabetes (FDRs) share a common genetic background with patients with diabetes. Insulin resistance is recognized as a common contributor to diabetes and nonalcoholic fatty liver disease (NAFLD). The present study aimed to investigate the association between a first-degree family history of diabetes (FHD) and NAFLD and the influence of glucose metabolic status.

The present work analyzed a part of the baseline data of the REACTION study conducted in a community population. A total of 11,162 participants with an average age of 55.57±9.66years were enrolled, including 9870 non-FDRs and 1292 FDRs. First-degree FHD was defined as at least one patient with diabetes among parents, siblings or children. The fatty liver index (FLI) was calculated to identify NAFLD.

The proportions of subjects without NAFLD, with intermediate FLI, and with NAFLD differed significantly between non-FDRs and FDRs (P<0.001). FLI was one of the metabolic factors independently associated with first-degree FHD (P=0.006). Multivariate variance analysis revealed positive associations of first-degree FHD and glucose metabolic status (both P<0.001) with FLI, which were independent of each other (P for interaction=0.182). Multiple stepwise linear regression analysis identified that first-degree FHD was independently and positively associated with FLI in men, premenopausal women, and postmenopausal women (all P<0.05).

A first-degree FHD was an independent risk factor for NAFLD. Regardless of the status of glucose metabolism, FDRs were more susceptible to NAFLD.
A first-degree FHD was an independent risk factor for NAFLD. Regardless of the status of glucose metabolism, FDRs were more susceptible to NAFLD.Since the ground-breaking work of Gomez in the 1970s and the later epidemiological studies of Webb and Osborne [1], the link between early onset epilepsy, especially infantile spasms (IS), and intellectual disability in tuberous sclerosis complex (TSC) has been accepted. This association raises the question of whether prevention of epilepsy in early life in TSC patients may improve the longer-term cognitive outcome.Considering the importance of glycopeptides in the clinical diagnosis of cancer and some serious diseases, the identification of glycopeptides from complex biological samples has attracted considerable attention. Effective pre-enrichment before mass spectrometry analysis plays an important role. In this work, a kind of hydrophilic two-dimensional composites (denoted as GO@MPDA@Arg) based on mesoporous polydopamine-graphene oxide were used to selectively enrich glycopeptides in biological samples. The mesoporous polydopamine (MPDA) layer self-assembled with template Pluronic F127 provided more binding sites to load arginine, and bound arginine enhanced the hydrophilicity of the material. As a result, GO@MPDA@Arg composites exhibited excellent enrichment performance for glycopeptides, containing good selectivity (IgG digests BSA digests = 150, molar ratio), low detection limit for IgG digests (10 fmol μL-1), high loading capacity for IgG digests (200 μg mg-1), and good size exclusion (IgG digests IgG BSA = 1100100, mass ratio). In addition, mouse brain tissue was selected as the actual biological sample to further study the enrichment effect of GO@MPDA@Arg composites. In three parallel experiments, a total of 401 glycopeptides belonging to 233 glycoproteins were enriched from 200 μg digestion of mouse brain extract. The enrichment results demonstrate that GO@MPDA@Arg composites have application potential for glycopeptides enrichment in protein post-translational modification research.Emerging evidence has suggested that bexarotene, a nearly 20-year-old skin cancer drug, may be a potential drug candidate to treat Alzheimer's disease (AD) and other neurodegenerative disorders. As described in this study, a highly sensitive and rapid method, using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to determine bexarotene in mouse plasma and brain tissue, was established and validated for the first time. Single-step protein precipitation utilizing methanol solution (containing 0.05 % acetic acid) as precipitation agent was employed to prepare the samples of plasma and brain tissue. Chromatographic separation in gradient elution mode was conducted via an Agilent ZORBAX SB-C18 column (50 mm × 4.6 mm, 5 µm) employing methanol-ammonium acetate buffer (5 mM, pH adjusted to 4.6 with acetic acid) as mobile phase which flowed at 0.45 mL/min. The total run time was 6 min for each sample. Detection through mass spectrometric technique was operated by selected reaction monitoring (SRM) in negative electrospray ionization mode.
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