Background Aplastic anemia is a rare, life-threatening condition marked by pancytopenia and bone marrow hypocellularity. Despite therapeutic advances, clinical practice remains variable, and uncertainties persist regarding diagnosis and optimal management. To address these gaps, the American Society of Hematology (ASH) developed evidence-based guidelines to provide standardized, patient-centered recommendations. Objective The recommendations are intended to support patients, clinicians, and other health care professionals in their decisions about the management and diagnosis of severe and very severe immune-acquired aplastic anemia. Methods ASH formed a multidisciplinary guideline panel of content experts, methodologists, and a patient representative. An evidence synthesis team supported the guideline development process by conducting systematic evidence reviews. The panel prioritized clinical questions and used the grading of recommendations assessment, development, and evaluation approach, including the evidence-to-decision frameworks, to assess evidence and make recommendations, which were subject to public comment. Results The panel agreed on 33 recommendations and 4 good practice statements addressing the use of diagnostic tests, treatment strategies and supportive care. Additional recommendations covered the incorporation of eltrombopag into immunosuppressive regimens and the use of antimicrobial prophylaxis for patients at high risk. For most clinical questions, the certainty in the evidence was rated as low or very low, largely due to the reliance on small, nonrandomized studies. Conclusions Recommendations emphasize prioritizing hematopoietic cell transplantation for younger individuals with an available matched sibling or unrelated donor and as a second-line option after failure of immunosuppressive therapy. The panel also recommended adding eltrombopag to immunosuppressive regimens and using antibiotic and antifungal prophylaxis for patients with neutropenia.

Telomere shortening reflects cumulative cell replication and functions as a mitotic clock. It is influenced by age and body mass, as both increase the demand for cell proliferation. The GH/IGF-I axis plays a central role in cell proliferation. The Itabaianinha cohort in Brazil, with severe isolated congenital GH deficiency (IGHD) due to a homozygous mutation in the GHRH receptor gene (GHRHR), represents a unique human model of markedly reduced stature and body mass with preserved lifespan, extended healthspan, and normal brain aging. To evaluate leukocyte telomere length (LTL) in individuals with untreated congenital IGHD and its association with the GH/IGF axis and metabolic parameters. LTL was assessed in 34 IGHD subjects homozygous for the GHRHR c.57 + 1G→A mutation (aged 24–89 years) and 36 controls homozygous for the wild-type allele (aged 26–79 years). LTL was measured by quantitative PCR using the telomere-to-single copy gene (T/S) ratio. T/S ratio Z-scores used the control-group mean and standard deviation. Circulating IGF-I, IGF-II, and metabolic parameters were evaluated. IGHD subjects had markedly reduced height and weight, while BMI was similar between groups. IGF-I and IGF-II levels were significantly lower in IGHD (p < 0.0001 for both). LTL did not differ between IGHD,0.96 (0.3), and controls),1.01 (0.4), and age-related telomere decline was comparable. Z-scores confirmed no deviation from expected values. LTL correlated modestly with IGF-II, but not with IGF-I or HOMA-IR. LTL in individuals with untreated IGHD was like that of controls. Age-related LTL decline was also comparable between the groups.

Telomere biology disorders (TBDs) have a heterogeneous presentation deepened by variable, age-dependent, multisystem manifestations. In low- and middle-income countries, delayed diagnosis is common due to limited access to confirmatory testing. As a result, diagnosis frequently relies on clinical pattern recognition by hematologists and geneticists. This review summarizes practical approaches to suspecting, evaluating, and managing TBDs in resource-constrained settings. We highlight pivotal clinical signs and "red flag" combinations that should strengthen the suspicion of a TBD, including persistent cytopenias, hypocellular bone marrow, mucocutaneous features, early-onset idiopathic pulmonary fibrosis, unexplained chronic liver disease, immunodeficiency, and early malignancy. We present pragmatic diagnostic algorithms when specialized tests are unavailable, emphasizing careful family history recording, thorough full-body examination, and use of basic laboratory test tools, such as serial complete blood counts (CBC), spirometry with diffusing capacity for carbon monoxide, and noninvasive hepatic assessment, for strong suspicion of TBDs. Current modalities for telomere length (TL) assessment are reviewed with attention to feasibility and limitations in LMICs, including Terminal Restriction Fragment analysis, quantitative PCR, Flow-fluorescence in situ hybridization, and emerging long-read sequencing approaches. Management requires structured, multidisciplinary surveillance for hematologic decline, detection of clonal evolution, pulmonary and hepatic complications, and cancer risk. We review implementable monitoring strategies and discuss key therapeutic considerations in LMICs, including androgen therapy as a widely applicable disease-modifying option and the substantial logistical barriers to hematopoietic stem cell transplantation, donor evaluation, and long-term follow-up. Resource-stratified care pathways and regional referral networks are essential to improve outcomes for patients with TBDs in developing countries.

Here we show that somatic genetic rescue is frequent in telomere biology disorders (TBDs) caused by germline ZCCHC8 variants. Our results highlight the critical intrinsic role of ZCCHC8 in human hematopoiesis and a potential mechanism for disease modification in TBDs.

ABSTRACT:Pathogenic germ line variants causing excessive telomere shortening may result in bone marrow failure, hematopoietic malignancy, and extramedullary complications, such as pulmonary fibrosis, liver cirrhosis, and solid tumors. Patients with short telomeres also develop immunodeficiency with low CD4+ T cells and impaired general immunosurveillance, particularly against solid neoplasms. We investigated a broad spectrum of lymphocyte subsets and myeloid immune cells from human patients with telomere biology disorders (TBDs) and matched healthy volunteers to understand further how the immune system is affected by telomere dysfunction. We used mass cytometry for deep-immunophenotyping peripheral blood mononuclear cells, followed by high-dimensional data analysis. Cytokines, chemokines, and growth factors were assessed in serum. Our results showed profound immune alterations in TBDs beyond those observed in aging, with low naïve lymphocytes and thymic hypofunction. We further observed that T helper (Th) subsets were markedly skewed, with an inverted Th2/Th1 ratio, and low Th17 and Th17.1 levels. T-cell activation and exhaustion markers were upregulated, whereas circulating mucosal-associated invariant T cells were significantly decreased and overactivated. Several serum cytokine levels were positively correlated with telomere length and blood counts, suggesting an association with marrow function. In aggregate, these findings suggest a proinflammatory profile in TBDs. Our data provide new details on how TBD affects immune cells, particularly lymphocytes, which may contribute to the clinical phenotypes.

Introduction:Chimeric Antigen Receptor (CAR)-based therapies have transformed cancer treatment, especially in hematological malignancies. While the impact of co-stimulatory domains on CAR-T cell efficacy is well established, the optimal signaling modules for CAR-natural killer (CAR-NK) cells remain less defined. Identifying NK-tailored co-stimulatory domains is essential for maximizing CAR-NK cytotoxicity and clinical potential. Methods:Using the NK-92 cell line as a controlled proof-of-concept platform, we engineered CAR19 constructs incorporating NK-specific co-stimulatory domains, including 2B4 and DAP12. We performed functional assays to quantify cytotoxicity and cytokine production, and conducted transcriptomic profiling to evaluate transcriptional programs associated with each CAR design. To assess pharmacologic modulation, we exposed CAR-NK cells to transient dasatinib treatment and evaluated its reversible effects on CAR signaling and function. In vivo antitumor activity was tested in a xenograft model. Results:Both 2B4- and 2B4-DAP12-containing CARs enhanced NK cytotoxic programming as demonstrated by functional assays and transcriptomic signatures. Short-term dasatinib exposure reversibly suppressed CAR-NK effector function but led to enhanced activity upon drug withdrawal. In vivo, 2B4-DAP12 CAR19-NK-92 cells pretreated with dasatinib displayed superior tumor control relative to conventional 4-1BBζ CAR19-NK-92 cells. Discussion:These results highlight the importance of selecting NK-specific co-stimulatory domains and leveraging reversible Src-family kinase inhibition to optimize CAR-NK performance. The use of NK-92 cells enabled controlled mechanistic dissection of CAR signaling and pharmacologic effects, providing insights with translational relevance for engineering next-generation CAR-NK therapies in primary NK cells.Chimeric Antigen Receptor (CAR)-based therapies have transformed cancer treatment, especially for hematological malignancies. While the choice of co-stimulatory domains is a well-established determinant of CAR-T success, the optimal signaling modules for CAR-natural killer (CAR-NK) cells remain less defined. In this proof-of-concept study, we used the NK-92 cell line as a controlled experimental platform to evaluate CAR constructs incorporating NK-specific co-stimulatory domains, including 2B4 (CD244) and DAP12. Functional assays and transcriptomic profiling demonstrated that 2B4- and 2B4-DAP12-based CARs promoted NK cytotoxic programming. We further explored transient pharmacologic modulation with dasatinib, showing that short-term exposure reversibly suppressed CAR-NK activity but enhanced function upon withdrawal. In vivo, 2B4-DAP12 CAR19-NK-92 cells pretreated with dasatinib achieved superior tumor control compared to conventional 4-1BBζ CAR19-NK-92 cells. These findings underscore the value of different settings of co-stimulatory domains and reversible kinase inhibition as strategies to optimize CAR design. Importantly, by employing NK-92 cells as a proof-of-concept system, this work provides mechanistic insights that will guide the development of next-generation CAR-NK therapies in primary NK cells.

The repercussions and outcomes of the coronavirus disease 2019 (COVID-19) pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has raised concerns about potential adverse effects on the male reproductive system. Telomeres are crucial in maintaining the integrity and stability of genomic DNA, and viral infections can induce changes in telomere biology. In this study, the repercussions of SARS-CoV-2 infection in male reproductive health were analyzed. This case–control study enrolled subjects who donated blood and semen samples. Fifty-six men with and 56 without prior COVID-19 infection, ages 18–45 years, were included. Semen analysis and hormonal levels were evaluated. The presence of SARS-CoV-2 RNA in semen and the sperm telomere length were assessed by quantitative polymerase chain reaction and associated with clinical and laboratory data. To reduce interference factors, known variables that influence telomere length were analyzed independently. Sperm telomere length was significantly diminished in the COVID-19 positive group with a mean difference of 0.635 compared to the negative group (p = 0.041). Most individuals in the COVID-19 positive group were clinically classified as asymptomatic/mild illness, and all samples were collected more than 90 days after recovery. No statistically significant differences were observed between the groups in terms of clinical data, semen parameters, and serum levels of follicle-stimulation hormone, estradiol, and testosterone. Persistent or subgenomic SARS-CoV-2 RNA was not detected in the semen samples. This study revealed that SARS-CoV-2 infection reduced sperm telomere length without alterations in semen parameters or hormonal levels. These results provide further evidence that SARS-CoV-2 infection can induce genomic alterations in human sperm.

Chimeric antigen receptor (CAR) T-cell therapy has significantly improved outcomes for patients with hematologic neoplasms, with expanding indications and increasing global use. However, access remains highly unequal across countries. This review outlines the main barriers to CAR-T implementation in resource-limited regions, structured into four domains: cost and reimbursement, regulatory frameworks, manufacturing logistics, and clinical infrastructure. The high cost of commercial CAR-T products remains a major limitation, especially in settings where public reimbursement is unavailable and private coverage is inconsistent. Academic programs have emerged as alternatives in countries such as Brazil, India, Turkey, and Spain, demonstrating the feasibility of lower-cost, non-commercial production models. Regulatory gaps also contribute to limited access. While high-income countries have developed specific frameworks for advanced therapy medicinal products (ATMPs), many resource-limited regions still lack clear pathways for clinical trials, product approval, or post-marketing surveillance. Brazil stands out for its recent regulatory innovations, including a dedicated resolution for ATMPs and integration with public health goals. Logistical challenges related to manufacturing capacity, reagent supply, and product-release testing further constrain local implementation. Clinical infrastructure is also insufficient in many resource-limited regions, especially regarding intensive care support, multidisciplinary teams, and access to key medications such as tocilizumab. Ongoing national and regional efforts point to possible strategies for expanding access. These include decentralization of manufacturing, investment in public infrastructure, and regulatory adaptations to support context-specific solutions.

COVID-19 continues to be a health issue, mainly due to virus circulation and the emergence of new variants of concern and interest. This is a single-center, randomized, double-blind, active-controlled dose-escalating phase I clinical trial to evaluate the immunogenicity and safety of NDV-HXP-S (1 μg, 3 μg, and 10 μg), an inactivated COVID-19 vectored-vaccine virus using the Newcastle Disease Virus (NDV) expressing stabilized pre-fusion S protein from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Healthy SARS-CoV-2-naïve participants aged 18 to 59 years were randomized in a 3:3:3:1 ratio to receive two equal shots of 1 μg, 3 μg or 10 μg of NDV-HXP-S formulations or placebo/CoronaVac intramuscular 28 days apart, respectively. Primary endpoints were solicited adverse events (AEs) determined within 7 days after each dose (safety) and proportion of seroconversion and geometric mean of 50 % neutralizing titer ratios against SARS-CoV-2 Wuhan-hu-1, Beta, and Gamma strains, measured on Day 42 after the first dose (immunogenicity). Follow-up occurred for 12 months for safety and immunogenicity evaluation. This study had substantial protocol amendments, the last one for early terminating the recruitment, as well as unblinding on Day 42. We included 311 subjects were in the safety population and 301 of them (97 %) received the second dose. More frequent solicited AEs were pain at the application site (<89 %), headache (<69 %), fatigue (<68 %), and myalgia (<61 %); most were classified as mild or moderate. There was no vaccine-related serious or grade-4 solicited AE. The proportion of participants reporting a vaccine-related unsolicited AE within 28 days after each dose ranged from 30 % to 33 % after the first dose and 14 % and 18 % after the second in NDV-HXP-S, comparable to the control group. The 10 μg NDV-HXP-S formulation was the one that elicited the higher seroconversion values and neutralizing antibodies on Day 42 against SARS-CoV-2 strains. Up to 1-year follow-up, levels of bind antibodies remains about 2 log10 BAU/mL and no vaccine-related serious adverse event was reported. Two NDV-HXP-S shots at 10 μg elicited the higher seroconversion and neutralizing antibody titers against the SARS-CoV-2. The vaccine also displayed a very favorable safety profile. ClinicalTrials.gov,NCT04993209.

[This corrects the article DOI: 10.3389/fimmu.2024.1468229.].

Abstract: In the phase 3 AGILE study, after a 12.4-month median follow-up, ivosidenib, a mutant isocitrate dehydrogenase 1 (IDH1) inhibitor, combined with azacitidine significantly improved event-free survival, overall survival (OS), and complete remission rates compared with placebo-azacitidine in patients with newly diagnosed IDH1-mutated acute myeloid leukemia (AML), who were unfit for intensive chemotherapy. This post hoc analysis reports long-term follow-up results from AGILE after a median follow-up of 28.6 months. Overall, 148 patients were randomized to receive ivosidenib-azacitidine (n = 73) or placebo-azacitidine (n = 75). Median OS was significantly longer with ivosidenib (29.3 months; 95% confidence interval [CI], 13.2 to not reached) than with placebo (7.9 months; 95% CI, 4.1-11.3; hazard ratio, 0.42 [95% CI, 0.27-0.65]; P < .0001). Hematologic recovery was faster, more durable, and conversion to transfusion independence (53.8% vs 17.1%; P = .0004) was more common with ivosidenib than with placebo. Of 33 ivosidenib-treated patients evaluable for molecular measurable residual disease (MRD), 10 converted to MRD negativity. Although OS did not differ significantly between MRD-negative and MRD-positive responders at the 0.1% variant allele frequency (VAF) threshold, MRD-negative patients had numerically longer survival. MRD status appeared more predictive of long-term OS when an exploratory 1% VAF threshold was applied. MRD response was not associated with IDH1 variant, VAF, inferred clonality, or number of baseline comutations. The previously reported safety profile was maintained. These long-term efficacy and safety results confirm the benefit of ivosidenib-azacitidine in this challenging-to-treat population and support its use as a standard of care with the longest reported survival benefit for intensive chemotherapy–ineligible patients with IDH1-mutated AML. This trial was registered at www.ClinicalTrials.gov as #NCT03173248.

Polycystic ovary syndrome (PCOS) is a multifactorial disorder and obesity occurs in 38% to 88% of these women. Although hyperandrogenism may contribute to telomere lengthening, increased body mass index (BMI) is associated with telomere erosion. We sought to compare leukocyte telomere length (LTL) in PCOS women with normal, overweight, and obese BMI. We evaluated the relationship between LTL and clinical variables of PCOS and inflammatory biomarkers independent of BMI. A total of 348 women (243 PCOS and 105 non-PCOS) were evaluated for anthropometric measures, total testosterone, androstenedione, estradiol (E2), follicle-stimulating hormone (FSH), luteinizing hormone (LH), sex hormone-binding globulin (SHBG), free androgen index (FAI), fasting insulin and glycemia, lipid profile, homocysteine, C-reactive protein (CRP) and homeostatic model of insulin resistance (HOMA-IR). LTL was measured by qPCR. The PCOS group presented higher weight, waist circumference, BMI, testosterone, LH, fasting insulin, FAI, and HOMA-IR, and lower E2, SHBG, and fasting glycemia measures compared with the non-PCOS. When stratified by BMI, LTL was increased in all subgroups in PCOS compared to non-PCOS. However, in the PCOS group, LTL was lower in overweight ( P = 0.0187) and obese ( P = 0.0018) compared to normal-weight women. The generalized linear model showed that BMI, androstenedione, homocysteine, and CRP were associated with telomere biology. Women with PCOS had longer LTL, however, overweight or obesity progressively contributes to telomere shortening and may affect reproductive outcomes of PCOS, while androstenedione may increase LTL.

Objetivo O estudo visa descrever dados clínicos, laboratoriais e genéticos de portadores de insuficiência medular com encurtamento telomérico, bem como dados de sobrevida. Materiais e métodos Foram incluídos pacientes com insuficiência medular em seguimento no ambulatório de citopenias de um hospital terciário em São Paulo entre 2016 e 2022, sendo excluídos aqueles com comprimento telomérico normal. Os dados foram coletados através de revisão de prontuários eletrônicos e entrevistas presenciais. Foram realizados elastografia hepática e análise genômica por NGS (Next Generation Sequencing). Resultados Houve 144 pacientes com comprimentos teloméricos analisados, dos quais foram incluídos 30 com comprimento curto/muito curto. Após a junção de dados clínicos, laboratoriais e NGS, 10 pacientes foram classificados como tendo telomeropatias hereditárias (TH) (34%), apresentando mutações nos genes TERT (N = 4), RTEL1 (3), DKC1 (1), TERC (1), ACD (1). Seis pacientes foram diagnosticados com outras aplasias hereditárias (20%), sendo 4 anemias de Fanconi (FANCA, FANG e BRCA2), 1 síndrome de deficiência de GATA 2 (GATA2) e 1 anemia de Blackfan-Diamond (RP19). Sete foram considerados como tendo aplasia adquirida (23%), não tendo nenhuma mutação germinativa, e 7 como casos indeterminados (23%), por terem algum sinal clínico sugestivo, porém sem mutação germinativa identificada. Quando se compara o diagnóstico presuntivo clínico-laboratorial de Síndrome de falência medular hereditária ou adquirida com os resultados de NGS, a acurácia foi de 95%, com 100% de sensibilidade e 92% de especificidade. Na coorte em que se confirmou TH (N = 10), a mediana de idade ao diagnóstico foi de 25 anos, sendo majoritariamente masculina (70%) e branca (80%). Todos tinham algum sinal sugestivo de doença germinativa, sendo os mais frequentes fibrose hepática (60%), canície precoce (60%) e histórico familiar de doença hematológica (40%). Apenas 1 deles apresentava citopenias graves; clone de hemoglobinúria paroxística noturna não foi detectado e medula óssea hipocelular e sem displasia relevante foi observado em 8 casos. Apenas 1 paciente apresentava o protótipo clássico de Disceratose congênita, com tríade muco-cutânea e mutação DKC1. Discussão: O encurtamento telomérico não é exclusivo das telomeropatias hereditárias. A história clínica somada a exames iniciais apresentou alta acurácia e correlação com o NGS. Mesmo com acesso a painel para mutações germinativas, 23% dos pacientes não tiveram diagnóstico definitivo. Conclusão Clínica e NGS permitiram o diagnóstico assertivo da maior parte dos casos de TH.

Background SARS-CoV-2 variants have distinct features of transmissibility, infectivity, and aggressiveness that may cause different clinical manifestations. A better understanding of the disease presentation and progression could help to outline more precise preventive and treatment frameworks. This study describes the differences in COVID-19 presentation and outcomes across five variant waves. Methods This prospective cohort was conducted in Serrana, São Paulo State, Brazil. Clinical and demographic data was obtained from June 2020 to December 2022 as part of an enhanced health surveillance system for COVID-19, based on increasing access to diagnostic testing for SARS-CoV-2 and patient follow-up. Individuals were assessed for COVID-19 symptoms and comorbidities. Mild cases were followed up for at least 14 days, and severe cases until discharge or death. Samples were genetically sequenced, and variant waves were determined based on global SARS-CoV-2 variant predominance (>90 % sequenced samples), being as follows: Ancestral, Delta, Gamma, Omicron BA.1, and Omicron BA.2 waves. The relationship between clinical data and disease outcomes was analyzed in each variant wave. Results Patients infected during the Delta wave were the youngest (36.1 ± 18.2 years, p < 0.001). The proportion of female patients was higher across all waves. Positivity rate, disease severity, and COVID-19-related deaths varied among them. Ageusia and anosmia were related to SARS-CoV-2 positivity during the Ancestral, Gamma, and Delta waves but not in Omicron BA.1 and Omicron BA.2 waves. Diarrhea presented a lower chance of positivity only in Omicron BA.1 and Omicron BA.2. Dyspnea was the most consistent risk factor for severity across all waves. Conclusions Although patients with COVID-19 from different SARS-CoV-2 variants shared some clinical-epidemiological characteristics, each variant presented distinguishable features related to positivity and severity. This could help to understand the dynamics of COVID-19 variants and update recommendations for clinical practice.

Introduction: Telomere-biology disorders (TBD) are caused by germline defects in genes involved in telomere maintenance, resulting in excessive telomere shortening and limited cell proliferation. Clinically, TBD corresponds to a spectrum of phenotypes associated with bone marrow failure and lung and liver diseases. It also is associated with a higher predisposition to cancer, including myelodysplastic syndrome and acute myeloid leukemia. Patients with affected hematopoiesis usually present cytopenias and hypocellular marrow with reduced numbers of CD34+ cells to maintain adequate hematopoiesis. Treatment options for marrow failure patients are restricted. The most effective approach is allogeneic bone marrow transplantation, but the availability of compatible donors and complications of the conditioning regimen limit it. Alternatively, androgens may alleviate cytopenias, but their long-term effectiveness may be restricted (Townsley et al. 2016; Clé et al. 2023; Pagliuca et al. 2024). There is no evidence that TPO agonists have any effects in these cases. Fares et al. (2014) demonstrated that the small molecule UM171 expands the CD34+ cell subpopulations from human umbilical cord blood with superior engraftment potential and better clinical outcomes (Cohen et al. 2022). UM171 is a pyrimido-indole derivative that activates the CRL3KBTBD4 E3 ubiquitin ligase, targeting the CoREST1 complex and maintaing the epigenetic landscape required for hematopoietic stem cell properties (Chagraoui et al. 2021). Here, we assessed the potential of UM171 to expand the hematopoietic progenitor and stem cell (HPSC) compartment of patients with TBD and marrow failure. Methods: Bone marrow samples were collected from six patients diagnosed with TBD (four females; median age, 39.5 years; range, 16 to 56 years). All patients had short telomeres and a hypocellular bone marrow. Two patients were diagnosed with aplastic anemia, three with cytopenias, two with pulmonary disease, and one with liver cirrhosis. Heterozygous TERT mutations were found in four patients, TERC mutations in two, RTEL1 in one, and POT1 in one, all in heterozygosis. Bone marrow samples from six healthy controls (all males; median age, 27,5 years; range, 24 to 71 years) were studied as controls. CD34+ cells were enriched using immunomagnetic labeling with human CD34 microbeads and a magnetic separator. Cells were cultured for 7 days in ACF medium supplemented with cytokines that support HSC expansion and UM171 or DMSO (control). To assess the capacity of the cultured cells to generate hematopoietic progenitors, 1,000 cells/mL were resuspended in methylcellulose in triplicate. After 14 days, the colonies were counted and classified according to morphology. Results: Patients had fewer CD34+ cells in the bone marrow compared to controls (median, 0.68% vs. 1.69%, respectively; P=0.03). After a 7-day expansion, the percentage of CD34+ cells was higher when treated with UM171 (UM171, 56.9 ±5.7% vs. DMSO, 34.9% ±6.5% [median ±standard error] n=6; P=0.003). The cell surface EPCR is a marker for the purification of the HSPC compartment, and the CD34+EPCR+ subpopulation was increased after UM171 treatment (UM171, 3.35±1.1% vs. DMSO, 0.2% ±0.1%; n=6; P=0.03). UM171-treated cells gave rise to more progenitor cells, as observed by the CFU assay (UM171, 142±18 vs. DMSO, 94%±9; n=4; P=0.01). No significant telomere attrition was observed with the expansion. We also analyzed the appearance of abnormal clones during expansion by NSG for myeloid-malignancy somatic mutations and chromosomal abnormalities by single nucleotide polymorphism array (SNP-array) in CD34+ cells from three patients and two healthy controls. No abnormal clones were observed after UM171 expansion. Conclusions: Our results reveal UM171 as a potent HSPC expander in TBD patients. Our data suggest that UM171 may enhance the ex vivo production of HSPC from TBD patients. These findings contribute the understanding of the effect of UM171 on patient-derived cells.

Background In hematologic cancers, including leukemia, cells depend on amino acids for rapid growth. Anti-metabolites that prevent their synthesis or promote their degradation are considered potential cancer treatment agents. Amino acid deprivation triggers proliferation inhibition, autophagy, and programmed cell death. l -lysine, an essential amino acid, is required for tumor growth and has been investigated for its potential as a target for cancer treatment. l -lysine α-oxidase, a flavoenzyme that degrades l -lysine, has been studied for its ability to induce apoptosis and prevent cancer cell proliferation. In this study, we describe the use of l -lysine α-oxidase (LO) from the filamentous fungus Trichoderma harzianum for cancer treatment. Results The study identified and characterized a novel LO from T. harzianum and demonstrated that the recombinant protein (rLO) has potent and selective cytotoxic effects on leukemic cells by triggering the apoptotic cascade through mitochondrial dysfunction. Conclusions The results support future translational studies using the recombinant LO as a potential drug for the treatment of leukemia.

Monoclonal gammopathy-related peripheral neuropathies encompass a spectrum of clinical presentations in which the monoclonal protein directly damages the tissues, including the peripheral nervous system. Given the prevalence of both peripheral neuropathy and monoclonal gammopathy in the general population, these conditions may overlap in clinical practice, posing a challenge for clinicians in determining causality. Therefore, a comprehensive understanding of primary clinical syndromes and their neurophysiological patterns is of great importance for accurate differential diagnoses and effective treatment strategies. In this article, we examine the main forms of monoclonal gammopathies that affect the peripheral nerve. We explore the clinical and electrophysiological aspects and their correlation with each syndrome's corresponding monoclonal protein type. This knowledge is essential for healthcare professionals to diagnose better and manage patients presenting with monoclonal gammopathy-related peripheral nervous system involvement.