Rodrigo T Calado

• MD, PhD
• University of São Paulo

Telomere-biology disorders (TBD) are caused by germline defects in telomere maintenance genes, most commonly in TERT, TERC, DKC1, TINF2 and RTEL1. Recently, ZCCHC8 was added to the list of genes that cause an adult-onset TBD as it is required for TERC maturation and telomerase function. The heterozygous ZCCHC8 p.P186L and p.E192K germline mutations...

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 high...

Introduction Breast cancer is a significant public health problem around the world, ranking first in deaths due to cancer in females. The therapy to fight breast cancer involves different methods, including conventional chemotherapy. However, the acquired resistance that tumors develop during the treatment is still a central cause of cancer-associa...

Telomere biology disorders (TBD), caused by pathogenic germline variants in telomere-related genes, present with multi-organ disease and a predisposition to cancer. Clonal hematopoiesis (CH) as a marker of cancer development and survival in TBD is poorly understood. Here, we characterized the clonal landscape of a large cohort of 207 TBD patients w...

Background Patients with telomere biology disorders (TBD) develop hepatic disease, including hepatitis, cirrhosis, and hepatopulmonary syndrome. No specific treatment exists for TBD-related liver disease, and the role of liver transplantation (LT) remains controversial. Our study objectives were to describe the clinical characteristics, management,...

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 p...

Background Telomeropathies are a group of inherited disorders caused by germline pathogenic variants in genes involved in telomere maintenance, resulting in excessive telomere attrition that affects several tissues, including hematopoiesis. RecQ and RTEL1 helicases contribute to telomere maintenance by unwinding telomeric structures such as G-quadr...

Telomeres, repetitive DNA sequences and associated protein complexes at the ends of eukaryotic chromosomes are critical guardians of genome integrity and play an essential role in cellular longevity. These specialized structures undergo dynamic changes during cellular divisions and act as protective caps, preventing the loss of coding genetic mater...

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 BM...

Regulator of TElomere Length Helicase 1 (RTEL1) is a helicase required for telomere maintenance and genome replication and repair. RTEL1 has been previously shown to participate in the nuclear export of small nuclear RNAs. Here we show that RTEL1 deficiency leads to a nuclear envelope destabilization exclusively in cells entering S-phase and in dir...

Objectives Ageing and inflammation are associated with clonal haematopoiesis (CH), the emergence of somatic mutations in haematopoietic cells. This study details CH in patients with systemic vasculitis in association with clinical, haematological and immunological parameters. Methods Patients with three forms of vasculitis were screened for CH in...

Telomeres are structures responsible for the maintenance of chromosomal stability. Telomere length is maintained by the telomerase complex, shelterin proteins, and others involved in telomere biology. Germline variants in telomere-biology genes may cause excessive telomere shortening, cell senescence, and genomic instability, which in humans may cl...

Excessive telomere shortening caused by pathogenic germline variants in telomere-biology genes may result in bone marrow failure, hematopoietic malignancy and extramedullary complications, such as idiopathic pulmonary fibrosis (IPF), liver cirrhosis, and solid tumors. Patients with short telomeres also may develop immunodeficiency with low counts o...

TERRA (telomeric repeat-containing RNA) is a class of long non-coding RNAs transcribed from subtelomeric and telomeric regions. TERRA binds to the subtelomeric and telomeric DNA forming R-loops (DNA-RNA hybrids), which are involved in telomere maintenance and telomerase function, but the role of TERRA in human cells is not well characterized. Here,...

Introduction Natural killer 92 (NK-92) cells are an attractive therapeutic approach as alternative chimeric antigen receptor (CAR) carriers, different from T cells, once they can be used in the allogeneic setting. The modest in vivo outcomes observed with NK-92 cells continue to present hurdles in successfully translating NK-92 cell therapies into...

Background aims: Amidst the success of cell therapy for the treatment of onco-hematological diseases, the first recently Food and Drug Administration-approved gene therapy product for patients with transfusion-dependent β-thalassemia (TDT) indicates the feasibility of gene therapy as curative for genetic hematologic disorders. This work analyzed t...

7012 Background: Ivosidenib (IVO) is a potent oral targeted inhibitor of mutant IDH1. In the AGILE study in patients (pts) with newly diagnosed IDH1-mutated acute myeloid leukemia, IVO plus azacitidine (AZA) significantly improved event-free survival (EFS), overall survival (OS), complete remission (CR), and CR or CR with partial hematologic recove...

VEXAS is caused by somatic mutations in UBA1 (UBA1mut) and characterized by heterogenous systemic auto-inflammation and progressive hematologic manifestations, meeting criteria for myelodysplastic syndrome (MDS) and plasma cell dyscrasias. The landscape of myeloid-related gene mutations leading to typical clonal hematopoiesis (CH) in these patients...

COVID‐19 is a complex disease manifesting in a broad severity spectrum and involving distinct organs and systems. Hyperinflammation, including complement over‐activation, has a pivotal role in severe COVID‐19 pathobiology, stimulating the inflammatory response, causing microangiopathy, platelet–neutrophil activation, and hypercoagulability. SARS‐Co...

Androgens have been reported to elongate telomeres in retrospective and prospective trials with patients with telomeropathies, mainly with bone marrow failure. In our single-arm prospective clinical trial, 17 patients with short telomeres and/or germline pathogenic variants in telomere-biology genes associated with at least one cytopenia and/or rad...

The choice to postpone treatment while awaiting genetic testing can result in significant delay in definitive therapies in severely pancytopenic patients. Conversely, inherited bone marrow failure (BMF) misdiagnosis can expose patients to ineffectual and expensive therapies, toxic transplant conditioning regimens, and inappropriate use of an affect...

Context: Isocitrate dehydrogenase 1 (IDH1) mutations are oncogenic drivers in acute myeloid leukemia (AML), with 6-10% of AML patients harboring mutant IDH1 (mIDH1). Ivosidenib (IVO) is a small molecule mIDH1 inhibitor that silences the oncogenic pathways activated by this mutation. Objective: Assess efficacy/safety of IVO+azacitidine (AZA) as f...

Objetivo Telomeropatias são doenças humanas herdadas causadas por defeitos genéticos na manutenção dos telômeros, afetando principalmente a medula óssea, pulmões e fígado. Na medula óssea, a anemia aplástica é a manifestação mais comum, entretanto os mecanismos que modulam o declínio funcional das células-tronco hematopoéticas sob as condições de e...

Introduction Telomeric repeat-containing RNA (TERRA) are long non-coding RNAs transcribed from subtelomeric regions towards telomere ends. TERRA binds to subtelomeric and telomeric regions, forming R-loops, structures composed of DNA-RNA hybrids and displaced single-stranded DNA. TERRA R-loops protect telomeres from DNA damage and promote telomere...

Objetivos Utilizando abordagem diagnóstica baseada no genótipo, em 2020, Beck et al. descreveu pela primeira vez a síndrome VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic), decorrente da expansão de clone contendo mutação somática no gene UBA1, no cromossomo X. A mutação resulta em alteração da isoforma funcionante da enzima UBA1,...

Objectives Telomeropathies, also referred to as telomere biology disorders (TBD), correspond to a spectrum of diseases characterized by genetic defects in the maintenance mechanisms of telomeres and telomerase. Individuals carrying variants in the genes involved in telomeres machinery may have critically short or dysfunctional telomeres, which lead...

PURPOSE Secondary myeloid neoplasms (sMNs) remain the most serious long-term complications in patients with aplastic anemia (AA) and paroxysmal nocturnal hemoglobinuria (PNH). However, sMNs lack specific predictors, dedicated surveillance measures, and early therapeutic interventions. PATIENTS AND METHODS We studied a multicenter, retrospective co...

Complement C3 activation contributes to COVID-19 pathology, and C3 targeting has emerged as a promising therapeutic strategy. We provide interim data from ITHACA, the first randomized trial evaluating a C3 inhibitor, AMY-101, in severe COVID-19 (PaO2/FiO2 ≤ 300 mmHg). Patients received AMY-101 (n = 16) or placebo (n = 15) in addition to standard of...

Objective: To describe the successful implementation of an enhanced public health surveillance system based on early detection, tracing contacts, and patient follow-up and support. Study design: A prospective observational cohort study conducted in Serrana, São Paulo State, Brazil. Methods: The implementation was based on four axes: increasing the...

Background Administration of convalescent plasma may serve as an adjunct to supportive treatment to prevent COVID-19 progression and death. We aimed to evaluate the efficacy and safety of 2 volumes of intravenous convalescent plasma (CP) with high antibody titers for the treatment of severe cases of COVID-19. Methods We conducted a Bayesian, rando...

e19024 Background: Ivosidenib (IVO) is a potent, targeted inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1) that is approved for acute myeloid leukemia (AML). IVO plus azacitidine (AZA) demonstrated clinical benefit compared with placebo (PBO) and AZA in the AGILE study (NCT03173248), and here we report the impact of IVO+AZA versus PBO+AZA on...

7019 Background: Acute myeloid leukemia (AML) is a disease with a dynamic mutational landscape; 6–10% of patients (pts) have somatic mutations in isocitrate dehydrogenase 1 ( IDH1), which can drive oncogenesis. Ivosidenib (IVO) is a potent oral targeted inhibitor of mutant IDH1 (mIDH1). IVO 500 mg QD + azacitidine (AZA) 75 mg/m ² SC or IV for 7 day...

7042 Background: Ivosidenib (IVO) is a potent oral targeted inhibitor of mutant isocitrate dehydrogenase 1 (mIDH1). IVO plus azacitidine (AZA) significantly improved event-free survival (EFS), overall survival and complete remission + partial hematologic recovery rates compared with placebo (PBO) + AZA, in patients (pts) with newly diagnosed IDH1-m...

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare hematological disorder caused by the expansion of a hematopoietic clone harboring a somatic genetic variant in the PIG-A gene translating into a wide spectrum of clinical and laboratory changes, from intravascular hemolysis, thrombosis, and bone marrow failure to subclinical presentation. In this...

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with a hyperinflammatory state and lymphocytopenia, a hallmark that appears as both signature and prognosis of disease severity outcome. Although cytokine storm and sustained inflammatory state are commonly associated with immune cell depletion, it is still unc...

Background: The combination of ivosidenib - an inhibitor of mutant isocitrate dehydrogenase 1 (IDH1) - and azacitidine showed encouraging clinical activity in a phase 1b trial involving patients with newly diagnosed IDH1-mutated acute myeloid leukemia. Methods: In this phase 3 trial, we randomly assigned patients with newly diagnosed IDH1-mutate...

[This corrects the article DOI: 10.3389/fcell.2021.713415.].

In acquired immune aplastic anemia (AA), pathogenic cytotoxic Th1 cells are activated and expanded, driving an immune response against the hematopoietic stem and progenitor cells (HSPCs) that provokes cell depletion and causes bone marrow failure. However, additional HSPC defects may contribute to hematopoietic failure, reflecting on disease outcom...

Fanconi anemia, telomeropathies and ribosomopathies are members of the inherited bone marrow failure syndromes (IBMFS), rare genetic disorders that lead to failure of hematopoiesis, developmental abnormalities, and cancer predisposition. While each disorder is caused by different genetic defects in seemingly disparate processes of DNA repair, telom...

Introduction: Telomere Biology Disorders (TBD) are due to germline variants in telomere maintenance and repair genes. Clinical manifestations include bone marrow failure (BMF), liver and lung fibrosis, and risk of cancer, especially myeloid neoplasia. We characterized clinical phenotype, pathology, and clonal landscape of patients with TBD and myel...

Despite therapeutic successes, AA patients (pts) exhibit a much higher risk of leukemic evolution than the general population. Secondary myeloid neoplasia (sMN) remains the most serious AA complication with major therapeutic and prognostic implications. Historically, multiple theories have been proposed as to the origin of leukemic evolution. For i...

Introduction: Telomere biology (TBD) disorders are caused by pathogenic germline variants in genes related to telomere maintenance. In TBD, clonal hematopoiesis (CH) has been hypothesized to compensate for restricted cell fitness and to lead to development of myelodysplastic syndromes and acute myeloid leukemia (MDS/AML). We sought to characterize...

COVID-19 is an infectious disease caused by the virus SARS-CoV-2, which was first described at the end of 2019. Since then, it has affected a growing portion of the world's population because of its high transmissibility. Most patients are asymptomatic or present with mild symptoms, but approximately 5-10% of cases can develop more serious manifest...

Introduction: Treatment of diffuse large B cell lymphoma (DLBCL) may be a challenge for Latin American countries. Thus, novel strategies to reduce the economic burden of oncological care are necessary. In Brazil, the DLBCL annual incidence is approximately 6.000 cases, among which 30% will relapse or become refractory (R/R). In this scenario, the l...

Background: Severe aplastic anemia (SAA) is a rare bone marrow failure disorder associated with significant morbidity and mortality. SAA is characterized by severe pancytopenia and a hypocellular (<25%) bone marrow. The standard of care treatment is hemopoietic stem cell transplant or immunosuppressive therapy (IST) for patients (pts) who are ineli...

Genetic testing has been increasingly used to assist with differential diagnosis of acquired vs inherited bone marrow failure syndromes (IBMFS), a group of rare and heterogeneous diseases. However, the assay is still costly and not routinely available for many hematologists. To improve decision-making for genetic testing, we developed a genomic-bas...

Background: Somatic mutations in isocitrate dehydrogenase 1 (IDH1) occur in 6-10% of patients with acute myeloid leukemia (AML). Ivosidenib - an oral, potent inhibitor of the mutant IDH1 (mIDH1) enzyme - is FDA-approved for adults with relapsed/refractory m IDH1 AML and adults with newly diagnosed m IDH1 AML who are ≥ 75 years or have comorbidities...

Objectives Immune aplastic anemia (AA) is a hematological disease characterized by pancytopenia and bone marrow (BM) hypocellularity. It is caused by an immune attack against hematopoietic stem and progenitor cells (HSPC). Its treatment is based on allogeneic BM transplantation and immunosuppressive therapy. More recently, the addition of eltrombop...

Background Eltrombopag actively promotes hematological response in association with immunosuppressive therapy (IST) as a first-line treatment for severe aplastic anemia (SAA). This study analyzes the cost-effectiveness of the combination of IST plus eltrombopag in the first line in SAA from the Brazilian public healthcare system perspective. Metho...

TERRA (do inglês telomeric repeat-containing RNA) é um RNA longo não-codificante transcrito a partir das regiões subteloméricas e teloméricas. Os transcritos de TERRA possuem sequências repetidas em tandem ricas em Guanina oriundas das sequências teloméricas TTAGGG e formam híbridos de DNA:RNA nas regiões teloméricas denominados R-loops. A alta exp...

The Leishmania developmental cycle comprises three main life forms in two hosts, indicating that the parasite is continually challenged due to drastic environmental changes. The disruption of this cycle is critical for discovering new therapies to eradicate leishmaniasis, a neglected disease that affects millions worldwide. Telomeres, the physical...

Objectives Evaluate the impact of ABO histo-blood group type on COVID-19 severity. Background ABO histo-blood type has been associated with different outcomes in infectious diseases. It has also shown a higher proportion of type A patients with SARS-CoV-2. In this observational study, extracted from an ongoing clinical trial on the efficacy of con...

SARS-CoV-2 has a high risk of outbreak in long-term skilled nursing facilities (SNF). Coronavirus disease (COVID-19) has high mortality rates among the elderly with chronic health conditions. Following identification of COVID-19 index case in a SNF, serial point-prevalence was implemented with reverse transcription–polymerase chain reaction (RT-PCR...

Introduction The telomere length is a biomarker of cellular proliferative history. In healthy individuals, the leukocyte telomere length shortens with age and associates with the lifespan of men and women. However, most of studies had used linear regression models to address the association of the LTL attrition, aging and sex. Methods We evaluated...

Eltrombopag has been added to first‐line treatment of immune aplastic anaemia (AA), resulting in higher responses. We analysed marrow samples of AA patients who responded to immunosuppressive therapy (IST) alone or in combination with eltrombopag for the composition of the haematopoietic stem and progenitor cell (HSPC) compartment. The number of CD...

Eltrombopag (EPAG), a thrombopoietin receptor agonist, has been recently added to first-line immunosuppressive therapy (IST) in immune aplastic anemia (AA), significantly improving hematologic recovery and survival (Townsley et al. NEJM 2017), corroborating preclinical data suggesting a direct effect of EPAG on hematopoietic precursors. Here, we an...

Understanding the social determinants of telomere length is critical to evaluate the risk of early biological aging. We investigated sex differences on the association between socioeconomic status (SES) and demographic markers and leukocyte telomere length (LTL) in Brazilian adults. This cross-sectional study was conducted in a subsample (women=228...

Growing clinical evidence has implicated complement as a pivotal driver of COVID-19 immunopathology. Deregulated complement activation may fuel cytokine-driven hyper-inflammation, thrombotic microangiopathy and NET-driven immunothrombosis, thereby leading to multi-organ failure. Complement therapeutics have gained traction as candidate drugs for co...

Growing clinical evidence has implicated complement as a pivotal driver of COVID-19 immunopathology. Deregulated complement activation may fuel thrombotic microangiopathy and NET-driven immunothrombosis, thereby exacerbating cytokine-driven hyper-inflammation and multi-organ failure. Complement therapeutics have gained traction as candidate drugs f...

Haploinsufficiency of GATA2 caused by heterozygous loss-of-function mutations is associated with cytopenias and predisposition to myelodysplasia and AML with other variable extrahematopoietic manifestions, including lymphedema, pulmonary alveolar proteinosis, and hearing loss. The authors report on 2 siblings with the disorder whose father was asym...

Metaphase II oocytes (MII) from polycystic ovary syndrome (PCOS) frequently have impaired oocyte competence. Since telomere maintenance is important for folliculogenesis, oocyte maturation, and early embryonic development, we sought to verify the implications of PCOS on telomere length and telomerase activity in immature oocytes and cumulus cells....

Phenotypic heterogeneity is often observed in patients with telomeropathies caused by pathogenic variants in telomere biology genes. However, the roles of recessive variants in these different phenotypes are not fully characterized. Our goal is to describe the biological roles of a novel homozygous RTEL1 variant identified in a consanguineous Leban...

Aplastic anemia (AA) is characterized by a hypoplastic bone marrow associated with low peripheral blood counts. In acquired cases, the immune system promotes hematopoietic stem and progenitor cell (HSPC) depletion by the action of several pro-inflammatory Th1 cytokines. The current treatment options for severe cases consist of sibling-matched allog...

Telomeres are a complex of hexameric repetitive DNA sequences at the end of linear chromosomes. Telomeres erode during mitosis, and this process is accelerated in patients carrying germline pathogenic mutations in telomere-biology genes (Calado and Young, NEJM 2009). In vitro, the exposition to androgens stimulates TERT transcription and telomerase...

Introduction Eculizumab (Ecu) is the standard treatment for paroxysmal nocturnal hemoglobinuria (PNH), as it results in sustained control of intravascular hemolysis and prevention of thrombosis, and significant improvement of long-term survival. However, the hematological benefits remain heterogeneous among patients, and most response analyses are...

Background: Somatic heterozygous mutations in isocitrate dehydrogenase 1 (IDH1) occur in 6-10% of acute myeloid leukemia (AML) cases. Ivosidenib (AG-120) is a first-in-class, oral, targeted inhibitor of the mutant IDH1 (mIDH1) enzyme, and is FDA-approved for the treatment of mIDH1 newly diagnosed AML in patients ≥75 years of age or who have comorbi...

Telomeropathies are a group of phenotypically heterogeneous diseases molecularly unified by pathogenic mutations in telomere-maintenance genes causing critically short telomeres. X-linked dyskeratosis congenita (DC), the prototypical telomere disease, manifested with ectodermal dysplasia, cancer predisposition, and severe bone marrow failure, is ca...

Background: Physical activity is prescribed as a component of primary management for polycystic ovary syndrome (PCOS). This nonrandomized, therapeutic, open, single-arm study investigated the effects of progressive resistance training (PRT) on obesity indices in women with PCOS, and the relationship between obesity indices and telomere content. M...

The treatment of paroxysmal nocturnal hemoglobinuria has been revolutionized by the introduction of the anti-C5 agent eculizumab; however, eculizumab is not the cure for Paroxysmal nocturnal hemoglobinuria (PNH), and room for improvement remains. Indeed, the hematological benefit during eculizumab treatment for PNH is very heterogeneous among patie...

Varicocele pathophysiology is related to increased oxidative stress, which might result in loss sperm DNA integrity as well as in genomic instability. Sperm telomere shortening and loss of global DNA methylation are the main features of genomic instability, leading to cell senescence and death, whereas sperm DNA fragmentation (SDF) characterizes th...