Review
Oncology
Agata Pastorczak, Andishe Attarbaschi, Simon Bomken, Arndt Borkhardt, Jutte van der Werff ten Bosch, Sarah Elitzur, Andrew R. Gennery, Eva Hlavackova, Arpad Kerekes, Zdenka Krenova, Wojciech Mlynarski, Tomasz Szczepanski, Tessa Wassenberg, Jan Loeffen
Summary: Ataxia Telangiectasia (AT) and Nijmegen breakage syndrome (NBS) are common DNA repair disorders that increase the risk of developing hematological malignancies. Treatment of lymphoproliferative diseases in patients with these disorders is challenging due to the complications of the underlying disorder and the toxicity of chemotherapy. There is a lack of treatment guidelines specifically designed for these patients, but clinical recommendations can be used as a reference.
Article
Cell Biology
Amandine Bery, Olivier Etienne, Laura Mouton, Sofiane Mokrani, Christine Granotier-Beckers, Laurent R. Gauthier, Justyne Feat-Vetel, Thierry Kortulewski, Elodie A. Peres, Chantal Desmaze, Philippe Lestaveal, Vilma Barroca, Antony Laugeray, Fawzi Boumezbeur, Vincent Abramovski, Stephane Mortaud, Arnaud Menuet, Denis Le Bihan, Jean-Pierre de Villartay, Francois D. Boussin
Summary: XLF/Cernunnos is a crucial component of the ligation complex involved in cNHEJ, a DNA repair pathway. In Xlf-/- mice, neurodevelopmental delays, behavioral alterations, microcephaly, and apoptosis of neural cells are observed, resembling clinical features in humans deficient in cNHEJ. Premature neurogenesis in these mice is caused by asymmetric chromosome segregation, suggesting a link between chromosome dynamics and neurodevelopmental pathologies associated with NHEJ deficiency or genotoxic stress.
Review
Microbiology
Yesim Yilmaz Demirdag, Sudhir Gupta
Summary: DNA repair defects encompass a wide range of conditions with diverse clinical manifestations, including increased cancer risk, accelerated aging, and developmental defects in organs and systems. Some of these disorders can also affect the immune system, leading to susceptibility to infections and autoimmunity. Infections in DNA repair defects may result from primary defects in immune cells or other factors, causing a spectrum of infections ranging from mild respiratory tract infections to severe opportunistic and potentially fatal infections with various pathogens. This article discusses infections in 15 rare and sporadic DNA repair defects associated with immunodeficiencies, highlighting the limited information available due to the rarity of these conditions.
Review
Health Care Sciences & Services
Sharon A. McGrath-Morrow, Cynthia C. Rothblum-Oviatt, Jennifer Wright, Haley Schlechter, Maureen A. Lefton-Greif, Valerie A. Natale, Thomas O. Crawford, Howard M. Lederman
Summary: Ataxia telangiectasia (A-T) is a rare autosomal recessive disease characterized by progressive ataxia, oculocutaneous telangiectasias, and immune system impairment. Patients with A-T have an increased risk of malignancy, leading to premature death.
JOURNAL OF MULTIDISCIPLINARY HEALTHCARE
(2021)
Article
Biochemistry & Molecular Biology
Jakub Czarny, Marta Andrzejewska, Olga Zajac-Spychala, Elzbieta Latos-Grazynska, Agata Pastorczak, Kamila Wypyszczak, Aleksandra Szczawinska-Poplonyk, Izabela Niewiadomska-Wojnalowicz, Agnieszka Wziatek, Patrycja Marciniak-Stepak, Michal Dopierala, Jadwiga Maldyk, Katarzyna Jonczyk-Potoczna, Katarzyna Derwich
Summary: Ataxia-telangiectasia (AT) is a rare genetic disorder characterized by DNA repair defect, chromosomal instability, and hypersensitivity to radiation. Successful clinical management of patients with AT is challenging due to poor treatment response, high toxicity, and the need to avoid radiation exposure. This case report describes a 7-year-old female patient with AT and LBCL with IRF4 rearrangement who achieved a favorable outcome through treatment.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Biochemistry & Molecular Biology
Sapir Schlam-Babayov, Ariel Bensimon, Michal Harel, Tamar Geiger, Ruedi Aebersold, Yael Ziv, Yosef Shiloh
Summary: This study conducted a comprehensive phosphoproteomic analysis in human wild-type and A-T cells to reveal the fine-tuned dynamics and relationships between PIKKs in the response to genotoxic stress. The results highlight the complex interactions among ATM, ATR, and DNA-PK in the DDR.
Article
Immunology
Stefan Zielen, Ruth Pia Duecker, Sandra Woelke, Helena Donath, Sharhzad Bakhtiar, Aileen Buecker, Hermann Kreyenberg, Sabine Huenecke, Peter Bader, Nizar Mahlaoui, Stephan Ehl, Sabine M. El-Helou, Barbara Pietrucha, Alessandro Plebani, Michiel van der Flier, Koen van Aerde, Sara S. Kilic, Shereen M. Reda, Larysa Kostyuchenko, Elizabeth McDermott, Nermeen Galal, Claudio Pignata, Juan Luis Santos Perez, Hans-Juergen Laws, Tim Niehues, Necil Kutukculer, Markus G. Seidel, Laura Marques, Peter Ciznar, John David M. Edgar, Pere Soler-Palacin, Horst von Bernuth, Renate Krueger, Isabelle Meyts, Ulrich Baumann, Maria Kanariou, Bodo Grimbacher, Fabian Hauck, Dagmar Graf, Luis Ignacio Gonzalez Granado, Seraina Prader, Ismail Reisli, Mary Slatter, Carlos Rodriguez-Gallego, Peter D. Arkwright, Claire Bethune, Elena Deripapa, Svetlana O. Sharapova, Kai Lehmberg, E. Graham Davies, Catharina Schuetz, Gerhard Kindle, Ralf Schubert
Summary: The study analyzed mortality and immunity data of patients with ataxia-telangiectasia (A-T) in relation to IgA deficiency, finding that patients with IgA deficiency have significantly lower survival rates, lymphocyte counts, and subsets compared to A-T patients without IgA deficiency. This suggests that IgA deficiency may indicate a poorer prognosis for classical A-T patients.
JOURNAL OF CLINICAL IMMUNOLOGY
(2021)
Article
Biochemistry & Molecular Biology
Divya A. Shiroor, Kuang-Tse Wang, Bhargav D. Sanketi, Justin K. Tapper, Carolyn E. Adler
Summary: Stem cells acquire mutations during division, but can activate the DNA damage response network to repair or induce apoptosis. In planarian flatworms, ATM promotes radiation-induced apoptosis, which is important for long-term animal survival.
Article
Biochemistry & Molecular Biology
Sayanthooran Saravanabavan, Gopala K. Rangan
Summary: Increased DNA damage response signaling in kidney cyst-lining epithelial cells (CECs) may be a target for therapy in ADPKD. However, inhibiting ATM kinase and low-dose cisplatin together does not selectively induce cell death in CECs.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Immunology
Ulrich Baumann, Johannes H. Schulte, Jonathan P. Gross, Rita Beier, Marius Ludwig, Volker Wahn, Jorg Hofmann, Britta Maecker-Kolhoff, Martin Sauer, Petra Kaiser-Labusch, Negin Karimian, Ulrike Blume-Peytavi, Franziska Ghoreschi, Hagen Ott, Ludmila Perelygina, Christian Klemann, Oliver Blankenstein, Horst von Bernuth, Renate Krueger
Summary: We report two patients with DNA repair disorders who developed destructive skin granulomas after receiving live-attenuated rubella vaccinations. Both patients exhibited reduced naive T cells. Hematopoietic stem cell transplantation resulted in rapid resolution of skin lesions. However, one patient with severe complications died 6 months after HSCT. Newborn screening may be beneficial in preventing patients with moderate T-cell deficiencies from receiving rubella vaccine that may lead to granulomas.
FRONTIERS IN IMMUNOLOGY
(2022)
Article
Immunology
Raissa Bernardes da Silva, Willian dos Reis Bertoldo, Lucila Langoni Naves, Fernanda Bernadelli de Vito, Jeziel Dener Damasceno, Luiz Ricardo Orsini Tosi, Carlos Renato Machado, Andre Luiz Pedrosa
Summary: In this study, the DNA damage response pathways in promastigote forms of L. major were investigated. The overexpression of LmjEXO1 made the cells more susceptible to genotoxic damage, while ATR-specific inhibition made the control cells more susceptible to oxidative damage.
FRONTIERS IN CELLULAR AND INFECTION MICROBIOLOGY
(2022)
Review
Pharmacology & Pharmacy
Bhanu Priya, Srimadhavi Ravi, Sivapriya Kirubakaran
Summary: The DNA Damage and Response (DDR) pathway is crucial for maintaining genome integrity and preventing cancer development. The DDR pathway, particularly the ATM and ATR kinases, plays a vital role in recognizing and repairing DNA double-strand breaks (DSBs), a severe DNA damage that can lead to genomic instability. Cancer cells, with a high burden of DSBs, heavily rely on efficient DSB repair mechanisms for their survival. Therefore, targeting DSB repair pathways, such as ATM and ATR, can enhance the efficacy of DNA-damaging agents in cancer treatment. This review focuses on the roles of ATM and ATR in the DDR pathway, challenges in targeting these kinases, and current clinical trials of their inhibitors.
DRUG DISCOVERY TODAY
(2023)
Review
Genetics & Heredity
Motohiro Yamauchi
Summary: Chromosome rearrangements are structural variations in chromosomes and are associated with a variety of human diseases. Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterized by chromosome rearrangements at the cellular level, particularly in T lymphocytes. The defective gene in A-T is ataxia-telangiectasia mutated (ATM), which plays a central role in cellular response to DNA damage, including suppressing chromosome rearrangements.
Article
Oncology
Beata Wolska-Kusnierz, Agata Pastorczak, Wojciech Fendler, Anna Wakulinska, Bozena Dembowska-Baginska, Edyta Heropolitanska-Pliszka, Barbara Piatosa, Barbara Pietrucha, Krzysztof Kalwak, Marek Ussowicz, Anna Pieczonka, Katarzyna Drabko, Monika Lejman, Sylwia Koltan, Jolanta Gozdzik, Jan Styczynski, Alina Fedorova, Natalia Miakova, Elena Deripapa, Larysa Kostyuchenko, Zdenka Krenova, Eva Hlavackova, Andrew R. Gennery, Karl-Walter Sykora, Sujal Ghosh, Michael H. Albert, Dmitry Balashov, Mary Eapen, Peter Svec, Markus G. Seidel, Sara S. Kilic, Agnieszka Tomaszewska, Ewa Wiesik-Szewczyk, Alexandra Kreins, Johann Greil, Jochen Buechner, Bendik Lund, Hanna Gregorek, Krystyna Chrzanowska, Wojciech Mlynarski
Summary: Nijmegen breakage syndrome (NBS) patients have a high predisposition to cancer, but undergoing hematopoietic stem cell transplantation (HSCT) in their first complete remission can improve long-term survival and reduce the risk of cancer development.
CLINICAL CANCER RESEARCH
(2021)
Review
Biochemistry & Molecular Biology
Jacquelyne Ka-Li Sun, Genper Chi-Ngai Wong, Kim Hei-Man Chow
Summary: Cerebellar ataxia, a symptom of ataxia-telangiectasia (A-T), is the irreversible consequence of selective degeneration of cerebellar Purkinje neurons. A-T is caused by loss-of-function mutations in the ATM gene, which regulates DNA damage response and central carbon metabolic network. The review aims to explore the unexpected connections between these two cellular functions and their impact on the specific vulnerability of Purkinje neurons.
JOURNAL OF NEUROCHEMISTRY
(2023)
Article
Hematology
Morgane Cheminant, Thomas A. Fox, Mickael Alligon, Olivier Bouaziz, Benedicte Neven, Despina Moshous, Stephane Blanche, Aurelien Guffroy, Claire Fieschi, Marion Malphettes, Nicolas Schleinitz, Antoinette Perlat, Jean-Francois Viallard, Nathalie Dhedin, Francoise Sarrot-Reynauld, Isabelle Durieu, Sebastien Humbert, Fanny Fouyssac, Vincent Barlogis, Benjamin Carpenter, Rachael Hough, Arian Laurence, Ambroise Marcais, Ronjon Chakraverty, Olivier Hermine, Alain Fischer, Siobhan O. Burns, Nizar Mahlaoui, Emma C. Morris, Felipe Suarez
Summary: Allogeneic hematopoietic stem cell transplantation (alloSCT) is a curative treatment for severe inborn errors of immunity (IEIs). Recent data suggests that alloSCT is safe and effective in selected adult patients. However, questions remain regarding the indications and optimal timing of the transplant.
Article
Hematology
C. Schuetz, J. Gerke, M. Ege, J. Walter, M. Kusters, A. Worth, J. A. Kanakry, D. Dimitrova, B. Wolska-Kusnierz, K. Chen, E. Unal, M. Karakukcu, O. Pashchenko, J. Leiding, T. Kawai, P. J. Amrolia, D. Berghuis, J. Buechner, D. Buchbinder, M. J. Cowan, A. R. Gennery, T. Gungor, J. Heimall, M. Miano, I. Meyts, E. C. Morris, J. Riviere, S. O. Sharapova, P. J. Shaw, M. Slatter, M. Honig, P. Veys, A. Fischer, M. Cavazzana, D. Moshous, A. Schulz, M. H. Albert, J. M. Puck, A. C. Lankester, L. D. Notarangelo, B. Neven
Summary: Patients with hypomorphic mutations in the RAG1 or RAG2 gene can present with various clinical phenotypes, such as Omenn syndrome or atypical combined immunodeficiency. Hematopoietic stem cell transplantation (HSCT) is a potential cure for these patients, but information about its outcomes is limited. We report on a global cohort of 60 patients with hypomorphic RAG variants who underwent HSCT, with 78% experiencing infections (29% active at HSCT), 72% developing autoimmunity, and 18% having granulomas before transplantation. These complications often lead to organ damage. Eight individuals (13%) were diagnosed through newborn screening or family history. HSCT was performed at a median age of 3.4 years (range 0.3-42.9 years) from matched unrelated donors, matched sibling or matched family donors, or mismatched donors in 48%, 22%, and...
Article
Allergy
Yuka Hosotani, Koubun Yasuda, Makoto Nagai, Kiyofumi Yamanishi, Nobuo Kanazawa, Fumi Gomi, Yasutomo Imai
Summary: ILC2 cells play a crucial role in IL-33-induced keratoconjunctivitis. Through single-cell RNA sequencing analysis, it was found that ILC2 cells infiltrated the conjunctival epithelium and subepithelial tissue. Moreover, the use of tacrolimus in treatment can inhibit cytokine production from ILC2 cells and alleviate IL-33-induced keratoconjunctivitis.
ALLERGOLOGY INTERNATIONAL
(2023)
Editorial Material
Hematology
Mary Eapen
Summary: This article reports on the outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) and conservative management for adult patients with inborn errors of immunity (IEI).
Article
Oncology
Theodore W. Laetsch, Shannon L. Maude, Susana Rives, Hidefumi Hiramatsu., Henrique Bittencourt., Peter. Bader, Andre Baruchel, Michael Boyer, Barbara De Moerloose, Muna Qayed, Jochen Buechner, Michael A. Pulsipher, Gary Douglas Myers, Heather E. Stefanski, Paul L. Martin, Eneida Nemecek, Christina Peters, Gregory Yanik, Seong Lin Khaw, Kara L. Davis, Joerg Krueger, Adriana Balduzzi, Nicolas Boissel, Ranjan Tiwari, Darragh O'Donovan, Stephan A. Grupp
Summary: Clinical trials often have multiple endpoints with different maturity times. Clinical Trial Updates provide an opportunity to publish additional results beyond the initial report based on the primary endpoint. This update on the ELIANA trial demonstrates the long-term efficacy, safety, and quality of life improvements in pediatric and young adult patients with R/R B-ALL treated with tisagenlecleucel.
JOURNAL OF CLINICAL ONCOLOGY
(2023)
Article
Oncology
Mary Eapen, Ruta Brazauskas, David A. Williams, Mark C. Walters, Andrew St Martin, Benjamin L. Jacobs, Joseph H. Antin, Kira Bona, Sonali Chaudhury, Victoria H. Coleman-Cowger, Nancy L. DiFronzo, Erica B. Esrick, Joshua J. Field, Courtney D. Fitzhugh, Julie Kanter, Neena Kapoor, Donald B. Kohn, Lakshmanan Krishnamurti, Wendy B. London, Michael A. Pulsipher, Sohel Talib, Alexis A. Thompson, Edmund K. Waller, Ted Wun, Mary M. Horowitz
Summary: This study investigates the incidence and risk factors for secondary neoplasm after transplantation for sickle cell disease. The results show that the 10-year incidence of leukemia/MDS was 1.7% and of any secondary neoplasm was 2.4%. Low-intensity regimens were associated with higher risks for leukemia/MDS or any secondary neoplasm compared with more intense regimens.
JOURNAL OF CLINICAL ONCOLOGY
(2023)
Article
Immunology
Nel Dabrowska-Leonik, Barbara Piatosa, Ewa Slominska, Nadezda Bohynikova, Katarzyna Bernat-Sitarz, Ewa Bernatowska, Beata Wolska-Kusnierz, Krzysztof Kalwak, Sylwia Koltan, Anna Dabrowska, Jolanta Gozdzik, Marek Ussowicz, Malgorzata Pac
Summary: This study retrospectively evaluated the clinical course and test results of 7 patients diagnosed with ADA deficiency in Poland from 2010 to 2022. The patients demonstrated immune and non-immune symptoms, and 5 of them underwent hematopoietic stem cell transplantation. Early diagnosis is crucial to prevent irreversible multi-organ failure.
FRONTIERS IN IMMUNOLOGY
(2023)
Letter
Allergy
Kanako Kita, Yasutomo Imai, Makoto Nagai, Masaru Natsuaki, Nobuo Kanazawa
Summary: Dupilumab treatment reduces serum SCCA2 levels in patients with atopic dermatitis, even if the skin eruptions are not fully resolved.
JOURNAL OF CUTANEOUS IMMUNOLOGY AND ALLERGY
(2023)
Article
Pediatrics
Katarzyna Bobeff, Agata Pastorczak, Zuzanna Urbanska, Walentyna Balwierz, Edyta Juraszewska, Jacek Wachowiak, Katarzyna Derwich, Magdalena Samborska, Krzysztof Kalwak, Iwona Dachowska-Kalwak, Pawel Laguna, Iwona Malinowska, Katarzyna Smalisz, Jolanta Gozdzik, Aleksandra Oszer, Bartosz Urbanski, Maciej Zdunek, Tomasz Szczepanski, Wojciech Mlynarski, Szymon Janczar
Summary: Venetoclax has shown significant clinical activity in relapsed or refractory leukemias in paediatric patients in Poland. Although not currently incorporated into paediatric treatment schedules, it has been used in patients who have failed conventional therapy. This study aims to gather clinical data and correlates of paediatric patients treated with Venetoclax to guide its clinical use and stimulate further research.
Review
Immunology
Kunihiko Moriya, Kanako Mitsui-Sekinaka, Yujin Sekinaka, Akifumi Endo, Hirokazu Kanegane, Tomohiro Morio, Kohsuke Imai, Shigeaki Nonoyama
Summary: Activated phosphatidyl inositol 3-kinase-delta syndrome (APDS) is caused by gain-of-function variant in the class IA PI3K catalytic subunit p110 delta. The disease is characterized by recurrent airway infections and bronchiectasis. It is associated with hyper-IgM syndrome, immune dysregulations, and T-cell dysfunction. Different causative genes lead to different types of APDS with varying severity levels. Proper treatment and management are crucial for patients with APDS.
IMMUNOLOGICAL MEDICINE
(2023)
Review
Medicine, General & Internal
Meinolf Suttorp, Stephanie Sembill, Krzysztof Kalwak, Markus Metzler, Frederic Millot
Summary: Pediatric chronic myeloid leukemia (CML) is a rare malignancy with priapism observed in approximately 3.2% of boys with pediatric CML. Priapism duration varied from hours to months, with intermittent priapism being the most common presentation. All patients exhibited splenomegaly and massive leukocytosis. Interventions for priapism included intravenous fluids, heparin, penile puncture, sympathomimetics, and surgical shunt operations. Long-term survivors responded well to treatment and maintained full erectile function.
JOURNAL OF CLINICAL MEDICINE
(2023)
Article
Oncology
Malgorzata Czogala, Wojciech Czogala, Katarzyna Pawinska-Wasikowska, Teofila Ksiazek, Karolina Bukowska-Strakova, Barbara Sikorska-Fic, Pawel Laguna, Anna Falkowska, Katarzyna Drabko, Katarzyna Muszynska-Roslan, Maryna Krawczuk-Rybak, Marta Kozlowska, Ninela Irga-Jaworska, Karolina Zielezinska, Tomasz Urasinski, Natalia Bartoszewicz, Jan Styczynski, Jolanta Skalska-Sadowska, Jacek Wachowiak, Anna Rodziewicz-Konarska, Krzysztof Kalwak, Malgorzata Ciebiera, Radoslaw Chaber, Agnieszka Mizia-Malarz, Agnieszka Chodala-Grzywacz, Grazyna Karolczyk, Katarzyna Bobeff, Wojciech Mlynarski, Katarzyna Mycko, Wanda Badowska, Renata Tomaszewska, Tomasz Szczepanski, Katarzyna Machnik, Natalia Zamorska, Walentyna Balwierz, Szymon Skoczen
Summary: Mutations in the FLT3 gene are associated with poor outcomes in pediatric AML. A retrospective analysis of a nationwide pediatric AML database showed that FLT3-ITD-positive patients had worse survival compared to FLT3-ITD-negative patients. Treatment protocols and the use of FLT3 inhibitors and stem cell transplantation showed potential for improving outcomes. Additional genetic mutations, such as WT1 and NPM1, significantly influenced prognosis.
Article
Oncology
Aleksandra Kowaluk, Katarzyna Siewierska, Marie Choniawkova, Petr Sedlacek, Krzysztof Kalwak, Iwona Malicka
Summary: This study aimed to assess the level of physical activity (PA) and quality of life of cancer-treated children, depending on their place of residence (Poland vs. the Czech Republic, where incidence and mortality rates of childhood malignancies are similar). The study showed significant differences in PA levels between Polish and Czech children. Physically active children engaging in more frequent PA reported higher physical performance, higher energy levels, and less mood disturbance. Our study emphasized the importance of promoting tailored PA programs for cancer-treated children to improve well-being and quality of life.
Meeting Abstract
Pediatrics
Paul Charles Grimm, Cynthia Wong, Debra Jordi Goldstein-Fuchs, Abanti Chaudhuri, Gerri James, Darcy Boyd, Julie Good, Mayna Woo, Amy Gallo, Alice Bertaina
PEDIATRIC NEPHROLOGY
(2023)
Meeting Abstract
Critical Care Medicine
Vijith Vijayan, Hao Yan, Juliane Lohmeyer, Kolten Peterson, James Harden, Rachana Patil, Giulia Barbarito, Alice Bertaina, Robert Negrin, Daria Mochly-Rosen, Kenneth Weinberg, Bereketeab Haileselassie
CRITICAL CARE MEDICINE
(2023)