Manish Butte

Front Pediatr. 2022 Mar 23;10:812590. doi: 10.3389/fped.2022.812590. eCollection 2022.

ABSTRACT

X-linked lymphoproliferative disease type 1 (XLP1), an X-linked recessive genetic disorder, is associated with primary immunodeficiency. Patients with XLP1 are susceptible to Epstein-Barr virus (EBV) infection. SH2D1A gene is known as the causative gene. We found a novel hemizygous variant of SH2D1A, c.162_201+31delinsTACAAGGACATATACA, from a 5-year-old male patient who had been diagnosed with EBV infection and Hodgkin’s lymphoma. In targeted next-generation sequencing (NGS), complex variants at exon 2 were not consistently identified with two software programs. They showed a soft-clipped read pattern. The variant had a 71-bp deletion and a 16-bp insertion across exon 2 as confirmed by direct sequencing. As the variant was located within the exon-intron boundary, two aberrant transcripts were shown by RNA study. Although NGS method has a limitation in detecting large deletion/duplication variants, proper bioinformatics pipeline and careful review of data might enable the detection of complex variants.

PMID:35402355 | PMC:PMC8984122 | DOI:10.3389/fped.2022.812590

Front Pediatr. 2022 Mar 25;10:852943. doi: 10.3389/fped.2022.852943. eCollection 2022.

ABSTRACT

BACKGROUND: Zellweger syndrome (ZS) is a congenital autosomal recessive disease within the spectrum of peroxisome biogenesis disorders, characterized by the impairment of peroxisome assembly. The presence of peroxisome enzyme deficiencies leads to complex developmental sequelae, progressive disabilities, and multiorgan damage, due to intracellular accumulation of very-long-chain fatty acids (VLCFAs).

CASE PRESENTATION: We report the case of an infant affected by ZS in which agammaglobulinemia, detected through neonatal screening of congenital immunodeficiencies, appeared as a peculiar trait standing out among all the other classical characteristics of the syndrome. The exome analysis through next-generation sequencing (NGS), which had previously confirmed the diagnostic suspicion of ZS, was repeated, but no mutations causative of inborn error of immunity (humoral defect) were detected.

CONCLUSION: In this case, no genetic variants accountable for the abovementioned agammaglobulinemia were detected. Given that the scientific literature reports the involvement of peroxisomes in the activation of Nuclear Factor κ-light-chain-enhancer of activated B cells (NF-κB) pathway, which is crucial for B-cell survival, with this work, we hypothesize the existence of a link between ZS and humoral immunodeficiencies. Further studies are required to confirm this hypothesis.

PMID:35402347 | PMC:PMC8990230 | DOI:10.3389/fped.2022.852943

Transl Cancer Res. 2022 Mar;11(3):436-443. doi: 10.21037/tcr-21-2296.

ABSTRACT

BACKGROUND: The role of cystic fibrosis transmembrane conductance regulator (CFTR) in hematopoiesis and adult leukemia has been demonstrated using a zebrafish model and leukemia cell lines in our previous works. Here, we continue to explore the association between CFTR and human childhood B-cell acute lymphoblastic leukemia (B-ALL).

METHODS: We continued to collect the peripheral blood and bone marrows of human childhood patients diagnosed with primary B-ALL as well as non-leukemia controls and isolated lymphocytes for analysis using western blotting and quantitative real-time polymerase chain reaction (qPCR) assay. Then, we used immunofluorescence, co-immunoprecipitation, western blotting, luciferase, 3-(4,5)-dimethylthiahiazo (-z-y1)-3,5-di-phenytetrazoliumromide (MTT) assays to identify the interaction of CFTR with Wnt signaling in B-ALL. Finally, we established B-ALL xenograft model in non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mice using SUP-B15 cells, and examined whether the CFTR inhibitor CFTR-inh172 could active against SUP-B15-Dependent B-ALL in vivo.

RESULTS: Highly expressed CFTR protein and mRNA are associated with primary childhood B-ALL patients. Aberrantly upregulated CFTR and Wnt signaling, our previously reported CFTR-Dvl2-β-catenin pathway, is found in human childhood B-ALL patients. Interference with CFTR in B-ALL cell lines induces the downregulation of DVL2/β-catenin and Wnt downstream target accompanied by a reduction of cell proliferation. Furthermore, B-ALL cell lines SUP-B15 cell-transplanted NOD/SCID mice treated with CFTR inhibitor CFTRinh-172 had significantly longer survival and slower leukemia progression compared with mice treated with vehicle dimethyl sulfoxide (DMSO).

CONCLUSIONS: These findings demonstrate that highly expressed CFTR is associated with human childhood B-ALL and the potential of CFTR inhibitor CFTR-inh172 for the treatment of human B-ALL.

PMID:35402186 | PMC:PMC8990221 | DOI:10.21037/tcr-21-2296

Surg Neurol Int. 2022 Mar 11;13:83. doi: 10.25259/SNI_1064_2021. eCollection 2022.

ABSTRACT

BACKGROUND: Histoplasmosis is a fungal disease endemic in some regions of the United States of America, Canada, and Latin America. The geographic characteristics, humidity, soil, and climate are responsible for such distribution. In Brazil, there are case reports of histoplasmosis throughout its territory, being considered an endemic region. It is considered an opportunistic disease, affecting mostly immunocompromised patients. To the present date, scientific publications dealing with pediatric cases of histoplasmosis are restricted to case series. Spinal cord injuries caused by histoplasmosis are rare, even in the adult population, being described in few studies.

CASE DESCRIPTION: The present report deals with a 4-year-old patient, from the southeast region of Brazil, who started a condition of fever, weight loss, cervicobrachialgia, and symmetrical tetraparesis, with evolution over 2 months. In the diagnostic investigation, she was found to have primary immunodeficiency and neuroimaging examinations showed a cervical spinal cord lesion at the level of C4-C6. The anatomopathological diagnosis of histoplasmosis was possible after surgery for decompression and biopsy of the lesion.

CONCLUSION: According to our research, there are no reports in the literature that address the situation of spinal cord compression syndrome due to histoplasmosis in the pediatric population.

PMID:35399893 | PMC:PMC8986645 | DOI:10.25259/SNI_1064_2021

Allergy Asthma Clin Immunol. 2022 Apr 9;18(1):32. doi: 10.1186/s13223-022-00667-1.

ABSTRACT

BACKGROUND AND OBJECTIVES: Safety and effectiveness concerns may preclude physicians from recommending vaccination in mild/moderate inborn errors of immunity (IEI). This study describes attitudes and practices regarding vaccination among physicians who care for patients with mild/moderate B cell or mild/moderate combined immunodeficiencies (CID) and vaccination completeness among patients diagnosed with IEIs.

METHODS: Canadian physicians caring for children with IEI were surveyed about attitudes and practices regarding vaccination in mild/moderate IEI. Following informed consent, immunization records of pediatric patients with IEI evaluated before 7 years of age were reviewed. Vaccine completeness was defined at age 2 years as 4 doses of diphtheria-tetanus-pertussis (DTaP), 3 doses pneumococcal conjugate (PCV), and 1 dose measles-mumps-rubella (MMR) vaccines. At 7 years 5 doses of DTP and 2 doses MMR were required.

RESULTS: Forty-five physicians from 8 provinces completed the survey. Most recommended inactivated vaccines for B cell deficiency: (84% (38/45) and CID (73% (33/45). Fewer recommended live attenuated vaccines (B cell: 53% (24/45), CID 31% (14/45)). Of 96 patients with IEI recruited across 7 centers, vaccination completeness at age 2 was 25/43 (58%) for predominantly antibody, 3/13 (23%) for CID, 7/35 (20%) for CID with syndromic features, and 4/4 (100%) for innate/phagocyte defects. Completeness at age 7 was 15%, 17%, 5%, and 33%, respectively.

CONCLUSION: Most physicians surveyed recommended inactivated vaccines in children with mild to moderate IEI. Vaccine completeness for all IEI was low, particularly at age 7. Further studies should address the reasons for low vaccine uptake among children with IEI and whether those with mild-moderate IEI, where vaccination is recommended, eventually receive all indicated vaccines.

PMID:35397595 | DOI:10.1186/s13223-022-00667-1

Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2022 Apr;30(2):511-515. doi: 10.19746/j.cnki.issn.1009-2137.2022.02.031.

ABSTRACT

OBJECTIVE: To identify the key genes and explore mechanisms in the development of myelodysplastic syndrome (MDS) by bioinformatics analysis.

METHODS: Two cohorts profile datasets of MDS were downloaded from Gene Expression Omnibus (GEO) database. Differentially expressed gene (DEG) was screened by GEO2R, functional annotation of DEG was gained from GO database, gene ontology (GO) enrichment analysis was performed via Kyoto Encyclopedia of Genes and Genomes (KEGG) database, and key genes were screened by Matthews correlation coefficient (MCC) based on STRING database.

RESULTS: There were 112 DEGs identified, including 85 up-regulated genes and 27 down-regulated genes. GO enrichment analysis showed that biological processes were mainly enriched in immune response, etc, cellular component in cell membrane, etc, and molecular function in protein binding, etc. KEGG signaling pathway analysis showed that main gene enrichment pathways were primary immunodeficiency, hematopoietic cell lineage, B cell receptor signaling pathway, Hippo signaling pathway, and asthma. Three significant modules were screened by Cytoscape software MCODE plug-in, while 10 key node genes (CD19, CD79A, CD79B, EBF1, VPREB1, IRF4, BLNK, RAG1, POU2AF1, IRF8) in protein-protein interaction (PPI) network were screened based on STRING database.

CONCLUSION: These screened key genes and signaling pathways are helpful to better understand molecular mechanism of MDS, and provide theoretical basis for clinical targeted therapy.

PMID:35395988 | DOI:10.19746/j.cnki.issn.1009-2137.2022.02.031

J Scleroderma Relat Disord. 2021 Oct;6(3):306-310. doi: 10.1177/23971983211007669. Epub 2021 Apr 13.

ABSTRACT

Systemic sclerosis is a rare systemic autoimmune disease characterized by microvascular impairment and fibrosis of the skin and other organs with poor outcomes. Toxic causes may be involved. We reported the case of a 59-year-old woman who developed an acute systemic sclerosis after two doses of adjuvant chemotherapy by docetaxel and cyclophosphamide for a localized hormone receptor + human epithelial receptor 2-breast cancer. Docetaxel is a major chemotherapy drug used in the treatment of breast, lung, and prostate cancers, among others. Scleroderma-like skin-induced changes (morphea) have been already described for taxanes. Here, we report for the first time a case of severe lung and kidney flare with thrombotic microangiopathy after steroids for acute interstitial lung disease probably induced by anti-RNA polymerase III + systemic sclerosis after docetaxel.

PMID:35387214 | PMC:PMC8922668 | DOI:10.1177/23971983211007669

Ann Med Surg (Lond). 2022 Feb 24;75:103398. doi: 10.1016/j.amsu.2022.103398. eCollection 2022 Mar.

ABSTRACT

BACKGROUND: Radical prostatectomy, a standard management approach for localized Prostate Cancer (PC), may cause a stress response associated with immune modulating effects. Regional anesthesia was hypothesized to reduce the immune effects of surgery by minimizing the neuroendocrine surgical stress response, thus mitigating tumor cells dissemination. Our primary objective was to investigate whether the use of spinal blocks attenuates PC tumor cells dissemination on an animal model. We also assessed the number of circulating NK cells and the amount of inflammatory and anti-inflammatory cytokines.

MATERIALS AND METHODS: A subcutaneous tumor model, with PC-3M cell line transfected with a luciferase-producing gene (PC-3M-luc-C6) was used. After proper tumor establishment and before tumors became metastatic, animals were submitted to tumor excision surgeries under general or combined (general and spinal) anesthesia. A control group was only anesthetized with general anesthesia.

RESULTS: The subcutaneous tumor model with PC-3M-luc-C6 cells was effective in causing distant metastasis after 35 days. The number of circulating tumor cells increased in animals that underwent surgery under general anesthesia alone compared to the group submitted to combined anesthesia. Interleukin 6 levels were different in all groups, with increase in the general anesthesia group.

CONCLUSION: Our results suggest that combination of spinal and general anesthesia may attenuate the suppression of innate tumor immunity and it might be related to a reduction in the neuroendocrine response to surgery.

INSTITUTIONAL PROTOCOL NUMBER: Animal Ethics Committee 1332/2019.

PMID:35386811 | PMC:PMC8977895 | DOI:10.1016/j.amsu.2022.103398

Skin Therapy Lett. 2022 Mar;27(2):1-5.

ABSTRACT

Warts, Hypogammaglobulinemia, Infections and Myelokathexis (WHIM) is a primary immunodeficiency syndrome. Patients with WHIM syndrome are more susceptible to human papillomavirus (HPV) infections and commonly present to a dermatologist with recalcitrant to treatment warts. Other cardinal features of WHIM syndrome include recurrent sinopulmonary bacterial infections, neutropenia/lymphopenia, low levels of immunoglobulins (IgG, IgA, IgM) and myelokathexis. Research demonstrated that truncating gain-of-function mutations of the C-X-C chemokine receptor type 4 gene (CXCR4) are responsible for this disease. Plerixafor, a specific small molecule antagonist of CXCR4, is currently used for peripheral blood hematopoietic stem cell (HSC) mobilization in stem cell transplant recipients. It has recently shown promise for the treatment of WHIM syndrome in phase I/II clinical trials. In this paper we review the emerging patient clinical data for this medication and highlight the role of CXCR4 in other important skin diseases including keratinocyte carcinomas, psoriasis and cutaneous T-cell lymphoma.

PMID:35385630

Clin Transl Med. 2022 Apr;12(4):e769. doi: 10.1002/ctm2.769.

NO ABSTRACT

PMID:35384344 | DOI:10.1002/ctm2.769