Manish Butte

Ital J Pediatr. 2023 Aug 2;49(1):95. doi: 10.1186/s13052-023-01496-7.

ABSTRACT

BACKGROUND: Chronic Granulomatous Disease (CGD) is a primary immunodeficiency that causes susceptibility to recurrent fungal and bacterial infections. The CYBB gene encodes gp91^phox component of the Phagocytic Nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and specifically, X-linked CGD is caused by mutations in the CYBB gene, located on the X chromosome. The aim of the study was to characterize functional and genetic mutations in X-linked CGD.

METHODS: Functional analysis was conducted on the whole blood of seventeen male individuals who were suspected to have X-linked chronic granulomatous disease (CGD). Flow cytometry was employed to assess the capacity of NADPH oxidase, measuring both H₂O₂ production and gp91^phox protein expression in neutrophils. Additionally, DNA Sanger sequencing was performed for genetic analysis. The pathogenicity of novel mutations was assessed by pathogenicity prediction tools.

RESULT: Among the seventeen patients evaluated, five patients (P1, P2, P3, P4, and P5) displayed impaired H₂O₂ production by their neutrophils upon stimulation with Phorbol myristate acetate (PMA), accompanied by abnormal gp91^phox expression. DNA sequencing of the CYBB gene identified specific mutations in each patient. In P1 and P2 (previously reported cases), a hemizygous missense mutation, c.925G > A/p.E309K was identified. In P3 and P4 (novel cases), hemizygous nonsense mutations, c.216T > A/p.C72X were found. Lastly, in P5 (also a novel case), a hemizygous missense mutation, c.732T > G/p.C244W was detected. These mutations reside in exons 9,3 and 7 of the CYBB gene, respectively.

CONCLUSIONS: The current study contributes to the understanding of the clinical and genetic spectrum associated with X-linked chronic granulomatous disease (CGD). It highlights the significance of early diagnosis in CGD and emphasizes the importance of lifelong prophylaxis to prevent severe infections.

PMID:37533075 | DOI:10.1186/s13052-023-01496-7

Blood Adv. 2023 Aug 2:bloodadvances.2023010330. doi: 10.1182/bloodadvances.2023010330. Online ahead of print.

ABSTRACT

Lymphomas are not infrequently associated with Epstein-Barr virus, with EBV-positivity linked to worse outcomes in several subtypes. Nanatinostat is a Class-I selective oral histone deacetylase inhibitor (HDACi) that induces expression of lytic EBV BGLF4 protein kinase in EBV+ tumor cells, activating ganciclovir via phosphorylation, resulting in tumor cell apoptosis. This Phase 1b/2 study (NCT03397706) investigated the combination of nanatinostat with valganciclovir in patients aged >=18 with EBV+ lymphomas relapsed/refractory to >=1 prior systemic therapies with no viable curative treatment options. In the Phase 1b part, 25 patients were enrolled into 5 dose escalation cohorts to determine the recommended Phase 2 dose (RP2D) for Phase 2 expansion. Phase 2 patients (n=30) received the RP2D (nanatinostat 20 mg daily, 4 days per week with valganciclovir 900 mg orally daily) in 28-day cycles. Primary endpoints were safety and RP2D determination (Phase 1b) and overall response rate (ORR; Phase 2). Overall, 55 patients were enrolled (B-NHLs [n=10], T/NK-NHLs [n=21], classical Hodgkin lymphoma [n=11], and immunodeficiency-associated lymphoproliferative disorders (IA-LPD) [n=13]). The ORR was 40% in 43 evaluable patients (complete response rate [CRR] 19% [n=8]) with a median duration of response of 10.4 months. For T/NK-NHLs (n=15; all refractory to last prior therapy), the ORR/CRR was 60%/27%. The most common adverse events (AEs) were nausea (38% any grade) and cytopenias (Grade 3/4 neutropenia [29%], thrombocytopenia [20%], and anemia [20%]). This novel oral regimen provided encouraging efficacy across several EBV+ lymphoma subtypes and warrants further evaluation; a confirmatory Phase 2 study (NCT05011058) is underway.

PMID:37530631 | DOI:10.1182/bloodadvances.2023010330

Turk J Biol. 2022 Feb 8;46(3):207-215. doi: 10.55730/1300-0152.2609. eCollection 2022.

ABSTRACT

Phosphoinositide 3-kinase (PI3K) signaling pathway is essential for normal physiology and is impaired in diseases such as premalignant hyperproliferative disorders, primary immunodeficiency, metabolic disorders, and cancer. Although the core PI3K pathway components are known today, a long-standing gap in our knowledge of PI3K signaling concerns how distinct PI3K isoforms and their activity patterns contribute to the functional consequences of pathway upregulation. In order to address this issue, we devised a molecular genetic cell model, which allowed temporal regulation of the indispensable PI3K isoform, p110α in distinct stages of the cell cycle. We found that late M and early G1 presence of p110α is key for proper cell cycle progression, whereas its S-phase abundance was redundant. Our results also emphasize a critical dependence of cell cycle reentry on early G1 activity of p110α. Collectively, our findings provide a temporal perspective to p110α activation and offer insight into which wave of PI3K activity could be essential for cell cycle progression.

PMID:37529255 | PMC:PMC10388040 | DOI:10.55730/1300-0152.2609

Front Immunol. 2023 Jul 13;14:1209315. doi: 10.3389/fimmu.2023.1209315. eCollection 2023.

ABSTRACT

INTRODUCTION: With increased diagnostic capabilities and treatment modalities in the field of primary immunodeficiencies (PID), many pediatric patients survive beyond childhood and experience a change of care to the adult-oriented healthcare system. Unfortunately, the transition pathways for PID are less clearly defined, resulting in deterioration of quality of care in adulthood. Hence, this is the first regional study to address PID clinicians’ opinions on practices and challenges of transition care in 7 Southeast Asia (SEA) countries.

METHODS: We adopted a cross-sectional study design through an online survey platform to enquire opinions of transition practices from expert representatives in 7 SEA countries.

RESULTS: Regionally, 3 out 7 countries reported having no practice of transition care. Among cited challenges were reluctant adaptation by patients and caregivers to unfamiliarized adult healthcare systems, inadequate ratio of adult immunologists to patients and lack of facilities for transfer.

DISCUSSION AND CONCLUSION: Our study provides evidence to advocate policy makers on the importance of standardized integration of transition practice towards betterment of transiting PID patients into adulthood.

PMID:37529038 | PMC:PMC10390097 | DOI:10.3389/fimmu.2023.1209315

Zhonghua Nei Ke Za Zhi. 2023 Aug 1;62(8):1007-1011. doi: 10.3760/cma.j.cn112138-20220819-00610.

ABSTRACT

We wished to summarize the clinical features of common variable immunodeficiency (CVID) complicated by non-cirrhotic portal hypertension (NCPH) and to deepen our understanding of it. The case data of CVID complicated with NCPH admitted to Peking Union Medical College Hospital from January 1983 to May 2021 were analyzed retrospectively to summarize their clinical characteristics. Six patients with CVID combined with NCPH (three of each sex; 16-45 years) were assessed. Four patients had portal hypertension. All patients had anemia, splenomegaly, a normal serum level of albumin and transaminases, and possibly increased levels of alkaline phosphatase and gamma-glutamyl transpeptidase. Two patients were diagnosed with esophagogastric fundic varices by gastroscopy. Two patients underwent splenectomy (which improved hematologic abnormalities partially). Four patients had autoimmune disease. Two cases were diagnosed with nodular regenerative hyperplasia (NRH) upon liver biopsy. Six patients were administered intravenous immunoglobulin-G (0.4-0.6 g/kg bodyweight) once every 3-4 weeks as basic therapy. Often, CVID complicated with NCPH has: (1) The manifestations of portal hypertension as the primary symptom. (2) Autoimmune-related manifestations. Imaging can provide important diagnostic clues. The etiology may be related to hepatic NRH and splenomegaly due to recurrent infections.

PMID:37528040 | DOI:10.3760/cma.j.cn112138-20220819-00610

Pediatr Dermatol. 2023 Jul 29. doi: 10.1111/pde.15400. Online ahead of print.

ABSTRACT

Serine/threonine kinase 4 deficiency (STK4 or MST1, OMIM:614868) is an autosomal recessive (AR) combined immunodeficiency that can present with skin lesions such as epidermodysplasia verruciformis-like lesions (EVLL). Herein, we describe a 17-year-old male patient born from consanguineous parents presenting with recurrent respiratory infections, verruciform plaques, poikiloderma, chronic benign lymphoproliferation, and Sjögren syndrome with suspected interstitial lymphocytic pneumonia.

PMID:37515487 | DOI:10.1111/pde.15400

Vaccines (Basel). 2023 Jul 6;11(7):1211. doi: 10.3390/vaccines11071211.

ABSTRACT

The emergence of vaccine-derived polioviruses (VDPVs) in patients with Primary Immunodeficiency (PID) is a threat to the polio-eradication program. In a first of its kind pilot study for successful screening and identification of VDPV excretion among patients with PID in India, enteroviruses were assessed in stool specimens of 154 PID patients across India in a period of two years. A total of 21.42% of patients were tested positive for enteroviruses, 2.59% tested positive for polioviruses (PV), whereas 18.83% of patients were positive for non-polio enteroviruses (NPEV). A male child of 3 years and 6 months of age diagnosed with Hyper IgM syndrome was detected positive for type1 VDPV (iVDPV1) with 1.6% nucleotide divergence from the parent Sabin strain. E21 (19.4%), E14 (9%), E11 (9%), E16 (7.5%), and CVA2 (7.5%) were the five most frequently observed NPEV types in PID patients. Patients with combined immunodeficiency were at a higher risk for enterovirus infection as compared to antibody deficiency. The high susceptibility of PID patients to enterovirus infection emphasizes the need for enhanced surveillance of these patients until the use of OPV is stopped. The expansion of PID surveillance and integration with a national program will facilitate early detection and follow-up of iVDPV excretion to mitigate the risk for iVDPV spread.

PMID:37515027 | DOI:10.3390/vaccines11071211

Pediatr Pulmonol. 2023 Jul 28. doi: 10.1002/ppul.26607. Online ahead of print.

NO ABSTRACT

PMID:37503872 | DOI:10.1002/ppul.26607

J Prev (2022). 2023 Jul 26. doi: 10.1007/s10935-023-00733-3. Online ahead of print.

ABSTRACT

Non-communicable diseases (NCDs) are the leading cause of death worldwide. NCDs also increase mortality from COVID-19 and primary health care (PHC) services are an important component in the prevention and control of long-term NCDs. The main goal of the present study was to review primary healthcare services for the NCDs patients via primary healthcare network during COVID-19 pandemic. In this scoping review, Search engines including PubMed, Scopus, and Science-direct up to 1st February 2022 were searched to identify studies regarding primary care services for NCDs patients via primary health care during COVID-19 pandemic. A total of 42 studies met the inclusion criteria and were included in our analysis. 24 studies were about the status and changes of primary health services for NCDs patients in PHC settings, while 18 studies focused on adaptive strategies used during COVID-19 in different countries including United States, Canada, United Kingdom, Portugal, Georgia, South Africa, Thailand, Mexico, India, Kenya, Guatemala and Saudi Arabia. These strategies included remote monitoring, follow up, consultation, empowerment and educational services as well as home visiting Disruption of NCDs services in PHC during the COVID-19 pandemic was observed in different countries, which highlights the urgency of attention of researchers and policy-makers to development of appropriate and adaptive policies to improve PHC service coverage and its quality during the pandemics.

PMID:37495870 | DOI:10.1007/s10935-023-00733-3

Acta Neuropathol. 2023 Jul 26. doi: 10.1007/s00401-023-02613-w. Online ahead of print.

ABSTRACT

Immunodeficiency-associated primary CNS lymphoma (PCNSL) represents a distinct clinicopathological entity, which is typically Epstein-Barr virus-positive (EBV⁺) and carries an inferior prognosis. Genetic alterations that characterize EBV-related CNS lymphomagenesis remain unclear precluding molecular classification and targeted therapies. In this study, a comprehensive genetic analysis of 22 EBV⁺ PCNSL, therefore, integrated clinical and pathological information with exome and RNA sequencing (RNASeq) data. EBV⁺ PCNSL with germline controls carried a median of 55 protein-coding single nucleotide variants (SNVs; range 24-217) and 2 insertions/deletions (range 0-22). Genetic landscape was largely shaped by aberrant somatic hypermutation with a median of 41.01% (range 31.79-53.49%) of SNVs mapping to its target motifs. Tumors lacked established SNVs (MYD88, CD79B, PIM1) and copy number variants (CDKN2A, HLA loss) driving EBV^– PCNSL. Instead, EBV⁺ PCNSL were characterized by SOCS1 mutations (26%), predicted to disinhibit JAK/STAT signaling, and mutually exclusive gain-of-function NOTCH pathway SNVs (26%). Copy number gains were enriched on 11q23.3, a locus directly targeted for chromosomal aberrations by EBV, that includes SIK3 known to protect from cytotoxic T-cell responses. Losses covered 5q31.2 (STING), critical for sensing viral DNA, and 17q11 (NF1). Unsupervised clustering of RNASeq data revealed two distinct transcriptional groups, that shared strong expression of CD70 and IL1R2, previously linked to tolerogenic tumor microenvironments. Correspondingly, deconvolution of bulk RNASeq data revealed elevated M2-macrophage, T-regulatory cell, mast cell and monocyte fractions in EBV⁺ PCNSL. In addition to novel insights into the pathobiology of EBV⁺ PCNSL, the data provide the rationale for the exploration of targeted therapies including JAK-, NOTCH- and CD70-directed approaches.

PMID:37495858 | DOI:10.1007/s00401-023-02613-w