Plasma Cells Research Articles

Abstract A047: Neighborhood disadvantage and multiple myeloma risk among Black women living in the United States

Abstract Introduction: Multiple myeloma (MM) is a rare cancer of the plasma cells. Black men and women are at a greater than 2-fold increased risk of MM as compared to other racial/ethnic groups. In 2021, Black women living in the United States (U.S.) were diagnosed with MM at a rate of 13.9 per 100,000 women, and incidence has increased by more than 30% since 2000. Factors associated with the neighborhood in which Black women live and work may be one area to consider to disentangle this racial disparity in MM incidence and reduce the burden of disease for Black women. Methods: We evaluated the association between two neighborhood-level indices and MM within the Black Women’s Health Study, a longitudinal cohort of 59,000 self- identified Black women ages 21-69 at enrollment in 1995. Participant addresses at baseline were geocoded and linked with U.S. Census Bureau and American Community Survey data. We conducted a factor analysis to a create neighborhood concentrated disadvantage (nDIS) score, which included 6 variables: percentage of individuals below the poverty line, percentage of individuals on public assistance, percentage of female headed households, percentage unemployed, percentage of individuals ≤18 years, and percentage of Black residents. A neighborhood socioeconomic status (nSES) score included median household income, median housing value, percentage of households receiving interest, dividend or net rental income, percentage of adults aged ≥25 years who completed college, percentage of employed persons aged ≥16 years in occupations classified as managerial, executive or professional, and percentage of families with children that are not headed by a single female. We used Cox proportional hazards regression to calculate hazard ratios (HRs) and 95% confidence intervals (CI) for the association of quartiles of nSES and nDIS in relation to MM risk. Multivariable models were adjusted for age, body mass index, educational attainment, alcohol consumption, physical activity, and cigarette smoking. Results: During follow-up through 2021, we identified 276 incident cases of MM. Multivariable-adjusted HRs were 1.43 (95% CI: 1.00, 2.03) for women living in the highest quartile of neighborhood disadvantage relative to the lowest quartile, and 1.23 (95% CI: 0.86, 1.76) for women living in neighborhoods in the lowest quartiles of nSES compared to the highest. Conclusions: Black women in the U.S. living in neighborhoods of high concentrated disadvantage have an increased risk for MM compared to women who live in more advantaged communities, even after adjustment for individual SES as measured by educational attainment. Future studies to further tease apart specific neighborhood-level factors (e.g., walkability, chronic stress, environmental pollution, opportunities to engage in healthy behaviors) that might influence risk of MM would be beneficial. Ultimately, community reinvestment may offer an opportunity to reduce the increasing burden of MM among Black women. Citation Format: Etienne X. Holder, Julie R. Palmer, Kimberly A. Bertrand. Neighborhood disadvantage and multiple myeloma risk among Black women living in the United States [abstract]. In: Proceedings of the 17th AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2024 Sep 21-24; Los Angeles, CA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2024;33(9 Suppl):Abstract nr A047.

Compromiso gástrico por enfermedad relacionada con IgG4

Introduction: IgG4-related disease (IgG4-RD) is a recently described entity, characterized by IgG4+ infiltration of plasma cells and storiform pattern sclerosis mediated by CD4+ lymphocytes and follicular helper T-cells (Tfhs). Most patients present with adenopathy and weight loss. Among the most affected sites are the pancreas, salivary and lacrimal glands, aorta, and retroperitoneum. Gastric involvement is rare. Diagnosis is based on histopathological examination of the involved organ, clinical manifestations, and serological results. Glucocorticoid therapy is the first line management. Case report: a 38-year-old male patient with symptoms suggestive of upper gastrointestinal (GI) bleeding, upper GI endoscopy revealed a gastric corpus ulcer, suspicious of an ulcerated gastric subepithelial lesion, possibly a gastrointestinal stromal tumor (GIST). Consequently, laparoscopic subtotal gastrectomy was performed. Histology was compatible with an ulcerated IgG4-related fibrosclerosing tumor. Glucocorticoid therapy was started with patient´s favorable response. Conclusion: in this paper, we will review the cases of IgG4-RD with gastric involvement reported in the literature to describe the most important features of this condition.

Solitary erythematous nodule on the breast

In this clinicopathological case, we describe the case of a female in her sixties with relapsed IgG kappa plasma cell myeloma, commonly known as multiple myeloma (MM), on no active therapy who presented to dermatology with a solitary erythematous nodule on her right breast, biopsied as cutaneous involvement by MM. We include clinical, dermoscopic, and histopathologic images of the patient’s striking lesion. We then provide a brief review of the literature on cutaneous infiltration by MM along with discussion of the differential of plasma cell neoplasms of the skin, which can appear similar on H&E, but are differentiated by immunohistochemical staining.

Effects of anticoagulants time storage on stable isotope values of crocodilians’ blood tissues

ABSTRACT Rapid coagulation of reptile blood often hinders its use in studies in remote and difficult-to-access areas, necessitating chemical preservation. Therefore, understanding the potential effects of anticoagulants on the isotopic compositions of blood is essential to avoid issues in interpreting the results for ecological studies. In this study we aimed to verify whether the storage time of the blood tissue in anticoagulants can influence its isotopic compositions of the broad-snouted caiman (Caiman latirostris), an ectothermic top predator from eastern South America. Blood samples were obtained from ten adult females of C. latirostris from a commercial breeding facility in 2015. Samples were stored in vials containing ethylenediaminetetraacetic acid (EDTA) and sodium heparin (SH) and centrifuged after 2 and 8 h to separate red blood cells and plasma. No effect of time was found on the δ13C and δ15N of whole blood, plasma, and red blood cells in contact with the two types of anticoagulants, EDTA and SH. The findings have practical implications for researchers in this field, as they suggest that anticoagulants can be used effectively for at least eight hours under refrigeration.

Attributes of Pathological Fractures in a Nigerian myeloma cohort

Multiple Myeloma (MM) is a plasma cell tumor usually characterized by lytic bone lesions. Pathological Fracture (PF) is a debilitating condition that usually affects a patient’s psychomotor functions, treatment modality, morbidity, and outcome. We evaluated the associations, characteristics, and impact of PF on survival in a group of Nigerian myeloma cohort. A 10-year (2011-2021) retrospective review of MM data from Nigerian tertiary hospital haemato-oncology unit to evaluate attributes of PFs in myeloma cohort. Sixty-six patients had MM of which 23 had PF while forty-three had no fractures. Of the number with PF, 18 had lytic bone lesions, while 20 had bone pains. Monoclonal Immunoglobulin G was predominant followed by Immunoglobulin A. Significant correlations existed between hemoglobin level (r=0.446, p=0.002); platelet count (r=-0.347, p=0.041), serum calcium (r=0.471, p=0.006) and bone pains; as well as between urea level (r=-0.787, p=001), creatinine level (r=-0.853, p=0.001) and renal impairment respectively. PFs are associated with diabetes, peptic ulcer disease, hypertension, nephropathy, and arthritis. Bortezomib-based regimen was the choice treatment. Overall survival was 16 (69.6%) with 7 (30.4%) mortality. PF is common amongst the myeloma cohort with the spine being the most common site. It is associated with significant comorbidities like hypertension, diabetes, peptic ulcer disease, and paraplegia and is characterized by severe debilitating bone pains, anemia, hypercalcemia, raised plasma monoclonal immunoglobulin, renal impairment, loss of man-hour at work, and psychosocial imbalance. The impact of the fracture has increased morbidity and mortality and has reduced the median survival duration to as low as 4 years.

Serum IgG4-Negative Focal Autoimmune Pancreatitis Type 1 That Was Difficult to Diagnose Preoperatively Even with Frequent Endoscopic Ultrasound-Guided Fine-Needle Aspiration and Fine-Needle Biopsy: A Surgical Case Report

Introduction: Focal autoimmune pancreatitis (AIP) without elevated serum IgG4 levels presents a diagnostic challenge compared to pancreatic tumors, often leading to surgical intervention. Case Presentation: We report a case of serum IgG4-negative focal AIP type 1 in a 52-year-old male. Despite repeated endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) and fine-needle biopsy (FNB), preoperative diagnosis was elusive. Initially, a 30-mm hypoechoic mass in the pancreatic head was detected by ultrasonography, with dynamic computed tomography revealing well-defined borders and homogeneous delayed enhancement. Serum IgG4 levels were within the normal range (115 mg/dL). Two EUS-FNAs and one EUS-FNB failed to provide a definitive diagnosis, leading to suspicion of a solid pseudopapillary neoplasm and subsequent pancreaticoduodenectomy. Postoperative histopathology confirmed focal AIP type 1 with IgG4-positive plasma cells. After 38 months, there is no recurrence, and serum IgG4 levels remain normal. Conclusion: Diagnosis of focal AIP, particularly when serum IgG4 is negative, warrants consideration despite its difficulty. Imaging findings, such as a well-defined mass with homogeneous delayed enhancement, should prompt evaluation for characteristic features like capsule-like rim, pancreatic duct penetration, and biliary tract wall thickening.

Infectious meningitis. Why are the leptomeninges preferentially involved? Electron microscopic insights.

In infectious meningitis, pathogens preferentially attack the leptomeninges (pia mater and arachnoid) rather than the pachymeninges (dura mater). This study aims to provide ultra-anatomical insights from our extensive collection of electron microscopy images and propose mechanisms, highlighting structures that favor the introduction, adherence, colonization, and proliferation of microorganisms leading to spinal meningitis. Over several years, we analyzed an extensive collection of transmission and scanning electron microscopy images of human spinal meninges captured in our laboratories. Upon examining 378 of those images, we identified potential sites for the iatrogenic or hematogenic introduction and adherence of microorganisms, as well as sites for their colonization and proliferation. These included the outer surface of the spinal dural sac, structures within the epidural space, and the spinal dural sac itself, which comprises compact dura mater with interwoven collagen fibers and tightly bound arachnoid cells. Also, the subdural (extra-arachnoid) compartment, consisting of fragile neurothelial cells prone to rupture under force, formed an acquired spinal subdural space, a new subarachnoid compartment, limited by arachnoid trabeculae, that surrounded the nerve roots and spinal cord and the pia mater. Macrophages, fibroblasts, mast cells, and plasma cells were also observed within the dura mater, arachnoid layer, arachnoid trabeculae, and pia mater. These images illustrate how the characteristics of the meningeal layers could contribute to bacterial adhesion and proliferation at various locations, inducing selective inflammation during (iatrogenic) spinal meningitis. In addition, the images help to explain why magnetic resonance imaging enhancement appears preferentially at specific sites.

Cytogenetic abnormality in non-systemic light chain amyloidosis monoclonal gammopathy of renal significance: A field needs to be explored.

The role of cytogenetic abnormalities in non-systemic light chain amyloidosis monoclonal gammopathy of renal significance diseases still needs to be clarified. Bhutani etal. present the results of a study investigating the underlying plasma cell cytogenetic abnormalities in monoclonal immunoglobulin deposition disease (MIDD). The results show that translocation (11;14) is a common abnormality in MIDD and affects the presentation and outcomes. Commentary on: Bhutani etal. Translocation (11;14) is a common cytogenetic abnormality in clonal plasma cells in monoclonal immunoglobulin deposition disease. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19748.

Cohort profile update: the Johns Hopkins HIV clinical cohort, 1989-2023.

The Johns Hopkins HIV Clinical Cohort, established in 1989, links comprehensive, longitudinal clinical data for adults with HIV receiving care in the Johns Hopkins John G. Bartlett Specialty Practice in Baltimore, Maryland, USA, to aid in understanding HIV care and treatment outcomes. Data include demographics, laboratory results, inpatient and outpatient visit information and clinical diagnoses, and prescribed and dispensed medications abstracted from medical records. A subset of patients separately consents to self-report patient-centric outcomes on standardized instruments approximately every 6 months, and another subset separately consents to contribute plasma and peripheral blood mononuclear cells to a linked specimen repository approximately annually. The cohort has cumulatively enrolled over 8000 people, with just under 2000 on average attending ≥ 1 HIV primary care visit in any given year. The cohort reflects the HIV epidemic in Baltimore: in 2021, median age was 57, 64% of participants were male, 77% were non-Hispanic Black, and 37% acquired HIV through injection drug use. This update to the cohort profile of the Johns Hopkins HIV Clinical Cohort illustrates both how the population of people with HIV in Baltimore, Maryland, USA has changed over three decades, and we have adapted data collection procedures over three decades to ensure this long-running cohort remains responsive to patient characteristics and research gaps in the provision of care to people with HIV and substance use.

Preclinical Evaluation of STI-8811, a Novel Antibody Drug Conjugate Targeting BCMA for the Treatment of Multiple Myeloma.

Treatment for patients with Multiple Myeloma (MM) has experienced rapid development and improvement in recent years, however, patients continue to experience relapse and MM remains largely incurable. B cell maturation antigen (BCMA) has been widely recognized as a promising target for treatment of MM due to its exclusive expression in B cell linage cells and its critical role in the growth and survival of malignant plasma cells. Here, we introduce STI-8811, a BCMA-targeting antibody drug conjugate linked to an auristatin-derived duostatin payload via an enzymatically cleavable peptide linker, using our proprietary C-lock technology. STI-8811 exhibits target specific binding activity and rapid internalization, leading to G2/M cell cycle arrest, caspase 3/7 activation and apoptosis in BCMA-expressing tumor cells in vitro. Soluble BCMA (sBCMA) is shed by MM cells into the blood and increases with disease progression, competing for ADC binding and reducing its efficacy. We report enhanced cytotoxic activity in the presence of high levels of sBCMA compared to a belantamab mafodotin biosimilar (J6M0-mcMMAF). STI-8811 demonstrated greater in vivo activity than J6M0-mcMMAF in solid and disseminated multiple myeloma models, including tumor models with low BCMA expression and/or in large solid tumors representing soft tissue plasmacytomas. In Cynomolgus monkeys, STI-8811 was well tolerated, with toxicities consistent with other BCMA targeting ADCs with auristatin payloads in clinical studies. STI-8811 has the potential to outperform current clinical candidates with lower toxicity and higher activity under conditions found in patients with advanced disease.

A single dose of an ALVAC vector-based RABV virus-like particle candidate vaccine induces a potent immune response in mice, cats and dogs

Rabies, caused by the Rabies virus (RABV), is a highly fatal zoonotic disease. Existing rabies vaccines have demonstrated good immune efficacy, but the complexity of immunization procedures and high cost has impeded the elimination of RABV, particularly in the post-COVID-19 era. There is a pressing need for safer and more effective rabies vaccines that streamline vaccination protocols and reduce expense. To meet this need, we have developed a potential rabies vaccine candidate called ALVAC-RABV-VLP, utilizing CRISPR/Cas9 gene editing technology. This vaccine employs a canarypox virus vector (ALVAC) to generate RABV virus-like particles (VLPs). In mice, a single dose of ALVAC-RABV-VLP effectively activated dendritic cells (DCs), follicular helper T cells (Tfh), and the germinal center (GC)/plasma cell axis, resulting in durable and effective humoral immune responses. The survival rate of mice challenged with lethal RABV was 100%. Similarly, in dogs and cats, a single immunization with ALVAC-RABV-VLP elicited a stronger and longer-lasting antibody response. ALVAC-RABV-VLP induced superior cellular and humoral immunity in both mice and beagles compared to the commercial inactivated rabies vaccine. In conclusion, ALVAC-RABV-VLP induced robust protective immune responses in mice, dogs and cats, offering a novel, cost-effective, efficient, and promising approach for herd prevention of rabies.

Robust and persistent B-cell responses following SARS-CoV-2 vaccine determine protection from SARS-CoV-2 infection

IntroductionA clear immune correlate of protection from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has not been defined. We explored antibody, B-cell, and T-cell responses to the third-dose vaccine and relationship to incident SARS-CoV-2 infection.MethodsAdults in a prospective cohort provided blood samples at day 0, day 14, and 10 months after the third-dose SARS-CoV-2 vaccine. Participants self-reported incident SARS-CoV-2 infection. Plasma anti–SARS-CoV-2 receptor-binding domain (RBD) and spike-subunit-1 and spike-subunit-2 antibodies were measured. A sub-study assessed SARS-CoV-2–specific plasma and memory B-cell and memory T-cell responses in peripheral blood mononuclear cells by enzyme-linked immunospot. Comparative analysis between participants who developed incident infection and uninfected participants utilised non-parametric t-tests, Kaplan–Meier survival analysis, and Cox proportional hazard ratios.ResultsOf the 132 participants, 47 (36%) reported incident SARS-CoV-2 infection at a median 16.5 (16.25–21) weeks after the third-dose vaccination. RBD titres and B-cell responses, but not T-cell responses, increased after the third-dose vaccine. Whereas no significant difference in day 14 antibody titres or T-cell responses was observed between participants with and without incident SARS-CoV-2 infection, RBD memory B-cell frequencies were significantly higher in those who did not develop infection [10.0% (4.5%–16.0%) versus 4.9% (1.6%–9.3%), p = 0.01]. RBD titres and memory B-cell frequencies remained significantly higher at 10 months than day 0 levels (p < 0.01).DiscussionRobust antibody and B-cell responses persisted at 10 months following the third-dose vaccination. Higher memory B-cell frequencies, rather than antibody titres or T-cell responses, predicted protection from subsequent infection, identifying memory B cells as a correlate of protection.

Anaplastic Plasma Cell Myeloma With Peritoneal Involvement.

Multiple myeloma (MM) is a B-cell neoplasm that rounds 15% of all hematological malignancies. The typical clinical presentation of MM includes hypercalcemia, renal failure, anemia and bone lesion (CRAB). Effusions due to MM may occur due to secondary involvement of other organs and rarely are present at the initial diagnosis. Anaplastic myeloma (AMM) is rare morphological variant of multiple myeloma with predisposition of extramedullary affection. Herein, we describe a case of malignant plasmacytic ascites at disease onset of anaplastic multiple myeloma.

A case of Mycoplasma pneumoniae‐induced rash and mucositis with recent influenza vaccination

AbstractA 33‐year‐old female presented with coryzal symptoms, facial swelling, severe haemorrhagic stomatitis, blistering oral mucositis, conjunctival injection and a sparse targetoid rash on the back and face, requiring admission to hospital. She had received the seasonal influenza vaccination 3 days prior to feeling unwell. Differential diagnosis included erythema multiforme major (EMM) secondary to the influenza vaccine or Mycoplasma pneumoniae‐induced rash and mucositis (MIRM). Oropharyngeal swabs were negative on PCR for cutaneous viruses and Mycoplasma pneumoniae (MP). A skin biopsy from a targetoid lesion on the body showed full thickness epidermal necrosis with epidermal–dermal clefting, numerous civatte bodies and a moderate perivascular infiltrate of lymphocytes and plasma cells in the papillary dermis. She was successfully treated with oral prednisolone and azithromycin. Following discharge from hospital, the paired serological testing for MP returned positive, confirming a diagnosis of MIRM. Our case highlights the difficulties in detecting MP as two diagnostic methods yielded different results, and so we advocate performing both MP PCR and serology to maximise the yield and speed of diagnosis. Secondly, our case highlights the clinical challenge in differentiating MIRM from EMM or Stevens–Johnson syndrome, particularly if there is a potential drug trigger (in our case the influenza vaccine), as all these conditions can feature a severe mucositis with often indistinguishable histological findings. Correct diagnosis of MIRM is important for appropriate and timely administration of anti‐MP antibiotic therapy to facilitate recovery and minimise complications.

Immunomodulation of severe graves' disease: graves'-plasma cell depletion (PCD) trial

Immunomodulation of severe graves' disease: graves'-plasma cell depletion (PCD) trial

Abstract B047: Antigenic properties determine the outcome of B cell driven anti-tumor immunity

Abstract B cells have the capacity to elicit both anti- and pro-tumorigenic effects; yet the determinants of productive B cell responses in cancer remain elusive. Using a system where a B cell neoantigen is either soluble or tethered to the surface of pancreatic cancer cells, we demonstrate that membrane-tethered antigen is sufficient to elicit activation of anti-tumor immunity and reduce tumor growth in an NK cell-dependent manner. We also show that decreased antigen affinity to the BCR promotes regulatory B cell function which can be overcome by increased avidity of membrane-tethered antigen. Furthermore, soluble and membrane-tethered antigens drive qualitatively distinct germinal center, plasma cell, memory B cell, and Treg responses. Finally, we describe two classes of membrane-associated antigens that correlate with GC B cell signature and improved survival in pancreatic cancer patients. Thus, antigen localization impacts basic mechanisms governing B cell differentiation and the resulting immune response to solid malignancy with implications for vaccine engineering. Citation Format: Colleen Sturdevant, Nancy Kren, Harrison Silva, Ismael Gomez, Austin Hepperla, Yuliya Pylayeva-Gupta. Antigenic properties determine the outcome of B cell driven anti-tumor immunity [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B047.

Plasma cell granuloma middle ear: A rare lesion at a rare site

Plasma cell granuloma middle ear: A rare lesion at a rare site

Bone mechanical properties were altered in a mouse model of multiple myeloma bone disease

Multiple myeloma bone disease (MMBD) is characterized by the growth of malignant plasma cells in bone marrow, leading to an imbalance in bone (re)modeling favoring excessive resorption. Loss of bone mass and altered microstructure characterize MMBD in humans and preclinical animal models, although, no study to date has examined bone composition or material properties. We hypothesized that MMBD alters bone composition, mineral crystal properties and mechanical properties in the MOPC315.BM.Luc model after intra-tibial injection of myeloma cells and three weeks of daily in vivo tibial loading. Decreased cortical bone elastic modulus and hardness measured by nanoindentation of tibiae were observed in MM-injected mice compared to PBS-injected mice, whereas cortical bone composition, mineral crystal properties measured by Fourier-transform infrared imaging or small angle X-ray scattering, respectively remained unchanged. However, MM-injected mice had thinner cancellous bone mineral particles compared to PBS-injected mice. Mechanical loading did not lead to altered cortical bone composition, mineral structure, or mechanical properties in the context of MM. Unexpectedly, we observed the intra-tibial injection itself altered the material composition of bone, manifested by increased matrix mineralization and crystal size of the hydroxyapatite crystals in the bone matrix. In conclusion, our data suggest that mechanical stimuli can be used as an adjuvant bone anabolic therapy in patients with MMBD to rebuild bone with unaltered composition and mineral structure to reduce subsequent fracture risk.

Single-cell sequencing analysis of multiple myeloma heterogeneity and identification of new theranostic targets

Multiple myeloma (MM) is a heterogeneous and incurable tumor characterized by the malignant proliferation of plasma cells. It is necessary to clarify the heterogeneity of MM and identify new theranostic targets. We constructed a single-cell transcriptome profile of 48,293 bone marrow cells from MM patients and health donors (HDs) annotated with 7 continuous B lymphocyte lineages. Through CellChat, we discovered that the communication among B lymphocyte lineages between MM and HDs was disrupted, and unique signaling molecules were observed. Through pseudotime analysis, it was found that the differences between MM and HDs were mainly reflected in plasma cells. These differences are primarily related to various biological processes involving mitochondria. Then, we identified the key subpopulation associated with the malignant proliferation of plasma cells. This group of cells exhibited strong proliferation ability, high CNV scores, high expression of frequently mutated genes, and strong glucose metabolic activity. Furthermore, we demonstrated the therapeutic potential of WNK1 as a target. Our study provides new insights into the development of B cells and the heterogeneity of plasma cells in MM and suggests that WNK1 is a potential therapeutic target for MM.

A rare case of concurrent JAK2V617F-positive essential thrombocythemia, multiple myeloma, and colorectal adenocarcinoma

ABSTRACT Multiple myeloma (MM), essential thrombocythemia (ET), and colorectal adenocarcinoma (CA) are three distinct diseases. The co-occurrence of MM, ET, and CA in a single patient is exceedingly rare. Our study presents a remarkable case involving a 75-year-old patient who was simultaneously diagnosed with these three diseases. The JAK2V617F mutation was detected in the bone marrow with a variant allele frequency (VAF) of 13.38%, whereas the isolated CD138-positive plasma cells exhibited a significantly lower VAF of 0.38%. This notable difference implies the potential for separate origins of MM and ET. Additionally, the patient responded well to a bortezomib-based treatment regimen, despite the absence of specific therapy for ET. We believe that our findings add new understanding to these rare diseases and encourage further research in this area.