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SAGE Open Medical Case Reports 2024Multiple intestinal atresia with combined immune deficiency is a severe autosomal recessive disorder caused by the tetratricopeptide repeat domain 7A () gene deficiency,...
Multiple intestinal atresia with combined immune deficiency is a severe autosomal recessive disorder caused by the tetratricopeptide repeat domain 7A () gene deficiency, which is characterized by extensive intestinal defects with immune deficiency. This report describes a fetus with deficiency who developed meconium peritonitis in utero. Evidence suggests that patients with deficiency present with intestinal defects as early as in utero. In this case, intestinal abnormalities were considered during the prenatal examination at week 28, and chromosome and genetic tests were performed. The results indicated that the fetus had a complex heterozygous mutation. The male infant underwent surgical treatment after birth and developed severe infection and sepsis, which confirmed the presence of multiple intestinal atresia with combined immune deficiency. Our case suggests an association between meconium peritonitis and the gene deficiency, indicating the possibility of severe intestinal defects and immune deficiencies after birth and guiding subsequent fetal treatment choices.
PubMed: 38292879
DOI: 10.1177/2050313X241227129 -
The Journal of Allergy and Clinical... May 2024During the past 20 years, gene editing has emerged as a novel form of gene therapy. Since the publication of the first potentially therapeutic gene editing platform for... (Review)
Review
During the past 20 years, gene editing has emerged as a novel form of gene therapy. Since the publication of the first potentially therapeutic gene editing platform for genetic disorders, increasingly sophisticated editing technologies have been developed. As with viral vector-mediated gene addition, inborn errors of immunity are excellent candidate diseases for a corrective autologous hematopoietic stem cell gene editing strategy. Research on gene editing for inborn errors of immunity is still entirely preclinical, with no trials yet underway. However, with editing techniques maturing, scientists are investigating this novel form of gene therapy in context of an increasing number of inborn errors of immunity. Here, we present an overview of these studies and the recent progress moving these technologies closer to clinical benefit.
Topics: Humans; Gene Editing; Genetic Therapy; Animals; CRISPR-Cas Systems; Agammaglobulinemia; Severe Combined Immunodeficiency; Hematopoietic Stem Cell Transplantation
PubMed: 38246560
DOI: 10.1016/j.jaip.2024.01.019 -
AMIA ... Annual Symposium Proceedings.... 2023Electronic health records (EHRs) contain a wealth of information that can be used to further precision health. One particular data element in EHRs that is not only...
Leveraging informative missing data to learn about acute respiratory distress syndrome and mortality in long-term hospitalized COVID-19 patients throughout the years of the pandemic.
Electronic health records (EHRs) contain a wealth of information that can be used to further precision health. One particular data element in EHRs that is not only under-utilized but oftentimes unaccounted for is missing data. However, missingness can provide valuable information about comorbidities and best practices for monitoring patients, which could save lives and reduce burden on the healthcare system. We characterize patterns of missing data in laboratory measurements collected at the University of Pennsylvania Hospital System from long-term COVID-19 patients and focus on the changes in these patterns between 2020 and 2021. We investigate how these patterns are associated with comorbidities such as acute respiratory distress syndrome (ARDS), and 90-day mortality in ARDS patients. This work displays how knowledge and experience can change the way clinicians and hospitals manage a novel disease. It can also provide insight into best practices when it comes to patient monitoring to improve outcomes.
Topics: Humans; COVID-19; SARS-CoV-2; Pandemics; Respiratory Distress Syndrome
PubMed: 38222425
DOI: No ID Found -
MedRxiv : the Preprint Server For... Dec 2023Electronic health records (EHRs) contain a wealth of information that can be used to further precision health. One particular data element in EHRs that is not only...
Leveraging informative missing data to learn about acute respiratory distress syndrome and mortality in long-term hospitalized COVID-19 patients throughout the years of the pandemic.
Electronic health records (EHRs) contain a wealth of information that can be used to further precision health. One particular data element in EHRs that is not only under-utilized but oftentimes unaccounted for is missing data. However, missingness can provide valuable information about comorbidities and best practices for monitoring patients, which could save lives and reduce burden on the healthcare system. We characterize patterns of missing data in laboratory measurements collected at the University of Pennsylvania Hospital System from long-term COVID-19 patients and focus on the changes in these patterns between 2020 and 2021. We investigate how these patterns are associated with comorbidities such as acute respiratory distress syndrome (ARDS), and 90-day mortality in ARDS patients. This work displays how knowledge and experience can change the way clinicians and hospitals manage a novel disease. It can also provide insight into best practices when it comes to patient monitoring to improve outcomes.
PubMed: 38196626
DOI: 10.1101/2023.12.18.23300181 -
BMC Cancer Jan 2024Most cancer patients ultimately die from the consequences of distant metastases. As metastasis formation consumes energy mitochondria play an important role during this...
Most cancer patients ultimately die from the consequences of distant metastases. As metastasis formation consumes energy mitochondria play an important role during this process as they are the most important cellular organelle to synthesise the energy rich substrate ATP, which provides the necessary energy to enable distant metastasis formation. However, mitochondria are also important for the execution of apoptosis, a process which limits metastasis formation. We therefore wanted to investigate the mitochondrial content in ovarian cancer cells and link its presence to the patient's prognosis in order to analyse which of the two opposing functions of mitochondria dominates during the malignant progression of ovarian cancer. Monoclonal antibodies directed against different mitochondrial specific proteins, namely heat shock proteins 60 (HSP60), fumarase and succinic dehydrogenase, were used in immunohistochemistry in preliminary experiments to identify the antibody most suited to detect mitochondria in ovarian cancer cells in clinical tissue samples. The clearest staining pattern, which even delineated individual mitochondria, was seen with the anti-HSP60 antibody, which was used for the subsequent clinical study staining primary ovarian cancers (n = 155), borderline tumours (n = 24) and recurrent ovarian cancers (n = 26). The staining results were semi-quantitatively scored into three groups according to their mitochondrial content: low (n = 26), intermediate (n = 50) and high (n = 84). Survival analysis showed that high mitochondrial content correlated with a statistically significant overall reduced survival rate In addition to the clinical tissue samples, mitochondrial content was analysed in ovarian cancer cells grown in vitro (cell lines: OVCAR8, SKOV3, OVCAR3 and COV644) and in vivo in severe combined immunodeficiency (SCID) mice.In in vivo grown SKOV3 and OVCAR8 cells, the number of mitochondria positive cells was markedly down-regulated compared to the in vitro grown cells indicating that mitochondrial number is subject to regulatory processes. As high mitochondrial content is associated with a poor prognosis, the provision of high energy substrates by the mitochondria seems to be more important for metastasis formation than the inhibition of apoptotic cell death, which is also mediated by mitochondria. In vivo and in vitro grown human ovarian cancer cells showed that the mitochondrial content is highly adaptable to the growth condition of the cancer cells.
Topics: Animals; Mice; Humans; Female; Ovarian Neoplasms; Apoptosis; Cell Line, Tumor; Neoplasm Recurrence, Local; Mitochondria; Antibodies, Monoclonal
PubMed: 38191325
DOI: 10.1186/s12885-023-11667-8 -
Journal of Translational Autoimmunity Jun 2024Thymoma with Immunodeficiency (Good's Syndrome, GS) is a rare association between thymoma and immunodeficiency, first described over 60 years ago. Patients with GS...
Thymoma with Immunodeficiency (Good's Syndrome, GS) is a rare association between thymoma and immunodeficiency, first described over 60 years ago. Patients with GS typically present with thymomas, reduced or absent B cells in the peripheral blood, hypogammaglobulinemia, and defects in cell-mediated immunity. We report the case of a 67-year-old woman diagnosed with GS following the development of a progressive, severe, refractory pulmonary infection and diffuse panbronchiolitis (DPB). She also had diabetes, characterized by anti-glutamic acid decarboxylase antibody positivity, leading to a diagnosis of latent autoimmune diabetes in adults (LADA). A thorough review of existing literature revealed that GS is often confirmed after multiple episodes of opportunistic infections or autoimmune diseases post-thymoma surgery. Due to their immunodeficiency, GS patients frequently suffer from recurrent infections over extended periods, and some succumb to severe infections. Regular immunoglobulin infusions may be effective in treating GS.
PubMed: 38188041
DOI: 10.1016/j.jtauto.2023.100230 -
The Journal of Allergy and Clinical... Feb 2024Cartilage-hair hypoplasia (CHH) is a syndromic inborn error of immunity caused by variants in the gene. Disease manifestations vary, and their ability to predict...
Shorter birth length and decreased T-cell production and function predict severe infections in children with non-severe combined immunodeficiency cartilage-hair hypoplasia.
BACKGROUND
Cartilage-hair hypoplasia (CHH) is a syndromic inborn error of immunity caused by variants in the gene. Disease manifestations vary, and their ability to predict outcome is uncertain. The optimal management of infants with CHH who do not fulfill classical severe combined immunodeficiency (SCID) criteria is unknown.
OBJECTIVE
We described longitudinal changes in lymphocyte counts during childhood and explored correlations of early childhood clinical and laboratory features with clinical outcomes on long-term follow-up of CHH patients.
METHODS
Immunologic laboratory parameters, birth length, the presence of Hirschsprung disease, and severe anemia correlated to the primary end points of respiratory and severe infections. We implemented traditional statistical methods and machine learning techniques.
RESULTS
Thirty-two children with CHH were followed up for 2.7 to 22.1 years (median, 8.2 years, in total 331.3 patient-years). None of the patients had classical SCID. Median lymphocyte subclass counts, apart from CD16/56 cells, were subnormal throughout childhood, but did not show age-related decline seen in healthy children. Low immunoglobulin levels were uncommon and often transient. Respiratory and/or severe infections developed in 14 children, 8 of whom had low naive T-cell counts, absent T-cell receptor excision circles, and/or partial "leaky" SCID-level lymphopenia. Shorter birth length correlated with lower lymphocyte counts and the occurrence of infections. Of the laboratory parameters, decreased naive T-cell counts and abnormal lymphocyte proliferation responses contributed most to the development of severe infections. In addition, all participants with absent T-cell receptor excision circles developed severe infections. Opportunistic infections occurred only in children with leaky SCID-level lymphopenia.
CONCLUSIONS
Shorter birth length and a combination of laboratory abnormalities can predict the development of severe infections in children with CHH.
PubMed: 38187867
DOI: 10.1016/j.jacig.2023.100190 -
Journal of Clinical Immunology Jan 2024Newborn screening (NBS) for severe combined immunodeficiency (SCID) has been introduced in various countries with the aim of reducing morbidity and mortality. However,...
Newborn screening (NBS) for severe combined immunodeficiency (SCID) has been introduced in various countries with the aim of reducing morbidity and mortality. However, studies analyzing outcomes before and after the implementation of NBS programs remain limited. This study sought to compare the outcomes of SCID patients identified through Switzerland's national SCID NBS program, introduced in January 2019, with those of a historical cohort diagnosed between 2007 and 2019. The study included seven patients (32%) identified through NBS, and 15 (68%) born before NBS implementation and diagnosed based on clinical signs. Children in the NBS group were younger at diagnosis (median age 9 days vs 9 months, P = .002) and at hematopoietic stem cell transplantation (HSCT, median age 5 months vs 11 months, P = .003) compared to the clinical group. The NBS group had a lower incidence of infections before HSCT (29% vs 93%, P = .004). Although not statistically significant, the overall survival rate on last follow-up was higher in the NBS group (86% vs 67%, P = .62). Importantly, patients with active infections undergoing HSCT had a significantly lower overall survival probability compared to those without (P = .01). In conclusion, the introduction of NBS in Switzerland has led to earlier and often asymptomatic diagnosis of affected children, enabling timely intervention, infection prevention, and prompt treatment. These factors have contributed to higher survival rates in the NBS group. These findings underscore the critical importance of NBS for SCID, offering potential life-saving benefits through early detection and intervention.
Topics: Child; Infant, Newborn; Humans; Infant; Switzerland; Neonatal Screening; Severe Combined Immunodeficiency; Morbidity; Hematopoietic Stem Cell Transplantation
PubMed: 38165471
DOI: 10.1007/s10875-023-01640-2 -
Journal of Clinical Immunology Dec 2023
Topics: Humans; Infant, Newborn; B-Cell CLL-Lymphoma 10 Protein; Neonatal Screening; Severe Combined Immunodeficiency
PubMed: 38159157
DOI: 10.1007/s10875-023-01646-w -
Molecules (Basel, Switzerland) Dec 2023We describe the development and validation of an HPLC-MS/MS method to assess the pharmacokinetics and tumour distribution of ZST316, an arginine analogue with inhibitory...
Development of a HPLC-MS/MS Method to Assess the Pharmacokinetics and Tumour Distribution of the Dimethylarginine Dimethylaminohydrolase 1 Inhibitors ZST316 and L-257 in a Xenograft Model of Triple-Negative Breast Cancer in Mice.
We describe the development and validation of an HPLC-MS/MS method to assess the pharmacokinetics and tumour distribution of ZST316, an arginine analogue with inhibitory activity towards dimethylarginine dimethylaminohydrolase 1 (DDAH1) and vasculogenic mimicry, and its active metabolite L-257 in a xenograft model of triple-negative breast cancer (TNBC). The method proved to be reproducible, precise, and highly accurate for the measurement of both compounds in plasma and tumour tissue following acute and chronic (five days) intraperitoneal administration of ZST316 (30 mg/Kg daily) in six-week-old severe combined immunodeficiency disease (SCID) mice inoculated with MDA-MB-231 TNBC cells. ZST316 was detected in tumour tissue and plasma after 1 h (6.47 and 9.01 μM, respectively) and 24 h (0.13 and 0.16 μM, respectively) following acute administration, without accumulation during chronic treatment. Similarly, the metabolite L-257 was found in tumour tissue and plasma after 1 h (15.06 and 8.72 μM, respectively) and 24 h (0.17 and 0.17 μM, respectively) following acute administration of ZST316, without accumulation during chronic treatment. The half-life after acute and chronic treatment ranged between 4.4-7.1 h (plasma) and 4.5-5.0 h (tumour) for ZST316, and 4.2-5.3 h (plasma) and 3.6-4.9 h (tumour) for L-257. The results of our study demonstrate the (a) capacity to accurately measure ZST316 and L-257 concentrations in plasma and tumour tissue in mice using the newly developed HPLC-MS/MS method, (b) rapid conversion of ZST316 into L-257, (c) good intra-tumour penetration of both compounds, and (d) lack of accumulation of both ZST316 and L-257 in plasma and tumour tissue during chronic administration. Compared to a previous method developed by our group to investigate ZST316 in plasma, the main advantages of the new method include a wider range of linearity which reduces the need for dilutions and the combined assessment of ZST316 and L-257 in plasma and tumour tissue which limits the required amount of matrix. The new HPLC-MS/MS method is useful to investigate the in vivo effects of ZST316 and L-257 on vasculogenic mimicry, tumour mass, and metastatic burden in xenograft models of TNBC.
Topics: Humans; Mice; Animals; Triple Negative Breast Neoplasms; Tandem Mass Spectrometry; Heterografts; Liquid Chromatography-Mass Spectrometry
PubMed: 38138547
DOI: 10.3390/molecules28248056