Explore the vast range of titles available.

Despite the clinical success of anti-CD20 monoclonal antibodies (mAbs) such as rituximab in the treatment of B-cell lymphoma, therapeutic resistance and relapse remain significant challenges, particularly in tumors with low or heterogeneous CD20 expression resulting from antigen loss or phenotypic shifts. To address this limitation, new therapeutic strategies are needed that act independently of CD20 while maintaining robust immune effector engagement. CO-005 is a humanized anti-CD47 fusion protein designed to simultaneously disrupt the CD47-SIRPα checkpoint and induce direct programmed cancer cell death (PCCD) distinct from other anti-CD47 agents. The capacity of therapeutic mAbs to induce PCCD was assessed in lymphoma cell lines by flow cytometric detection of cell death and apoptotic markers. Antibody binding, phagocytic activity, and mechanistic analyses assessed intracellular signaling events associated with PCCD were measured by flow cytometry following treatment. The antitumor activity of CO-005 was evaluated in NOD-scid IL2Rγnull (NSG) mice bearing subcutaneous lymphoma xenografts, with efficacy and survival outcomes assessed for CO-005 as monotherapy and in combination with rituximab. CO-005 demonstrated potent and durable antitumor activity across multiple lymphoma xenograft models, including rituximab-resistant tumors model. CO-005 shares key mechanistic features with therapeutic anti-CD20 antibodies independent of CD20 signaling, including the induction of type III programmed cell death via receptor capping, calcium flux, reactive oxygen species generation, and actin cytoskeleton dependence, accompanied by surface calreticulin exposure. In vivo, CO-005 triggered robust intratumoral PCCD and remodelled the tumor microenvironment, characterized by increased macrophage and neutrophil infiltration, thereby enhancing innate immune activation and supporting a dual-mechanism mode of action that couples direct cancer cell killing with myeloid engagement. These findings position CO-005 as a mechanistically distinct and immunologically active therapeutic with the potential to overcome limitations of both CD20- and CD47-directed therapies and expand treatment options for B-cell lymphoma.

Untreated vitamin B12 (B12) deficiency may cause delayed development in infants. Several newborn screening (NBS) programs have reported an increased detection rate of B12 deficiency when second-tier dried blood spot (DBS) analyses of total homocysteine (tHcy) and methylmalonic acid (MMA) are included. This is a retrospective study of newborns reported from NBS during 2012–2021 with confirmed B12 deficiency. DBSs were retrieved from the NBS biobank for second-tier MMA and tHcy analysis. Thirty-one newborns were diagnosed with B12 deficiency out of 552970 screened. Twenty-five were ascertained from sixty-one false positive (FP) cases of methylmalonic acidemia and propionic acidemia (PA), and six infants screened positive for other NBS metabolic diseases with propionylcarnitine (C3) in the normal range. In the original DBS, 7/23 (30%) and 12/23 (52%) of B12-deficient newborns with FP methylmalonic acidemia/PA had MMA and tHcy > 99th percentile. B12 deficiency was a common differential diagnosis of screening positive for methylmalonic and PA. C3 failed to identify a subset of newborns with B12 deficiency. Second-tier MMA and tHcy analyses in the DBS showed suboptimal sensitivity for identifying infants with B12 deficiency. The shortcomings of NBS should be acknowledged when considering B12 deficiency as a primary target of NBS panels.

Newborn screening for congenital hypothyroidism remains challenging decades after broad implementation worldwide. Testing protocols are not uniform in terms of targets (TSH and/or T4) and protocols (parallel vs. sequential testing; one or two specimen collection times), and specificity (with or without collection of a second specimen) is overall poor. The purpose of this retrospective study is to investigate the potential impact of multivariate pattern recognition software (CLIR) to improve the post-analytical interpretation of screening results. Seven programs contributed reference data (N = 1,970,536) and two sets of true (TP, N = 1369 combined) and false (FP, N = 15,201) positive cases for validation and verification purposes, respectively. Data were adjusted for age at collection, birth weight, and location using polynomial regression models of the fifth degree to create three-dimensional regression surfaces. Customized Single Condition Tools and Dual Scatter Plots were created using CLIR to optimize the differential diagnosis between TP and FP cases in the validation set. Verification testing correctly identified 446/454 (98%) of the TP cases, and could have prevented 1931/5447 (35%) of the FP cases, with variable impact among locations (range 4% to 50%). CLIR tools either as made here or preferably standardized to the recommended uniform screening panel could improve performance of newborn screening for congenital hypothyroidism.

Severe combined immunodeficiency (SCID) and other T cell lymphopenias can be detected during newborn screening (NBS) by measuring T cell receptor excision circles (TRECs) in dried blood spot (DBS) DNA. Second tier next generation sequencing (NGS) with an amplicon based targeted gene panel using the same DBS DNA was introduced as part of our prospective pilot research project in 2015. With parental consent, 21 000 newborns were TREC-tested in the pilot. Three newborns were identified with SCID, and disease-causing variants in , and were confirmed by NGS on the initial DBS DNA. The molecular findings directed follow-up and therapy: the -SCID underwent early hematopoietic stem cell transplantation (HSCT) without any complications; the leaky SCID received prophylactic antibiotics, antifungals, and immunoglobulin infusions, and underwent HSCT at 1 year of age. The child with -SCID had complete Hirschsprung disease and died at 1 month of age. Since January 2018, all newborns in Norway have been offered NBS for SCID using 1st tier TRECs and 2nd tier gene panel NGS on DBS DNA. During the first 20 months of nationwide SCID screening an additional 88 000 newborns were TREC tested, and four new SCID cases were identified. Disease-causing variants in , and were molecularly confirmed on day 8, 15, 8 and 6, respectively after birth, using the initial NBS blood spot. Targeted gene panel NGS integrated into the NBS algorithm rapidly delineated the specific molecular diagnoses and provided information useful for management, targeted therapy and follow-up i.e., X rays and CT scans were avoided in the radiosensitive SCID. Second tier targeted NGS on the same DBS DNA as the TREC test provided instant confirmation or exclusion of SCID, and made it possible to use a less stringent TREC cut-off value. This allowed for the detection of leaky SCIDs, and simultaneously reduced the number of control samples, recalls and false positives. Mothers were instructed to stop breastfeeding until maternal (CMV) status was determined. Our limited data suggest that shorter time-interval from birth to intervention, may prevent breast milk transmitted CMV infection in classical SCID.

In the fetus, the cardiac neural crest gives rise to both the thymus and the conotruncus of the heart. In newborn screening for severe T-cell lymphopenia neonates with congenital heart defects may be detected. In this study, we investigated the occurrence of T-cell lymphopenia in neonates with or without 22q11.2 deletion syndrome (del) suffering from heart defects. This retrospective cohort study included 125 patients with heart defects. T-cell receptor excision circles (TRECs), a measure for T-cell lymphopenia, were quantified by RT-PCR using stored newborn screening blood spots. Three patient groups were compared: non-conotruncal defects ( n  = 57), conotruncal defects ( n  = 42), and 22q11.2 del with conotruncal defects ( n  = 26). Significantly lower TREC values were detected in patients with 22q11.2 del and conotruncal heart defects compared to those with non-syndromic conotruncal ( p  < 0.001) and non-conotruncal ( p  < 0.001) defects. In contrast, no significant difference was found between patients with non-syndromic conotruncal and non-conotruncal heart defects ( p  = 0.152). Low TREC levels were obtained in neonates treated with heart surgery/intervention within 2 weeks after birth and in those with a fatal outcome ( p  = 0.02) independent of patient group. A correlation was found between low TREC numbers and oxygen saturation, SpO 2 below 95% ( p  = 0.017). The SpO 2 was significantly lower in the non-syndromic conotruncal group compared to non-conotruncal ( p  < 0.001) and 22q11.2 del group ( p  = 0.015). No correlation was found between low neonatal TRECs and infections needing hospitalization later in life ( p  = 0.135). Patients with 22q11.2 del and conotruncal defects have significantly lower TREC levels compared to patients with heart defects without this syndrome.

PurposeImmunodeficiency is one of the key features of 22q11.2 deletion syndrome (del), and it is seen in approximately 75% of the patients. The degree of immunodeficiency varies widely, from no circulating T cells to normal T cell counts. It has been hypothesized that the low number of T cells may at least in part be due to increased apoptosis of T cells. Increased spontaneous T cell apoptosis has been reported in one patient with 22q11.2del, but this has not been further investigated.MethodsA national cohort of patients with a proven heterozygous deletion of chromosome 22q11.2 diagnosed by FISH or MLPA and a group of age and sex matched controls were studied. Spontaneous and activation-induced apoptosis, in addition to FAS expression on lymphocytes, were measured using flow cytometry. Serum levels of FASL were analyzed using ELISA.ResultsThere was no increased spontaneous apoptosis in patients with 22q11.2del. Upon activation, anti-FAS-induced apoptosis was significantly increased in patients compared to those in controls, while there was no difference in activation induced cell death or activated cell autonomous death. We also found a significant increase in expression of FAS on freshly isolated lymphocytes from patients, while there was no difference in serum levels of FASL. Patients with congenital heart defects (CHD) had significantly higher serum levels of FASL compared to non-CHD patients.ConclusionWe have shown increased FAS expression on lymphocytes from patients with 22q11.2del as well as increased levels of FASL in patients with CHD. Those changes may contribute to the pathophysiology of the 22q11.2del.

Purpose Newborns with severe T-cell lymphopenia, including those with 22q11.2 deletion syndrome (DS), have low numbers of T-cell receptor excision circles (TRECs). The aim of this study was to determine a possible correlation between neonatal TRECs in 22q11.2DS and the development of different phenotypes to elucidate the prognostic value of TREC in this disease. Methods In this national survey including 46 patients with 22q11.2DS born after 2005, TREC levels were determined using stored newborn screening blood spots on filter cards. Patients were grouped into quartiles according to their TREC values, except the two infants with thymus aplasia. Results The two patients with thymic aplasia had no detectable TREC. The rest had no severe clinical immunodeficiency. There was a significant correlation between low TRECs and the proportion of patients with CD3 + CD4 + T-cells below the 5th percentile of healthy infants ( p  = 0.027) as well as the proportion with an abnormal thymus feature either no thymus or remnant thymus as observed during heart surgery ( p  = 0.022). Significantly lower TRECs ( p  = 0.019) were found in patients with cardiac defects compared to no such defects. Patients within the lowest quartile of TREC values (<71 TRECs/μL, n  = 11) had more frequent severe cardiac defects than the other quartiles ( p  = 0.010). Eight of these patients in the lowest quartile needed an operation/intervention within two weeks after birth or died because of a cardiac defect. Conclusion The low TREC values not only correlate with decreased T-cell immunity, but also with the occurrence of heart defects in the patients.

Neonatal screening (NBS) was initiated in Europe during the 1960s with the screening for phenylketonuria. The panel of screened disorders (“conditions”) then gradually expanded, with a boost in the late 1990s with the introduction of tandem mass spectrometry (MS/MS), making it possible to screen for 40–50 conditions using a single blood spot. The most recent additions to screening programmes (screening for cystic fibrosis, severe combined immunodeficiency and spinal muscular atrophy) were assisted by or realised through the introduction of molecular technologies. For this survey, we collected data from 51 European countries. We report the developments between 2010 and 2020 and highlight the achievements reached with the progress made in this period. We also identify areas where further progress can be made, mainly by exchanging knowledge and learning from experiences in neighbouring countries. Between 2010 and 2020, most NBS programmes in geographical Europe matured considerably, both in terms of methodology (modernised) and with regard to the panel of conditions screened (expanded). These developments indicate that more collaboration in Europe through European organisations is gaining momentum. We can only accomplish the timely detection of newborn infants potentially suffering from one of the many rare diseases and take appropriate action by working together.

Newborn screening (NBS) is an important part of public healthcare systems in many countries. The provision of information to parents about NBS is now recognised as an integral part of the screening process. Informing parents on all aspects of screening helps to achieve the benefits, promote trust and foster support for NBS. Therefore, policies and guidelines should exist to govern how the information about NBS is provided to parents, taking into account evidence-based best practices. The purpose of our survey was to explore whether any legally binding provisions, guidelines or recommendations existed pertaining to the provision of information about NBS to parents across Europe. Questions were designed to determine the regulatory process of when, by whom and how parents should be informed about screening. Twenty-seven countries participated in the survey. The results indicated that most countries had some sort of legal framework or guidelines for the provision of information to parents. However, only 37% indicated that the provision of information was required prenatally. The majority of countries were verbally informing parents with the aid of written materials postnatally, just prior to sample collection. Information was provided by a neonatologist, midwife or nurse. A website dedicated to NBS was available for 67% of countries and 89% had written materials about NBS for parents. The survey showed that there is a lack of harmonisation among European countries in the provision of information about NBS and emphasised the need for more comprehensive guidelines at the European level.

Children with high-risk neuroblastoma (NB) have a poor clinical outcome. The purpose of the present study was to evaluate different strategies for immunotherapy of high-risk NB based on vaccination with antigen-loaded dendritic cells (DCs). DCs are professional antigen-presenting cells with the ability to induce antitumor T-cell responses. We have compared DCs either loaded with apoptotic tumor cells or transfected with mRNA from the NB cell line HTB11 SK-N-SH, for their capacity to induce T-cell responses in vitro . Monocyte-derived DCs from healthy donors were loaded with tumor-derived antigens in the form of apoptotic cells or mRNA, matured and used to prime autologous T cells in vitro . After 1 week, T-cell responses against antigen-loaded DCs were measured by ELISPOT assay. DCs loaded with apoptotic NB cells or transfected with NB-cell mRNA were both able to efficiently activate autologous T cells. Both T cells of the CD8+ and CD4+ subset were activated. T cells activated by NB mRNA transfected DCs extensively crossreacted with DCs loaded with apoptotic NB cells and vice versa . The results indicate that loading of DCs with apoptotic NB cells or transfection with tumor mRNA represent promising strategies for development of individualized cancer vaccines/cancer gene therapy in treatment of NB.