The genetic landscape of chromosomal aberrations in 3776 Vietnamese fetuses with clinical anomalies during pregnancy.

Background: Copy number variation sequencing (CNV-seq) is a powerful tool to discover structural genomic variation, but limitations associated with its retrospective study design and inadequate diversity of participants can be impractical for clinical application. Aim: This study aims to use CNV-seq to assess chromosomal aberrations in pregnant Vietnamese women. Materials & methods: A large-scale study was conducted on 3776 pregnant Vietnamese women with abnormal ultrasound findings. Results: Chromosomal aberrations were found in 448 (11.86%) women. Of these, 274 (7.26%) had chromosomal aneuploidies and 174 (4.61%) carried pathogenic/likely pathogenic CNVs. Correlations were established between chromosomal aberrations and various phenotypic markers. Conclusion: This comprehensive clinical study illuminates the pivotal role of CNV-seq in prenatal diagnosis for pregnancies featuring fetal ultrasound anomalies.

[Box: see text].

De novo variants of dominant monogenic disorders in Vietnam detected by a noninvasive prenatal test: a case series.

Background: Noninvasive prenatal tests for monogenic diseases (NIPT-SGG) have recently been reported as helpful in early-stage antenatal screening. Our study describes the clinical and genetic features of cases identified by NIPT-SGG. Materials & methods: In a cohort pregnancy with abnormal sonograms, affected cases were confirmed by invasive diagnostic tests concurrently, with NIPT-SGG targeting 25 common dominant single-gene diseases. Results: A total of 13 single-gene fetuses were confirmed, including Noonan and Costello syndromes, thanatophoric dysplasia, achondroplasia, osteogenesis imperfecta and Apert syndrome. Two novel variants seen were tuberous sclerosis complex (TSC2 c.4154G>A) and Alagille syndrome (JAG1 c.3452del). Conclusion: NIPT-SGG and standard tests agree on the results for 13 fetuses with monogenic disorders. This panel method of screening can benefit high-risk Vietnamese pregnancies, but further research is encouraged to expand on the causative gene panel.

Bluegrass Biodesign: Why an Integrated Biomedical Engineering Curriculum is Crucial for Medical Education.

Background Medical education often overlooks the significance of design and innovation literacy, resulting in a knowledge gap in undergraduate medical education (UME) regarding formal training in these areas. Incorporating innovation into UME's core curriculum is crucial as future physicians will encounter evolving technologies, and fostering a transdisciplinary approach can enable collaborative problem-solving and improve patient health outcomes. Methodology We developed a comprehensive medical biodesign curriculum focused on innovation, including problem identification, prototype testing, and product commercialization. Participants were selected based on applications, interviews, and diverse criteria. A survey was conducted before and after the program to assess students' biodesign experiences and knowledge, with data analyzed using descriptive statistics and paired t-tests. Results Of the 41 participants, 24 (58.5%) completed both pre- and post-program surveys. These five-point Likert surveys showed a significant shift from pre-program to responses demonstrating increased "comfort levels in explaining and applying biodesign principles" (p < 0.0001). Specifically, the "comfort level in taking a product to market" increased from 33% to 67% (p = 0.01), while the "comfort level in applying the biodesign process" increased from 29% to 92% (p < 0.0001). Moreover, 58.3% of participants expressed interest in continuing their current projects, and 70.8% of students stated feeling confident in generating ideas and solutions with their team members. Conclusions The medical biodesign curriculum demonstrated success in exposing undergraduate medical and engineering students to the concepts of medical innovation and biodesign. The program has led to a significant improvement in students' knowledge and comfort levels in applying the biodesign process and taking a product to market. The high level of interest and participation in the program highlight the need for incorporating innovative training in UME to foster creativity and prepare future physicians to contribute to the advancements in healthcare.

Screening Y Chromosome Microdeletion in 1121 Men with Low Sperm Concentration and the Outcomes of Microdissection Testicular Sperm Extraction (mTESE) for Sperm Retrieval from Azoospermic Patients.

Background: The Y chromosome has a specific region, namely the Azoospermia Factor (AZF) because azoospermia is typically reported in the microdeletion of the AZF region. This study aims to assess the characteristics of AZF microdeletion after screening a massive number of low sperm concentration men; and the Microdissection testicular sperm extraction (mTESE) outcomes for retrieving sperm from azoospermic patients. Materials and Methods: This retrospective multiple-center study enrolled a total of 1121 men with azoospermia, cryptozoospermia, and severe oligozoospermia from December 2016 to June 2022. An extension analysis used a total of 17 STSs to detect the position-occurring microdeletion in the AZF region (AZFa, b, c, and/or d loci). Microdissection testicular sperm extraction (mTESE) was performed to retrieve sperm in azoospermic men diagnosed AZFc microdeletion. Results: One hundred and fifty-three men carried AZF microdeletion were detected in the 1121 participants (13.64%). The incidences of AZF microdeletion were confined to AZF a, c, and d regions, both individual and concurrence, with the most common in the AZFc region accounting for 49.67%; There was no significant difference in clinical and paraclinical characteristics between the deleted regions, except FSH level (highest in AZFa microdeletion, p = 0.043). The AZFc region was the most common type of AZF microdeletion (49.67%), including complete microdeletion (4 patients) and gr/gr partial microdeletion (39 patients) with 50.00% and 63.63% in the success rate of mTESE, separately. Conclusion: The absence of AZFa and/or AZFb regions often express the most severe phenotype - azoospermia and the increasing FSH level. The AZFc region played the most common microdeletion. Microdissection testicular sperm extraction (mTESE) was the possible therapy for sperm retrieval from the testis of azoospermia men having AZFc microdeletion.

Developing and validating noninvasive prenatal testing for de novo autosomal dominant monogenic diseases in Vietnam.

Background: Over 60% of single-gene diseases in newborns are autosomal dominant variants. Noninvasive prenatal testing for monogenic conditions (NIPT-SGG) is cost-effective and timesaving, but not widely applied. This study introduces and validates NIPT-SGG in detecting 25 monogenic conditions. Methods: NIPT-SGG with a 30-gene panel applied next-generation sequencing and trio assays to confirm de novo variants. Diagnostic tests confirmed NIPT-detected cases. Results: Among 93 pregnancies with ultrasound findings, 11 (11.8%) fetuses were screened and diagnosed with monogenic diseases, mostly with Noonan syndrome. NIPT-SGG determined >99.99% of actual positive and negative cases, confirmed by diagnostic tests. No false-negatives or false-positives were reported. Conclusion: NIPT-SGG effectively identifies the fetuses affected with monogenic diseases, which is a promisingly safe and timely antenatal screening option for high-risk pregnancies.

Refractory Immune Thrombocytopenic Purpura with Abdominal Splenosis: A Complex Case.

Immune thrombocytopenia (ITP) is an acquired thrombocytopenia resulting from immune-mediated platelet destruction via antiplatelet antibodies and T cells. Medical management of ITP includes corticosteroids and multiple other adjunct therapies, with splenectomy generally being reserved for severe, refractory cases. In this clinical case report, we describe the evaluation of a 35-year-old male with a history of prior traumatic splenic injury who presented to the emergency department endorsing easy bruising and a petechial rash, ultimately found to have severe thrombocytopenia. The patient was diagnosed with primary ITP that proved to be refractory to a number of first- and second-line medical therapies. His course was complicated by the presence of abdominal splenosis discovered at the time of planned splenectomy and intra-abdominal hemorrhage requiring splenic artery embolization thereafter. To our knowledge, this is one of few published cases of ITP complicated by abdominal splenosis, highlighting the need to consider splenosis and the presence of accessory splenic tissue in cases of refractory ITP.

Utilization of 2-nitrophenols in annulations with aryl isothiocyanates towards the synthesis of 2-aminobenzoxazoles.

A method for the annulation of 2-nitrophenols with aryl isothiocyanates is reported. The reactions proceeded in the presence of an iron(iii) acetylacetonate catalyst, elemental sulfur, NaOH as a base, and DMSO as a solvent. Derivatives of 2-aminobenzoxazoles bearing nitro, cyano, acetyl, sulfone, secondary amine, and pyrrolyl groups were successfully isolated.

Prevalence of Thalassemia in the Vietnamese Population and Building a Clinical Decision Support System for Prenatal Screening for Thalassemia.

Introduction: The prevalence of thalassemia among the Vietnamese population was studied, and clinical decision support systems for prenatal screening of thalassemia were created. The aim of this report was to investigate the prevalence of thalassemia in the Vietnamese population, building a clinical decision support system for prenatal screening for thalassemia. Methods: A cross-sectional study was conducted on pregnant women and their husbands visiting the Vietnam National Hospital of Obstetrics and Gynecology from October 2020 to December 2021. A total of 10112 medical records of first-time pregnant women and their husbands were collected. Results: A clinical decision support system was built, including 2 different types of systems for prenatal screening for thalassemia (an expert system and 4 AI-based CDSS). One thousand nine hundred ninety-two cases were used to train and test machine learning models, while 1555 cases were used for specialized expert system evaluation. There were ten key variables for AI-based CDSS for machine learning. The four most important features in thalassemia screening were identified. The accuracy of the expert system and AI-based CDSS was compared. The rate of patients with Alpha thalassemia is 10.73% (1085 patients), the rate of patients with beta-thalassemia is 2.24% (227 patients), and 0.29% (29 patients) of patients carry both alpha-thalassemia and beta-thalassemia gene mutations. The expert system showed an accuracy of 98.45%. Among the AI-based CDSS developed, the multilayer perceptron (MLP) model was the most stable regardless of the training database (accuracy of 98,5% using all features and 97% using only the four most important features). Conclusions: When comparing the expert system with the AI-based CDSS, the accuracy of the expert system and AI-based models was comparable. The developed expert system for prenatal thalassemia screening showed high accuracy. AI-based CDSS showed satisfactory results. Further development of such systems is promising with a view to their introduction into clinical practice.

High prevalence of maternal mosaic monosomy X in pregnant women in Vietnam.

OBJECTIVE: To demonstrate the prevalence of maternal mosaic monosomy X (MMXO) in a cohort of pregnant women in Vietnam. METHODS: All 105,594 singleton pregnant women undergoing noninvasive prenatal screening (NIPS) between January 2019 and February 2021 in Vietnam were analyzed by measuring discordance between size- and count-based z-scores for chromosome X (ChrX) to identify suspected cases of MMXO and validated by fluorescence in situ hybridization (FISH) on maternal blood. RESULTS: We identified 295 (0.279%) suspected MMXO cases. After FISH analysis, MMXO was confirmed in 125 cases (42.37%), revealing the MMXO prevalence of 0.118% (95% CI: 0.097-0.139%) in this cohort. CONCLUSION: We found a relatively high prevalence of MMXO in Vietnamese pregnant women and demonstrated a strong influence of MMXO on the ChrX z-score using a count-based method, resulting in false positives. The size-based method is not sensitive to MMXO and therefore achieves higher PPV.

Carbon Monoxide Activates PERK-Regulated Autophagy to Induce Immunometabolic Reprogramming and Boost Antitumor T-cell Function.

Mitochondria and endoplasmic reticulum (ER) share structural and functional networks and activate well-orchestrated signaling processes to shape cells' fate and function. While persistent ER stress (ERS) response leads to mitochondrial collapse, moderate ERS promotes mitochondrial function. Strategies to boost antitumor T-cell function by targeting ER-mitochondria cross-talk have not yet been exploited. Here, we used carbon monoxide (CO), a short-lived gaseous molecule, to test whether engaging moderate ERS conditions can improve mitochondrial and antitumor functions in T cells. In melanoma antigen-specific T cells, CO-induced transient activation of ERS sensor protein kinase R-like endoplasmic reticulum kinase (PERK) significantly increased antitumor T-cell function. Furthermore, CO-induced PERK activation temporarily halted protein translation and induced protective autophagy, including mitophagy. The use of LC3-GFP enabled differentiation between the cells that prepare themselves to undergo active autophagy (LC3-GFPpos) and those that fail to enter the process (LC3-GFPneg). LC3-GFPpos T cells showed strong antitumor potential, whereas LC3-GFPneg cells exhibited a T regulatory-like phenotype, harbored dysfunctional mitochondria, and accumulated abnormal metabolite content. These anomalous ratios of metabolites rendered the cells with a hypermethylated state and distinct epigenetic profile, limiting their antitumor activity. Overall, this study shows that ERS-activated autophagy pathways modify the mitochondrial function and epigenetically reprogram T cells toward a superior antitumor phenotype to achieve robust tumor control. SIGNIFICANCE: Transient activation of ER stress with carbon monoxide drives mitochondrial biogenesis and protective autophagy that elicits superior antitumor T-cell function, revealing an approach to improving adoptive cell efficacy therapy.

Modulating donor mitochondrial fusion/fission delivers immunoprotective effects in cardiac transplantation.

Early insults associated with cardiac transplantation increase the immunogenicity of donor microvascular endothelial cells (ECs), which interact with recipient alloreactive memory T cells and promote responses leading to allograft rejection. Thus, modulating EC immunogenicity could potentially alter T cell responses. Recent studies have shown modulating mitochondrial fusion/fission alters immune cell phenotype. Here, we assess whether modulating mitochondrial fusion/fission reduces EC immunogenicity and alters EC-T cell interactions. By knocking down DRP1, a mitochondrial fission protein, or by using the small molecules M1, a fusion promoter, and Mdivi1, a fission inhibitor, we demonstrate that promoting mitochondrial fusion reduced EC immunogenicity to allogeneic CD8+ T cells, shown by decreased T cell cytotoxic proteins, decreased EC VCAM-1, MHC-I expression, and increased PD-L1 expression. Co-cultured T cells also displayed decreased memory frequencies and Ki-67 proliferative index. For in vivo significance, we used a novel murine brain-dead donor transplant model. Balb/c hearts pretreated with M1/Mdivi1 after brain-death induction were heterotopically transplanted into C57BL/6 recipients. We demonstrate that, in line with our in vitro studies, M1/Mdivi1 pretreatment protected cardiac allografts from injury, decreased infiltrating T cell production of cytotoxic proteins, and prolonged allograft survival. Collectively, our data show promoting mitochondrial fusion in donor ECs mitigates recipient T cell responses and leads to significantly improved cardiac transplant survival.

Emergent versus planned delivery in patients with placenta accreta spectrum disorders: A retrospective study.

ABSTRACT: The aim of this study is to compare the clinical outcomes and to identify risk factors for emergent cesarean delivery and planned cesarean delivery in patients with placenta accreta spectrum (PAS) disorders in Vietnam.The medical records of patients admitted to our hospital with a diagnosis of PAS disorders >5 years were retrospectively reviewed.A total of 255 patients with PAS disorders were identified, including 95 cases in the emergent delivery group and 160 cases in the planned delivery group. The percentage of complete/partial placenta previa in the planned delivery group was significantly higher than that in the emergent delivery group (59.22% vs 32.16%, P = .027). Fewer patients in the planned group had vaginal bleeding compared with those in the emergent group (29 vs 36 cases, P < .001). The percentage of blood transfusion was similar between the 2 groups; however, the transfused units of pack red blood cells were greater in the emergent delivery group (5.3 ±â€Š0.33 vs 4.5 ±â€Š0.25 U, P = .036). When considering the neonatal outcomes, the data demonstrated that the planned delivery group had a significantly higher birth weight and a lower rate of preterm delivery than the emergent group (P < .001). The mean gestational age at delivery for the emergent group was 35.1 ±â€Š0.27 weeks compared with 38.0 ±â€Š0.10 weeks for the planned group (P < .001). The increased risk factors for emergent delivery were vaginal bleeding (odds ratio 2.86, 95% confidence interval 1.59-5.26) and preterm delivery (odds ratio 5.26, 95% confidence interval 2.13-14.29).Planned delivery is strongly associated with a lower need for blood transfusion and better neonatal outcomes compared with emergent delivery. Antenatal vaginal bleeding and preterm labor are risk factors for emergent delivery among patients with PAS disorders. Based on the results of this study, we recommend that the management strategies for patients with PAS disorders should be individualized to determine the optimal timing of delivery and to decrease the rate of emergent cesarean delivery.

Leiomyomatosis peritonealis dissemianata five years after laparoscopic uterine myomectomy: A case report.

INTRODUCTION: Leiomyomatosis peritonealis disseminata (LPD) is a rare disease that can be challenging to diagnose. In this report, we present a case of LPD arising 5 years after laparoscopic uterine myomectomy using a power morcellator. PRESENTATION OF CASE: A 32-year-old woman was admitted to our hospital with complaints of vaginal bleeding and abdominal discomfort. Five years previously, she had undergone laparoscopic uterine myomectomy using a power morcellator. Pelvic ultrasonography and magnetic resonance imaging demonstrated multiple pelvic tumors closely attached to peritoneum with no indication of malignancy. An exploratory laparotomy revealed multiple sites of leiomyomatosis in the peritoneum, especially on the parietal peritoneum at the port site of the previous laparoscopic surgery. We surgically removed all visible tumors and performed a total hysterectomy. Histologic examination confirmed the diagnosis of LPD. DISCUSSION: The use of a power morcellator without in-bag containment system might have played a role in the pathogenesis of LPD in our case. Ultrasonography, computed tomography, and MRI are among the most effective to distinguish between leiomyomas and other solid tumors in the pelvis, but they are not of great help in the differential diagnosis of malignancies. CONCLUSION: The physicians need to combine medical history, clinical findings, imaging techniques and histopathological examination to establish a correct diagnosis of LPD. The application of containment bags in the setting of power morcellation should be considered to reduce the risk of developing LPD. The optimal intervention strategy should be chosen according to the particular features of each patient.

T-cell Immunometabolism: Therapeutic Implications in Organ Transplantation.

Although solid-organ transplantation has evolved steadily with many breakthroughs in the past 110 y, many problems remain to be addressed, and advanced therapeutic strategies need to be considered. T-cell immunometabolism is a rapidly advancing field that has gathered much attention recently, providing ample mechanistic insight from which many novel therapeutic approaches have been developed. Applications from the field include antitumor and antimicrobial therapies, as well as for reversing graft-versus-host disease and autoimmune diseases. However, the immunometabolism of T cells remains underexplored in solid-organ transplantation. In this review, we will highlight key findings from hallmark studies centered around various metabolic modes preferred by different T-cell subtypes (categorized into naive, effector, regulatory, and memory T cells), including glycolysis, glutaminolysis, oxidative phosphorylation, fatty acid synthesis, and oxidation. This review will discuss the underlying cellular signaling components that affect these processes, including the transcription factors myelocytomatosis oncogene, hypoxia-inducible factor 1-alpha, estrogen-related receptor alpha, and sterol regulatory element-binding proteins, along with the mechanistic target of rapamycin and adenosine monophosphate-activated protein kinase signaling. We will also explore potential therapeutic strategies targeting these pathways, as applied to the potential for tolerance induction in solid-organ transplantation.

Genetic diversity of leafy amaranth (Amaranthus tricolor L.) resources in Vietnam.

Leafy amaranths, which are consumed as traditional food in Asia and Africa, are now considered among the most promising vegetables. In Vietnam, leafy amaranths, particularly Amaranthus tricolor L., are important summer vegetables due to their excellent nutritional values and high tolerance to biotic and abiotic stresses. However, this species has not been subjected to systematic breeding. Here we describe species identification and evaluation of the genetic diversity of Vietnamese amaranth collection by using matK and simple sequence repeats (SSR) markers. Our phylogenetic analysis based on the matK marker classified the species of 68% of the accessions, of which 120 belonged to A. tricolor. We developed 21 SSR markers, which amplified a total of 153 alleles in 294 A. tricolor accessions originating from Vietnam and overseas, with a mean allelic richness of 7.29 per marker, observed heterozygosity of 0.14, expected heterozygosity of 0.38, and polymorphic information content of 0.35. The STRUCTURE and FST analysis indicated a positive relationship between geographic distance and genetic differentiation among most of the overseas groups and the Vietnamese collection, but not among geographic groups within the Vietnamese collection. Vietnamese amaranths could be divided into two major types, one common in East Asia and the other one unique to Vietnam.

Organ preservation with targeted rapamycin nanoparticles: a pre-treatment strategy preventing chronic rejection in vivo.

Hypothermic preservation is the standard of care for storing organs prior to transplantation. Endothelial and epithelial injury associated with hypothermic storage causes downstream graft injury and, as such, the choice of an ideal donor organ preservation solution remains controversial. Cold storage solutions, by design, minimize cellular necrosis and optimize cellular osmotic potential, but do little to assuage immunological cell activation or immune cell priming post transplantation. Thus, here we explore the efficacy of our previously described novel Targeted Rapamycin Micelles (TRaM) as an additive to standard-of-care University of Wisconsin preservation solution as a means to alter the immunological microenvironment post transplantation using in vivo models of tracheal and aortic allograft transplantation. In all models of transplantation, grafts pre-treated with 100 ng mL-1 of TRaM augmented preservation solution ex vivo showed a significant inhibition of chronic rejection post-transplantation, as compared to UW augmented with free rapamycin at a ten-fold higher dose. Here, for the first time, we present a novel method of organ pretreatment using a nanotherapeutic-based cellular targeted delivery system that enables donor administration of rapamycin, at a ten-fold decreased dose during cold storage. Clinically, these pretreatment strategies may positively impact post-transplant outcomes and can be readily translated to clinical scenarios.

Impact of Mitochondrial Permeability on Endothelial Cell Immunogenicity in Transplantation.

BACKGROUND: Microvascular endothelial cells (ECs) are central to an allograft's immunogenicity. Cold ischemia and reperfusion injury associated with static cold storage and warm reperfusion activates ECs and increases the immunogenicity of the allograft. After reperfusion, mitochondrial permeability transition pore (mPTP) opening contributes to mitochondrial dysfunction in the allograft, which correlates to alloimmune rejection. Current understanding of this relationship, however, centers on the whole allograft instead of ECs. This study aimed to elucidate the relationship between EC mPTP opening and their immunophenotype. METHODS: Mitochondrial metabolic fitness and glycolysis in ECs were assessed in parallel with metabolic gene microarray postreperfusion. NIM811 was used to inhibit mPTP opening to rescue mitochondrial fitness. The immunogenicity of NIM811-treated ECs was determined via levels of EC's proinflammatory cytokines and allogeneic CD8 T cell cocultures. Finally, EC surface expression of adhesion, costimulatory, coinhibitory, MHC-I molecules, and MHC-I machinery protein levels were characterized. RESULTS: Genes for glycolysis, tricarboxylic acid cycle, fatty acid synthesis, gluconeogenesis were upregulated at 6 hours postreperfusion but either normalized or downregulated at 24 hours postreperfusion. As mitochondrial fitness was reduced, glycolysis increased during the first 6 hours postreperfusion. Endothelial cell treatment with NIM811 during the early postreperfusion period rescued mitochondrial fitness and reduced EC immunogenicity by decreasing CCL2, KC release, and VCAM-1, MHC-I, TAP1 expression. CONCLUSIONS: Static cold storage and warm reperfusion leads to a reduction in mitochondrial fitness in microvascular ECs due to mPTP opening. Further, mPTP opening promotes increased EC immunogenicity that can be prevented by NIM811 treatment.

Nanotechnological Approaches to Immunosuppression and Tolerance Induction.

PURPOSE OF REVIEW: Several preclinical studies have engineered nanoparticles for immune regulation, and have shown promising results in the fields of autoimmunity and cancer. In solid organ transplantation, the use of nanoparticle-based immune regulation has only just begun to emerge but holds significant promise for the improvement of our current standard of care immunosuppressive regimens. In this review, we will shed light on the current status of nanoparticle-engineered immunotherapeutics, and the potential application of these technologies to the field of organ transplantation. Further we discuss different strategies for delivery and potential cellular targeting moieties that could be utilized to obviate the need for high dose systemic immunosuppressive regimens. RECENT FINDINGS: Recent studies have shown the potential of immunosuppressive laden nanoparticles to increase bioavailability, drug release, and specifically target immune cell compartments as methods to provide recipient immunosuppressive sparing strategies. SUMMARY: Nanoparticle centered immunosuppressive strategies hold the potential to usher in a new era in transplant recipient management and could hold the key to minimizing off-target effects of immunosuppressants, along with prolonging transplant survival.

Notch-independent RBPJ controls angiogenesis in the adult heart.

Increasing angiogenesis has long been considered a therapeutic target for improving heart function after injury such as acute myocardial infarction. However, gene, protein and cell therapies to increase microvascularization have not been successful, most likely because the studies failed to achieve regulated and concerted expression of pro-angiogenic and angiostatic factors needed to produce functional microvasculature. Here, we report that the transcription factor RBPJ is a homoeostatic repressor of multiple pro-angiogenic and angiostatic factor genes in cardiomyocytes. RBPJ controls angiogenic factor gene expression independently of Notch by antagonizing the activity of hypoxia-inducible factors (HIFs). In contrast to previous strategies, the cardiomyocyte-specific deletion of Rbpj increased microvascularization of the heart without adversely affecting cardiac structure or function even into old age. Furthermore, the loss of RBPJ in cardiomyocytes increased hypoxia tolerance, improved heart function and decreased pathological remodelling after myocardial infarction, suggesting that inhibiting RBPJ might be therapeutic for ischaemic injury.

Anti-CD138-targeted interferon is a potent therapeutic against multiple myeloma.

Multiple myeloma (MM), a plasma cell malignancy, is the second most prevalent hematologic malignancy in the US. Although much effort has been made trying to understand the etiology and the complexities of this disease with the hope of developing effective therapies, MM remains incurable at this time. Because of their antiproliferative and proapoptotic activities, interferons (IFNs) have been used to treat various malignancies, including MM. Although some success has been observed, the inherent toxicities of IFNs limit their efficacy. To address this problem, we produced anti-CD138 antibody fusion proteins containing either IFNα2 or a mutant IFNα2 (IFNα2(YNS)) with the goal of targeting IFN to CD138-expressing cells, thereby achieving effective IFN concentrations at the site of the tumor in the absence of toxicity. The fusion proteins inhibited the proliferation and induced apoptosis of U266, ANBL-6, NCI-H929, and MM1-144 MM cell lines. The fusion proteins decreased the expression of IFN regulatory factor 4 (IRF4) in U266. In addition, the fusion proteins were effective against primary cells from MM patients, and treatment with fusion proteins prolonged survival in the U266 murine model of MM. These studies show that IFNα antibody fusion proteins can be effective novel therapeutics for the treatment of MM.