Bortezomib in relapsed/refractory immune thrombotic thrombocytopenic purpura: A single-centre retrospective cohort and systematic literature review.

Immune thrombotic thrombocytopenic purpura (iTTP) is a rare and life-threatening haematological condition. Initial treatment involves plasma exchange (PLEX), corticosteroids, caplacizumab and rituximab. In relapsed and refractory cases despite initial treatments, further immune-modulating therapy includes the proteasome inhibitor, bortezomib. Evidence for bortezomib in this setting is limited to case reports and case series. We report our experience and perform a systematic review of the literature. We identified 21 publications with 28 unique patients in addition to our cohort of eight patients treated with bortezomib. The median age of patients was 44 years (IQR: 27-53) and 69% female. They were usually in an initial, refractory presentation of iTTP where they had received PLEX, corticosteroids, rituximab and another line of therapy. After bortezomib administration, 72% of patients had a complete response, with 85% maintaining a durable response without relapse at the last follow-up.

How do we manage hyperhemolysis syndrome.

BACKGROUND: Hyperhemolysis syndrome (HHS) is a catastrophic anemia characterized by destruction of both donor and patient red blood cells (RBC). HHS occurs after transfusion and can cause significant morbidity and mortality. Given the difficulty in diagnosing and managing this process, we provide a detailed overview of our treatment protocol. STUDY DESIGN AND METHODS: Members of the Transfusion Medicine and Hematology faculty at our institution collaborated in an iterative process to produce a consensus approach to patients with HHS. RESULTS: We present diagnostic criteria for HHS: recent transfusion within past 7 days (up to 21 days), rapid hemoglobin decline to below the pretransfusion level (usually hemoglobin drop >25% from pretransfusion), a significant decrease in HbA% (in patients with sickle cell disease or beta thalassemia), low or decreasing reticulocyte count in a patient with worsening anemia, and laboratory evidence of hemolysis. We also describe an in-depth approach to management focusing on optimizing hematopoiesis while dampening the immune response. CONCLUSION: We provide a comprehensive approach to the diagnosis and management of HHS based on contemporary literature and clinical experience designed to optimize outcomes for patients.

Electronic and Atomic Structural Properties Associated with Enhanced Photodegradation Activity in Mo-Doped TiO2 Nanoparticles.

The efficacy and structural evolution of Mo-doped titania nanoparticles (MTNPs) as advanced photocatalysts for degrading methyl blue (MB) are investigated by X-ray absorption spectroscopy (XAS). The 3 wt % MTNP, characterized by uniform size and anatase structure, exhibits higher efficiency. The spectral analyses unveiled structural variations in the TiO6 octahedral structure and revealed an active site of the distorted square pyramidal structure symmetry (C4v). The in situ XAS spectra illustrate that MTNPs, particularly at 3 wt % doping, effectively enhanced the hole carriers in Ti 3d orbitals with a charge transfer to Mo 4d orbitals and impeded electron-hole pair merging, significantly enhancing the photodegradation under light illumination. This study deepens our understanding of the crucial role of Mo doping in optimizing TiO2 nanoparticle performance for efficient environmental remediation, showcasing the potential of MTNPs as sustainable photocatalytic materials.

Protein Phosphatase 2A Activation Via ApoER2 in Trophoblasts Drives Preeclampsia in a Mouse Model of the Antiphospholipid Syndrome.

[Figure: see text].

Successful use of lenalidomide to treat refractory acquired von Willebrand disease associated with monoclonal gammopathy.

Acquired von Willebrand syndrome (AVWS) is a rare hematologic disorder characterized by quantitative or qualitative defects of von Willebrand factor (vWF), a protein crucial for normal hemostasis. AVWS has been described in association with several pathologic entities with varied mechanisms. Among these, lymphoproliferative disorders are the most common, with monoclonal gammopathy of undetermined significance (MGUS) being the most frequently reported. AVWS in this setting is commonly associated with the development of bleeding that is clinically challenging to manage due to accelerated clearance of vWF, limiting the utility of many conventional treatment modalities such as DDAVP or vWF/FVIII. We report a case of a 43-year-old male who was sent to our institution for new-onset easy bruising and laboratories concerning for von Willebrand disease (vWD). Further diagnostic workup revealed evidence of an IgG monoclonal gammopathy and findings suggestive of vWF inhibition. Ultimately, he was found to have monoclonal gammopathy of clinical significance (MGCS)-associated AVWS refractory to conventional treatment but responsive to lenalidomide and dexamethasone. This case suggests that lenalidomide may be suitable for patients with AVWS secondary to MGCS.

Utilization of emicizumab in acquired hemophilia A: A case report.

BACKGROUND: Acquired Hemophilia A (AHA) is a rare autoimmune disorder associated with the development of autoantibodies against factor VIII (FVIII). Although obtaining hemostatic control through the use of recombinant factor VIIa, activated prothrombin complex concentrate and recombinant porcine FVIII are cornerstones in the clinical management of AHA, these therapies have several disadvantages, including a higher risk for the development of thromboembolic events, unpredictable efficacy and short half-lives. While emicizumab has been FDA licensed for use in bleeding prophylaxis for patients with Congenital Hemophilia A (CHA) with and without inhibitors, it has not been approved for use in AHA, with only a few reports describing its use in this context. CASE REPORT: We report our experience with the use of emicizumab in an 83-year old male with AHA, complicated by the onset of atrial fibrillation following admission, drug-induced thrombocytopenia, infectious complications, and the identification of a low-grade lymphoproliferative disorder, in which emicizumab prophylaxis was used for bleeding prophylaxis in the context of persistently elevated inhibitor titers without evidence of thrombotic events or thrombotic microangiopathy.

Antiphospholipid antibodies induce thrombosis by PP2A activation via apoER2-Dab2-SHC1 complex formation in endothelium.

In the antiphospholipid syndrome (APS), antiphospholipid antibody (aPL) recognition of ß2 glycoprotein I promotes thrombosis, and preclinical studies indicate that this is due to endothelial nitric oxide synthase (eNOS) antagonism via apolipoprotein E receptor 2 (apoER2)-dependent processes. How apoER2 molecularly links these events is unknown. Here, we show that, in endothelial cells, the apoER2 cytoplasmic tail serves as a scaffold for aPL-induced assembly and activation of the heterotrimeric protein phosphatase 2A (PP2A). Disabled-2 (Dab2) recruitment to the apoER2 NPXY motif promotes the activating L309 methylation of the PP2A catalytic subunit by leucine methyl transferase-1. Concurrently, Src homology domain-containing transforming protein 1 (SHC1) recruits the PP2A scaffolding subunit to the proline-rich apoER2 C terminus along with 2 distinct regulatory PP2A subunits that mediate inhibitory dephosphorylation of Akt and eNOS. In mice, the coupling of these processes in endothelium is demonstrated to underlie aPL-invoked thrombosis. By elucidating these intricacies in the pathogenesis of APS-related thrombosis, numerous potential new therapeutic targets have been identified.

Long-term safety and efficacy of factor IX gene therapy in hemophilia B.

BACKGROUND: In patients with severe hemophilia B, gene therapy that is mediated by a novel self-complementary adeno-associated virus serotype 8 (AAV8) vector has been shown to raise factor IX levels for periods of up to 16 months. We wanted to determine the durability of transgene expression, the vector dose-response relationship, and the level of persistent or late toxicity. METHODS: We evaluated the stability of transgene expression and long-term safety in 10 patients with severe hemophilia B: 6 patients who had been enrolled in an initial phase 1 dose-escalation trial, with 2 patients each receiving a low, intermediate, or high dose, and 4 additional patients who received the high dose (2×10(12) vector genomes per kilogram of body weight). The patients subsequently underwent extensive clinical and laboratory monitoring. RESULTS: A single intravenous infusion of vector in all 10 patients with severe hemophilia B resulted in a dose-dependent increase in circulating factor IX to a level that was 1 to 6% of the normal value over a median period of 3.2 years, with observation ongoing. In the high-dose group, a consistent increase in the factor IX level to a mean (±SD) of 5.1±1.7% was observed in all 6 patients, which resulted in a reduction of more than 90% in both bleeding episodes and the use of prophylactic factor IX concentrate. A transient increase in the mean alanine aminotransferase level to 86 IU per liter (range, 36 to 202) occurred between week 7 and week 10 in 4 of the 6 patients in the high-dose group but resolved over a median of 5 days (range, 2 to 35) after prednisolone treatment. CONCLUSIONS: In 10 patients with severe hemophilia B, the infusion of a single dose of AAV8 vector resulted in long-term therapeutic factor IX expression associated with clinical improvement. With a follow-up period of up to 3 years, no late toxic effects from the therapy were reported. (Funded by the National Heart, Lung, and Blood Institute and others; ClinicalTrials.gov number, NCT00979238.).

A case of autoimmune severe acquired von Willebrand syndrome (type 3-like).

Von Willebrand disease (VWD) is the most common congenital bleeding disorder and is due to quantitative or qualitative defects of von Willebrand factor (VWF). Acquired defects of VWF, termed acquired von Willebrand syndrome (AVWS), are due to a host of different mechanisms. Autoantibody-mediated AVWS may be associated with lymphoproliferative or immunological disorders, such as systemic lupus erythematosus (SLE). A large majority of AVWS cases are type 1 or type 2A-like and patients tend to have a mild to moderate bleeding tendency. We report a case of severe autoimmune AVWS in a woman with SLE who presented with clinical and laboratory features of type 3 VWD (undetectable VWF antigen, ristocetin cofactor activity, and VWF multimers). A mixing study demonstrated an inhibitor to VWF (6BU/mL). Her bleeds were managed with antifibrinolytics, recombinant activated factor VII, and activated prothrombin complex concentrate. She was initially treated with steroids and intravenous immunoglobulin therapy. However, her bleeding symptoms continued until she was treated with rituximab, and her VWF parameters normalized. She relapsed two years later due to non-compliance with her immunosuppressive medications and expired another two years later secondary to complications of sepsis and uremic pericarditis. This case emphasizes the importance of aggressive initial therapy of SLE to reduce secondary complications, frequent patient monitoring, and continued treatment of the underlying autoimmune disorder in patients with AVWS.

Clinical evaluation of thrombotic microangiopathy: identification of patients with suspected atypical hemolytic uremic syndrome.

Atypical hemolytic uremic syndrome (aHUS) is a rare genetic disorder caused by defective complement regulation resulting in thrombotic microangiopathy (TMA). Patients can present as children or adults. The syndrome consists of hemolytic anemia with schistocytosis, thrombocytopenia, significant renal damage, and/or other organ system dysfunction(s). Patients with aHUS may succumb to the complications of the disease with the very first manifestation; surviving patients often suffer from progressive organ dysfunction with significant morbidity and mortality despite plasma infusion or plasma exchange. Eculizumab, a humanized monoclonal antibody to C5, was approved for treatment of aHUS in 2011. This is an expensive but highly effective therapy changing the lives and improving the outcome of patients with aHUS. Making timely and accurate diagnosis of aHUS can be life-saving if eculizumab treatment is begun promptly. Finding a genetic mutation in a complement regulatory protein is diagnostic with the appropriate clinical syndrome, but at least 30 % of patients do not have defined or reported mutations. Thus the diagnosis rests on the clinical acumen of the physician. However, the clinical manifestations of aHUS are shared by other etiologies of thrombotic microangiopathy. While laboratory finding of undetectable ADAMTS13 activity defines TTP, distinguishing aHUS from the other causes of TMA remains an art. In addition, aHUS can be unmasked by conditions with enhanced complement activation, such as systemic lupus erythematosus, pregnancy, malignant hypertension, and hematopoietic stem cell transplantation. Thus if TMA occurs in the setting of enhanced complement activation, one must consider aHUS as an underlying etiology, especially if treatment of the condition does not resolve the TMA.

Can an anti-Xa assay for low-molecular-weight heparin be used to assess the presence of rivaroxaban?

BACKGROUND: Due to the convenience afforded by the lack of required laboratory monitoring, direct oral anticoagulants (DOACs) are increasingly used as alternatives to Vitamin-K antagonists for certain medical conditions. However, there are circumstances in which assessment of DOAC plasma concentrations may be helpful in guiding clinical decisions, including patients presenting with either bleeding or thrombosis, or patients requiring urgent invasive procedures. Evaluating the anticoagulant effects of DOACs is often difficult because of the limited availability of DOAC-specific assays in most laboratories. OBJECTIVE: To evaluate the correlation between ex vivo plasma concentrations of rivaroxaban and a chromogenic anti-Xa assay for low-molecular-weight heparin (LMWH) routinely used in our coagulation laboratory. MATERIALS AND METHODS: Twenty-nine blood samples from 20 patients anticoagulated with rivaroxaban (dose; 10-20 mg/day) were evaluated using an anti-Xa assay for LMWH and results were correlated with rivaroxaban plasma concentrations using a rivaroxaban specific assay. RESULTS: A linear dose-dependent relationship was demonstrated between plasma concentrations of rivaroxaban and the chromogenic anti-Xa assay for LMWH (R2 = 0.92). PT and PTT demonstrated poor correlations (R2 = 0.03; and R2 = 0.01, respectively) with rivaroxaban plasma concentrations. CONCLUSION: Findings from this study suggest that if specific assays for rivaroxaban are unavailable, then the chromogenic anti-Xa assay for LMWH may be useful for assessing the anticoagulant effects of rivaroxaban.

Fine mapping of S37, a locus responsible for pollen and embryo sac sterility in hybrids between Oryza sativa L. and O. glaberrima Steud.

KEY MESSAGE: Hybrid sterility locus S37 between Oryza glaberrima and Oryza sativa results in both pollen and embryo sac sterility. Interspecific crossing between African cultivated rice Oryza glaberrima and Oryza sativa cultivars is hindered by hybrid sterility. To dissect the mechanism of interspecific hybrid sterility, we developed a near-isogenic line (NIL)-S37 using Dianjingyou1 (DJY1) as the recipient parent and an African cultivated rice variety as the donor parent. Empty pollen and embryo sac sterility were observed in F1 hybrids between DJY1 and NIL-S37. Cytological analyses showed that pollen abortion in the F1 hybrids occurred at the late binucleate stage due to a failure of starch accumulation in pollen grains. In addition, partial abortion of the embryo sac in the F1 hybrid was observed during function megaspore developing into mature embryo sac. Molecular analysis revealed that the semi-sterility was largely caused by the abortion of male and female gametophytes carrying the S37 allele from DJY1. A population of 25,600 plants derived from the hybrid DJY1/NIL-S37 was developed to fine map S37. Based on the physical location of molecular markers, S37 locus was finally delimited to a region of 205 kb on the short arm of chromosome 1 in terms of reference sequences of cv. Nipponbare. Interestingly, an about 97-kb DNA segment was deleted in the NIL-S37 based on BAC clone information of O. glaberrima. Fifty-four open reading frames (ORF) were predicted in this 205-kb region of DJY1, whereas only 31 ORFs were in that of NIL-S37. These results are valuable for cloning of S37 gene and further breaking reproductive isolation between Oryza glaberrima and Oryza sativa cultivars, as well as marker-assisted transferring of the corresponding neutral allele in rice breeding programs.

Bortezomib for chronic relapsing thrombotic thrombocytopenic purpura: a case report.

BACKGROUND: Acquired thrombotic thrombocytopenic purpura (TTP) is an autoimmune disorder characterized by a severe deficiency of ADAMTS13 activity. Although therapeutic plasma exchange (PLEX) is the standard of care, 30% to 50% patients develop exacerbation or relapse, requiring immunomodulatory agents. Of these agents, glucocorticoids, rituximab, and cyclosporine A are the most frequently used. CASE REPORT: We report a case of chronic relapsing TTP in a patient who had eight relapses over a 14-year period. After her seventh relapse, the patient demonstrated only partial response to glucocorticoids, two courses of rituximab, and cyclophosphamide. The eighth relapse occurred 58 days after her last PLEX and subsequent to this she received a course of bortezomib (Velcade, Millennium Pharmaceuticals, Inc.). After treatment with bortezomib the patient demonstrated a complete response with a progressive increase in ADAMTS13 activity from less than 5% to 22% accompanied by undetectable inhibitor, and she has remained PLEX free for more than 169 days. CONCLUSION: Bortezomib may serve as an adjunct treatment in patients with acquired TTP who exhibit an incomplete response or are refractory to conventional management.

A cocatalytic nanozyme based on metal-organic framework-embedded iron porphyrin for the sensitive detection of Salmonella typhimurium in milk.

The nanozyme, acting as the signal labeling reporter, is widely employed in colorimetric immunoassays due to its exceptional catalytic activity and reliable performance. Nonetheless, when immobilized on the nanozyme's surface, there is a decline in catalytic activity, which hinders its ability to meet the escalating demand for advanced colorimetric immunoassays. Herein, we introduce a novel MILL-88@TcP nanozyme, formed by encapsulating iron porphyrins (TcP) within metal-organic frameworks (MILL-88), where the catalytic activity of TcP is fully preserved through ethanol-induced release. Leveraging the superior encapsulation capacity and enzyme-mimicking characteristics of MILL-88, the MILL-88@TcP nanozyme demonstrates a remarkable colorimetric performance, 1430-fold higher than that of MILL-88 alone. Furthermore, we developed the MILL-88@TcP nanozyme-based Enzyme-Linked Immunosorbent Assay (N-ELISA) for enhanced sensitivity in detecting Salmonella typhimurium, achieving a detection limit of 1.68 × 102 CFU/mL, approximately 500-fold enhancement compared to the traditional HRP-based ELISA (8.35 × 104 CFU/mL). Notably, the average recoveries ranged from 91.50 % to 108.50 % with a variation of 3.53 %-10.41 %, indicating high accuracy and precision. Collectively, this study highlights that the MILL-88@TcP nanozyme, with its superior catalytic performance and anti-interference capabilities, holds promise as a colorimetric labeling reporter to enhance the detection efficacy of colorimetric immunoassays and has the potential to establish a more stable and sensitive colorimetric assay platform.

Role of ADAMTS13 in the management of thrombotic microangiopathies including thrombotic thrombocytopenic purpura (TTP).

The clinical presentation of thrombotic thrombocytopenia purpura (TTP) and other thrombotic microangiopathies (TMAs) can often be similar. The role of a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13 (ADAMTS13) in diagnosing TTP is accepted by most researchers but continues to be debated in a few studies. We report the experience of our single-centre academic institution, where ADAMTS13 is used to diagnose TTP and guide plasma exchange (PLEX). Patients presenting to our institution with thrombotic microangiopathy (60 patients) between January 2006 and December 2012 were divided into two groups based on ADAMTS13 activity and clinical history. Patients with ADAMTS13 activity <10% were included in the TTP (n = 30) cohort while patients with activity >11% were classified as 'other microangiopathies' (TMA, n = 30). PLEX was only initiated in patients with a high likelihood of TTP and discontinued when the baseline ADAMTS13 activity was >11%. Patients with severe ADAMTS13 deficiency (TTP group) showed significant presenting differences: lower platelet counts, less renal dysfunction, higher presence of neurological abnormalities, and greater haemolysis markers as compared to non-deficient patients (TMA group). Most importantly, patients without severe ADAMTS13 deficiency were safely managed without increased mortality despite receiving no PLEX or discontinuing PLEX after a short course (upon availability of ADAMTS13 results). In conclusion, ADAMTS13 can be used to diagnose TTP and guide appropriate PLEX therapy.

PBFT optimization algorithm based on community contributions.

Community governance is the basic unit of social governance, and it is also an important direction for building a social governance pattern of co-construction, co-governance and sharing. Previous studies have solved the problems of data security, information traceability and participant enthusiasm in the process of community digital governance by building a community governance system based on blockchain technology and incentive mechanisms. The application of blockchain technology can solve the problems of low data security, difficulty in sharing and tracing and low enthusiasm on the part of multiple subjects regarding participation in community governance. The process of community governance involves the cooperation of multiple government departments and multiple social subjects. Under the blockchain architecture, the number of alliance chain nodes will reach 1000 with the expansion of community governance. The existing consensus algorithms for coalition chains are difficult to meet the high concurrent processing requirements under such large-scale nodes. An optimization algorithm has improved the consensus performance to a certain extent, but the existing systems still cannot meet the data needs of the community and are not suitable for community governance scenarios. Since the community governance process only involves the participation of relevant departments in users, all nodes in the network are not required to participate in the consensus under the blockchain architecture. Therefore, a practical Byzantine fault tolerance (PBFT) optimization algorithm based on community contribution (CSPBFT) is proposed here. First, consensus nodes are set according to different roles of participants in community activities, and participants are given different consensus permissions. Second, the consensus process is divided into different stages, and the amount of data processed by each consensus step is reduced. Finally, a two-level consensus network is designed to perform different consensus tasks, and reduce unnecessary communication between nodes to reduce the communication complexity of consensus among nodes. Compared with the PBFT algorithm, CSPBFT reduces the communication complexity from O(N2) to O(N2/C3). Finally, the simulation results show that, through rights management, network level setting and consensus phase division, when the number of nodes in the CSPBFT network is 100-400, the consensus throughput can reach 2000 TPS. When the node in the network is 1000, the instantaneous concurrency is guaranteed to be above 1000 TPS, which can meet the concurrent needs of the community governance scenario.