Weight loss treatment for COVID-19 in patients with NCDs: a pilot prospective clinical trial.

COVID-19 comorbid with noncommunicable chronic diseases (NCDs) complicates the diagnosis, treatment, and prognosis, and increases the mortality rate. The aim is to evaluate the effects of a restricted diet on clinical/laboratory inflammation and metabolic profile, reactive oxygen species (ROS), and body composition in patients with COVID-19 comorbid with NCDs. We conducted a 6-week open, pilot prospective controlled clinical trial. The study included 70 adult patients with COVID-19 comorbid with type 2 diabetes (T2D), hypertension, or nonalcoholic steatohepatitis (NASH). INTERVENTIONS: a restricted diet including calorie restriction, hot water drinking, walking, and sexual self-restraint. PRIMARY ENDPOINTS: COVID-19 diagnosis by detecting SARS-CoV-2 genome by RT-PCR; weight loss in Main group; body temperature; C-reactive protein. Secondary endpoints: the number of white blood cells; erythrocyte sedimentation rate; adverse effects during treatment; fasting blood glucose, glycosylated hemoglobin A1c (HbA1c), systolic/diastolic blood pressure (BP); blood lipids; ALT/AST, chest CT-scan. In Main group, patients with overweight lost weight from baseline (- 12.4%; P < 0.0001); 2.9% in Main group and 7.2% in Controls were positive for COVID-19 (RR: 0.41, CI: 0.04-4.31; P = 0.22) on the 14th day of treatment. Body temperature and C-reactive protein decreased significantly in Main group compared to Controls on day 14th of treatment (P < 0.025). Systolic/diastolic BP normalized (P < 0.025), glucose/lipids metabolism (P < 0.025); ALT/AST normalized (P < 0.025), platelets increased from baseline (P < 0.025), chest CT (P < 0.025) in Main group at 14 day of treatment. The previous antidiabetic, antihypertensive, anti-inflammatory, hepatoprotective, and other symptomatic medications were adequately decreased to completely stop during the weight loss treatment. Thus, the fast weight loss treatment may be beneficial for the COVID-19 patients with comorbid T2D, hypertension, and NASH over traditional medical treatment because, it improved clinical and laboratory/instrumental data on inflammation; glucose/lipid metabolism, systolic/diastolic BPs, and NASH biochemical outcomes, reactive oxygen species; and allowed patients to stop taking medications. TRIAL REGISTRATION: ClinicalTrials.gov NCT05635539 (02/12/2022): https://clinicaltrials.gov/ct2/show/NCT05635539?term=NCT05635539&draw=2&rank=1 .

Plasma membrane Ca2+ pump isoform 4 function in cell migration and cancer metastasis.

The Ca2+ ion is a universal second messenger involved in many vital physiological functions including cell migration and development. To fulfil these tasks the cytosolic Ca2+ concentration is tightly controlled, and this involves an intricate functional balance between a variety of channels and pumps of the Ca2+ signalling machinery. Among these proteins, plasma membrane Ca2+ ATPases (PMCAs) represent the major high-affinity Ca2+ extrusion systems in the cell membrane that are effective in maintaining free Ca2+ concentration at exceedingly low cytosolic levels, which is essential for normal cell function. An imbalance in Ca2+ signalling can have pathogenic consequences including cancer and metastasis. Recent studies have highlighted the role of PMCAs in cancer progression and have shown that a particular variant, PMCA4b, is downregulated in certain cancer types, causing delayed attenuation of the Ca2+ signal. It has also been shown that loss of PMCA4b leads to increased migration and metastasis of melanoma and gastric cancer cells. In contrast, an increased PMCA4 expression has been reported in pancreatic ductal adenocarcinoma that coincided with increased cell migration and shorter patient survival, suggesting distinct roles of PMCA4b in various tumour types and/or different stages of tumour development. The recently discovered interaction of PMCAs with basigin, an extracellular matrix metalloproteinase inducer, may provide further insights into our understanding of the specific roles of PMCA4b in tumour progression and cancer metastasis.

Response to Neoadjuvant Therapy and Long-Term Survival in Patients With Triple-Negative Breast Cancer.

PURPOSE: Triple-negative breast cancer (TNBC) is defined by the lack of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) expression. In this study, we compared response to neoadjuvant chemotherapy and survival between patients with TNBC and non-TNBC. PATIENTS AND METHODS: Analysis of a prospectively collected clinical database was performed. We included 1,118 patients who received neoadjuvant chemotherapy at M.D. Anderson Cancer Center for stage I-III breast cancer from 1985 to 2004 and for whom complete receptor information were available. Clinical and pathologic parameters, pathologic complete response rates (pCR), survival measurements, and organ-specific relapse rates were compared between patients with TNBC and non-TNBC. RESULTS: Two hundred fifty-five patients (23%) had TNBC. Patients with TNBC compared with non-TNBC had significantly higher pCR rates (22% v 11%; P = .034), but decreased 3-year progression-free survival rates (P < .0001) and 3-year overall survival (OS) rates (P < .0001). TNBC was associated with increased risk for visceral metastases (P = .0005), lower risk for bone recurrence (P = .027), and shorter postrecurrence survival (P < .0001). Recurrence and death rates were higher for TNBC only in the first 3 years. If pCR was achieved, patients with TNBC and non-TNBC had similar survival (P = .24). In contrast, patients with residual disease (RD) had worse OS if they had TNBC compared with non-TNBC (P < .0001). CONCLUSION: Patients with TNBC have increased pCR rates compared with non-TNBC, and those with pCR have excellent survival. However, patients with RD after neoadjuvant chemotherapy have significantly worse survival if they have TNBC compared with non-TNBC, particularly in the first 3 years.

SARS-CoV-2 infection in HIV-infected patients: potential role in the high mutational load of the Omicron variant emerging in South Africa.

A new variant of SARS-CoV-2 named Omicron (B.1.1.529) was isolated from an HIV-infected patient in Botswana, South Africa, in November 2021. Whole genome sequencing revealed a multitude of mutations and its relationship to the mutation-rich Alpha variant that had been isolated from a cancer patient. It is conceivable that very high prevalence of HIV-infected individuals as susceptible hosts in South Africa and their immunocompromised state may predispose for accumulation of coronavirus mutations. Coronaviruses uniquely code for an N-terminal 3' to 5'exonuclease (ExoN, nsp14) that removes mismatched nucleotides paired by the RNA dependent RNA polymerase. Its activity depends preferably on Mg2+ and other divalent cations (manganese, cobalt and zinc). On the contrary, methyl transferase activity of non-structural protein (nsp) 14 and nsp16 both complexed with nsp10 requires Mn2+. Enzymes in successive stages of HIV infections require the same cations. In HIV-infected organisms, a subsequent coronavirus infection encounters with altered homeostasis of the body including relative starvation of divalent cations induced by interleukin production of HIV-infected cells. It is hypothesized that selective diminished efficacy of ExoN in the absence of sufficient amount of magnesium may result in the accumulation of mutations. Unusual mutations and recombinations of heterologous viruses detected in AIDS patients also suggest that long-lasting persistence of superinfecting viruses may also contribute to the selection of genetic variants. Non-nucleoside reverse transcriptase inhibitors partially restore divalent cations' equilibrium. As a practical approach, implementation of highly active antiretroviral therapy against HIV replication and vaccination against coronaviruses may be a successful strategy to reduce the risk of selection of similar mutants.

The Correlation Between Platelet Count and Survival in Prostate Cancer.

Purpose: A number of studies have confirmed that elevated platelet count accompanying various solid tumours is associated with worse survival. However, only meagre data are available on the relationship between thrombocytosis and survival in prostate cancer. Methods: We conducted a retrospective analysis on clinical-pathological data accumulated from 316 patients during on average 51 months of follow-up after laparoscopic prostatectomy performed for prostate cancer. We analyzed the relationship between platelet count, risk factors, prostate-specific antigen (PSA) and cancer stage with use the Tumor, Node, Metastase system (TNM), as well as surgical margin, and prognosis. Results: Thrombocytosis occurred in only one out of the 316 patients. The multivariate Cox proportional hazard model showed that preoperative PSA, risk group, preoperative haemoglobin level, and surgical margin status were significant, independent predictors of biochemical progression-free survival. By contrast, age at diagnosis and thrombocytosis had no such predictive value. Conclusion: We could not demonstrate an association between elevated platelet count and worse survival in our study population of patients with prostate cancer.

Secondary primary malignancies after treatment with chemo-immunotherapy in treatment-naïve patients with CLL: a systematic literature review.

OBJECTIVES: In chronic lymphocytic leukemia (CLL), therapy-related cytotoxicity and the resulting immunodeficiency are thought to contribute to the development of secondary primary malignancies (SPM). Here, we analyzed clinical trial data on the occurrence of SPM following chemo-immunotherapy (CIT) regimens in treatment-naïve CLL patients. METHODS: A systematic literature search was conducted covering multiple databases between 2003 and 2019. Data from relevant clinical trials on the proportion of patients with SPMs were extracted. Then, the number of SPM patients/person-years was calculated by taking into account the trials' follow-up time. Finally, a random-effects meta-analysis to pool the rates from individual studies was performed. RESULTS: We identified 22 studies reporting SPM data available for analysis. Random-effects meta-analysis estimated that the number of SPM patients/1000 person-years was 24 (95%CI: 19-29). Results from trials with cancer-specific data indicated 19 (95%CI: 14-26) solid and 9 (95%CI: 6-12) hematological SPM patients/1000 person-years. These estimations did not change significantly when sub-groups were analyzed by CIT regimens. CONCLUSION: Although pooling data with the intention to analyze adverse event rates is challenging, our study concluded that for CIT regimens, SPM should be considered an important adverse outcome. Different regimens showed similar trends; however, other clinical and demographic factors also have profound impact.

Association between COVID-19 morbidity, mortality, and gross domestic product, overweight/ obesity, non-communicable diseases, vaccination rate: A cross-sectional study.

BACKGROUND: The spread of COVID-19 depends on a lot of social and economic factors. THE AIM: to study the influence of country's gross domestic product, population prevalence of overweight/ obesity, NCD mortality, and vaccination on COVID-19 morbidity and mortality rates. METHODS: A cross-sectional study with two phases: correlation-regression interrelations in 1) all world countries; 2) all world non-island countries. The study includes the following data from 218 world countries: COVID-19 morbidity/mortality rates, GDP per capita, the prevalence of overweight/ obesity, NCD mortality among adults (both sexes), people fully vaccinated against COVID-19. RESULTS: An average percentage of the prevalence of overweight among adults in world countries by 2019 was 47.31 ± 15.99%, obesity 18.34 ± 9.64%, while the prevalence by 2016 were 39% and 13%, respectively. Overweight and obesity among adults during three years grew by 21.2% and 40.8%, respectively. Data from the world countries provide significant correlations (p < 0.0001) between COVID-19 morbidity, and: GDP (r = 0.517), overweight (r = 0.54), obesity (r = 0.528), NCD mortality (r = 0.537); COVID-19 mortality, and: GDP (r = 0.344), overweight (r = 0.514), obesity (r = 0.489), NCD mortality (r = 0.611); GDP, and: overweight (r = 0.507), obesity (r = 0.523), NCD mortality (r = 0.35), fully vaccinated people (r = 0.754). An increase in fully vaccinated people, from 3% to 30% of world population, decreases new confirmed COVID-19 cases, although the dependence was not significant (p = 0.07). Data from non-island world countries provides more highly significant correlations (p < 0.0001) between COVID-19 morbidity, and: GDP (r = 0.616), overweight (r = 0.581), obesity (r = 0.583); COVID-19 mortality, and: GDP (r = 0.43), overweight (r = 0.556), obesity (r = 0.539); GDP, and: overweight (r = 0.601), obesity (r = 0.633). The differences of correlation coefficients between data of 176 world countries and data of 143 world non-island countries were not significant (Z-scores<1.29; p > 0.05). CONCLUSION: The study provides evidence of a significant impact of overweight/obesity prevalence on the increase in COVID-19 morbidity/mortality. Countries with higher GDP have a high overweight/obesity prevalence and possibility to get vaccinated.

Early Transfusion of Convalescent Plasma Improves the Clinical Outcome in Severe SARS-CoV2 Infection.

INTRODUCTION: Plasma harvested from convalescent COVID-19 patients (CCP) has been applied as first-line therapy in the early phase of the SARS-CoV2 pandemic through clinical studies using various protocols. METHODS: We present data from a cohort of 267 hospitalized severe COVID-19 patients who received CCP. No transfusion-related complications were reported, indicating the overall safety of CCP therapy. RESULTS: Patients who eventually died from COVID-19 received CCP significantly later (3.95 versus 5.22 days after hospital admission) and had higher interleukin 6 (IL-6) levels (28.9 pg/ml versus 102.5 pg/ml) than those who survived. In addition, CCP transfusion caused a significant reduction in the overall inflammatory status of the patients regardless of the severity of disease or outcome, as evidenced by decreasing C-reactive protein, IL6 and ferritin levels. CONCLUSION: We conclude that CCP transfusion is a safe and effective supplementary treatment modality for hospitalized COVID-19 patients characterized by better expected outcome if applied as early as possible. We also observed that IL-6 may be a suitable laboratory parameter for patient selection and monitoring of CCP therapy effectiveness.

National level adjustments to the challenges of the SARS-CoV2 pandemic on blood banking operations.

BACKGROUND: SARS-CoV2 causing coronavirus disease (COVID-19) is responsible for an unprecedented worldwide pandemic severely affecting all activities of societies including blood banking. We aimed to systematically collect key indicators in a nationally centralized blood banking system and to perform comparisons between 2020 and 2019. METHODS: Count data for January-December 2020 and 2019 were extracted from the integrated informatics system of Hungarian National Blood Transfusion Service and analyzed by simple graphics, tabulations, and statistics. RESULTS: Whole blood donation activity showed a highly significant decline due to a sharp decrease in field donations by an average fall of 24% (range:17%-28%) during March-May 2020 compared to identical period of 2019. A second, more moderate decline accompanied the second wave in late fall. The simultaneous increase in institutional donations did not counterbalance this decline. Donor exclusion rates fell significantly by an average of 1,1% (range:0.9%-1.6%) in the three spring lockdown-affected months. First-time and repeat donors showed decreased turn-out in larger proportions compared to highly repeat donors. Interestingly, among repeat and highly repeat donors, females showed less-pronounced declines compared to males while this was not observed among first-time donors. In June-September, a remarkable swing-back was observed among highly repeat female donors. Product utilization fell most notably for RBC (mean:26.2%) but also for PLT (mean:19.8%) and FFP (mean:24.3%) and showed a full recovery in June-September followed by a second decline. CONCLUSION: Trends and reaction patterns of blood banking reported by our study may be useful in future planning and adjustments of blood banking activities.

The transport pathway in the ABCG2 protein and its regulation revealed by molecular dynamics simulations.

Atomic-level structural insight on the human ABCG2 membrane protein, a pharmacologically important transporter, has been recently revealed by several key papers. In spite of the wealth of structural data, the pathway of transmembrane movement for the large variety of structurally different ABCG2 substrates and the physiological lipid regulation of the transporter has not been elucidated. The complex molecular dynamics simulations presented here may provide a breakthrough in understanding the steps of the substrate transport process and its regulation by cholesterol. Our analysis revealed drug binding cavities other than the central binding site and delineated a putative dynamic transport pathway for substrates with variable structures. We found that membrane cholesterol accelerated drug transport by promoting the closure of cytoplasmic protein regions. Since ABCG2 is present in all major biological barriers and drug-metabolizing organs, influences the pharmacokinetics of numerous clinically applied drugs, and plays a key role in uric acid extrusion, this information may significantly promote a reliable prediction of clinically important substrate characteristics and drug-drug interactions.

Two common polymorphic variants of OATP4A1 as potential risk factors for colorectal cancer.

Genetic variations in the organic-anion-transporting polypeptide (OATP)-encoding solute carrier of organic anions (SLCO) genes can promote cancer development and progression. The overexpression of solute carrier organic anion transporter family member 4A1 (OATP4A1), a transporter for steroid hormones, prostaglandins, and bile acids, has been previously associated with tumor recurrence and progression in colorectal cancer (CRC). Therefore, the present study aimed to investigate the association between 2 frequent single nucleotide polymorphisms (SNPs) in SLCO4A1 (rs34419428, R70Q; rs1047099G, V78I) and CRC predisposition. Following restriction fragment length polymorphism-PCR analysis in 178 patients with CRC [Union for International Cancer Control (UICC) stage I/II] and 65 healthy controls, no significant difference was observed in allele frequency and the number of heterozygous/homozygous individuals between the groups. Notably, the R70Q minor allele was identified to be associated with the V78I minor allele in the genome. Comparing of the individual genotypes of CRC patients to clinical data, including sex, UICC-stage and relapse revealed no increased risk for CRC. In addition, the OATP4A1 immunoreactivity assay in paraffin-embedded CRC and adjacent non-tumorous mucosa sections, examined using quantitative microscopy image analysis, did not reveal any association with these polymorphisms. No significant differences were observed in the expression levels, localization, and sodium fluorescein transport capacity among the OATP4A1 variants, which was studied using functional assays in Sf9-insect and A431 tumor cells overexpressing the 2 single and a double mutant OATP4A1 SNP variants. These results suggested that the 2 most frequent polymorphisms located in the first intracellular loop of OATP4A1 do not associate with CRC predisposition and tumor recurrence. They are unlikely to affect the outcome of CRC in patients.

Investigation of TGFB1 -1347C>T variant as a biomarker after allogeneic hematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapeutic option for malignant hematopoietic diseases. Cytokines including transforming growth factor ß1 (TGFß1) play a pivotal role in immune reconstruction, and the development of graft versus host disease (GvHD) or infections. The aim of this study was to investigate the role of TGFB1 gene -1347C>T variant in the outcome of HSCT in a cohort of 409 adult recipient-donor pairs. TGFB1 variant was analysed from genomic DNA with LightCycler hybridisation probe method. In case of myeloablative conditioning, donor TGFB1 genotype correlated with overall survival (60-month OS for CC: 62.1 ± 4.8%; CT: 46.8 ± 4.8%; TT: 35.6 ± 9.3%; p = 0.032), which was independent of age, donor type and GvHD prophylaxis in multivariate analysis (HR:2.35, 95%CI:1.35-4.10, p = 0.003). The cumulative incidence of acute GvHD grade III-IV [CC:10%; CT:17%; TT:24%], and non-relapse mortality was higher in TT-carriers (24-month NRM: CC:24%; CT:26%; TT:46%, p = 0.035). We did not find any association between recipient TGFB1 -1347C>T polymorphism and HSCT outcome. Our results suggest that donor TGFB1 -1347C>T may exert an adverse influence on the outcome of myeloablative conditioning transplantation.

Discovering the chloride pathway in the CFTR channel.

Cystic fibrosis (CF), a lethal monogenic disease, is caused by pathogenic variants of the CFTR chloride channel. The majority of CF mutations affect protein folding and stability leading overall to diminished apical anion conductance of epithelial cells. The recently published cryo-EM structures of full-length human and zebrafish CFTR provide a good model to gain insight into structure-function relationships of CFTR variants. Although, some of the structures were determined in the phosphorylated and ATP-bound active state, none of the static structures showed an open pathway for chloride permeation. Therefore, we performed molecular dynamics simulations to generate a conformational ensemble of the protein and used channel detecting algorithms to identify conformations with an opened channel. Our simulations indicate a main intracellular entry at TM4/6, a secondary pore at TM10/12, and a bottleneck region involving numerous amino acids from TM1, TM6, and TM12 in accordance with experiments. Since chloride ions entered the pathway in our equilibrium simulations, but did not traverse the bottleneck region, we performed metadynamics simulations, which revealed two possible exits. One of the chloride ions exits includes hydrophobic lipid tails that may explain the lipid-dependency of CFTR function. In summary, our in silico study provides a detailed description of a potential chloride channel pathway based on a recent cryo-EM structure and may help to understand the gating of the CFTR chloride channel, thus contributing to novel strategies to rescue dysfunctional mutants.

Current Trends in Applications of Circulatory Microchimerism Detection in Transplantation.

Primarily due to recent advances of detection techniques, microchimerism (the proportion of minor variant population is below 1%) has recently gained increasing attention in the field of transplantation. Availability of polymorphic markers, such as deletion insertion or single nucleotide polymorphisms along with a vast array of high sensitivity detection techniques, allow the accurate detection of small quantities of donor- or recipient-related materials. This diagnostic information can improve monitoring of allograft injuries in solid organ transplantations (SOT) as well as facilitate early detection of relapse in allogeneic hematopoietic stem cell transplantation (allo-HSCT). In the present review, genetic marker and detection platform options applicable for microchimerism detection are discussed. Furthermore, current results of relevant clinical studies in the context of microchimerism and SOT or allo-HSCT respectively are also summarized.

Donor KIR2DS1 reduces the risk of transplant related mortality in HLA-C2 positive young recipients with hematological malignancies treated by myeloablative conditioning.

BACKGROUND: Recognition of HLA-C2 group alleles on recipient cells by activating killer immunoglobulin like receptors, KIR2DS1 on donor natural killer cells may lead to increased graft-versus-leukemia effect or immunomodulation in patients treated by allogeneic hematopoietic stem cell transplantation (allo-HSCT) influencing disease free and overall survival (OS). OBJECTIVE: In the present study, 314 consecutive, allo-HSCT recipient and donor pairs were included with retrospective donor KIR-genotyping and clinical parameters analyzes. RESULTS: After a median follow-up of 23.6 months, recipients with HLA-C2 group allele (rC2) showed improved (p = 0.046) OS if transplanted with KIR2DS1 positive donors (d2DS1) compared to those without one or both of this genetic attribute. Within the myeloablative conditioning (MAC) subgroup (n = 227), rC2 homozygous+d2DS1 patients (n = 14) showed a 5 years OS of 93% followed by rC2 heterozygous+d2DS1 patients (n = 48, 65%) compared to rC2 and/or d2DS1 negatives (47%, p = 0.018). Multivariate analyses indicated rC2+d2DS1 positivity as an independent predictor of OS (HR:0.47, 0.26-0.86, p = 0.014) besides donor type, presence of CMV-reactivation or chemoresistant disease. Among MAC-treated patients, the combined rC2+d2DS1 presence was associated with a markedly decreased cumulative incidence of transplant related mortality (p = 0.0045). CONCLUSION: The combination of rC2+d2DS1 may be a favorable genetic constellation in allo-HSCT with MAC potentially reducing transplant related mortality.

A systematic literature review of incidence, mortality, and relapse of patients diagnosed with chronic graft versus host disease.

INTRODUCTION: Chronic graft-versus-host disease (chronic GVHD) is a leading cause of late death and contributes significantly to morbidity following hematopoietic stem cell transplantation. This study aims to provide a systematic literature review on incidence, mortality, and relapse of chronic GVHD patients. Areas covered: The authors searched for English-language articles published between 2007 and 2017 using PubMed. Studies that applied the 2005 or 2015 NIH Consensus Criteria for the diagnosis and staging of chronic GVHD, and had a cohort size of at least 100 patients were included. Expert opinion: The authors found a wide variation of incidence rates, which can be explained by heterogeneity in the characteristics of study samples and applied transplantation protocols. Chronic GVHD was associated with higher non-relapse mortality (NRM), superior overall survival (OS) and lower risk of relapse. Studies indicated an increased risk for NRM and worse OS in the presence of more severe disease. Future therapies should focus to reach a delicate balance between controlling disease severity among patients diagnosed with chronic GVHD and preserving the graft versus tumor effect which goes along with chronic GVHD and results in improved OS and decreased relapse rate. Nonetheless, factors predicting disease severity still need to be further understood.

Concentration and Subclass Distribution of Anti-ADAMTS13 IgG Autoantibodies in Different Stages of Acquired Idiopathic Thrombotic Thrombocytopenic Purpura.

BACKGROUND: The acquired form of idiopathic thrombotic thrombocytopenic purpura (TTP) is an autoimmune disease, in which the underlying deficiency of the ADAMTS13 protease is caused by autoantibodies, predominantly of the IgG isotype. Certain HLA-DR-DQ haplotypes were associated with the risk of developing TTP. OBJECTIVES: To investigate the development of the ADAMTS13-specific antibody response during the course of the disease, we analyzed the concentration, subclass distribution, and inhibitory potential of anti-ADAMTS13 IgG autoantibodies in samples of TTP patients drawn during the first acute phase, in remission, and during relapse. Additionally, we compared the anti-ADAMTS13 IgG levels between patients carrying and not carrying risk and protective HLA-DR-DQ haplotypes. PATIENTS AND METHODS: We determined the anti-ADAMTS13 IgG concentration and subclass distribution in 101 antibody-positive samples of 81 acquired TTP patients by ELISA methods. The presence and semi-quantitative amount of anti-ADAMTS13 inhibitors were determined in 97 of 100 deficient samples, and the specific inhibitory potential of anti-ADAMTS13 autoantibodies was determined in 49 selected samples, by mixing ADAMTS13-activity assays. HLA-DR-DQ typing and haplotype prediction were performed in 70 of the above patients. RESULTS: We found that IgG1 and IgG4 were the predominant subclasses, present in almost all samples. While IgG1 was the dominant subclass in almost half of the samples taken during the first acute episode, IgG4 was dominant in all samples taken during or following a relapse. The inhibitory potential of the samples correlated with levels of the IgG4 subclass. Anti-ADAMTS13 antibodies of IgG4-dominant samples had higher specific inhibitory potentials than IgG1-dominant samples, independently of disease stage. Interestingly, we found that patients carrying the protective DR7-DQ2 and DR13-DQ6 haplotypes had higher anti-ADAMTS13 IgG levels. CONCLUSION: Our results indicate that IgG4 becomes the dominant subtype at some point of the disease course, apparently before the first relapse, parallel to the increase in inhibitory potential of the anti-ADAMTS13 autoantibodies. Furthermore, we found an association between the genetic background and the antibody response in TTP.

The adverse effect of FOPNL genomic variant is reversed by bortezomib-based treatment protocols in multiple myeloma.

Fibroblast growth factor receptor 1 oncogene partner N-terminal like gene (FOPNL) rs72773978 polymorphism was identified as an adverse prognostic factor in multiple myeloma (MM). We aimed to investigate the associations of rs72773978 with clinical characteristics and treatment outcome in 373 Hungarian MM patients. In our cohort, FOPNL polymorphism showed differential prognostic effect that depended on the treatment applied. Among patients treated with non-proteasome inhibitor (PI)-based therapy, carriership of the minor allele was significantly associated with adverse overall survival (p=.022). In contrast, the adverse effect was overcome by the application of PI-containing treatment (p=.048). Multivariate analyses revealed the independent adverse effect of rs72773978 on survival in the non-PI-treated group (p=.045), but not in PI treatment (OS: p=.093). We confirmed the adverse prognostic effect of rs72773978 associated with non-PI-based treatment regimens. Our results point to the importance of genotypic prognostic information associated with complex clinical background MM.