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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.

Background COVID-19 in comorbidity with non-communicable chronic diseases (NCDs) complicate the diagnosis, treatment, prognosis, and increase mortality rate. Objective. To evaluate the effects of the weight loss treatment on clinic/laboratory inflammation and metabolic profile, reactive oxygen species (ROS) body composition in patients with COVID-19 in comorbidity with NCDs. Design: A 6-week open, pilot prospective clinical trial. Setting: The study included 72 adult patients with COVID and influenza in comorbidity with type 2 diabetes (T2D), hypertension, and NASH. Interventions: The treatment involved a fast-weight-loss-method (Analimentary detoxication, ANADETO) including calorie restriction to 50–100 kcal/day, salt intake to 5–6 gr/day, hot water drinking 1000–1500 ml/day, walking > 2,000 steps/day, and sexual self-restraint. Main outcome measures: Primary endpoints: Clinic/infectious/inflammation tests for COVID/Influenza; weight loss during 14 days. Secondary endpoints: fasting blood glucose, HbA1c, blood insulin; systolic/diastolic BP; blood lipids; ALT/AST, chest-CT-scan. Results The patients weight lost from baseline (-9,14 − 12,4%; P 96.3% patients at the 14 days. Systolic/diastolic BP normalized (P P P P P

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.

Összefoglaló. A vérkészítmény-irradiáció célja a transzfúzió-asszociált graft-versus-host betegség (TA-GVHD) megelőzése a magvas sejtek nukleinsav-állományának szelektív károsításával. Az irradiáció hátránya a káliumtartalom növekedése, az általános sejtkárosító hatás, a körülményesebb előállítással járó időveszteség és a többletköltség. A legújabb nemzetközi ajánlásokban az utóbbi évtizedek szisztematikus adatgyűjtése alapján részletesen definiálták, mely klinikai helyzetekben javasolják csak az irradiált vérkészítmények adását. A pontos indikációs kör meghatározása lehetővé teszi az indokolatlan rendelések csökkentését. Egyáltalán nem indokolt a friss fagyasztott plazma irradiációja. A készítménygyártás során alkalmazott módosítások közül a leukoredukció szignifikáns mértékben csökkenti a TA-GVHD kockázatát. Nem indokolt patogén redukciós eljárással kezelt készítmény irradiációja. A Hodgkin-lymphomában élethosszig alkalmazott irradiált készítményindikáció nem evidenciaalapú, és várható az indikáció egyre kiterjedtebb módosítása és szűkítése. A hazai gyakorlatban újszerű kezdeményezésként a Semmelweis Egyetem II. Gyermekgyógyászati Klinika Hematológiai osztálya a jelenleg hatályos Transzfúziós Szabályzat kevéssé meghatározott indikációs körét meghaladva bevezette a Magyar Gyermekonkológusok és Gyermekhematológusok Társasága által kidolgozott és jóváhagyott új körülírt indikációs körét. A változtatás kezdeti fél éves időszaka alatt a korábbi kizárólagosan irradiált készítményhasználatról a klinika szintjén 1 alá csökkent az irradiált/nem irradiált készítmény arány. A változtatás 6 hónap alatt mintegy 2,4 millió Ft-os költségmegtakarítást eredményezett. A vizsgált időszakban beadott 526 vérkészítmény közül mindössze 45-nél (8,6%) állt fenn az irradiáció indikációja, további 43 (8,2%) transzfúzió indikáció hiányában történt irradiált készítménnyel. A tapasztalatok arra utalnak, hogy a korábbi gyakorlat biztonságosan racionalizálható, a vérkészítmény-irradiáció indikációja hozzáigazítható a fejlett országok irányelveihez és ez jelentős közvetlen költségmegtakarítást jelent az ellátóhely számára. Summary. The goal of blood product irradiation is the prevention of transfusion-associated graft-versus-host disease (TA-GVHD) by the selective alteration of the DNA-content of nucleated blood cells. The disadvantages of irradiation include increases in potassium content, general cell damage, time-loss due to production associated extra work and additional costs. Based on systematic data collection, the recent recommendations provide detailed definitions as to what are the clinical situations in which only irradiated blood products are indicated. This allows the avoidance of unjustified orders of irradiated products. Irradiation of fresh frozen plasma is not indicated at all. Leukoreduction, a modification applied during production significantly decreases the risk of TA-GVHD. Pathogen reduced products should not be irradiated. Indication for lifelong irradiated products for patients with Hodgkin-lymphoma is not evidence-based and its modification and narrowing are expected. As a novel initiative of II. Department of Pediatrics at Semmelweis University, ordering irradiated blood products has started according to new guidelines of the Hungarian Society of Pediatric Hematologists and Oncologists instead of the currently nationally effective Transfusion Guidelines. During the initial 6 months of change, savings of 2.4 million HUF were observed. Out of 526 products transfused during these 6 months, the new guidelines recommended irradiated products only in 45 cases (8.6%) and in 43 other cases (8.2%), irradiated products were transfused in the absence of appropriate indications. The experiences suggest that the old practice can safely be rationalized, and the indications can be adjusted according to the new international guidelines resulting in direct cost savings.

Purpose: We used high-resolution oligonucleotide comparative genomic hybridization (CGH) arrays and matching gene expression array data to identify dysregulated genes and to classify breast cancers according to gene copy number anomalies.Experimental Design: DNA was extracted from 106 pretreatment fine needle aspirations of stage II-III breast cancers that received preoperative chemotherapy. CGH was done using Agilent Human 4 × 44K arrays. Gene expression data generated with Affymetrix U133A gene chips was also available on 103 patients. All P values were adjusted for multiple comparisons.Results: The average number of copy number abnormalities in individual tumors was 76 (range 1-318). Eleven and 37 distinct minimal common regions were gained or lost in >20% of samples, respectively. Several potential therapeutic targets were identified, including FGFR1 that showed high-level amplification in 10% of cases. Close correlation between DNA copy number and mRNA expression levels was detected. Nonnegative matrix factorization (NMF) clustering of DNA copy number aberrations revealed three distinct molecular classes in this data set. NMF class I was characterized by a high rate of triple-negative cancers (64%) and gains of 6p21. VEGFA, E2F3, and NOTCH4 were also gained in 29% to 34% of triple-negative tumors. A gain of ERBB2 gene was observed in 52% of NMF class II and class III was characterized by a high rate of estrogen receptor–positive tumors (73%) and a low rate of pathologic complete response to preoperative chemotherapy (3%).Conclusion: The present study identified dysregulated genes that could classify breast cancer and may represent novel therapeutic targets for molecular subsets of cancers.

Supplementary Data from Molecular Characterization of Breast Cancer with High-Resolution Oligonucleotide Comparative Genomic Hybridization Array

BackgroundCOVID and Influenza with non-communicable chronic diseases (NCDs) complicate the diagnosis, treatment, prognosis, and increase mortality rate. The aim: to evaluate the effects of the fast weight loss on clinic and laboratory inflammation profile, metabolic profile, reactive oxygen species (ROS) and body composition in patients with COVID and Influenza in comorbidity with NCDs.MethodsA 6-week open, pilot prospective clinical trial including 62 adult patients with COVID (n=27) and influenza (n=35) in comorbidity with T2D, hypertension, and NASH. Overweight in 33 patients (53.2%) with BMI 28.14±0.39 kg/m2, and 29 patients without overweight with BMI 23.37 ± 0.38 kg/m2. T2D in 26 (41.9%); Hypertension in 38 (61.3%) (incl. 12 patients with T2D); NASH in 51 patients (82.2%) (incl. 8 patients with NASH, T2D and Hypertension; 6 patients with NASH and T2D; 18 patients with NASH and Hypertension; 19 patients with only NASH). Primary endpoints: Clinic/infectious/inflammation tests for COVID and Influenza; weight loss during 14 days. Secondary endpoints: fasting blood glucose, HbA1c, blood insulin; systolic/diastolic BP; blood lipids; ALT, AST, chest CT-scan.ResultsThe patients with overweight lost -12,4% from baseline or BMI= -4.2 kg/m2, and patients without overweight lost -9,14% from baseline or BMI= -2.2 kg/m2(−9.7±0.7 kg vs. - 6.4±0.6 kg, respectively;PPSputum production increased in 1.0-1.5 liter/day on 2-3 days, decreased in 7-9 days. Body temperature normalized in 6-9 days. On 3-5 days, in most patients their urine became turbid/muddy/intensively colored. Urine microscopy showed organic and non-organic salts, and leukocyturia (20-35/sight).White blood cells, lymphocytes, NLR normalized at 14 days (PPCOVID and Influenza were a negative in >96.3% patients at 14-day. Systolic/diastolic BP decreased (161.3±1.31/101.6±0.85 vs. 118.3±0.46/80.89±0.66,P9/L) at 14-day of treatment (238.5±5.8, ×109/L) (P9/L) (PPPConclusionsThe fast weight loss is clinical/laboratory benefit in treatment of patients with COVID-19 and Influenza in comorbidity with T2D, hypertension, and NASH.Trial RegistrationClinicalTrials.govNCT05635539. Registered 1 December 2022.

Background Behavioral habits and parental rearing during physical and sexual growth of men can influence to their penis size. Aim To assess the erect penis size in adult Kazakh males and study the influence of their physiological events and behavioral habits during their body growth on their penis size. Methods A cross-sectional survey pilot study with the intention-to-treat. The study included 282 adult Kazakh fertility males aged 23-35 years. Interventions: paper-based survey administration; erect penis length and girth measurement. Two-tailed Student’s t-test, Pearson correlation, and multivariate tests of the MANOVA/MANCOVA were used. The Ethics Committee of the National Research oncology center approved the study. Outcomes In Kazakh men a mean age 29.6±4.4 years; body height 171.56±6.64 cm; BMI 24.53±3.40 kg/m2; erect penis length 13.41±1.04 cm and girth 11.62±0.91 cm. Results There was a significant correlation between erect penis length and girth (PPConclusions Sexual abstinence to coitus and masturbation during childhood has a positive increasing affect on the penis size in adulthood. The more males in childhood abstains from ejaculation, the larger their penis size in adulthood. A long-lasting extended erection during body growth has a positive effect on penis enlargement.

BACKGROUND: The authors aim to publish the results of their studies in peer-reviewed targeted international journals with a high impact-factor as possible, but they are also exposing to “predatory” publishers. AIM: The aim of the study was to offer some advices for authors to help to identify relevant medical journals, avoid “predatory” journals and publishers, use intermediary services, know a journal policy, and expectations of good journal editor(s). RECOMMENDATIONS: During the publication process authors should find suitable journals, assume a risk to encounter “predatory” or “hijacked” journals, know the advantages and disadvantages of using intermediary publishing services, understand expectations of editor(s), and make payment for article processing. CONCLUSIONS: The advices can help many researchers to publish their papers in relevant journals with cited indexes, and avoid many problems within the publication process.

Tünde Mezei,1 Imre B&odblac;de,1 Péter Tenke,1 Valéria Jósa,2 Keresztély Merkel,3 Zsuzsanna Szilasi,4 Attila Tordai,5 Domokos Máthé,6 Zsolt Baranyai7 1Department of Urology, Jahn Ferenc South-Pest Hospital, Budapest, Hungary; 2Department of Otorhinolaryngology and Head and Neck Surgery, Jahn Ferenc South-Pest Hospital, Budapest, Hungary; 3Department of Surgery, Szent Imre Hospital, Budapest, Hungary; 4Department of Otorhinolaryngology and Head and Neck Surgery, HDF Medical Centre, Budapest, Hungary; 5Institute of Pathophysiology, Semmelweis University, Budapest, Hungary; 6Department of Biophysics and Radiation Biology, Semmelweis University, Budapest, Hungary; 7Semmelweis University, Department of Transplantation and Surgery, Budapest, HungaryCorrespondence: Tünde Mezei, Jahn Ferenc South-Pest Hospital, Department of Urology, Budapest, Hungary, Köves str 1, Budapest, 1204, Hungary, Tel +3620/2013038, Email stiffnesskft@gmail.comPurpose: 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.Keywords: prostate cancer, thrombocytosis, prognosis, pathomechanism, solid tumor

Background: The hypothesis that metabolic rate is inversely correlated with lifespan has long been debating. Another area of controversy is an evidence of a relationship between metabolic rate (MR) and time-flow perception (TFP), and aging. Aim: to study the impact of overweight and food intake on MR, TFP, chronic diseases, aging, lifespan; difficulties in weight loss.Methods. Design: a systematic review. Settings: Web of Science, Scopus, Science Direct, Kopernio, PubMed, Mendeley were searched for articles published from January 1979 until February 2022. The study bases on a viewpoint supported by a systematic literature review of 3612 articles published worldwide.Results: In total, 107 full-text articles were assessed for eligibility. From them, 22 articles were excluded with reasons. Overweight and overeating accelerate MR, leading to hyper-metabolic mode of the body. MR and lifespan are inversely correlated. TFP depends on MR; accelerated MR leads to deceleration of TFP. Every person has an individual ability to gain weight up to 'maximum bodyweight', which indicates the individual potential energy to weight gain. Overweight excessively consumes the body ‘vital energy’, is a soil to grow diseases; devours body potential energy. Weightloss creates ‘body power to weight gain’ that increases physical/mental activity, recovering from diseases, or weight regain. The body needs less calorie intake due to the decrease in MR by age. For weight loss should use very-low-calorie diets and manage metabolic intoxication.Conclusions: Our findings support that overweight and overeating increase metabolic rate, which delays time-flow perception, accelerates aging, limits lifespan. For weight loss should manage very-low-calorie diets.

Absztrakt: A súlyos akut légúti szindrómát kiváltó, új típusú koronavírus, a SARS-CoV2 olyan példátlan világjárványt okozott, amely szélsőséges terhelést jelent a még a legfejlettebb országok egészségügyi rendszereire is és azok társadalmaira. Az újonnan emberi kórokozóvá váló vírus ellen sem védőoltás, sem hatékony célzott terápia nem áll rendelkezésre. A járványhelyzetre reagálva a világszerte, köztük Magyarországon is, meghozott szigorú korlátozások a vérellátás tevékenységét egyfelől a donációs hajlandóság és aktivitás kifejezett csökkenése, másfelől a felhasználók igényeinek nehezebben jósolható csökkenése révén érintették. Az OVSz országos adatai szerint a vörösvérsejt-, illetve plazmakészítmények felhasználása mintegy 30%-os, míg a thrombocytakészítményeké mintegy 20%-os csökkenést mutatott 2020. április hónapban az előző év azonos időszakához képest. Ugyanebben az időszakban a mobil véradási események száma országosan 61%-kal, a véradásra megjelent donorok száma pedig 28%-kal csökkent. A korábban járványt okozó légúti vírusokkal és a SARS-CoV2-vel is meglevő klinikai tapasztalatok alapján nem valószínűsíthető az új koronavírus hematogén úton történő átvitele, így a véradás előtti szűrés sem indokolt a potenciálisan fertőzöttek kiszűrését segítő általános óvintézkedések betartása mellett. A hematológiai betegellátásban a vérkészítmények felhasználásának csökkenése kisebb mértékű volt, és kifejezett szóródást mutatott a vizsgált szegedi és budapesti egyetemi központok összehasonlításában. Az új kórokozó elleni vakcina és célzott kezelés hiányában a SARS-CoV2 elleni konvaleszcens plazmaterápia ígéretes és racionális, azonnal hozzáférhető terápiás lehetőség. Az FDA kivételesen gyorsan meghozott bátorító állásfoglalása és irányelve hatására több párhuzamos, nagyobb esetszámú és a korszerű klinikai kutatási szempontokat is figyelembe vevő, a SARS-CoV2 elleni konvaleszcens plazmaterápiára irányuló klinikai vizsgálat indult az USA-ban és más nyugati országokban, köztük Magyarországon is a vérellátó szolgálatok aktív részvételével.

Background: The hypothesis that metabolic rate is inversely correlated with lifespan has long been debating. Another area of controversy is an evidence of a relationship between metabolic rate (MR) and time-flow perception (TFP), and aging. Aim: to study the impact of overweight and food intake on MR, TFP, chronic diseases, aging, lifespan; difficulties in weight loss.Methods. Design: a systematic review. Settings: Web of Science, Scopus, Science Direct, Kopernio, PubMed, Mendeley were searched for articles published from January 1979 until February 2022. The study bases on a viewpoint supported by a systematic literature review of 3612 articles published worldwide.Results: In total, 107 full-text articles were assessed for eligibility. From them, 22 articles were excluded with reasons. Overweight and overeating accelerate MR, leading to hyper-metabolic mode of the body. MR and lifespan are inversely correlated. TFP depends on MR; accelerated MR leads to deceleration of TFP. Every person has an individual ability to gain weight up to 'maximum bodyweight', which indicates the individual potential energy to weight gain. Overweight excessively consumes the body ‘vital energy’, is a soil to grow diseases; devours body potential energy. Weightloss creates ‘body power to weight gain’ that increases physical/mental activity, recovering from diseases, or weight regain. The body needs less calorie intake due to the decrease in MR by age. For weight loss should use very-low-calorie diets and manage metabolic intoxication.Conclusions: Our findings support that overweight and overeating increase metabolic rate, which delays time-flow perception, accelerates aging, limits lifespan. For weight loss should manage very-low-calorie diets.

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. 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. 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. 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.

Introduction: The aim of the study was to show an atmospheric pressure change by indirect measurement in hermetically closed vessels during four years of follow-up.Methods: Study design: an observational study. In hermetically sealed elastic bottles with different liquids were measured differences in liquid and air volumes from baseline to final follow-up period. The physical law of flotation was used to measure liquid and air volume above liquid in bottles. To measure liquid and air (above liquid) volumes in each bottle was used the physical law of buoyancy. The follow-up period was four years.Results: The volumes of liquid and air in all bottles were decreased after the follow-up period to 14.38±2.40 and 36.25±3.37 ml, respectively. Air volume in comparison to liquid volume decreased more than two times significantly (P=0.0007) after the follow-up period.Conclusions: Thus, atmospheric pressure increased during the last 4-year follow-up period. Further investigations are needed.

Absztrakt: Klinikai szempontbol az ABO a legjelentősebb vercsoportrendszer, amelyről a korabbi kiterjedt kutatasok ellenere meg mindig jelentős uj felfedezesek szuletnek. A vercsoportrendszer genet...

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapeutic option for malignant hematopoietic diseases. Cytokines including transforming growth factor β1 (TGFβ1) 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.

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. Electronic supplementary material The online version of this article (10.1007/s00018-019-03211-4) contains supplementary material, which is available to authorized users.

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. 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. 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. 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.

Background: Studies showed that mortality and morbidity rates from COVID-19 are uneven across world countries. The spread of COVID-19 depends on a lot of social and economic factors. Aim of the study was to study an influence of country’s gross domestic product, population prevalence of overweight and obesity on COVID-19 morbidity and mortality. Methods: A cross-sectional study with correlation-regression. The study has two phases: correlation-regression interrelations in 1) all world countries; 2) all world non-island countries. The study includes data from 218 world countries: COVID-19 morbidity rate, COVID-19 mortality rate, GDP (at purchasing power parity) per capita, the prevalence of overweight among adults (both sexes), and prevalence of obesity among adults (both sexes). Pearson correlation, regression analysis, and Fisher’s r to z transformation (Z-score) were used. Results: An average percent of the prevalence of overweight among adults (both sexes) in included 176 world countries to the 2019 year was 47.31± 15.99%, prevalence of obesity was 18.34± 9.64%. During three years (2016-2019) the prevalence of overweight and obesity among adults has grown by 21.2% and 40.8%, respectively. Data of the 176 world countries provides significant correlations between COVID-19 morbidity and: GDP (r=0.517; p

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. Electronic supplementary material The online version of this article (10.1007/s00018-020-03651-3) contains supplementary material, which is available to authorized users.

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.

The role of HLA system in allogeneic haematopoietic stem cell transplantation (allo-HSCT) outcome is unarguable. In this study we investigated association of HLA-A,-B and-DRB1 alleles with overall survival (OS) in 186 patients undergoing allo-HSCT for lymphoid malignancies. Analyses confirmed significantly better OS for HLA-DRB1∗04 carriers compared with non-carriers (p = 0.01). Survival benefit was confined to male patients (in multivariate analyses p = 0.034, hazard ratio 0.35, 95% confidence interval 0.13-0.92), whereas in females no difference was noted (p = 0.82). Furthermore, donor gender also affected outcome and transplantation from female HLA-DRB1∗04 carrier donors resulted in superior survival compared with female non-carrier donors (p = 0.01). Combined analyses including recipient/donor gender and HLA-DRB1∗04 showed that survival of male patients varied significantly according to donor gender and HLA-DRB1∗04 carriership (p = 0.04) with best survival among HLA-DRB1∗04 carriers transplanted from female donors. Of relevance to our results, HLA-DRB1∗04 has been documented as risk allele group for lymphoid malignancies, and studies described a male-specific risk. We believe that our findings provide further supporting evidence for sex-specific alterations secondary to HLA-DRB1∗04 or related genes. Further studies are warranted to evaluate whether in contrast to general favour of male donors HLA-DRB1∗04 carrier patients with lymphoid malignancies could benefit from transplantation from female donors.

Background Proteasome subunit beta type 1 ( PSMB1 ) rs12717 polymorphism, a single nucleotide polymorphism with unknown functional effect, was recently reported to influence response to bortezomib-based therapy in follicular lymphoma. Patients and Methods We retrospectively analyzed the prognostic impact of this polymorphism in 211 consecutively diagnosed multiple myeloma cases, and performed in vitro experiments to look into its functional consequences. Results On univariate analysis, patients carrying the variant G allele showed significantly shorter progression-free survival (PFS) with a pattern suggestive of a gene-dose effect (PFS 26.4, 22.3, and 16.4 months in C/C, C/G, and G/G patients, respectively, P = .002). On multivariate analysis, carrying the G/G genotype was a significant independent risk factor for relapse (hazard ratio [HR] 2.29, P P = .097) when compared with the major allele carrier C/C cohort. Our subsequent in vitro analyses demonstrated significantly reduced protease activity in proteasomes of individuals with G/G genotype compared with that of C/C carriers, despite that PSMB1 expression and proteasome assembly remained unaltered. Bortezomib exhibited a lower inhibitory capacity on the caspase- and trypsin-like activity of proteasomes from G/G individuals. Conclusion Our results show that carriership of PSMB1 rs12717 minor allele is predictive for suboptimal response with bortezomib treatment, which could be explained by less active proteasomes that are less sensitive to bortezomib, and myeloma cells consequently relying on other escape mechanisms to cope with the abundance of misfolded proteins.

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.

The acquired form of idiopathic thrombotic thrombocytopenic purpura (TTP) is an autoimmune disease, in which the underlying ADAMTS13-deficiency is caused by inhibitory autoantibodies against the protease. Human leukocyte antigens (HLA), responsible for antigen presentation, play an important role in the development of antibodies. The loci coding HLA DR and DQ molecules are inherited in linkage as haplotypes. The c.1858C>T polymorphism of the PTPN22 gene, which codes a protein tyrosine phosphatase important in lymphocyte activation, predisposes to a number of autoimmune diseases. We determined the HLA-DRB1-DQB1 haplotypes and the PTPN22 c.1858C>T genotypes in 75 patients with acquired idiopathic TTP and in healthy controls, in order to assess the role of these genetic factors and their interactions in the susceptibility to TTP. We found that the carrier frequencies of the DRB1∗11-DQB1∗03 and DRB1∗15-DQB1∗06 haplotypes were higher, while those of the DRB1∗07-DQB1∗02 and DRB1∗13-DQB1∗06 haplotypes were lower in TTP patients. There was no difference in the overall frequency of the PTPN22 c.1858T allele between TTP patients and controls. In conclusion, we identified four HLA-DRB1-DQB1 haplotypes associated with an increased (DRB1∗11-DQB1∗03 and DRB1∗15-DQB1∗06) or a decreased (DRB1∗07-DQB1∗02 and DRB1∗13-DQB1∗06) susceptibility to acquired idiopathic TTP.

Abstract: Introduction and aim: The publication summarizes the 2548 stem cell transplantations performed in the period of 1993-2015 in Szent Laszló Hospital, Budapest and provides a detailed discussion of the 425 allogeneic transplantations during 2007–2013. Method: The analysis explains the major steps of the evolution of allogeneic stem cell transplantation and compares the results of the unique Hungarian allogeneic center. Results: The significant shift in the transplantation indications from chronic myeloid leukemia to myelodysplastic syndromes and the rising age of the recipients are in line with world wide tendencies. The latter one is the consequence of the introduction and improvement of the concept of reduced intensity conditioning regimens, originally arising from the idea of Endre Kelemen. The most limiting factor, the donor availability seems to be resolved with the use of a new immunomodulating regimen, the application of posttransplantation cyclophosphamide, which allows the transplantation through HLA barriers with haploidentical family donors with comparable results to the HLA matched volunteer unrelated donors. The above mentioned tendencies result the wider use of allogeneic stem cell transplantation less dependent from recipient age, comorbidities and even donor availability. Conclusions: The publication highlights the need of expanding the stem cell transplantation budget and the involvement of new centers in Hungary in allogeneic of stem cell transplantation. Orv. Hetil., 2017, 158(8), 291–297.

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.

BackgroundRecognition 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).ObjectiveIn the present study, 314 consecutive, allo-HSCT recipient and donor pairs were included with retrospective donor KIR-genotyping and clinical parameters analyzes.ResultsAfter 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).ConclusionThe combination of rC2+d2DS1 may be a favorable genetic constellation in allo-HSCT with MAC potentially reducing transplant related mortality.

Several genetic polymorphisms have been implicated to affect the outcome of allogeneic hematopoietic stem cell transplantation (allo-HSCT). The role of cytokines in acute graft-versus-host disease (aGvHD) is well established and many of the involved cytokines signal through the Janus kinase (JAK) pathways. In this study, we assessed the association of recipient and donor JAK2 46/1 haplotypes and allo-HSCT outcome in a cohort of 124 acute myeloid leukemia patients. Both, recipient and donor 46/1 haplotypes significantly affected aGvHD grades II-IV development (p = 0.006 and p = 0.031, respectively), furthermore the influence of the haplotypes seemed to be additive. In multivariate analyses the recipient haplotype remained independently related (p = 0.012) to aGvHD, while the donor not (p = 0.08). We observed significantly less relapses among haplotype carriers (p = 0.004), but overall survival did not differ (p = 0.732). Our findings suggest that recipient and donor JAK2 46/1 haplotypes might be involved in the regulation of aGvHD.

Background: The germline telomerase reverse transcriptase (TERT) rs2736100_C variant was identified as a susceptibility factor for a variety of solid tumors and recently for myeloproliferative neoplasms (MPN). Methods: LightCycler melting curve analysis was applied to detect risk alleles of TERT rs2736100_C and Janus kinase 2 (JAK2) rs12343867_C tagging 46/1 haplotype in 584 BCR-ABL1–negative MPN, 308 acute, and 86 chronic myeloid leukemia (AML and CML) patients and 400 healthy individuals. Results: TERT rs2736100_C showed an increased allele frequency in BCR-ABL1–negative MPN patients compared with controls (62.7%±2.8% vs. 48.8%±3.5%, P < 0.0001) regardless of molecular background or disease type, but not in CML or AML. Combined TERT and JAK2 hetero- or homozygosity conferred even higher risk for classic MPN. Common complications (thrombosis, myelofibrosis, or leukemia) were not associated with the TERT variant; however, adverse survival was noted in TERT variant carrier polycythemia vera patients. MPN patients with the TERT CC genotype had a higher probability (44.4%) to die from solid tumors compared with TERT AC/AA individuals (5.3%; P = 0.004). TERT rs2736100_C carriers had increased risk of solid tumors independently from cytoreductive treatment [3.08 (1.03–9.26), P = 0.045]. Conclusions: TERT rs2736100_C polymorphism predisposes to the development of BCR-ABL1–negative MPN with the co-occurrence of solid tumors, especially with the usage of cytoreductive treatment. Impact: The high frequency of TERT variant in the classic MPN population highlights the importance of the avoidance of long-term cytoreductive treatment in MPN patients. Cancer Epidemiol Biomarkers Prev; 25(1); 98–104. ©2015 AACR.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a potentially curative therapeutic option for malignant hematopoietic diseases. Cytokines including transforming growth factor β1 (TGFβ1) 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 -1347CT 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 -1347CT polymorphism and HSCT outcome. Our results suggest that donor TGFB1 -1347CT may exert an adverse influence on the outcome of myeloablative conditioning transplantation.

Transplantation-associated thrombotic microangiopathy (TA-TMA) is a serious complication of allogeneic haematopoietic stem cell transplantation (allo-HSCT) with high mortality rate. We retrospectively studied the frequency, clinical and genetic associations and prognostic effect of TA-TMA, in a total of 425 consecutive adult patients, who underwent allo-HSCT for a malignant haematological condition between 2007 and 2013 at our single centre. TA-TMA developed in 19% of the patients. Unrelated donor type (P

BACKGROUND & AIMS Pattern recognition receptors (PRRs) have a key role in the innate host defense. Functional polymorphisms of various PRRs have been established to contribute to an increased susceptibility to spontaneous bacterial peritonitis (SBP). Their role in the development of cirrhosis-associated bacterial infections (BI), beyond SBP or progressive disease course related to pathological bacterial translocation (BT) remains unknown. METHODS Three hundred and forty-nine patients with cirrhosis were genotyped for common NOD2 (R702W, G908R and L1007PfsinsC), TLR2 (-16934T>A), and TLR4 (D299G) variants. Incidence of BIs, decompensating events and liver-related death were assessed in a 5-year follow-up observational study. Pathological BT was assessed based on the presence of antimicrobial antibodies or lipopolysaccharide-binding protein (LBP) level. RESULTS In patients with ascites (n = 88) only NOD2 gene variants were associated with an increased cumulative probability of SBP (76.9% ± 19.9%) compared to wild-type (30.9% ± 6.9%, PLogRank = .047). Individual or combined PRR genetic profiles were associated with the risk of non-SBP type BI. Advanced disease stage (HR [95% CI]: 2.11 [1.38-3.25]) and prior history of a BI episode (HR: 2.42 [1.58-3.72]) were the major clinical risk factors of a subsequent BI. The risk of a non-SBP type BI in patients with advanced disease and a prior BI was even higher (HR: 4.74 [2.68-8.39]). The frequency of antimicrobial antibodies and LBP levels did not differ between various PRR genotypes. Correspondingly, PRR genetic profile was not able to predict the long-term disease course. CONCLUSIONS In cirrhosis, functional polymorphisms of PRRs did not improve the identification of patients with high risk of BI beyond SBP or progressive diseases course.

The publication summarizes the 2548 stem cell transplantations performed in the period of 1993-2015 in Szent Laszló Hospital, Budapest and provides a detailed discussion of the 425 allogeneic transplantations during 2007-2013.The analysis explains the major steps of the evolution of allogeneic stem cell transplantation and compares the results of the unique Hungarian allogeneic center.The significant shift in the transplantation indications from chronic myeloid leukemia to myelodysplastic syndromes and the rising age of the recipients are in line with world wide tendencies. The latter one is the consequence of the introduction and improvement of the concept of reduced intensity conditioning regimens, originally arising from the idea of Endre Kelemen. The most limiting factor, the donor availability seems to be resolved with the use of a new immunomodulating regimen, the application of posttransplantation cyclophosphamide, which allows the transplantation through HLA barriers with haploidentical family donors with comparable results to the HLA matched volunteer unrelated donors. The above mentioned tendencies result the wider use of allogeneic stem cell transplantation less dependent from recipient age, comorbidities and even donor availability.The publication highlights the need of expanding the stem cell transplantation budget and the involvement of new centers in Hungary in allogeneic of stem cell transplantation. Orv. Hetil., 2017, 158(8), 291-297.

Introduction: Mutations in Janus kinase 2, calreticulin and thrombopoietin receptor genes have been identified in the genetic background of Philadelphia chromosome negative, “classic” myeloproliferative neoplasms. Aim: The aim of the authors was to identify driver mutations in a large myeloproliferative cohort of 949 patients. Method: A complex array of molecular techniques (qualitative and quantitative allele-specific polymerase chain reactions, fragment analyzes, high resolution melting and Sanger sequencing) was applied. Results: All 354 patients with polycythemia vera carried Janus kinase 2 mutations (V617F 98.6%, exon 12: 1.4%). In essential thrombocythemia (n = 468), the frequency of V617F was 61.3% (n = 287), that of calreticulin 25.2% (n = 118), and that of thrombopoietin receptor mutations 2.1% (n = 10), while 11.3% (n = 53) were triple-negative. Similar distribution was observed in primary myelofibrosis (n = 127): 58.3% (n = 74) V617F, 23.6% (n = 30) calreticulin, 6.3% (n = 8) thrombopoietin receptor mutation positive and 11.8% (n = 15) triple-negative. Conclusions: The recent discovery of calreticulin gene mutations led to definite molecular diagnostics in around 90% of clonal myeloproliferative cases. Orv. Hetil., 2014, 155(52), 2074–2081.

Nuclear factor kappa B (NFKB) plays an important role in multiple myeloma (MM), and bortezomib affects this pathway. We retrospectively analysed the effect of the NFKB1 -94ins/delATTG polymorphism on the survival of 295 MM patients treated at a single centre. The median progression-free survival (PFS) was 790 (659-921) d in patients with NFKB1 homozygous insertion genotype (I/I, n = 99) and 624 (515-733) d in deletion-carriers (I/DD/D, n = 196, P = 0·013). In multivariate analysis, I/I carriers showed a favourable PFS compared to I/DD/D with a hazard ratio of 0·622 (0·457-0·847), P = 0·003, in addition to international staging system (ISS) score, fluorescence in situ hybridization (FISH) risk score, age and bortezomib treatment. I/I patients benefited more from bortezomib treatment [PFS 902 (703-1101) and 580 (343-817), P = 0·008] than I/DD/D patients [PFS 659 (487-831) and 488 (323-653), P = 0·531]; in addition the beneficial effect of low ISS score was not observed in the I/DD/D group [PFS 639 (454-824) and 650 (458-842), P = 0·226], while it was clear in I/I patients [PFS 1140 (803-1477) and 580 (408-752), P0·001]. We conclude that homozygous carriers of the insertion allele of the NFKB1 -94ins/delATTG polymorphism have a better prognosis and probably benefit more from bortezomib treatment than MM patients carrying the deletion allele.

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.

Controversy exists about the effectiveness of vaccine-induced immune response in patients with immunoregulatory disorders. Our aim was to determine the antibody titers to diphtheria and tetanus in patients with either of two autoimmune diseases.279 patients with SLE (205 females, aged 45.0 ± 13.8 years), 158 patients with myasthenia gravis (MG) (101 females, aged 55 ± 18.7 years) and 208 healthy subjects (122 females, aged 48 ± 14.6 years) were enrolled. Serum concentrations of diphtheria-antitoxin-IgG (A-DIPHTH) and tetanus-antitoxoid-IgG (A-TET) were determined with ELISA.Equal proportions of healthy subjects, as well as patients with SLE or MG exhibited proper antibody responses and immune protection against diphtheria and tetanus. In all three test groups, serum concentration of A-DIPHTH decreased significantly (p0.001) with age throughout the study population, while titers of A-TET dropped only in the elderly (60-years-old) subjects. There were no significant differences among the groups in the age-related changes of A-TET and A-DIPHTH except that in40-years-old subjects, A-DIPHTH level was significantly (p=0.029) lower in SLE patients than in controls.Our findings suggest that the level of vaccine-induced immunity against diphtheria and tetanus infections in patients with SLE or MG is comparable to the healthy population.