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Human leukocyte antigens (HLAs) are polymorphic glycoproteins expressed on the cell surface of nucleated cells and consist of two classes, HLA class I and HLA class II. In contrast, in mice, these molecules, known as H-2, are expressed on both nucleated cells and erythrocytes. HLA-I molecules (Face-1) are heterodimers consisting of a polypeptide heavy chain (HC) and a light chain, B2-microglobulin (B2m). The heterodimers bind to antigenic peptides and present them to the T-cell receptors of CD8+ cytotoxic T lymphocytes. The HCs can also independently emerge on the cell surface as B2m-free HC monomers without peptides (Face-2). Early investigators suggested that the occurrence of B2m-free HCs on the cell surface resulted from the dissociation of B2m from Face-1. However, others documented the independent emergence of B2m-free HCs (Face-2) from the endoplasmic reticulum (ER) to the cell surface. The clustering of such HC molecules on either the cell surface or on exosomes resulted in the dimerization of B2m-free HCs to form homodimers (if the same allele, designated as Face-3) or heterodimers (if different alleles, designated as Face-4). Face-2 occurs at low levels on the cell surface of several normal cells but is upregulated on immune cells upon activation by proinflammatory cytokines and other agents such as anti-CD3 antibodies, phytohemagglutinin, and phorbol myristate acetate. Their density on the cell surface remains high as long as the cells remain activated. After activation-induced upregulation, Face-2 molecules undergo homo- and heterodimerization (Face-3 and Face-4). Observations made on the structural patterns of HCs and their dimerization in sharks, fishes, and tetrapod species suggest that the formation of B2m-free HC monomers and dimers is a recapitalization of a phylogenetically conserved event, befitting the term Proto-HLA for the B2m-free HCs. Spontaneous arthritis occurs in HLA-B27+ mice lacking B2m (HLA-B27+ B2m−/−) but not in HLA-B27+ B2m+/+ mice. Anti-HC-specific monoclonal antibodies (mAbs) delay disease development. Some HLA-I polyreactive mAbs (MEM series) used for immunostaining confirm the existence of B2m-free variants in several cancer cells. The conformational alterations that occur in the B2m-free HCs enable them to interact with several inhibitory and activating receptors of cellular components of the innate (natural killer (NK) cells) and adaptive (T and B cells) immune systems. The NK cells express killer immunoglobulin-like receptors (KIRs), whereas leukocytes (T and B lymphocytes, monocytes/macrophages, and dendritic cells) express leukocyte immunoglobulin-like receptors (LILRs). The KIRs and LILRs include activating and inhibitory members within their respective groups. This review focuses on the interaction of KIRs and LILRs with B2m-free HC monomers and dimers in patients with spondylarthritis. Several investigations reveal that the conformational alterations occurring in the alpha-1 and alpha-2 domains of B2m-free HCs may facilitate immunomodulation by their interaction with KIR and LILR receptors. This opens new avenues to immunotherapy of autoimmune diseases and even human cancers that express B2m-free HCs.

Interest in citrate-based dialysate (Cit-D) is growing due to its benefits, including anticoagulation and dialysis efficacy. However, research on safety and efficiency of Cit-D in high-volume hemodiafiltration (HDF) via central concentrate delivery system (CCDS) is scarce. This study aimed to investigate the safety and efficacy of Cit-D when switching from acetate-based dialysate (Acet-D) in high-volume HDF via CCDS. This is a retrospective analysis of 28 patients who underwent post-dilution online HDF via CCDS, who switched from Acet-D to Cit-D. The study period was divided into 3 periods for analysis: 12 weeks using Acet-D (AD period), the first 12 weeks using Cit-D (CD-1 period), and the second 12 weeks using Cit-D (CD-2 period). We collected the laboratory, dialysis, and safety parameters in each period from electrical medical records. After switching from Acet-D to Cit-D, heparin dosage decreased by 17%, whereas the incidence of complications did not increase. Kt/VBUN and urea reduction ratio increased by 4.6% and 2.1%, respectively. Pre-dialysis beta2-microglobulin concentration decreased after using Cit-D. The corrected calcium levels decreased in the CD-1 period compared to the AD period, but in CD-2, they subsequently increased to levels similar to those observed during the AD period. Symptomatic hypocalcemia did not occur, and there was no significant difference in the incidence of hyperparathyroidism. Endotoxin levels and the bacterial culture of ultrapure dialysate were unremarkable throughout all periods. These results might suggest that Cit-D could potentially offer advantages over Acet-D, such as reducing the heparin dose and increasing dialysis efficiency, in patients undergoing high-volume HDF using CCDS.

Abstract Background Gliomas are the deadliest malignant tumors of the adult central nervous system. We previously discovered that beta2-microglobulin (B2M) is abnormally upregulated in glioma tissues and that it exerts a range of oncogenic effects. Besides its tissue presence, serum B2M levels serve as biomarkers for various diseases. This study aimed to explore whether serum B2M levels can be used in the diagnosis and prognosis of gliomas. Methods Medical records from 246 glioma patients were retrospectively analyzed. The relationship between preoperative serum B2M levels and clinicopathological features was examined. Kaplan-Meier analysis, alongside uni- and multivariate Cox regression, assessed the association between B2M levels, systemic inflammatory markers, and glioma patient prognosis. Receiver operating characteristic (ROC) curve analysis evaluated the diagnostic significance of these biomarkers specifically for glioblastoma (GBM). Results Patients with malignant gliomas exhibited elevated preoperative serum B2M levels. Glioma patients with high serum B2M levels experienced shorter survival times. Multivariate Cox analysis determined the relationship between B2M levels (hazard ratio = 1.92, 95% confidence interval: 1.05–3.50, P = 0.034) and the overall survival of glioma patients. B2M demonstrated superior discriminatory power in distinguishing between GBM and non-GBM compared to inflammation indicators. Moreover, postoperative serum B2M levels were lower than preoperative levels in the majority of glioma patients. Conclusions High preoperative serum B2M levels correlated with malignant glioma and a poor prognosis. Serum B2M shows promise as a novel biomarker for predicting patient prognosis and reflecting the therapeutic response.

Background: Gliomas are the deadliest malignant tumors of the adult central nervous system. We previously discovered that beta2-microglobulin (B2M) is abnormally upregulated in glioma tissues and that it exerts a range of oncogenic effects. Besides its tissue presence, serum B2M levels serve as biomarkers for various diseases. This study aimed to explore whether serum B2M levels can be used in the diagnosis and prognosis of gliomas. Methods: Medical records from 246 glioma patients were retrospectively analyzed. The relationship between preoperative serum B2M levels and clinicopathological features was examined. Kaplan-Meier analysis, alongside uni- and multivariate Cox regression, assessed the association between B2M levels, systemic inflammatory markers, and glioma patient prognosis. Receiver operating characteristic (ROC) curve analysis evaluated the diagnostic significance of these biomarkers specifically for glioblastoma (GBM). Results: Patients with malignant gliomas exhibited elevated preoperative serum B2M levels. Glioma patients with high serum B2M levels experienced shorter survival times. Multivariate Cox analysis determined the relationship between B2M levels (hazard ratio = 1.92, 95% confidence interval: 1.05–3.50, P = 0.034) and the overall survival of glioma patients. B2M demonstrated superior discriminatory power in distinguishing between GBM and non-GBM compared to inflammation indicators. Moreover, postoperative serum B2M levels were lower than preoperative levels in the majority of glioma patients. Conclusions: High preoperative serum B2M levels correlated with malignant glioma and a poor prognosis. Serum B2M shows promise as a novel biomarker for predicting patient prognosis and reflecting the therapeutic response. [ABSTRACT FROM AUTHOR]

Central nervous system (CNS) disorders represent the leading cause of disability and the second leading cause of death worldwide, and impose a substantial economic burden on society. In recent years, emerging evidence has found that beta2 -microglobulin (B2M), a subunit of major histocompatibility complex class I (MHC-I) molecules, plays a crucial role in the development and progression in certain CNS diseases. On the one hand, intracellular B2M was abnormally upregulated in brain tumors and regulated tumor microenvironments and progression. On the other hand, soluble B2M was also elevated and involved in pathological stages in CNS diseases. Targeted B2M therapy has shown promising outcomes in specific CNS diseases. In this review, we provide a comprehensive summary and discussion of recent advances in understanding the pathological processes involving B2M in CNS diseases (e.g., Alzheimer's disease, aging, stroke, HIV-related dementia, glioma, and primary central nervous system lymphoma). [ABSTRACT FROM AUTHOR]

Cell surface HLA-I molecules (Face-1) consist of a polypeptide heavy chain (HC) with two groove domains (G domain) and one constant domain (C-domain) as well as a light chain, B2-microglobulin (B2m). However, HCs can also independently emerge unfolded on the cell surface without peptides as B2m-free HC monomers (Face-2), B2m-free HC homodimers (Face 3), and B2m-free HC heterodimers (Face-4). The transport of these HLA variants from ER to the cell surface was confirmed by antiviral antibiotics that arrest the release of newly synthesized proteins from the ER. Face-2 occurs at low levels on the normal cell surface of the lung, bronchi, epidermis, esophagus, breast, stomach, ilium, colorectum, gall bladder, urinary bladder, seminal vesicles ovarian epithelia, endometrium, thymus, spleen, and lymphocytes. They are upregulated on immune cells upon activation by proinflammatory cytokines, anti-CD3 antibodies, antibiotics (e.g., ionomycin), phytohemagglutinin, retinoic acid, and phorbol myristate acetate. Their density on the cell surface remains high as long as the cells remain in an activated state. After activation-induced upregulation, the Face-2 molecules undergo homo- and hetero-dimerization (Face-3 and Face-4). Alterations in the redox environment promote dimerization. Heterodimerization can occur among and between the alleles of different haplotypes. The glycosylation of these variants differ from that of Face-1, and they may occur with bound exogenous peptides. Spontaneous arthritis occurs in HLA-B27+ mice lacking B2m (HLA-B27+ B2m−/−) but not in HLA-B27+ B2m+/− mice. The mice with HLA-B27 in Face-2 spontaneous configuration develop symptoms such as changes in nails and joints, hair loss, and swelling in paws, leading to ankyloses. Anti-HC-specific mAbs delay disease development. Some HLA-I polyreactive mAbs (MEM series) used for immunostaining confirm the existence of B2m-free variants in several cancer cells. The upregulation of Face-2 in human cancers occurs concomitantly with the downregulation of intact HLAs (Face-1). The HLA monomeric and dimeric variants interact with inhibitory and activating ligands (e.g., KIR), growth factors, cytokines, and neurotransmitters. Similarities in the amino acid sequences of the HLA-I variants and HLA-II β-chain suggest that Face-2 could be the progenitor of both HLA classes. These findings may support the recognition of these variants as a neo-HLA class and proto-HLA. [ABSTRACT FROM AUTHOR]

L’hémodialyse (HD) Longue Nocturne (HDLN) intermittente permet de combiner dialyse et sommeil. Ses avantages cliniques sont une vitesse d’ultrafiltration réduite, un meilleur contrôle de la volémie avec amélioration de la tolérance des séances et des performances cardiaques, une phosphatémie et des moyennes molécules mieux épurées et une meilleure survie dans les études de cohortes. La qualité de vie n’est pas altérée par la longueur des séances et elle s’améliore quand elle n’est pas optimale lors du transfert de l’HD standard vers l’HDLN. La qualité du sommeil n’est parfois perturbée mais elle n’est pas une cause importante de sortie du programme. La pérennité d’un programme d’HDLN passe par les volontés conjointes médicales et managériales, la sélection des patients stables, le respect des horaires et de la durée de séances, indispensable à la dialyse de sommeil. Les autorités de santé doivent jouer un rôle pour permettre cette modalité dans des conditions financières acceptables. L’information au patient de l’existence de l’HDLN avant le stade de la dialyse est essentielle, aidée par le témoignage des pairs. Les sociétés savantes doivent soutenir la recherche et l’information aux néphrologues. Enfin les conditions architecturales favorisant l’intimité et le sommeil sont une clé de réussite du programme.

To assess the level of β2-microglubulin (β2M) in systemic lupus erythematosus (SLE) patients and its association with disease activity and other disease parameters. 40 SLE patients and 22 matched controls were studied. Serum β2M was assessed using enzyme-linked immunosorbent assay (ELISA). SLE Disease Activity Index (SLEDAI) and the damage index were assessed. The patients were 36 females and 4 males (F:M 9:1) with a mean age of 28.5 ± 7.9 years and disease duration of 6.7 ± 3.3 years. The SLEDAI was 9.3 ± 5.2 and the damage index 1.83 ± 1.84. The mean level of serum β2M was significantly higher in SLE patients (6.42 ± 2.46 mg/L) than control (2.47 ± 0.4 mg/L) (p < 0.01).The serum level of β2M was significantly higher in patients with nephritis (n = 22) (7.45 ± 2.47 mg/L) compared to those without (n = 18) (5.17 ± 1.82 mg/L)(p = 0.002), And it was similar in those with and without arthritis (7.24 ± 2.3 mg/L vs 5.88 ± 2.4 mg/L (p0.07).The β2M significantly correlated with disease activity (r = 0.86, p 0.001), serum creatinine (r = 0.52, p > 0.001), urea (r = 0.63, p < 0.001), 24 h urinary protein (r = 0.56, p < 0.001), hematuria (r = 0.4, p < 0.01) and pyuria (r = 0.41; p < 0.01), ESR (r = 0.48; p < 0.01) and inversely with hemoglobin level (r = −0.34; p = 0.03). No significant correlation was found with C-reactive protein or with disease damage. Serum (β2M) significantly predicted nephritis and disease activity (sensitivity 63.6 %, specificity 77.8 %; p < 0.001 and 95 %CI: 0.25–0.41; p < 0.001 respectively). Serum β2M is significantly associated with disease activity and lupus nephritis, suggesting that serum β2M may serve as a potential biomarker to monitor the disease activity and predicting lupus nephritis. However its association to disease severity needs further longitudinal studies. [ABSTRACT FROM AUTHOR]

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Interest in citrate-based dialysate (Cit-D) is growing due to its benefits, including anticoagulation and dialysis efficacy. However, research on safety and efficiency of Cit-D in high-volume hemodiafiltration (HDF) via central concentrate delivery system (CCDS) is scarce. This study aimed to investigate the safety and efficacy of Cit-D when switching from acetate-based dialysate (Acet-D) in high-volume HDF via CCDS. This is a retrospective analysis of 28 patients who underwent post-dilution online HDF via CCDS, who switched from Acet-D to Cit-D. The study period was divided into 3 periods for analysis: 12 weeks using Acet-D (AD period), the first 12 weeks using Cit-D (CD-1 period), and the second 12 weeks using Cit-D (CD-2 period). We collected the laboratory, dialysis, and safety parameters in each period from electrical medical records. After switching from Acet-D to Cit-D, heparin dosage decreased by 17%, whereas the incidence of complications did not increase. Kt/V BUN and urea reduction ratio increased by 4.6% and 2.1%, respectively. Pre-dialysis beta 2 -microglobulin concentration decreased after using Cit-D. The corrected calcium levels decreased in the CD-1 period compared to the AD period, but in CD-2, they subsequently increased to levels similar to those observed during the AD period. Symptomatic hypocalcemia did not occur, and there was no significant difference in the incidence of hyperparathyroidism. Endotoxin levels and the bacterial culture of ultrapure dialysate were unremarkable throughout all periods. These results might suggest that Cit-D could potentially offer advantages over Acet-D, such as reducing the heparin dose and increasing dialysis efficiency, in patients undergoing high-volume HDF using CCDS.

Cell surface HLA-I molecules (Face-1) consist of a polypeptide heavy chain (HC) with two groove domains (G domain) and one constant domain (C-domain) as well as a light chain, B2-microglobulin (B2m). However, HCs can also independently emerge unfolded on the cell surface without peptides as B2m-free HC monomers (Face-2), B2m-free HC homodimers (Face 3), and B2m-free HC heterodimers (Face-4). The transport of these HLA variants from ER to the cell surface was confirmed by antiviral antibiotics that arrest the release of newly synthesized proteins from the ER. Face-2 occurs at low levels on the normal cell surface of the lung, bronchi, epidermis, esophagus, breast, stomach, ilium, colorectum, gall bladder, urinary bladder, seminal vesicles ovarian epithelia, endometrium, thymus, spleen, and lymphocytes. They are upregulated on immune cells upon activation by proinflammatory cytokines, anti-CD3 antibodies, antibiotics (e.g., ionomycin), phytohemagglutinin, retinoic acid, and phorbol myristate acetate. Their density on the cell surface remains high as long as the cells remain in an activated state. After activation-induced upregulation, the Face-2 molecules undergo homo- and hetero-dimerization (Face-3 and Face-4). Alterations in the redox environment promote dimerization. Heterodimerization can occur among and between the alleles of different haplotypes. The glycosylation of these variants differ from that of Face-1, and they may occur with bound exogenous peptides. Spontaneous arthritis occurs in HLA-B27+ mice lacking B2m (HLA-B27+ B2m−/−) but not in HLA-B27+ B2m+/− mice. The mice with HLA-B27 in Face-2 spontaneous configuration develop symptoms such as changes in nails and joints, hair loss, and swelling in paws, leading to ankyloses. Anti-HC-specific mAbs delay disease development. Some HLA-I polyreactive mAbs (MEM series) used for immunostaining confirm the existence of B2m-free variants in several cancer cells. The upregulation of Face-2 in human cancers occurs concomitantly with the downregulation of intact HLAs (Face-1). The HLA monomeric and dimeric variants interact with inhibitory and activating ligands (e.g., KIR), growth factors, cytokines, and neurotransmitters. Similarities in the amino acid sequences of the HLA-I variants and HLA-II β-chain suggest that Face-2 could be the progenitor of both HLA classes. These findings may support the recognition of these variants as a neo-HLA class and proto-HLA.

Objective To evaluate the results of extracorporeal shockwave lithotripsy (ESWL) versus retrograde intrarenal surgery (RIRS) for the treatment of calcium oxalate nephrolithiasis, as well as the damaging effects on renal function, taking into account the dynamics of blood cystatin C and urine beta2-microglobulin.Material and Methods Of 94 patients with calcium oxalate nephrolithiasis aged 23–78 included in the study, 42 patients were classified as having undergone ESWL (group I) and 52 patients as having undergone RIRS (group II). Group II patients were then stratified into subset 2A (n = 32) as having undergone RIRS through rigid ureteroscope and subset 2B (n = 20) as having undergone RIRS through flexible ureteroscope. We performed plain urography and nephrosonography at 24–48 hours postoperatively and unenhanced computed tomography 4–6 weeks after surgery. We measured concentrations of serum cystatin C and urinary beta2-microglobulin as a marker for kidney damage. In group I, samples of peripheral blood andurine were taken before and after the first, third sessions and 30 days after the last ESWL session. In group II, samples were analyzed before surgery, on the first and 30th postoperative days.Results The average size of calculi in the group with RIRS was 16.91 ± 2.79 mm, in the group with ESWL 12.31 ± 2.27 mm. The need for reoperation after RIRS was 19.2%, which was lower than after ESWL. Stone-free effect (no stones, or residual stones less than 3 mm) was observed in 95% of cases in patients with RIRS, and in 78% with ESWL. Group I patients demonstrated an increase in the blood leukocytes total number more often than subsets 2A (rigid RIRS) and 2B (flexible RIRS) patients. Leukocyturia was also a more common complication in group I. In the RIRS group, there was no statistically significant change in the level of blood cystatin C and urine beta2-microglobulin, on the contrary, a moderate increase in the endogenous marker of cystatin C was noted after one ESWL session. The increase in urine beta2-microglobulin levels in patients after the first and third ESWL sessions was significantly higher than after RIRS.Conclusion Flexible RIRS may be suggested as the preferred procedure for patients requiring additional protection of renal function in the treatment of renal stones less than 20 mm. ESWL of stones less than 20 mm can be used as an alternative treatment, since it is characterized by a rather long period of stone eradication from the urinary tract, a high frequency of residual calculi after the procedure, and also has a damaging effect on the renal tissue.

Human leukocyte antigens (HLAs) are polymorphic glycoproteins expressed on the cell surface of nucleated cells and consist of two classes, HLA class I and HLA class II. In contrast, in mice, these molecules, known as H-2, are expressed on both nucleated cells and erythrocytes. HLA-I molecules (Face-1) are heterodimers consisting of a polypeptide heavy chain (HC) and a light chain, B2-microglobulin (B2m). The heterodimers bind to antigenic peptides and present them to the T-cell receptors of CD8+ cytotoxic T lymphocytes. The HCs can also independently emerge on the cell surface as B2m-free HC monomers without peptides (Face-2). Early investigators suggested that the occurrence of B2m-free HCs on the cell surface resulted from the dissociation of B2m from Face-1. However, others documented the independent emergence of B2m-free HCs (Face-2) from the endoplasmic reticulum (ER) to the cell surface. The clustering of such HC molecules on either the cell surface or on exosomes resulted in the dimerization of B2m-free HCs to form homodimers (if the same allele, designated as Face-3) or heterodimers (if different alleles, designated as Face-4). Face-2 occurs at low levels on the cell surface of several normal cells but is upregulated on immune cells upon activation by proinflammatory cytokines and other agents such as anti-CD3 antibodies, phytohemagglutinin, and phorbol myristate acetate. Their density on the cell surface remains high as long as the cells remain activated. After activation-induced upregulation, Face-2 molecules undergo homo- and heterodimerization (Face-3 and Face-4). Observations made on the structural patterns of HCs and their dimerization in sharks, fishes, and tetrapod species suggest that the formation of B2m-free HC monomers and dimers is a recapitalization of a phylogenetically conserved event, befitting the term Proto-HLA for the B2m-free HCs. Spontaneous arthritis occurs in HLA-B27+ mice lacking B2m (HLA-B27+ B2m-/-) but not in HLA-B27+ B2m+/+ mice. Anti-HC-specific monoclonal antibodies (mAbs) delay disease development. Some HLA-I polyreactive mAbs (MEM series) used for immunostaining confirm the existence of B2m-free variants in several cancer cells. The conformational alterations that occur in the B2m-free HCs enable them to interact with several inhibitory and activating receptors of cellular components of the innate (natural killer (NK) cells) and adaptive (T and B cells) immune systems. The NK cells express killer immunoglobulin-like receptors (KIRs), whereas leukocytes (T and B lymphocytes, monocytes/macrophages, and dendritic cells) express leukocyte immunoglobulin-like receptors (LILRs). The KIRs and LILRs include activating and inhibitory members within their respective groups. This review focuses on the interaction of KIRs and LILRs with B2m-free HC monomers and dimers in patients with spondylarthritis. Several investigations reveal that the conformational alterations occurring in the alpha-1 and alpha-2 domains of B2m-free HCs may facilitate immunomodulation by their interaction with KIR and LILR receptors. This opens new avenues to immunotherapy of autoimmune diseases and even human cancers that express B2m-free HCs.

Nguyen Huu Dung,1 Nguyen Trung Kien,2 Nguyen Thi Thu Hai,1 Phan The Cuong,1 Nguyen Thi Thu Huong,3 Dao Bui Quy Quyen,4 Nguyen Minh Tuan,4 Do Manh Ha,2 Truong Quy Kien,2 Nguyen Thi Thuy Dung,2 Pham Quoc Toan,2 Hoang Trung Vinh,2 Tomoko Usui,5 Le Viet Thang21Bach Mai Hospital, Ha Noi, Vietnam; 2Military Hospital 103, Ha Noi, Vietnam; 3Ha Noi Kidney Hospital, Ha Noi, Vietnam; 4Cho Ray Hospital, Ho Chi Minh, Vietnam; 5University of Tokyo Hospital, Tokyo, JapanPurpose: Beta2-microglobulin (β2-M) is recognized as a surrogate marker relating to the mechanisms of dialysis-associated amyloidosis. Few studies have evaluated the association of serum β2-M with clinical outcome in hemodialysis patients using high-flux type. However, study on patients using low-flux dialyzer reuse has not been done yet.Patients and methods: Using serum β2-M level on predicting long-term mortality of hemodialysis patients was examined in 326 prevalent hemodialysis patients (45.59±14.46 years, hemodialysis duration of 47.5 (26–79) months, 186 males and 140 females). The patients were divided into 3 groups with equal number of patients, according to their serum β2-M levels: group A (n=109, serum β2-M concentration ≤55.7 mg/L), group B (n=109, serum β2-M level from 55.8 mg/L to 75.4 mg/L) and group C (n=108, serum β2-M concentration >75.4 mg/L).Results: During the follow-up period of 5 years, there were 75 all-cause deaths (23.0%). Kaplan–Meier analysis revealed that all-cause mortality in the higher β2-M group was significantly higher compared to that in the lower β2-M groups (p

Background: chronic kidney disease (CKD) increases the severity and risk of mortality in acute coronary syndrome (ACS) patients. The role of β2-M as a filtration and inflammation marker and FGF23 as a CKD-MBD process marker might be significant in the pathophysiology in ACS with CKD patients. This study aims to determine the association of β2-M and FGF23 with major adverse cardiac event (MACE) in ACS patients with CKD. Methods: we used cross sectional and retrospective cohort analysis for MACE. We collected ACS patients with CKD consecutively from January until October 2018 at Dr. Cipto Mangunkusumo General Hospital. Data were analyzed using logistic regression and Cox’s Proportional Hazard Regression. Results: a total of 117 patients were selected according to the study criteria. In bivariate analysis, β2-M, FGF23, and stage of CKD had significant association with MACE (p = 0.014, p = 0.026, p = 0.014, respectively). In multivariate analysis, β2-M - but not FGF 23- was significantly associated with MACE (adjusted HR 2.16; CI95% 1.15–4.05; p = 0.017). Conclusion: β2-M was significantly associated with MACE, while FGF23 was not so. This finding supports the role of inflammation in cardiovascular outcomes in ACS with CKD patient through acute on chronic effect.

Mismatch repair (MMR)-deficient cancers accumulate multiple insertion/deletion mutations at coding microsatellites (cMS), which give rise to frameshift peptide neoantigens. The high mutational neoantigen load of MMR-deficient cancers is reflected by pronounced anti-tumoral immune responses of the host and high responsiveness towards immune checkpoint blockade. However, immune evasion mechanisms can interfere with the immune response against MMR-deficient tumors. We here performed a comprehensive analysis of immune evasion in MMR-deficient colorectal cancers, focusing on HLA class I-mediated antigen presentation. 72% of MMR-deficient colorectal cancers of the DFCI database harbored alterations affecting genes involved in HLA class I-mediated antigen presentation, and 54% of these mutations were predicted to abrogate function. Mutations affecting the HLA class I transactivator NLRC5 were observed as a potential new immune evasion mechanism in 26% (6% abrogating) of the analyzed tumors. NLRC5 mutations in MMR-deficient cancers were associated with decreased levels of HLA class I antigen expression. In summary, the majority of MMR-deficient cancers display mutations interfering with HLA class I antigen presentation that reflect active immune surveillance and immunoselection during tumor development. Clinical studies focusing on immune checkpoint blockade in MSI cancer should account for the broad variety of immune evasion mechanisms as potential biomarkers of therapy success.

DNA mismatch repair (MMR)-deficient cancers accumulate high numbers of coding microsatellite mutations, which lead to the generation of highly immunogenic frameshift peptide (FSP) neoantigens. MMR-deficient cells can grow out to clinically manifest cancers either if they evade immune cell attack or if local T-cells get exhausted. Therefore, a subset of MSI cancer patients responds particularly well to treatment with immune checkpoint inhibitors. We analyzed whether immune evasion in MMR-deficient cancer mediated by loss of HLA class I or II antigens is related to local immune cell activation status. Microsatellites located in Beta2-microglobulin (B2M) and the HLA class II-regulatory genes RFX5 and CIITA were analyzed for mutations in MMR-deficient colorectal cancers (n = 53). The results were related to CD3-positive and PDCD1 (PD-1)-positive T-cell infiltration. PDCD1 (PD-1)-positive T-cell counts were significantly higher in B2M-mutant compared to B2M-wild type tumors (median: 22.2 cells per 0.25 mm2 vs. 2.0 cells per 0.25 mm2, Wilcoxon test p = 0.002). Increasing PDCD1 (PD-1)-positive T-cell infiltration was significantly related to an increased likelihood of B2M mutations (OR = 1.81). HLA class II antigen expression status was significantly associated with enhanced overall T-cell infiltration, but not related to PDCD1 (PD-1)-positive T-cells. These results suggest that immune evasion mediated by B2M mutation-induced loss of HLA class I antigen expression predominantly occurs in an environment of activated PDCD1 (PD-1)-positive T cell infiltration. If B2M mutations interfere with anti-PDCD1 (PD-1)/CD274 (PD-L1) therapy success, we predict that resistance towards anti-PDCD1 (PD-1) therapy may – counterintuitively – be particularly common in patients with MMR-deficient cancers that show high PDCD1 (PD-1)-positive T cell infiltration.

Real-time reverse transcription polymerase chain reaction (RT-PCR) is regarded as one of the most useful and powerful tools for characterizing hematopoietic stem cells (HSCs), because samples of extremely small cell numbers can be analyzed. The expression levels determined by RT-PCR are based on relative quantification; therefore, the selection of an appropriate reference gene with a relatively stable expression level under most conditions is crucial. Here, we determined that beta2-microglobulin (B2m) is an appropriate reference gene for analyzing mouse HSCs by a novel method using single-cell RT-PCR. Clonally sorted HSCs were subjected to RT reactions with exogenous RNA fragments and then to real-time PCR. Next, the relative gene expression levels of 4 well-known housekeeping genes were quantified in each single cell sample based on the threshold cycle of exogenous RNA. The analysis revealed that B2m expression was reproducibly detected in almost all HSCs and that B2m had the most stable expression level among the compared genes, even after the cells had been cultured under various conditions. Thus, our results indicate that B2m can reliably be used as a reference gene for the relative quantification of expression levels in HSCs across various conditions. Furthermore, our work proposes a novel method for the selection of appropriate reference genes.

Abstract We compared cerebrospinal fluid levels of lactate, β2-microglobulin and angiotensin-converting enzyme (ACE) between 438 untreated patients with multiple sclerosis and 276 patients with non-inflammatory neurological disorders. Age-adjusted β2-microglobulin and lactate were significantly higher and ACE was significantly lower in MS patients than in controls. β2-microglobulin and ACE positively correlated with high significance both in MS patients and controls. While disease duration negatively correlated and progression index, defined as EDSS score divided by disease duration in years, positively correlated with age-adjusted lactate levels, both did neither correlate with β2-microglobulin nor with ACE. Both CSF β2-microglobulin and ACE deserve further investigation as biomarkers of multiple sclerosis pathophysiology. Graphical abstract Unlabelled Image Highlights • CSF levels of β2-microglobulin, lactate and ACE significantly increase with age • Age-adjusted CSF β2-microglobulin and lactate are higher, while ACE is lower in multiple sclerosis patients than controls • Only lactate but not β2-microglobulin nor ACE correlates with MS disease duration and severity • CSF β2-microglobulin and ACE deserve further investigation as biomarkers of multiple sclerosis pathophysiology [ABSTRACT FROM AUTHOR]

Molecularly imprinted polymers (MIPs) for protein recognition have great application potential in the biological analysis. However, preparation of protein imprinted polymer is still facing challenge. Beta2-microglobulin (β 2 m) is a protein biomarker that can be used in diagnosis of different diseases. In this research, a novel MIP with ability of β 2 m recognition has been developed by epitope and surface-confined imprinting approaches. A peptide with sequence of MIQRTPKIQ was selected as template. A strategy of combination of hierarchical imprinting and template immobilization was employed in the β 2 m-MIP synthesis. Imprinted binding sites with open-entrance have been created that have good accessibility for β 2 m and facilitated fast reversible binding kinetics. The experimental results demonstrated that the MIP has good selectivity. It can differentiate the template from peptide with different sequence and distinguish the β 2 m from other proteins with similar size and pI values. After binding property study of the β 2 m-MIP, a method of β 2 m determination in serum was established in which β 2 m was on-line extracted by MIP and analyzed by HPLC process. The recoveries for spiked serum was ≥83% with RSD <1.1%, indicating that the method has good accuracy and precisions. The LOD and LOQ were 0.058 and 0.195 mg L −1 respectively, which meet the requirements of the β 2 m analysis. The successful application of the β 2 m-MIP demonstrated that β 2 m has reversible binding on the MIP with a kinetics that can meet the requirements of the HPLC analysis. It also indicated that the β 2 m-MIP has good mechanical strength and reusability that can be applied reliably in the practical analysis. As a synthetic antibody, β 2 m-MIP is advantageous compared to the biological molecules. [ABSTRACT FROM AUTHOR]

Background. Compared to high-flux dialysis membranes, novel medium cut-off (MCO) membranes show greater permeability for largermiddlemolecules. Methods. In two prospective, open-label, controlled, randomized, crossover pilot studies, 39 prevalent hemodialysis (HD) patients were studied in four dialysis treatments as follows: study 1, three MCO prototype dialyzers (AA, BB and CC with increasing permeability) and one high-flux dialyzer in HD; and study 2, two MCO prototype dialyzers (AA and BB) in HD and high-flux dialyzers in HD and hemodiafiltration (HDF). Primary outcome was lambda free light chain (kFLC) overall clearance. Secondary outcomes included overall clearances and pre-to-post-reduction ratios of middle and smallmolecules, and safety of MCO HD treatments. Results. MCO HD provided greater kFLC overall clearance [least square mean (standard error)] as follows: study 1: MCO AA 8.5 (0.54), MCO BB 11.3 (0.51), MCO CC 15.0 (0.53) versus high-flux HD 3.6 (0.51) mL/min; study 2: MCO AA 10.0 (0.58), MCO BB 12.5 (0.57) versus high-flux HD 4.4 (0.57) and HDF 6.2 (0.58) mL/min. Differences between MCO and high-flux dialyzers were consistently significant in mixed model analysis (each P < 0.001). Reduction ratios of kFLC were greater for MCO. Clearances of a1-microglobulin, complement factor D, kappa FLC (jFLC) and myoglobin were generally greater with MCO than with high-flux HD and similar to or greater than clearances with HDF. Albumin loss was moderate with MCO, but greater than with high-flux HD and HDF. Conclusions. MCO HD removes a wide range of middle molecules more effectively than high-flux HD and even exceeds the performance of high-volume HDF for large solutes, particularly λFLC. [ABSTRACT FROM AUTHOR]

Background: More potent antitumor activity is desired in Interferon (IFN)-treated cancer patients. This could be achieved by combining IFN alpha and IFN gamma. The aim of this work was to characterize the pharmacokinetics and pharmacodynamics of a novel formulation containing a co-formulated combination of IFNs alpha-2b and gamma (CIGB-128-A). Methods: A group of nine healthy male subjects received intramuscularly 24.5 × 106 IU of CIGB-128-A. IFN concentrations were evaluated for 48 h. Serum neopterin, beta2-microglobulin (β2M) and 2'-5' oligoadenylate synthetase (2'-5' OAS), classical IFN-inducible serum markers, were measured during 192 h by enzyme immunoassay and body temperature was used as pharmacodynamic variable as well. Results: Concerning pharmacokinetics, serum IFNs' profiles were better fitted to a mono-compartmental model with consecutive zero order and first order absorption, one bioavailability value. No interferences by simultaneous administered IFNs were observed in their typical similar systemic profiles. Neopterin and β2M time profiles showed a delay that was efficiently linked to pharmacokinetics by means of a zero order absorption rate constant. Neopterin level was nine-fold higher than initial values, 48 h post-administration, an increment not described before. At this time, mean serum β2M peaked around the double from baseline. Serum concentrations of the enzyme 2'-5' OAS was still elevated on the 8 day post-injection. The formulation was well tolerated. Most frequent adverse reactions were fever, headache, arthralgia and lymphopenia, mostly mild. Conclusions: The administration of co-formulated IFN alpha-2b and IFN gamma likely provides improved pharmacodynamic properties that may be beneficial to treat several malignancies. [ABSTRACT FROM AUTHOR]

Purpose: This study aims to determine extracorporeal shock wave lithotripsy (ESWL)-induced renal tubular damage and the affecting factors by measuring urinary beta2microglobulin (β2M) excretion. Materials and Methods: This is a cross-sectional study conducted on 91 patients with renal stones who underwent ESWL during 2012. Urinary beta2microglobulin was measured immediately before and after the procedure for each patient and analyzed based on different variables to evaluate factors affecting ESWL-induced renal tubular injury. Results: Mean ± SD urinary beta2-microglobulin values, before and after ESWL were 0.08 ± 0.07 and 0.22 ± 0.71 mg/dL respectively, the average difference between which was equal to 0.14 ± 0.07 mg/dL. These figures exhibited a 166.66% rise in the urinary β2M concentration after ESWL which was statistically significant (P < .001). Multivariate analysis showed that hypertension (P = .05) and the history of ESWL (P = .02) were predictive factors of higher post-ESWL urinary beta2-microglobulin excretion. Conclusion: Urinary excretion of beta2-microglobulin increased significantly immediately after ESWL. These changes could indicate that ESWL is a contributing factor to renal tubular damage. It also seems that in patients with hypertension and a previous history of ESWL the likelihood of this injury is higher than others. [ABSTRACT FROM AUTHOR]

Interaction of the dye Congo red (CR) with fibrils of three model proteins-hen egg lysozyme, recombinant human beta 2-microglobulin (b2M), and recombinant human transthyretin (TTR)-has been investigated using spectrophotometry. Considerable amounts of impurities were detected in the commercial dye formulation. A procedure of dye purification has been developed. The molar extinction coefficient of the dye at 490 nm (ε) has been measured; the coefficient was 3.3 × 10 M cm at pH > 6.0. The formation of a complex between CR and the fibrils was accompanied by a change in the absorption spectrum of the dye in the visible wavelength range. Titration of fibril solutions with excessive amounts of dye showed that the number of CR molecules bound to a protein monomer within the lysozyme fibrils was close to five, whereas the respective ratio for b2M was close to four, and the ratio for TTR fibrils was close to four molecules per protein subunit. [ABSTRACT FROM AUTHOR]

PURPOSE: The present study was designed to determine the normal range of serum beta 2-microglobulin (Sb2M) levels among healthy volunteers in Brazil. Levels of Sb2M are elevated in human immunodeficiency virus (HIV)-infected patients and have been shown to be the best predictor of HIV infection status and of some malignant disorders, especially multiple myeloma. In order to achieve its optimal use in Brazilian clinical diagnosis, an adequate reference interval study was performed for Sb2M IMMULITE® assay, based on the fact that its reference range limits were evaluated among European populations. METHODS: Ninety-six healthy blood donors were evaluated, and Sb2M levels were measured by chemiluminescent enzyme immunoassay using the IMMULITE® automated analyzer. RESULTS: A normal range of Sb2M values, established by a nonparametric statistical method, was 1.05 to 3.9 mg/mL, with the upper limit being higher than that reported elsewhere. CONCLUSIONS: This study presented new data indicating that there is a significant difference between the current reference limits for Sb2M IMMULITE® assay and those found in Brazil, providing evidence that significant differences in range of normal values may occur among different populations, and that these new values should be considered for Brazilian individuals.OBJETIVO: O objetivo do presente estudo foi determinar valores de referência de beta2-Microglobulina sérica (Sb2M) em voluntários saudáveis. Sabe-se que tal parâmetro apresenta-se elevado em pacientes infectados com o vírus da imunodeficiência humana (HIV) e tem se mostrado melhor marcador da infecção por HIV e de desordens malignas, especialmente mieloma múltiplo. De forma a se obter o melhor diagnóstico clínico, um intervalo de referência adequado de Sb2M para a população brasileira foi determinado empregando-se o ensaio IMMULITE®; já que este tem como parâmetro uma faixa de referência determinada a partir de populações européias. MÉTODOS: Noventa e seis doadores de sangue saudáveis foram avaliados e os valores de Sb2M foram medidos por método enzima imunoensaio quimiluminescente usando analisador automatizado IMMULITE®. RESULTADOS: Os valores de Sb2M, estabelecidos por método estatístico não paramétrico, apresentaram-se entre 1.05 e 3.9 mg/ml, sendo que o limite superior obtido foi maior que o relatado em outros trabalhos. CONCLUSÃO: Este estudo apresentou novos valores, indicando que existe uma diferença significante entre os limites de referência de Sb2M disponibilizados para o IMMULITE® e os encontrados no presente trabalho, evidenciando a ocorrência de variações importantes entre diferentes populações e que novos valores devem ser considerados para brasileiros.

Background: The main short-term advantages of haemodiafiltration (HDF) are supposedly better removal of Beta2- microglobulin (ß2-m) and phosphate, and better haemodynamic stability. The main disadvantage is higher costs. The aim of the study was to compare the clinical and biological parameters associated with HDF and high-flux haemodialysis (HD), using a cross-over design, while maintaining the same dialysis parameters. Methods: All patients on a 3 × 4 hours schedule were observed during 3 identical 6-months periods: HDF1 -- HD -- HDF2. The mean values for the 2 last months of each period were compared. Results: A total of 51 patients (76 % males, 45 % diabetic) with a mean age of 74 ± 15 years, and who had been on dialysis for 49 ± 60 months were included. The mean blood flow (329 ± 27 ml/min), dialysate flow (500 ml/min), and convection volumes (21.6 ± 3.2 L) were recorded. Patient medications were not changed. Predialysis blood pressure, phosphataemia, calcaemia, iPTH, Kt/V, nPNA and intradialytic events were similar throughout the 3 periods. Only serum albumin (34. 4 ± 3.6, 35.9 ± 3.4, 34.1 ± 4 g/L, p < 0. 0001) and ß2-m serum levels (26.1 ± 5.4, 28 ± 6, 26.5 ± 5 mg/L, p < 0.001, values shown for HDF1, HD, HDF2, respectively) were significantly lower during the HDF periods. Factor associated with higher delta serum albumin levels between HD and HDF periods was mainly a lower convection volume. Conclusion: Comparing HDF and HD, we did not observe any differences in haemodynamic stability or in serum phosphate levels. Only serum ß2-m (-6 % vs. HD) and albumin (-5 % vs. HD) levels changed. The long-term clinical consequences of these biochemical differences should be prospectively assessed. [ABSTRACT FROM AUTHOR]

Systemic sclerosis (SSc) is a chronic autoimmune connective tissue disease. Humoral immunity and B cells are thought to play an important role in the pathophysiology of the disease. B cells are activated, produce specific autoantibodies and profibrotic cytokines. One way to assess B cell activation is to measure serum free light chains of immunoglobulins (sFLC) levels. We assess here sFLC levels in patients with systemic sclerosis (SSc) and their correlation with the disease characteristics, activity and severity. One hundred and thirty-four SSc patients were prospectively enrolled and compared to 401 age- and sex-matched healthy controls. sFLC levels were measured by a new quantitative immunoassay. sFLC levels were significantly higher in SSc patients than in healthy controls. sFLC levels correlated with modified Rodnan skin score and were independently associated with the presence of interstitial lung disease and its severity. In univariate analysis, sFLC levels correlated with SSc activity, as measured by the European Scleroderma Study Group activity index, and severity, as measured by the Medsger's total severity score. In multivariate analysis, beta2-microglobulin levels correlated with disease activity, BAFF levels with severity and sFLC with neither of these. Other B-cell activation biomarkers (IgG, IgA, beta2-microglobulin and BAFF) were independently correlated with sFLC. sFLC levels are elevated in SSc and are independently associated with lung disease and its severity. B-cell activation biomarkers, including sFLC, beta2-microglobulin and BAFF, correlate with disease severity and activity. These results further support the role of B cell activation in the pathophysiology of SSc. [ABSTRACT FROM AUTHOR]

Highlights: [•] AGEs of β2-m were identified and characterized in in vitro conditions. [•] Carboxymethyl, carboxyethyl and methyl-imidazolinone Arg3 were identified in β2-m isolated from the urine of uremic subjects. [•] AGEs content of urinary β2-m were found to range from 0.2 to 1% in uremic subjects. [Copyright &y& Elsevier]

Endemic nephropathy (EN) is a chronic tubulointerstitial nephropathy with an early insidious and slow development into terminal renal failure. Proteomics is the systematic study of a proteome, which is the total protein content of a cell, organism or body fluids. Application of proteomic technologies in nephrology has enabled more detailed analyses of protein functions and examined their importance in various physiological and pathological states. Biomarkers with high specificity and sensitivity to early diagnosis are needed for a better understanding of the mechanisms of EN development and its consequences. Urine beta2-microglobulin (B2M) was mainly used as a tubular marker of EN but recently alpha1-microglobulin (AMBP) was proposed for the diagnosis of EN. We studied the urine proteins of 360 patients with EN, diabetic nephropathy (DN) and acute kidney injury (AKI) and the healthy population using proteomic tools. Protein maps from the urine of patients with EN showed significant differences in comparison to the healthy subjects and patients with DN and AKI. Our study highlights six proteins in urine that were differentially excreted in the urine of EN patients compared with the other groups and have potential to be markers for EN prediction. In one of our studies, using routine biomarkers, we investigated the potential of urine B2M, AMBP, albumin and total protein as diagnostic markers for EN, in comparison to glomerulonephritis, nephrosclerosis and a healthy state. Modern proteomic technologies are still robust investigation tools, but can access a vast amount of information from one set of experiments in comparison to a classic diagnostic approach. [ABSTRACT FROM AUTHOR]

The amyloid pathology associated with long-term haemodialysis is due to the deposition of β2-microglobulin, the non-polymorphic light chain of class I major histocompatibility complex, that accumulates at bone joints into amyloid fibrils. Several lines of evidence show the relevance of the tryptophan residue at position 60 for the fibrillogenic transition of the protein. A comparative 15N NMR relaxation analysis is presented for wild-type human β2-microglobulin and W60G β2-microglobulin, i.e. the mutant with a glycyne replacing the natural tryptophan residue at position 60. The experimental data, collected at 11.4 T and 310 K, were analyzed by means of the reduced spectral density approach. Molecular dynamics (MD) simulations and corresponding thermodynamic integration, together with hydrodynamic calculations were performed to support data interpretation. The analysis results for the mutant protein are consistent with a reduced aggregation with respect to the wild-type counterpart, as a consequence of an increased conformational rigidity probed by either NMR relaxation and MD simulations. Although dynamics in solution is other than fibrillar competence, the assessed properties of the mutant protein can be related with its reduced ability of forming fibrils when seeded in 20% trifluoroethanol. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

The article focuses on an evaluation of the relationship between Major Histocompatibility Complex (MHC) class I expression and prognosis through the use of tumor tissues removed from nine dogs with mammary gland carcinomas and 13 dogs with complex carcinomas. The findings of the evaluation in 9 dogs with mammary gland carcinomas and 13 dogs with complex carcinomas are discussed. Also mentioned is the methodology used in the evaluation.

Abstract: In this work we present for the first time the use of ion-exchange liquid chromatography to separate the native form and a partially structured intermediate of the folding of the amyloidogenic protein beta2-microglobulin. Using a strong anion-exchange column that accounts for the differences in charge exposure of the two conformers, a LC–UV method is initially optimised in terms of mobile phase pH, composition and temperature. The preferred mobile phase conditions that afford useful information were found to be 35mM ammonium formate, pH 7.4 at 25°C. The dynamic equilibrium of the two species is demonstrated upon increasing the concentration of acetonitrile in the protein sample. Then, the chromatographic method is transferred to MS detection and the respective charge state distributions of the separated conformers are identified. The LC–MS results demonstrate that one of the conformers is partially unfolded, compared with the native and more compact species. The correspondence with previous results obtained in free solution by capillary electrophoresis suggest that strong ion exchange LC–MS does not alter beta2-microglobulin conformation and maintains the dynamic equilibrium already observed between the native protein and its folding intermediate. [Copyright &y& Elsevier]

Upper aerodigestive tract natural killer (NK)/T-cell lymphoma (UNKTL) is the most common type of extranodal NK/T-cell lymphoma, nasal type. Serum beta2-microglobulin (β2-M) was found to be a predictor in some subtypes of B-cell lymphoma. However, its prognostic significance in NK/T-cell lymphoma has never been explored. We retrospectively analyzed 82 patients newly diagnosed as UNKTL. Serum β2-M was detected prior to treatment in this series. Various statistical analyses were performed to evaluate the significance of the relevant clinical parameters. High serum β2-M level was calculated as ≥2.5 mg/L by the median value. The number of patients with serum β2-M ≥2.5 mg/L at diagnosis was 39 (47.6%) and 43 patients (52.4%) with β2-M <2.5 mg/L. Patients with high serum β2-M level at diagnosis seemed to have more adverse clinical features: B symptoms ( p = 0.007) and elevated LDH level ( p < 0.001), and high KPI score ( p = 0.002). Serum β2-M ≥2.5 mg/L was significantly associated with poor overall survival (5-year OS, 35.2% vs 73.6%; p = 0.001) and progression-free survival (5-year PFS, 27.5% vs 55.9%; p = 0.028). For patients with early stage, serum β2-M at diagnosis could also help to distinguish those with favorable outcomes from those with poor outcomes. In multivariate analysis, high serum β2-M level remained its prognostic impact on survival (OS: p = 0.002; PFS: p = 0.039), independent of the International Prognostic Index score. Our study suggested high serum β2-M was a novel predictor of prognosis in patients with UNKTL. A simply and regular way might be established to identify UNKTL patients of different risks at diagnosis. [ABSTRACT FROM AUTHOR]

Abstract: Decay accelerating factor (DAF, CD55) is used by DAF-dependent (Daf+) variants of echovirus 11 (EV11) as a primary cellular receptor. The interaction of EV11 with DAF is completely reversible, therefore DAF-dependent variants require an unidentified coreceptor to initiate uncoating. Daf− variants of EV11, which do not interact with DAF, use an alternative primary cellular receptor. The aim of this study was to test the hypothesis whether the coreceptor, which is necessary for the uncoating of DAF-dependent variants, may act as an alternative primary receptor for the Daf− variants of EV11. By using the model of the two closely related daf+ and daf− clones of EV11 in rhabdomyosarcoma (RD) cell line, it was shown that a single amino acid substitution in the capsid protein VP2 could control the expression of the DAF-dependent phenotype. Anti-DAF monoclonal antibody has blocked the infection of RD cells by the DAF-dependent daf+ clone, but not by the daf− clone of EV11. Since the structural proteins of the two clones differed only in the receptor binding site for DAF, the unidentified non-DAF primary receptor for the daf− clone might have the same conformation as the uncoating coreceptor required for the daf+ clone. Despite the difference in primary receptors, both daf+ and daf− clones were equally inhibited by a monoclonal antibody to beta2-microglobulin. The monoclonal antibody B9.12.1 to class I human leukocyte antigen molecules showed no inhibitory effect in regards to either clone. The hypothesis of convergent intracellular traffic of Daf+ and Daf− variants of EV11 is discussed. [Copyright &y& Elsevier]

A novel monoclonal anti-pan human leukocyte antigen (HLA) class I heavy chain antibody, EMR8-5, was established. It could detect HLA-A, -B, and -C antigens in formalin-fixed paraffin embedded tissues. By immunohistochemical staining using the EMR8-5 antibody, various cancer tissues from 246 cases were examined for HLA class I expression. It was found that HLA class I expression was decreased in 20% to 42% of the cases of lung cancer, hepatocellular carcinoma, colon cancer, renal cell carcinoma, and urothelial carcinoma. In contrast, 85% of breast cancer cases had loss of or decreased HLA class I expression. Of the 35 breast cancer cases that had decreased HLA class I heavy chain expression, 33 (94%) also had decreased beta2-microglobulin expression detected by immunohistochemical staining. It was suggested that HLA class I down-regulation might be a common characteristic of breast cancer mostly caused by the down-regulation of beta2-microglobulin expression. [ABSTRACT FROM AUTHOR]

Background. Haemodiafiltration (HDF) may improve survival of chronic dialysis patients. This prospective, multicentre randomized cross-over study evaluated the effects of long-term on-line HDF on the levels of solutes of different molecular weight markers or causative agents of the most common metabolic derangements in uraemia.Methods. Sixty-nine patients from eight Italian centres were randomly assigned to two 6-month treatment sequences: A-B and B-A [A, low-flux haemodialysis (HD) and B, on-line HDF]. Comparative evaluation of basal levels of small, medium-sized and protein-bound solutes at the end of the two treatment periods and analysis of parameters dependence during the interventions were performed.Results. On-line HDF showed greater efficiency than low-flux HD in removing small solutes (eKt/Vurea 1.60 ± 0.31 versus 1.44 ± 0.26, P < 0.0001) and in reducing basal levels of beta2-microglobulin (22.2 ± 7.8 versus 33.5 ± 11.8 mg/L, P < 0.0001), total homocysteine (15.4 ± 5.0 versus 18.7 ± 8.2 μmol/L, P = 0 .003), phosphate (4.6 ± 1.3 versus 5.0 ± 1.4 mg/dL, P = 0.008) and, remarkably, of intact parathyroid hormone (202 ± 154 versus 228 ± 176 pg/mL, P = 0.03). Moreover, in on-line HDF, lower levels of C-reactive protein (5.5 ± 5.5 versus 6.7 ± 6.1 mg/L, P = 0.03) and triglycerides (148 ± 77 versus 167 ± 87 mg/dL, P = 0.008) and increased HDL cholesterol (49.2 ± 12.7 versus 44.7 ± 12.4 mg/dL, P = <0.0001) were observed. The asymmetric dimethylarginine level was not significantly affected (0.97 ± 0.4 versus 0.84 ± 0.37 μmol/L). Erythropoietin and phosphate binders’ doses could be reduced.Conclusions. On-line high-efficiency HDF resulted in enhanced removal and lower basal levels of small, medium-sized and protein-bound solutes, which are markers or causative agents of uraemic pathologies, mainly inflammation, secondary hyperparathyroidism and dyslipidaemia. This may contribute to reducing uraemic complications and possibly to improving patient survival. [ABSTRACT FROM AUTHOR]

Background: Urine beta2-microglobulin (beta2-MG) was mainly used as a tubular marker of Balkan endemic nephropathy (BEN) but recently alpha1-microglobulin (alpha1-MG) was proposed for the diagnosis of BEN. In this study, the potential of urine beta2-MG, alpha1-MG, albumin, and total protein in the differentiation of BEN from healthy persons and patients with glomerulonephritis (GN) and nephrosclerosis (NS) was examined. Methods: This study involved 47 patients with BEN, 36 with GN, 11 with NS, 30 healthy subjects from BEN families, and 46 healthy subjects from non-BEN families. Results: In BEN patients area under the curve (AUC) for urine beta2-MG (0.828) and alpha1-MG (0.782) was higher than for urine albumin (0.740), but in GN patients AUC for urine protein (0.854) and albumin (0.872) was significantly higher than for the two low molecular weight proteins. AUC for all four urinary markers in NS patients was significantly lower than in BEN patients, ranging between 500 and 595. Median urine beta2-MG excretion in BEN patients was 17.5 times higher than in GN patients and 18.3 times higher than in controls; median alpha1-MG excretion was higher only 3.0 and 2.25 times, respectively. In the differentiation of BEN from healthy controls, beta2-MG had higher sensitivity and specificity at the cutoff levels ( p < 0.001) than alpha1-MG ( p < 0.05). In the differentiation of BEN from GN, beta2-MG was the best marker. Conclusion: All four urinary markers can be used for the differential diagnosis of BEN, beta2-MG being the best. Like in aristolochic acid nephropathy, beta2-MG seems to be an early marker of tubular damage in BEN. [ABSTRACT FROM AUTHOR]

Abstract: Outbreaks of infectious diseases in cultured large yellow croaker have resulted in great economic losses. However, information regarding its immune defense is limited. In the present study, an approach by the combination of differential proteomics with EST resource was applied for investigation of a profile of serum immune response by large yellow croaker to Aeromonas hydrophila challenge after immunization and for characterizing of one of the targeted immune molecules. Of the twelve altered proteins involved in the response, eight were identified by MS, in which three were randomly selected for antiserum preparation and were further confirmed by Western blotting. Furthermore, three β2m clones, one of the altered molecules, were obtained from a previously constructed Kidney Smart cDNA library of this fish, and were compared for their identity, which contributed to the identification of β2m cDNA diversity. Meanwhile, the up-regulated β2m in response to the bacterial immunization and challenge was further confirmed by Western blotting. Our results indicate that β2m is involved in the immune response of large yellow croaker to the challenge by A. hydrophila after immunization, which suggests an efficient approach for characterizing of targeted molecules at both the gene and protein levels. [Copyright &y& Elsevier]

Background. Mid-dilution haemodiafiltration (MD-HDF), reported as a highly efficient convective-mixed technique, has demonstrated serious drawbacks in relation to the high pressure originating inside the blood compartment of the filter during clinical application. This randomized crossover design study was planned to optimize the efficiency of the MD-HDF technique while reducing its inherent risks. [ABSTRACT FROM PUBLISHER]

Even in the era of newer and sophisticated prognostic markers, beta2-microglobulin (B2M) remains a simple but very powerful predictor of treatment-free survival (TFS) and overall survival (OS) in patients with chronic lymphocytic leukaemia (CLL). However, B2M levels are heavily influenced by the patient’s glomerular filtration rate (GFR) and this study aimed to evaluate whether GFR-adjusted B2M (GFR-B2M) had improved prognostic value compared to unadjusted B2M in a cohort of over 450 consecutive CLL patients from two separate institutions. Multivariate analysis identified a significantly shorter TFS in patients who were ZAP-70 + ( P < 0·001), with increased GFR-B2M ( P < 0·001), and del(11q) or del(17p) as detected by fluorescence in situ hybridization (FISH; P < 0·001). When OS was evaluated by multivariate analysis, age 65 years or older ( P < 0·001) and poor risk FISH abnormalities ( P < 0·001) had a confirmed adverse prognostic impact, but the predictive value of GFR-B2M was lost in the validation analysis. In all survival models, B2M did not attain independent significance unless GFR-B2M was eliminated from the analysis. In conclusion, GFR-B2M is a better predictor of TFS than unadjusted B2M in CLL patients. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: In multiple myeloma (MM), serum beta-2-microglobulin (β2m)-free heavy chains (FHC) of HLA class I has been shown to reflect disease activity. We investigated the possibility of stratifying patients with active disease according to FHC and other clinical parameters. Experimental design: We studied 146 patients with MM, including 100 at diagnosis, 31 in relapse and 15 unresponsive to therapy. Univariate and multivariate analyses were used to assess the prognostic significance of FHC together with continuous variables (age, albumin, creatinine, hemoglobin, erythrocyte sedimentation rate, β2m, calcium, IgM, platelet count) and categorical variables (Durie–Salmon disease stage, gender, bone lesion burden, heavy and light chain isotypes of M-component, clinical status). Survival tree analysis on significant variables was used to develop an MM staging system. Results: FHC, IgM, platelet count and hemoglobin were independent predictors of prognosis. Survival tree analysis of these variables defined 2 three-risk-group staging systems involving FHC and either IgM or platelet count. Median survival for FHC/IgM stages II and III was 41.5 and 27.8 months, whereas it was not reached for stage I patients (p <0.0001). In the FHC/platelets system, median survival was 93.2 (stage I), 44.1 (stage II) or 27.8 (stage III) months (p <0.0001). Similar results were obtained for the 117 MM patients without renal insufficiency (FHC/IgM p <0.0001; FHC/platelets p =0.001). For the 100 patients at diagnosis, FHC/IgM (p =0.001) was more effective than FHC/platelets (p =0.04). Conclusions: The independent prognostic markers FHC, IgM and platelets provide two staging systems unaffected by renal insufficiency. Both are effective in evaluating MM patients with active disease. [Copyright &y& Elsevier]

To analyze the in vivo biological effect of anti-interferon beta (IFN-beta) neutralizing antibodies (NABs), blood concentrations of neopterin, beta2microglobulin (Beta2-MG), mRNA-dependent myxovirusresistant protein A (MxA) and dsRNA-dependent protein kinase (PKR) were measured before (predose) and 24 hours after (postdose) IFN-beta administration in 49 patients with multiple sclerosis (MS) with (n = 25) and without (n = 24) NABs. The results indicated that predose levels of MxA-mRNA and PKR-mRNA were highly variable [coefficient of variation (CV) > 100%] among patients. A lower inter-individual variability was observed for pre-dose levels of Beta2-MG and neopterin (CVs of 29% and 44%, respectively). Significantly lower pre- and post-dose blood levels of IFN induced markers, except for postdose PKR-mRNA (p = 0.09), were seen in NAB+ compared with NAB–patients and between patients with high (> 200 t1/10) and low (£ 200 t1/10) NAB titers. A significant inverse correlation between NAB titer and pre-dose levels of the above IFN-induced markers was found. In summary, our findings confirm that NABs affect absolute concentrations of IFN-beta induced markers and suggest that such an effect occurs in a titer-dependent manner. [ABSTRACT FROM AUTHOR]

Overview: In newborns with symptomatic congenital cytomegalovirus (CMV) infection, neuroimaging is the best available predictor of neurodevelopmental outcome. Cerebrospinal fluid (CSF) findings in congenital CMV infection have seldom been described. Neonates with central nervous system infections present high CSF Beta(2)-microglobulin (beta(2)-m) levels.Objectives: The objectives of this study were: (1) to determine whether CSF beta(2)-m is increased in newborns with symptomatic congenital CMV infection, and (2) to examine its correlation with neuroimaging findings.Materials and Methods: Fourteen newborns with symptomatic congenital CMV infection admitted to La Paz Hospital from 1990 through 2004 underwent determination of CSF beta(2)-m. Ninety-three newborns, constituting the comparison group, underwent CSF beta(2)-m determination as part of a sepsis or meningo/encephalitis work-up, and at discharge had sterile cultures and normal neurological status. Neuroimaging findings were scored according to a semiquantitative system: (0) no abnormalities; (1) single punctate periventricular (PV) calcification and/or hyperechogenic areas in the thalamus and basal ganglia; (2) multiple discrete PV calcifications and/or ventriculomegaly; and (3) extensive PV calcifications and/or brain atrophy.Discussion and Conclusion: CSF beta(2)-m was increased in newborns with CMV infection (median 6.21 mg/L) compared with controls (1.68 mg/L) (P<.001). beta(2)-m showed a correlation with neuroimaging scores (r (s)=0.753, P=.002). beta(2)-m was higher in patients who scored 2-3 (12.83 mg/L) than in patients who scored 0-1 (5.52 mg/L) (P=.028). CSF beta(2)-m is increased in newborns with symptomatic congenital CMV infection and correlates with neuroimaging abnormalities. beta(2)-m appears to be an indicator of the severity of brain involvement in congenital CMV infection. [ABSTRACT FROM AUTHOR]