Relationship Between High-Density Lipoprotein Cholesterol and Mortality in Elderly Hemodialysis Patients: Data From the Korean Society of Geriatric Nephrology Retrospective Cohort.

OBJECTIVES: The association between high-density lipoprotein (HDL) cholesterol levels and mortality in elderly patients undergoing hemodialysis is not well established. Thus, this study investigated HDL levels and mortality in elderly Korean patients undergoing hemodialysis. METHODS: We recruited 1860 incident hemodialysis patients aged greater than 70 years from a retrospective cohort of the Korean Society of Geriatric Nephrology. The primary outcome measure was all-cause mortality. RESULTS: The mean age of the cohort was 77.8 years, and 1049 (56.4%) were men. When we grouped the patients into HDL cholesterol tertiles, the T1 group (HDL level <30 mg/dL in men and <33 mg/dL in women) had a higher proportion of patients with end-stage kidney disease due to diabetic nephropathy. During the median follow-up period of 3.1 years, 1109 (59.7%) deaths occurred. In a multivariable Cox regression model, the T1 group had a significantly higher risk of mortality (hazard ratio [HR], 1.28; 95% confidence interval, 1.10-1.50; P = .002) compared to the T3 group. A nonlinear analysis using a restrictive spline curve showed that low HDL cholesterol levels were associated with increased HR when HDL cholesterol levels were <40 mg/dL; however, there was no association between HDL cholesterol and mortality when HDL cholesterol levels were >40 mg/dL. Triglyceride/HDL ratio was not significantly associated with the risk of mortality (HR per 1 log increase, 1.08; 95% confidence interval, 0.99-1.18; P = .069). CONCLUSIONS: Low HDL cholesterol levels are associated with an increased risk of mortality in elderly patients undergoing hemodialysis. However, there was no significant relationship between HDL cholesterol levels and mortality when levels were below 40 mg/dL. Therefore, low HDL cholesterol levels may be a useful risk factor for predicting mortality in elderly patients undergoing hemodialysis.

Accelerated Clearance and Degradation of Cell-Free HIV by Neutralizing Antibodies Occurs via FcγRIIb on Liver Sinusoidal Endothelial Cells by Endocytosis.

Neutralizing Abs suppress HIV infection by accelerating viral clearance from blood circulation in addition to neutralization. The elimination mechanism is largely unknown. We determined that human liver sinusoidal endothelial cells (LSEC) express FcγRIIb as the lone Fcγ receptor, and using humanized FcγRIIb mouse, we found that Ab-opsonized HIV pseudoviruses were cleared considerably faster from circulation than HIV by LSEC FcγRIIb. Compared with humanized FcγRIIb-expressing mice, HIV clearance was significantly slower in FcγRIIb knockout mice. Interestingly, a pentamix of neutralizing Abs cleared HIV faster compared with hyperimmune anti-HIV Ig (HIVIG), although the HIV Ab/Ag ratio was higher in immune complexes made of HIVIG and HIV than pentamix and HIV. The effector mechanism of LSEC FcγRIIb was identified to be endocytosis. Once endocytosed, both Ab-opsonized HIV pseudoviruses and HIV localized to lysosomes. This suggests that clearance of HIV, endocytosis, and lysosomal trafficking within LSEC occur sequentially and that the clearance rate may influence downstream events. Most importantly, we have identified LSEC FcγRIIb-mediated endocytosis to be the Fc effector mechanism to eliminate cell-free HIV by Abs, which could inform development of HIV vaccine and Ab therapy.

A robust heterodimeric Fc platform engineered for efficient development of bispecific antibodies of multiple formats.

Bispecific monoclonal antibodies can bind two protein targets simultaneously and enable therapeutic modalities inaccessible by traditional mAbs. Bispecific formats containing a heterodimeric Fc region are of particular interest, as a heterodimeric Fc empowers both bispecificity and altered valencies while retaining the developability and druggability of a monoclonal antibody. We present a robust heterodimeric Fc platform, called the XmAb® bispecific platform, engineered for efficient development of bispecific antibodies and Fc fusions of multiple formats. First, we engineer a purification solution for proteins containing a heterodimeric Fc using engineered isoelectric point differences in the Fc region that enable straightforward purification of the heterodimeric species. Then, we combine this purification solution with a novel set of Fc substitutions capable of achieving heterodimer yields over 95% with little change in thermostability. Next, we illustrate the flexibility of our heterodimeric Fc with a case study in which a wide range of tumor-associated antigen × CD3 bispecifics are generated, differing in choice of tumor antigen, affinities for both tumor antigen and CD3, and tumor antigen valency. Finally, we present manufacturing data reinforcing the robustness of the heterodimeric Fc platform at scale.

Application of Cultured Epidermal Homograft (Kaloderm) for Wide Scar Treatment.

BACKGROUND: For the treatment of wide scars, laser resurfacing procedures are generally used. However, sometimes their results are not satisfactory. Many clinical studies have reported that cultured epidermal allogenic sheets promote rapid and good quality wound healing. Therefore, the authors applied a cultured epidermal homograft (CEH) for scar management and investigated its outcomes. METHODS: Thirty-two patients who received a CEH (Kaloderm) after laser resurfacing (n = 14, under general anesthesia; n = 18, under local anesthesia) between February 2016 and June 2017 were enrolled. Patients treated with dermabrasion using laser resurfacing (n = 60) without CEH in the same period were used as controls. Clinical grading of the scars was performed using a Patient and Observer Scar Assessment Scale (POSAS) at postoperative 12 months. RESULTS: The authors conducted a comparative analysis between the control and CEH groups. Evaluation based on Patient and Observer Scar Assessment Scale showed that the mean scores in control/CEH groups for the 7 observer components (vascularity, pigmentation, thickness, relief, pliability, surface area, and overall opinion) were 4.5/3.2, 3.3/2.8, 2.8/2.5, 3.6/3.5, 3.7/2.1, 2.3/1.9, and 3.2/2.7, respectively, with significant differences observed in vascularity, pliability, and surface area (P values = 0.033, 0.021, and 0.048, respectively). Meanwhile, the mean scores in control/CEH groups for 7 patient components (pain, itching sense, color, stiffness, thickness, irregularity, and overall opinion) were 4.1/2.3, 3/3.1, 2.2/2.1, 2.2/1.7, 3.6/3.5, 1.8/1.5, and 2.2/1.9, respectively, with significant differences between groups observed in pain, stiffness, and overall opinion in the paired t test (P values = 0.041, 0.020, and 0.048, respectively). CONCLUSION: Cultured epidermal homograft provided good quality wound healing and improved scar pliability. Cultured epidermal homograft left less scarring with no pain or other specific complications. Therefore, dermabrasion with CEH is useful for scar management.

A Safer Non-surgical Filler Augmentation Rhinoplasty Based on the Anatomy of the Nose.

BACKGROUND: Filler augmentation rhinoplasty is a quick, non-surgical procedure that can produce outcomes comparable to open rhinoplasty surgery. However, the increased frequency of vascular complications has emerged as an important issue. The present study aimed to investigate measures to overcome the vascular complications based on the anatomy of the nose. METHODS: A colored filler was injected into cadavers for augmentation of the nasal dorsum using the retrograde injection technique and direct percutaneous injection technique. The concavity of the sellion area was measured using lateral view cephalography X-ray images. Lastly, we used ultrasonography to determine filler location in 20 Korean patients who had filler injected into the sellion area by injection at the infratip lobule. RESULTS: Filler was injected into the superficial layer by the retrograde injection technique in three cadavers and into the deep layer by direct percutaneous injection technique in another three cadavers. The average angle between the nasal dorsum skin and sellion was found to be 10.2 ± 2.8 degrees, while the minimum angle was 5.1 degrees. The average distance between the needle tip and nasal bone was 1.9 ± 0.3 mm, while the minimum distance was 0.4 mm. CONCLUSIONS: When performing filler augmentation rhinoplasty on the sellion area, direct percutaneous injection from the glabella can allow more accurate injection into the supraperiosteal level, which can reduce complications such as visual loss and skin necrosis due to vascular compromise. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Potent in vitro and in vivo activity of an Fc-engineered humanized anti-HM1.24 antibody against multiple myeloma via augmented effector function.

HM1.24, an immunologic target for multiple myeloma (MM) cells, has not been effectively targeted with therapeutic monoclonal antibodies (mAbs). In this study, we investigated in vitro and in vivo anti-MM activities of XmAb5592, a humanized anti-HM1.24 mAb with Fc-domain engineered to significantly enhance FcγR binding and associated immune effector functions. XmAb5592 increased antibody-dependent cellular cytotoxicity (ADCC) several fold relative to the anti-HM1.24 IgG1 analog against both MM cell lines and primary patient myeloma cells. XmAb5592 also augmented antibody dependent cellular phagocytosis (ADCP) by macrophages. Natural killer (NK) cells became more activated by XmAb5592 than the IgG1 analog, evidenced by increased cell surface expression of granzyme B-dependent CD107a and MM cell lysis, even in the presence of bone marrow stromal cells. XmAb5592 potently inhibited tumor growth in mice bearing human MM xenografts via FcγR-dependent mechanisms, and was significantly more effective than the IgG1 analog. Lenalidomide synergistically enhanced in vitro ADCC against MM cells and in vivo tumor inhibition induced by XmAb5592. A single dose of 20 mg/kg XmAb5592 effectively depleted both blood and bone marrow plasma cells in cynomolgus monkeys. These results support clinical development of XmAb5592, both as a monotherapy and in combination with lenalidomide, to improve patient outcome of MM.

Antibody-mediated coengagement of FcγRIIb and B cell receptor complex suppresses humoral immunity in systemic lupus erythematosus.

Engagement of the low-affinity Ab receptor FcγRIIb downregulates B cell activation, and its dysfunction is associated with autoimmunity in mice and humans. We engineered the Fc domain of an anti-human CD19 Ab to bind FcγRIIb with high affinity, promoting the coengagement of FcγRIIb with the BCR complex. This Ab (XmAb5871) stimulated phosphorylation of the ITIM of FcγRIIb and suppressed BCR-induced calcium mobilization, proliferation, and costimulatory molecule expression of human B cells from healthy volunteers and systemic lupus erythematosus (SLE) patients, as well as B cell proliferation induced by LPS, IL-4, or BAFF. XmAb5871 suppressed humoral immunity against tetanus toxoid and reduced serum IgM, IgG, and IgE levels in SCID mice engrafted with SLE or healthy human PBMC. XmAb5871 treatment also increased survival of mice engrafted with PBMC from a unique SLE patient. Unlike anti-CD20 Ab, coengagement of FcγRIIb and BCR complex did not promote B cell depletion in human PBMC cultures or in mice. Thus, amplification of the FcγRIIb inhibitory pathway in activated B cells may represent a novel B cell-targeted immunosuppressive therapeutic approach for SLE and other autoimmune diseases that should avoid the complications associated with B cell depletion.

Reduction of total IgE by targeted coengagement of IgE B-cell receptor and FcγRIIb with Fc-engineered antibody.

BACKGROUND: Sequestration of IgE to prevent its binding to high-affinity IgE receptor FcεRI on basophils and mast cells is an effective therapy for allergic asthma. IgE production requires differentiation of activated IgE(+) B cells into plasma cells upon allergen sensitization. B-cell receptor signaling is suppressed by the inhibitory IgG Fc receptor FcγRIIb; therefore, we reasoned that a therapeutic antibody that coengages FcγRIIb and IgE B-cell receptor would not only sequester IgE but also suppress its production by blocking IgE(+) B-cell activation and differentiation to IgE-secreting plasma cells. OBJECTIVE: To explore the effects of IgE sequestration versus IgE suppression by comparing omalizumab to FcγRIIb-optimized anti-IgE antibodies in humanized mouse models of immunoglobulin production. METHODS: By using a murine anti-IgE antibody as a template, we humanized, increased IgE binding, and modified its Fc domain to increase affinity for FcγRIIb. We next compared effects of this antibody (XmAb7195) versus omalizumab on the secretion of IgE and other isotypes in human PBMC cultures and in PBMC-engrafted severe combined immunodeficiency mice. RESULTS: Relative to omalizumab, XmAb7195 has a 5-fold higher affinity for human IgE and more than 400-fold higher affinity for FcγRIIb. In addition to sequestering soluble IgE, XmAb7195 inhibited plasma cell differentiation and consequent human IgE production through coengagement of IgE B-cell receptor with FcγRIIb. In PBMC-engrafted mice, XmAb7195 reduced total human IgE (but not IgG or IgM) levels by up to 40-fold relative to omalizumab. CONCLUSION: XmAb7195 acts by IgE sequestration coupled with an FcγRIIb-mediated inhibitory mechanism to suppress the formation of IgE-secreting plasma cells and reduce both free and total IgE levels.

Fc-engineered anti-CD40 antibody enhances multiple effector functions and exhibits potent in vitro and in vivo antitumor activity against hematologic malignancies.

CD40 is highly expressed on various B-lineage malignancies and represents an attractive immunotherapy target for neoplastic disease. Previous work showed that engineering the Fc domain of an antibody for increased binding to Fcγ receptors (FcγRs) significantly enhanced Fc-mediated immune effector function and antitumor activity in vitro and in vivo. We developed a humanized anti-CD40 antibody similarly Fc-engineered for increased FcγR binding (XmAbCD40) and compared its efficacy with that of an anti-CD40 native IgG1 analog and the anti-CD20 antibody rituximab. XmAbCD40 increased antibody-dependent cell-mediated cytotoxicity (ADCC) up to 150-fold relative to anti-CD40 IgG1 against B-lymphoma, leukemia, and multiple myeloma cell lines, and significantly enhanced ADCC against primary tumors. XmAbCD40 was also superior to rituximab in enhancing ADCC (both in cell lines and primary tumors) and in augmenting antibody-dependent cellular phagocytosis. XmAbCD40 significantly inhibited lymphoma growth in disseminated and established mouse xenografts and was more effective than the IgG1 analog or rituximab. An anti-CD40 antibody constructed to abrogate FcγR binding showed no reduction of tumor growth, indicating that the in vivo antitumor activity of XmAbCD40 is primarily mediated via FcγR-dependent mechanisms. These data demonstrate that XmAbCD40 displays potent antitumor efficacy and merits further evaluation for the treatment of CD40(+) malignancies.

Transmembrane tumour necrosis factor is neuroprotective and regulates experimental autoimmune encephalomyelitis via neuronal nuclear factor-kappaB.

Tumour necrosis factor mediates chronic inflammatory pathologies including those affecting the central nervous system, but non-selective tumour necrosis factor inhibitors exacerbate multiple sclerosis. In addition, TNF receptor SF1A, which encodes one of the tumour necrosis factor receptors, has recently been identified as a multiple sclerosis susceptibility locus in genome-wide association studies in large patient cohorts. These clinical data have emphasized the need for a better understanding of the beneficial effects of tumour necrosis factor during central nervous system inflammation. In this study, we present evidence that the soluble and transmembrane forms of tumour necrosis factor exert opposing deleterious and beneficial effects, respectively, in a multiple sclerosis model. We compared the effects, in experimental autoimmune encephalomyelitis, of selectively inhibiting soluble tumour necrosis factor, and of both soluble and transmembrane tumour necrosis factor. Blocking the action of soluble tumour necrosis factor, but not of soluble tumour necrosis factor and transmembrane tumour necrosis factor, protected mice against the clinical symptoms of experimental autoimmune encephalomyelitis. Therapeutic benefit was independent of changes in antigen-specific immune responses and focal inflammatory spinal cord lesions, but was associated with reduced overall central nervous system immunoreactivity, increased expression of neuroprotective molecules, and was dependent upon the activity of neuronal nuclear factor-κB, a downstream mediator of neuroprotective tumour necrosis factor/tumour necrosis factor receptor signalling, because mice lacking IκB kinase ß in glutamatergic neurons were not protected by soluble tumour necrosis factor blockade. Furthermore, blocking the action of soluble tumour necrosis factor, but not of soluble tumour necrosis factor and transmembrane tumour necrosis factor, protected neurons in astrocyte-neuron co-cultures against glucose deprivation, an in vitro neurodegeneration model relevant for multiple sclerosis, and this was dependent upon contact between the two cell types. Our results show that soluble tumour necrosis factor promotes central nervous system inflammation, while transmembrane tumour necrosis factor is neuroprotective, and suggest that selective inhibition of soluble tumour necrosis factor may provide a new way forward for the treatment of multiple sclerosis and possibly other inflammatory central nervous system disorders.

Retrospective analysis of efficacy and safety of oral paclitaxel for treatment of various cancers in dogs (2017-2021).

BACKGROUND: In humans, several safety evaluations have shown minimal adverse events with oral paclitaxel; however, its therapeutic efficacy and safety has not been well established in dogs with various cancers. OBJECTIVES: We aimed to retrospectively evaluate the efficacy and safety of oral paclitaxel in dogs with various cancers. METHODS: Twenty-one dogs diagnosed with various cancers were administered several doses of oral paclitaxel three times a month (group 1) or six times a month (group 2). RESULTS: The overall response rate was 6.25% (6.25%, complete response; 56.25%, stable disease; 37.5%, progressive disease) in dogs for which the treatment response could be evaluated. The median overall survival (OS) and progression-free survival (PFS) were 74 and 60.5 days, respectively. Regardless of the administration group, differences in OS and PFS of the two groups did not reach statistical significance. Most dogs tolerated the treatment regimen well, and although minor adverse events were observed in some dogs, they recovered after temporary drug discontinuation, dose reduction or symptomatic treatment. There was no significant difference in the prevalence of adverse events between the two groups. CONCLUSIONS: Based on the observed responses in certain types of cancers and the minimal adverse events, the study findings supported the efficacy and safety of oral paclitaxel administration in dogs. Thus, oral paclitaxel could play a role in the management of cancer in dogs.

Effects of Methylsulfonylmethane on UVB-induced Skin Damage: An Experimental Study in a Mouse Model.

BACKGROUND/AIM: The skin protects the body from ultraviolet rays and other external factors. Various studies have been conducted to identify methods to prevent skin aging and damage. To investigate the protective effects of methylsulfonylmethane (MSM), in this study, a hairless mouse model was used. PATIENTS AND METHODS: Mice divided into Groups B, C, and D were subjected to UVB irradiation for six weeks, and Group A was considered the control. Retinoic acid is a substance that has been proven to have anti-aging properties. Group C was injected with MSM, group D was injected with retinoic acid, and groups A and B were injected with saline. At the end of the experiment, the degree of senescence was confirmed through visual evaluation, histopathological analysis, immunohistochemistry, and elasticity measurement using SEM. RESULTS: After the end of the experiment, the wrinkle score was 0.4, 2.5, 1.8, 1.5 for Groups A, B, C, and D, respectively. Epidermal thickness was 40 µm, 70 µm, 60 µm, 55 µm in Groups A, B, C, and D, respectively. Group C showed less collagen confirmation loss and more angiogenesis and elastin precursor production. Elastic fiber linearity was 0.901±0.02, 0.551±0.04, 0.751±0.04, 0.822±0.03 for Groups A, B, C, and D, respectively. CONCLUSION: Injection of MSM in mice subjected to UVB-induced skin damage reduces the wrinkle score and protects against photoaging.

The impact of Fc engineering on an anti-CD19 antibody: increased Fcgamma receptor affinity enhances B-cell clearing in nonhuman primates.

CD19, a B cell-restricted receptor critical for B-cell development, is expressed in most B-cell malignancies. The Fc-engineered anti-CD19 antibody, XmAb5574, has enhanced Fcgamma receptor (FcgammaR) binding affinity, leading to improved FcgammaR-dependent effector cell functions and antitumor activity in murine xenografts compared with the non-Fc-engineered anti-CD19 IgG1 analog. Here, we use XmAb5574 and anti-CD19 IgG1 to further dissect effector cell functions in an immune system closely homologous to that of humans, the cynomolgus monkey. XmAb5574 infusion caused an immediate and dose-related B-cell depletion in the blood (to <10% of baseline levels) concomitant with a sustained reduction of natural killer (NK) cells. NK cells had fully recovered by day 15, whereas B-cell recovery was underway by day 57. B cells in secondary lymphoid tissues were depleted (to 34%-61% of vehicle), with involuted germinal centers apparent in the spleen. Anti-CD19 IgG1 had comparable serum exposure to XmAb5574 but demonstrated no B-cell depletion and no sustained NK-cell reduction. Thus, increasing FcgammaR binding affinity dramatically increased B-cell clearing. We propose that effector cell functions, possibly those involving NK cells, mediate XmAb5574 potency in cynomolgus monkeys, and that enhancing these mechanisms should advance the treatment of B-cell malignancies in humans.

Inhibition of B cell activation following in vivo co-engagement of B cell antigen receptor and Fcγ receptor IIb in non-autoimmune-prone and SLE-prone mice.

Engagement of Fcγ receptor IIb (FcγRIIb) suppresses B cell activation and represents a promising target for therapy in autoimmunity. Obexelimab is a non-depleting anti-human CD19 mAb with an Fc region engineered to have high affinity for human FcγRIIb, thereby co-engaging BCR and FcγRIIb. To assess its ability to suppress B cell activation in vivo, we generated non-autoimmune-prone C57BL/6 (B6) and SLE-prone NZM 2328 (NZM) mice in which the human FcγRIIb extracellular domain was knocked into the mouse Fcgr2b locus (B6.hRIIb and NZM.hRIIb mice, respectively, the latter retaining features of SLE). XENP8206, a mAb which bears the same FcγRIIb-enhanced human Fc domain as does obexelimab but which recognizes murine CD19 rather than human CD19, inhibited in vitro BCR-triggered activation of B cells from both B6.hRIIb and NZM.hRIIb mice. Following administration of XENP8206 to B6.hRIIb or NZM.hRIIb mice, B cell numbers in the spleen and lymph nodes remained stable but became hyporesponsive to BCR-triggered activation for at least 14 days. These findings demonstrate proof-of-principle that pharmacologic co-engagement of BCR and human FcγRIIb inhibits B cell activation in non-autoimmune and SLE-prone hosts while preserving B cell numbers. These observations lay a strong foundation for clinical trials in human SLE with agents that co-engage BCR and FcγRIIb. Moreover, B6.hRIIb and NZM.hRIIb should serve as powerful in vivo models in the elucidation of the cellular and molecular underpinnings of the changes induced by BCR/FcγRIIb co-engagement.

Enhanced drought tolerance in Arabidopsis via genetic manipulation aimed at the reduction of glucosamine-induced ROS generation.

In animals, high glucose exerts some of its deleterious effects by activation of the hexosamine biosynthesis pathway (HBP), a branch of the glycolytic pathway that produces amino sugars (Daniels et al. in Mol Endocrinol 7:1041-1048, 1993; Du et al. in Proc Natl Acad Sci USA 97:12222-12226, 2000). Glucosamine (GlcN) is a naturally occurring amino sugar produced by amidation of fructose-6-phosphate. Previously, we observed that glucosamine (GlcN) inhibits hypocotyl elongation in Arabidopsis thaliana by a process involving the significant increase of reactive oxygen species. The present study investigated the relationship between GlcN-induced ROS generation and abiotic stress responses in Arabidopsis by generating two types of transgenic plant. Scavenging of endogenous GlcN by ectopic expression of E. coli glucosamine-6-phosphate deaminase (NagB) was observed to confer enhanced tolerance to oxidative, drought, and cold stress. Consistent with this result, overproduction of GlcN by the ectopic expression of E. coli glucosamine-6-phosphate synthase (GlmS) induced cell death at an early stage. Taken together, these data suggest that genetic manipulation of endogenous GlcN level can effectively lead to the generation of abiotic stress-tolerant transgenic crop plants.

TNF ligands: is TALL-1 a trimer or a virus-like cluster?

Native TALL-1 (B-cell activation factor, BAFF; also known as BlyS) was initially described as a homotrimer, but Liu and colleagues claim that it is a 60-subunit complex on the basis of their results from X-ray crystallography and size-exclusion chromatography. They consider TALL-1 60-mers to be the biologically active form, and the arrangement of the 60-mers resembles that of the capsid of satellite tobacco necrosis virus. Here we show that active TALL-1 is trimeric under normal physiological conditions and that formation of higher-order oligomers is an artefact of tagging the amino terminus of the protein with a histidine tag.

Effects of polluted and non-polluted suspended sediments on the oxygen consumption rate of olive flounder, Paralichthys olivaceus.

The potential ecological impacts of elevated suspended sediments (SS) in coastal areas due to human activities remain unclear. In particular, physiological response of benthic fish to SS exposure in polluted environment has not been documented. We determined sub-lethal toxicity of polluted and non-polluted SS to olive flounder. Test organism was exposed to varying concentrations of SS (0-4000 mg L-1) and real-time oxygen consumption rate (OCR) was measured for 12 h. The early-juvenile was sensitive to SS, particularly at >500 mg L-1, but late-juvenile was tolerant up to 4000 mg SS L-1. Metal polluted SS (HQmetal > 1) increased OCR in general, particularly at >1000 SS mg L-1. Combined effect of copper and SS exposure on fish was either synergistic or antagonistic. Overall, potential adverse effect of polluted SS on fish greatly varied at different life stage and/or by metal pollution gradients.

Inhibition of B cell receptor-mediated activation of primary human B cells by coengagement of CD19 and FcgammaRIIb with Fc-engineered antibodies.

The humoral immune response requires antigen-specific B cell activation and subsequent terminal differentiation into plasma cells. Engagement of B cell antigen receptor (BCR) on mature B cells activates an intracellular signaling cascade, including calcium mobilization, which leads to cell proliferation and differentiation. Coengagement by immune complex of BCR with the inhibitory Fc receptor FcgammaRIIb, the only IgG receptor expressed on B cells, inhibits B cell activation signals through a negative feedback loop. We now describe antibodies that mimic the inhibitory effects of immune complex by high-affinity coengagement of FcgammaRIIb and the BCR coreceptor complex on human B cells. We engineered the Fc domain of an anti-CD19 antibody to generate variants with up to approximately 430-fold greater affinity to FcgammaRIIb. Relative to native IgG1, the FcgammaRIIb binding-enhanced (IIbE) variants strongly inhibited BCR-induced calcium mobilization and viability in primary human B cells. Inhibitory effects involved phosphorylation of SH2-containing inositol polyphosphate 5-phosphatase (SHIP), which is known to be involved in FcgammaRIIb-induced negative feedback of B cell activation by immune complex. Coengagement of BCR and FcgammaRIIb by IIbE variants also overcame the anti-apoptotic effects of BCR activation. The use of a single antibody to suppress B cell functions by coengagement of BCR and FcgammaRIIb may represent a novel approach in the treatment of B cell-mediated autoimmune diseases.

Comparisons among four types of absorbable plates used for internal fixation of zygomaticomaxillary complex fractures.

IMPORTANCE: Conventional plating systems include titanium plates for the fixation of facial bone fractures. However, titanium plates result in artifacts on computed tomography images and appear unstable on magnetic resonance images. Therefore, absorbable plates have been widely used for the fixation of facial bone fractures of late in Asia. OBJECTIVE: To compare stability and symmetry among four different absorbable plates used for internal fixation of zygomaticomaxillary complex fractures. PARTICIPANTS: The subjects were patients with zygomaticomaxillary complex fractures that were diagnosed and treated by internal fixation with absorbable plates between January 2012 and April 2018. Patients aged ≤14 years and ≥76 years were excluded. Patients with other fracture types were also excluded. All patients underwent surgery within 2 weeks of the injury. INTERVENTION: Internal fixation was performed with one of four types of absorbable plates, namely Inion®, Polymax®, Osteotrans®, and Biosorb®. MAIN OUTCOME MEASURES: The stability of the four plates was investigated by evaluation of the orbital height ratio (A'/A), zygoma angle (a'/a), distance (b'/b) from the midline, and gap (c) of the temporal process on three-dimensional facial computed tomography images obtained before, 3 weeks after, and 3-6 months after surgery. Any plate-associated complications were recorded. RESULTS: In total, 400 patients were enrolled, and there were 100 patients in each of the four groups. There were no significant differences with regard to postoperative stability and relapse among the four plates. Moreover, facial symmetry showed no changes over time in any group. Complications such as infection and sensory disturbance were not frequent. All plates except Biosorb® were palpable for more than 6 months after surgery, with Osteotrans® remaining palpable for several years. CONCLUSIONS AND RELEVANCE: Our findings suggest that all four types of absorbable plates are useful for treating isolated zygomaticomaxillary complex fractures. While Biosorb® is unsuitable for severe comminuted fractures. Polymax® and Inion® are not bendable at room temperature. It is important to select an appropriate absorbable plate according to each patient's condition and the fracture severity.

Optimizing engagement of the immune system by anti-tumor antibodies: an engineer's perspective.

A unique property of monoclonal antibodies, and a principal reason for their success as cancer therapeutics, is their ability to engage the immune system. A growing set of data supporting the relevance of Fc-mediated effector functions to anti-tumor efficacy has motivated efforts to enhance the interactions between antibodies and Fc receptors expressed on immune cells. Although current approaches have considerable promise for improved clinical performance, the immunobiology of tumors, antibodies, and Fc receptors continues to evolve. In this review we discuss what is known and what is not known about the interactions between therapeutic antibodies and the immune system, with the goal being progress toward clear target profiles for effector engineering efforts.