A "Prime and Expand" strategy using the multifunctional fusion proteins to generate memory-like NK cells for cell therapy.

Adoptive cellular therapy (ACT) using memory-like (ML) natural killer (NK) cells, generated through overnight ex vivo activation with IL-12, IL-15, and IL-18, has shown promise for treating hematologic malignancies. We recently reported that a multifunctional fusion molecule, HCW9201, comprising IL-12, IL-15, and IL-18 domains could replace individual cytokines for priming human ML NK cell programming ("Prime" step). However, this approach does not include ex vivo expansion, thereby limiting the ability to test different doses and schedules. Here, we report the design and generation of a multifunctional fusion molecule, HCW9206, consisting of human IL-7, IL-15, and IL-21 cytokines. We observed > 300-fold expansion for HCW9201-primed human NK cells cultured for 14 days with HCW9206 and HCW9101, an IgG1 antibody, recognizing the scaffold domain of HCW9206 ("Expand" step). This expansion was dependent on both HCW9206 cytokines and interactions of the IgG1 mAb with CD16 receptors on NK cells. The resulting "Prime and Expand" ML NK cells exhibited elevated metabolic capacity, stable epigenetic IFNG promoter demethylation, enhanced antitumor activity in vitro and in vivo, and superior persistence in NSG mice. Thus, the "Prime and Expand" strategy represents a simple feeder cell-free approach to streamline manufacturing of clinical-grade ML NK cells to support multidose and off-the-shelf ACT.

Immunotherapeutic HCW9218 augments anti-tumor activity of chemotherapy via NK cell-mediated reduction of therapy-induced senescent cells.

Therapy induced senescence (TIS) in tumors and TIS cancer cells secrete proinflammatory senescence-associated secretory phenotype (SASP) factors. SASP factors promote TIS cancer cells to re-enter the growth cycle with stemness characteristics, resulting in chemo-resistance and disease relapse. Herein, we show that the immunotherapeutic HCW9218, comprising transforming growth factor-ß (TGF-ß) receptor II and interleukin (IL)-15/IL-15 receptor α domains, enhances metabolic and cytotoxic activities of immune cells and reduces TIS tumor cells in vivo to improve the efficacy of docetaxel and gemcitabine plus nab-paclitaxel against B16F10 melanoma and SW1990 pancreatic tumors, respectively. Mechanistically, HCW9218 treatment reduces the immunosuppressive tumor microenvironment and enhances immune cell infiltration and cytotoxicity in the tumors to eliminate TIS cancer cells. Immuno-depletion analysis suggests that HCW9218-activated natural killer cells play a pivotal role in TIS cancer cell removal. HCW9218 treatment following docetaxel chemotherapy further enhances efficacy of tumor antigen-specific and anti-programmed death-ligand 1 (PD-L1) antibodies in B16F10 tumor-bearing mice. We also show that HCW9218 treatment decreases TIS cells and lowers SASP factors in off-target tissues caused by chemotherapy of tumor-bearing mice. Collectively, HCW9218 has the potential to significantly enhance anti-tumor efficacy of chemotherapy, therapeutic antibodies, and checkpoint blockade by eliminating TIS cancer cells while reducing TIS-mediated proinflammatory side effects in normal tissues.

Outcomes of the Aurolab aqueous drainage implant and trabeculectomy with mitomycin C in iridocorneal endothelial syndrome.

PURPOSE: To compare the surgical outcomes of the Aurolab aqueous drainage implant (AADI) and trabeculectomy with mitomycin C (MMC) in patients with glaucoma secondary to iridocorneal endothelial (ICE) syndrome. MATERIALS AND METHODS: This retrospective comparative case series included 41 eyes of 41 patients with ICE syndrome and glaucoma who underwent either a trabeculectomy with MMC (n = 20) or AADI surgery (n = 21) with a minimum of 2 years follow-up. Outcome measures included intraocular pressure (IOP), the use of glaucoma medications, visual acuity, additional surgical interventions, and surgical complications. Surgical failure was defined as IOP > 21 mmHg or reduced < 20% from baseline, IOP ≤ 5 mmHg, reoperation for glaucoma or a complication, or loss of light perception vision. RESULTS: The cumulative probability of failure at 2 years was 50% in the trabeculectomy group (95%CI = 31-83%) and 24% in the AADI group (95%CI = 11-48%) (p = 0.09). The IOP was consistently lower in the AADI group compared with the trabeculectomy group at 6 months and thereafter. Surgical complications occurred in 13 eyes (65%) in the trabeculectomy group and 12 eyes (57%) in the AADI group (p = 0.71). Reoperations for glaucoma or complications were performed in 12 eyes (60%) in the trabeculectomy group and 5 patients (24%) in the tube group (p = 0.06). Cox proportional hazards showed that AADI had a 53% lower risk of failure at 2 years (p = 0.18; HR = 0.47; 95%CI = 0.16-1.40). CONCLUSION: AADI surgery achieved lower mean IOPs than trabeculectomy with MMC in managing glaucoma secondary to ICE syndrome. A trend toward lower rates of surgical failure and reoperations for glaucoma and complications was observed following AADI placement compared with trabeculectomy with MMC in eyes with ICE syndrome.

Dysfunctional peripheral T follicular helper cells dominate in people with impaired influenza vaccine responses: Results from the FLORAH study.

Antigen-primed cluster of differentiation (CD) 4+ T follicular helper (Tfh) cells interact with B cells in the germinal centers (GCs) of lymph nodes to generate vaccine-induced antibody (Ab) responses. In the circulation, peripheral Tfh (pTfh) cells, a subset of memory CD4 T cells, serve as surrogates for GC Tfh because of several functional and phenotypic similarities between them. We investigated features of H1N1 influenza antigen-specific pTfh (Ag.pTfh) in virologically controlled HIV+ volunteers on antiretroviral therapy (ART) and healthy control (HC) participants selected from a seasonal influenza vaccine responsiveness study. Selection of the participants was made based on age, defined as young (18-40 y) and old (>60 y) and on their classification as a vaccine responder (VR) or vaccine nonresponder (VNR). VRs demonstrated expansion of CD40L+ and CD69+ Ag.pTfh, with induction of intracellular interleukin 21 (IL-21) and inducible costimulator (ICOS) post vaccination; these responses were strongest in young HC VRs and were less prominent in HIV+ individuals of all ages. Ag.pTfh in VNRs exhibited dramatically different characteristics from VRs, displaying an altered phenotype and a cytokine profile dominated by cytokines IL-2, tumor necrosis factor alpha (TNF-α), or IL-17 but lacking in IL-21. In coculture experiments, sorted pTfh did not support the B cell IgG production in VNRs and were predominantly an inflammatory T helper 1 (Th1)/T helper 17 (Th17) phenotype with lower ICOS and higher programmed cell death protein 1 (PD1) expression. Induction of IL-21 and ICOS on Ag.pTfh cells are negatively affected by both aging and HIV infection. Our findings demonstrate that dysfunctional Ag.pTfh cells with an altered IL-21/IL-2 axis contribute to inadequate vaccine responses. Approaches for targeting inflammation or expanding functional Tfh may improve vaccine responses in healthy aging and those aging with HIV infection.

Bifunctional TGF-ß trap/IL-15 protein complex elicits potent NK cell and CD8+ T cell immunity against solid tumors.

Advances in immunostimulatory and anti-immunosuppressive therapeutics have revolutionized cancer treatment. However, novel immunotherapeutics with these dual functions are not frequently reported. Here we describe the creation of a heterodimeric bifunctional fusion molecule, HCW9218, constructed using our soluble tissue factor (TF)-based scaffold technology. This complex comprises extracellular domains of the human transforming growth factor-ß (TGF-ß) receptor II and a human interleukin-15 (IL-15)/IL-15 receptor α complex. HCW9218 can be readily expressed in CHO cells and purified using antibody-based affinity chromatography in a large-scale manufacturing setting. HCW9218 potently activates mouse natural killer (NK) cells and CD8+ T cells in vitro and in vivo to enhance cell proliferation, metabolism, and antitumor cytotoxic activities. Similarly, human immune cells become activated with increased cytotoxicity following incubation with HCW9218. This fusion complex also exhibits TGF-ß neutralizing activity in vitro and sequesters plasma TGF-ß in vivo. In a syngeneic B16F10 melanoma model, HCW9218 displayed strong antitumor activity mediated by NK cells and CD8+ T cells and increased their infiltration into tumors. Repeat-dose subcutaneous administration of HCW9218 was well tolerated by mice, with a half-life sufficient to provide long-lasting biological activity. Thus, HCW9218 may serve as a novel therapeutic to simultaneously provide immunostimulation and lessen immunosuppression associated with tumors.

An analytical model of population level chronic conditions and COVID-19 related hospitalization in the United States.

BACKGROUND: The surge in the COVID-19 related hospitalization has been straining the US health system. COVID-19 patients with underlying chronic conditions have a disproportionately higher risk of hospitalization and intensive care unit (ICU) admission. We developed a retrospective analytical model of COVID-19 related hospitalizations and ICU admissions linked to each of the three major chronic conditions - hypertension, diabetes, and cardiovascular diseases (CVD). METHODS: Based on the differential probability of hospitalization of the COVID-19 patients with and without a chronic condition, we estimate a baseline cumulative hospitalization rate and ICU admission rate using the population level chronic condition prevalence from the 2019 Behavioral Risk Factor Surveillance System survey. Next, we estimate the hospitalization and ICU admission rates under an alternative scenario of a lower prevalence of the same chronic condition, aligned with the World Health Organization target of 25% relative reduction of prevalence by 2025. We then compare the outcomes of the baseline and the alternative scenarios. RESULTS: We estimate that the lower prevalence of hypertension would have lowered the cumulative hospitalization and ICU admission rates by more than 2.5%. The lower prevalence of diabetes and CVD would lower the cumulative hospitalization rate by 0.6% and 1.4% respectively. The decrease in the rates would have been relatively higher among Black and elderly (age 55+). CONCLUSIONS: Our model, thus, provides evidence on the importance of prevention, control, and management of chronic conditions to lessen the overwhelming financial and public health burden on the health system during a pandemic like the COVID-19.

Intermediate-term outcomes of combined phacoemulsification and Aurolab aqueous drainage implant in eyes with refractory glaucoma and coexistent cataract.

PURPOSE: To investigate the efficacy and safety of non-valved Aurolab aqueous drainage implant (AADI) surgery combined with phacoemulsification in eyes with refractory glaucoma and coexistent cataract. METHODS: Included patients of 18 years or older who underwent combined AADI-Phacoemulsification from June 2015 to January 2017 with at least 12 months of consecutive follow-up. The best-corrected visual acuity, intraocular pressure (IOP), and the number of IOP-lowering medications were recorded at baseline, 2 weeks, 1, 3, 6, 12, 18, and 24 months. Cumulative probability of success was defined as IOP < 18 mmHg or 30% reduction from the baseline at two consecutive postoperative visits after 3-months. Loss of light perception or reoperation for uncontrolled glaucoma or a complication was considered failure apart from IOP criteria. RESULTS: Seventeen eyes of 17 patients with a mean follow-up of 22.6 ± 4.0 months were included. Baseline IOP and ocular hypotensive drugs reduced significantly from 27.9 ± 7.6 mmHg to 14.0 ± 3.0 mmHg (p < 0.001) and 3.24 ± 0.7 to 1.33 ± 1.1 (p = 0.001), respectively, at 24 months. Cumulative probability of qualified success was 71.4% (95% Confidence Interval [CI] 40.6-88.2%) at 3 months and was maintained from 6 months onwards at 64.3% (95% CI 34.3-83.3%), up to 2 years. Intravitreal steroid was injected in one eye (5.9%) of chronic cystoid macular edema, and tube repositioning was done in another for focal corneal decompensation. CONCLUSIONS: Combined AADI-Phacoemulsification surgery is a safe and effective option in providing favorable visual and IOP outcomes at an affordable cost in eyes with refractory glaucoma and coexistent cataract.

Association of Bisphosphonate Therapy With Incident of Lower Extremity Fractures in Persons With Spinal Cord Injuries or Disorders.

OBJECTIVE: To investigate the association between prescriptions for bisphosphonates; calcium and vitamin D supplements; and receipt of dual-energy x-ray absorptiometry (DXA) screening, and incident fracture risk in men and women with a spinal cord injury (SCI) or disorder (SCID). DESIGN: Propensity-matched case-control analyses. SETTING: United States Veterans Affairs (VA) facilities. PARTICIPANTS: A total of 7989 men and 849 women with an SCID included in VA administrative databases between October 1, 2005 and October 1, 2015 were identified (N=8838). Cases included 267 men and 59 women with a bisphosphonate prescription propensity matched with up to 4 controls. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Incident lower extremity fractures. RESULTS: There was no significant association between prescriptions for bisphosphonates and incident lower extremity fractures in men (odds ratio [OR], 1.04; 95% confidence interval [CI], 0.62-1.77) or women (OR, 1.02; 95% CI, 0.28-3.75). In men, similar null associations were seen among those who were adherent to bisphosphonate therapy (OR, 1.25; 95% CI, 0.73-2.16), were concomitant users of vitamin D and calcium and a bisphosphonate (OR, 1.05; 95% CI, 0.57-1.96), had more than 1 fracture on different dates during the study period (OR, 0.13; 95% CI, 0.02-1.16) and in those who had undergone DXA testing prior to the date of the bisphosphonate prescription and incident fracture (OR, 1.26; 95% CI, 0.69-2.32). CONCLUSIONS: In men with a traumatic SCI and women with a traumatic SCID, bisphosphonate therapies for osteoporosis do not appear to significantly affect fracture risk. Adequately powered randomized controlled trials are needed to definitively demonstrate efficacy of bisphosphonates for fracture prevention in this population. There is a compelling need to identify new medications to prevent fractures in this high-risk population.

Robotic coronary artery surgery: Outcomes and pitfalls.

OBJECTIVE: Coronary artery bypass grafting is one of the most commonly performed surgical procedures in cardiovascular surgery with a steadily evolving minimally invasive approach. METHODS: Conventional coronary artery bypass grafting (CABG) is performed traditionally via midline sternotomy. Exciting advancements in technology and engineering over the last two decades have resulted in the transition from conventional to minimally invasive CABG including robotically assisted surgery. RESULTS: The minimally invasive techniques are continuously striving to promote coronary revascularization into the arena of minimally invasive surgery. Examination of 10 previously completed studies with relevant follow-up periods enables an insightful vision into the outcomes and pitfalls surrounding robot-assisted CABG (RACAB) as explored in this review. Studies indicate that RACAB is associated with decreased postoperative complications such as major adverse cardiac or cerebrovascular events without compromise in survival rates. Despite this, certain drawbacks such as incurring costs and technical complexity of the procedure cannot be dismissed. CONCLUSION: There exist patient-related benefits from minimally invasive techniques such as decreased certain postoperative complications. Furthermore, with experience and a specialized stepwise program, it is possible to perform the entire procedure from the console. However, certain pitfalls involving increased expenses, steep learning curve and the lack of proper haptic feedback currently withhold the worldwide expansion of RACAB and limit it to specialized institutions only.

Rhabdomyolysis - Go big or go home.

OBJECTIVE: To evaluate the occurrence of renal injury in hospitalized patients with the diagnosis of rhabdomyolysis among a series of patients presenting to an urban emergency department. METHODS: A retrospective chart review between January 2006 and February 2017 was conducted on patients aged 21-65 years old that were admitted with a diagnosis of Rhabdomyolysis. We included patients with an initial serum creatinine (Cr) level < 1.3 mg/dL and an initial serum creatine phosphokinase (CPK) level > 1000 U/L. We excluded patients with preexisting renal disease, hypertension, diabetes, patients currently on medications in the statin class, patients with muscular dystrophy and neuromuscular disorders. RESULTS: One hundred and fifteen patients (100 men, 15 women) were enrolled, with a mean age of 36 years old. The mean CPK at presentation was 18,965 U/L and the highest CPK was 168,300 U/L. The mean Cr upon presentation was 0.95 mg/dL. The average length of stay of our patients was 4.6 days. The longest length of stay was 30 days and the shortest was 1 day. Seven patients had hospital stays longer than 10 days. None of the patients had prolonged admissions due to rhabdomyolysis alone. The patient admitted for 30 days had a protracted admission due to liver failure and sepsis thought to be unrelated to Rhabdomyolysis. No patients that fit our inclusion criteria developed renal insufficiency (Cr > 1.3 mg/dL) or failure regardless of their CPK upon presentation, peak CPK or therapies received during their hospitalization. CONCLUSION: Patients in our data set that presented to the Emergency Department with a CPK of >1000 U/L and a Cr of <1.3 mg/dL that were hospitalized with a diagnosis of rhabdomyolysis are not at risk for developing renal insufficiency or failure if treated promptly with fluid rehydration, regardless of their initial CPK values.

Angiotensin II and the Natriuretic and Blood Pressure Response to Mental Stress in African Americans.

Objective: To test the hypothesis that Angiotensin II (Ang II) is a contributing factor to the response pattern in African Americans (AAs) who retain rather than excrete sodium during mental stress. Design/Study Participants: Double-blind, randomized, cross-over trial of 87 healthy AAs aged 18 to 50 years. Interventions: The study participants received either a placebo or irbesartan, (150 mg PO), an Ang II receptor antagonist, for seven days prior to stress testing. Urinary sodium excretion (UNaV) and systolic blood pressure (SBP) were collected prior to and throughout a mental stress protocol (rest and stress period). Setting: A southeastern university. Main Outcome Measures: Ang II, SBP, and sodium retention. Results: During the placebo condition, 62 participants showed the expected increase in UNaV (excreters) while 25 participants reduced UNaV during stress (retainers). Irbesartan retainers demonstrated a reversal in the direction of their natriuretic response, now increasing UNaV in response to stress (∆ UNaV of -.094 mmol/min with placebo vs .052 mmol/min on irbesartan; P<.001). In excreters, irbesartan reduced SBP levels during both rest (-2.36 mm Hg; P=.03) and stress (-4.59;P<.0001), and an even more pronounced reduction in SBP was demonstrated by retainers on treatment during both rest (-4.29 mm Hg; P=.03) and stress (-6.12; P<.001). Conclusions: Ang II contributes to sodium retention in retainers. Furthermore, our findings indicate that suppression of Ang II has a beneficial effect on SBP during rest and stress in this population.

Associations of Plasma Cytokine and Microbial Translocation Biomarkers With Immune Reconstitution Inflammatory Syndrome.

A nested case-cohort study was performed in participants of a clinical trial of first-line human immunodeficiency virus treatments to investigate plasma biomarkers of inflammation and microbial translocation for their association with immune reconstitution inflammatory syndrome (IRIS). Fifty-one of 1452 participants with baseline CD4 count <350 cells/µL developed IRIS. Plasma from 51 IRIS cases, including 6 stratified by preenrollment CD4 count ≤200 cells/µL, were analyzed and compared to 94 non-IRIS controls. At baseline, CXCL10, lipopolysaccharide, soluble CD14, 16S ribosomal DNA, and interferon-α2 were associated with greater risk of IRIS. Systemic inflammation through persistent monocyte activation and microbial translocation appear to be important in IRIS pathogenesis.

Differential methylation tests of regulatory regions.

Differential methylation of regulatory elements is critical in epigenetic researches and can be statistically tested. We developed a new statistical test, the generalized integrated functional test (GIFT), that tests for regional differences in methylation based on the methylation percent at each CpG site within a genomic region. The GIFT uses estimated subject-specific profiles with smoothing methods, specifically wavelet smoothing, and calculates an ANOVA-like test to compare the average profile of groups. In this way, possibly correlated CpG sites within the regulatory region are compared all together. Simulations and analyses of data obtained from patients with chronic lymphocytic leukemia indicate that GIFT has good statistical properties and is able to identify promising genomic regions. Further, GIFT is likely to work with multiple different types of experiments since different smoothing methods can be used to estimate the profiles of data without noise. Matlab code for GIFT and sample data are available at http://www.augusta.edu/mcg/biostatepi/people/software/gift.html.

HIV infection Worsens Age-Associated Defects in Antibody Responses to Influenza Vaccine.

BACKGROUND: Antibody responses to seasonal influenza vaccines are defective during older age and human immunodeficiency virus (HIV) infection. The effect of HIV on immune function in aging is relatively unknown. METHODS: HIV-infected and HIV-uninfected young women (age, 19-54 years) and older women (age, >55 years) were evaluated for B-cell and T-cell responses before and 4 weeks after influenza vaccination. RESULTS: Frequencies of seroprotection pre-vaccination and vaccine responsiveness (≥4-fold increase in antibody titer) were lower in HIV-infected participants than in age-matched HIV-uninfected participants. A subgroup of vaccine nonresponders were compared to responders and found to have reduced frequencies of memory B cells and antigen-specific antibody-secreting cells after vaccination. Frequencies of peripheral T-follicular helper (pTfh) cells correlated with memory B-cell function and influenza A(H1N1) antibody titers. Serologic and immunologic deficits were most frequent in older HIV-infected participants. Underlying CD4(+) T-cell immune activation and inflammation correlated negatively with antibody titers and B-cell function, which was not enhanced by exogenous interleukin 21 supplementation in HIV-infected, older vaccine nonresponders. CONCLUSIONS: Immune activation associated with HIV infection and impaired pTfh function heighten deficiencies in antibody responses to influenza vaccine in older individuals. Strategies to reduce immune activation or augment pTfh function may enhance antibody responses in the aging HIV-infected population.

A method to detect differentially methylated loci with next-generation sequencing.

Epigenetic changes, especially DNA methylation at CpG loci have important implications in cancer and other complex diseases. With the development of next-generation sequencing (NGS), it is feasible to generate data to interrogate the difference in methylation status for genome-wide loci using case-control design. However, a proper and efficient statistical test is lacking. There are several challenges. First, unlike methylation experiments using microarrays, where there is one measure of methylation for one individual at a particular CpG site, here we have the counts of methylation allele and unmethylation allele for each individual. Second, due to the nature of sample preparation, the measured methylation reflects the methylation status of a mixture of cells involved in sample preparation. Therefore, the underlying distribution of the measured methylation level is unknown, and a robust test is more desirable than parametric approach. Third, currently NGS measures methylation at over 2 million CpG sites. Any statistical tests have to be computationally efficient in order to be applied to the NGS data. Taking these challenges into account, we propose a test for differential methylation based on clustered data analysis by modeling the methylation counts. We performed simulations to show that it is robust under several distributions for the measured methylation levels. It has good power and is computationally efficient. Finally, we apply the test to our NGS data on chronic lymphocytic leukemia. The results indicate that it is a promising and practical test.

Impaired peripheral blood T-follicular helper cell function in HIV-infected nonresponders to the 2009 H1N1/09 vaccine.

The generation of Ab-secreting plasma cells depends critically on CD4 T-follicular helper (TFH) cells during the germinal center reaction. Germinal center TFH cells share functional properties with circulating CXCR5(+) CD4 T cells, referred to herein as peripheral TFH (pTFH) cells. Because deficient Ab production and CD4 T-cell loss are recognized features of HIV infection, in the present study, we investigated pTFH cells in 25 HIV-infected patients on antiretroviral therapy. pTFH frequency was equivalent in patients and healthy controls (HCs), and these cells displayed a central memory phenotype. Sixteen patients and 8 HCs in this group were given a single dose of H1N1/09 influenza vaccine during the 2009 H1N1 influenza outbreak. In the vaccine responders (n = 8) and HCs, pTFH cells underwent expansion with increased IL-21 and CXCL13 secretion in H1N1-stimulated PBMC culture supernatants at week 4 (T2). These changes were not seen in vaccine nonresponders (n = 8). In coculture experiments, sorted pTFH cells supported HIN1-stimulated IgG production by autologous B cells only in vaccine responders. At T2, frequencies of pTFH were correlated with memory B cells, serum H1N1 Ab titers, and Ag-induced IL-21 secretion. Characterization of pTFH cells may provide additional insight into cellular determinants of vaccine-induced Ab response, which may have relevance for vaccine design.

Chitosan-nanoclay embolic material for catheter-directed arterial embolization.

Minimally invasive transcatheter embolization is a common nonsurgical procedure in interventional radiology. It is used for the deliberate occlusion of blood vessels for the treatment of disease or injured vasculature, including vascular malformation and malignant/benign tumors. Here, we introduce a gel embolic agent comprising chitosan nanofibers and nanoclay with excellent catheter injectability and tunable mechanical properties for embolization. The properties of the gel were optimized by varying the ratio between each individual component and also adjusting the total solid content. The rheological studies confirm the shear thinning property and gel nature of the developed gel as well as their recoverability. Injection force was measured to record the force required to pass the embolic gel through a clinically relevant catheter, evaluating for practicality of hand-injection. Theoretical predicted injection force was calculated to reduce the development time and to enhance the physician's experience. The stability of occlusion was also tested in vitro by monitoring the pressure required to displace the gel. The engineered gels exhibited sterility, hemocompatibility and cell biocompatibility, highlighting their potential for transcatheter embolization.

Adams-Oliver syndrome associated with refractory glaucoma.

Adams-Oliver syndrome (AOS) is a rare inherited disorder characterized by aplasia cutis congenita, cutis marmorata telangiectatica congenita, and terminal limb defects. Ocular associations have been rarely reported. We report a 6-month-old boy with AOS associated with refractory glaucoma, megalocornea, and anterior polar cataract. To our knowledge, this is the first case of glaucoma to be reported in association with AOS.