T-SIGn tumor reengineering therapy and CAR T cells synergize in combination therapy to clear human lung tumor xenografts and lung metastases in NSG mice.

Although chimeric antigen receptor (CAR) T cells have emerged as highly effective treatments for patients with hematologic malignancies, similar efficacy has not been achieved in the context of solid tumors. There are several reasons for this disparity including a) fewer solid tumor target antigens, b) heterogenous target expression amongst tumor cells, c) poor trafficking of CAR T cells to the solid tumor and d) an immunosuppressive tumor microenvironment (TME). Oncolytic viruses have the potential to change this paradigm by a) directly lysing tumor cells and releasing tumor neoantigens, b) stimulating the local host innate immune response to release cytokines and recruit additional innate and adaptive immune cells, c) carrying virus-encoded transgenes to "re-program" the TME to a pro-inflammatory environment and d) promoting an adaptive immune response to the neoantigens in this newly permissive TME.

An Fc-free EGFR-specific 4-1BB-agonistic Trimerbody Displays Broad Antitumor Activity in Humanized Murine Cancer Models without Toxicity.

Purpose: The induction of 4-1BB signaling by agonistic antibodies can drive the activation and proliferation of effector T cells and thereby enhance a T-cell-mediated antitumor response. Systemic administration of anti-4-1BB-agonistic IgGs, although effective preclinically, has not advanced in clinical development due to their severe hepatotoxicity.

Experimental Design: Here, we generated a humanized EGFR-specific 4-1BB-agonistic trimerbody, which replaces the IgG Fc region with a human collagen homotrimerization domain.

A tumor-targeted trimeric 4-1BB-agonistic antibody induces potent anti-tumor immunity without systemic toxicity.

The costimulation of immune cells using first-generation anti-4-1BB monoclonal antibodies (mAbs) has demonstrated anti-tumor activity in human trials. Further clinical development, however, is restricted by significant off-tumor toxicities associated with FcγR interactions. Here, we have designed an Fc-free tumor-targeted 4-1BB-agonistic trimerbody, 1D8EGa1, consisting of three anti-4-1BB single-chain variable fragments and three anti-EGFR single-domain antibodies positioned in an extended hexagonal conformation around the collagen XVIII homotrimerization domain.

Screening and optimization of potential injection vehicles for storage of retinal pigment epithelial stem cell before transplantation.

Retinal pigment epithelial (RPE) cells are highly specialized neural cells that have several functions essential for vision. Progressive deterioration of RPE cells in elderly individuals can result in visual impairment and ultimately the blinding disease age-related macular degeneration. Subretinal transplantation of stem cell-derived RPE cell suspensions is being explored as a strategy to recover the damaged retina and improve vision.

Pregnancy in a woman with recurrent immunoglobulin a nephropathy: A case report.

Immunoglobulin A nephropathy (IgAN) is the most common form of primary glomerulonephritis and is increasingly encountered in pregnancy. The obstetric and renal outcomes of pregnancy are controversial, however. Women with IgAN are at higher risk of hypertension, preeclampsia and foetal loss; the prognosis is worse for those who have advanced chronic kidney disease and proteinuria.

[New methods for preterm birth prediction: the PAMG-1 test].

Background: The aim of this study was to assess the efficacy of PAMG-1 test (placental alpha microglobulin-1) in cervicovaginal secretions collected immediately following transvaginal ultrasound (TVUS) of women with signs and symptoms of preterm labor (PTL), clinically intact membranes and cervical length between 15 and 30 mm for the prediction of imminent spontaneous delivery (within 7 days of testing), as well as delivery <34 weeks of gestation.

Methods: Performing PAMG-1 test in 79 women with singleton pregnancy (240/7 -336/7 weeks' gestation) reporting signs and symptoms indicative of PTL and cervical length <30 mm.

Results: For PTB prediction risk within 7 days of testing in pregnant women with cervicale length between 15-30 mm sensitivity is 100% and specificity is 94%.

Polarized, Cobblestone, Human Retinal Pigment Epithelial Cell Maturation on a Synthetic PEG Matrix.

Cell attachment is essential for the growth and polarization of retinal pigment epithelial (RPE) cells. Currently, surface coatings derived from biological proteins are used as the gold standard for cell culture. However, downstream processing and purification of these biological products can be cumbersome and expensive.

Genome-Wide Association Study Identifies African-Specific Susceptibility Loci in African Americans With Inflammatory Bowel Disease.

Background & Aims: The inflammatory bowel diseases (IBD) ulcerative colitis (UC) and Crohn's disease (CD) cause significant morbidity and are increasing in prevalence among all populations, including African Americans. More than 200 susceptibility loci have been identified in populations of predominantly European ancestry, but few loci have been associated with IBD in other ethnicities.

Methods: We performed 2 high-density, genome-wide scans comprising 2345 cases of African Americans with IBD (1646 with CD, 583 with UC, and 116 inflammatory bowel disease unclassified) and 5002 individuals without IBD (controls, identified from the Health Retirement Study and Kaiser Permanente database).

Distinct Trafficking of Cell Surface and Endosomal TIM-1 to the Immune Synapse.

The T cell costimulatory molecule TIM-1 (T cell/transmembrane, mucin and immunoglobulin domain protein 1) sorts mainly to endosomes in lymphoid cells. At difference from the cell surface protein, endosomal TIM-1 translocates to the immune synapse (IS), where it can contribute to antigen-dependent T cell costimulation. TIM-1 ligands increase the amount of cell surface protein, preventing its traffic to the IS.

APRIL promotes breast tumor growth and metastasis and is associated with aggressive basal breast cancer.

APRIL (a proliferation-inducing ligand) is a cytokine of the tumor necrosis factor family associated mainly with hematologic malignancies. APRIL is also overexpressed in breast carcinoma tissue lesions, although neither its role in breast tumorigenesis nor the underlying molecular mechanism is known. Here, we show that several breast cancer cell lines express APRIL and both its receptors, B cell maturation antigen (BCMA) and transmembrane activator and CAML-interactor (TACI), independently of luminal or basal tumor cell phenotype, and that the mitogen-activated protein kinases p38, ERK1/2, and JNK1/2 are activated in response to APRIL.

NFκB activation by modified vaccinia virus as a novel strategy to enhance neutrophil migration and HIV-specific T-cell responses.

Neutrophils are antigen-transporting cells that generate vaccinia virus (VACV)-specific T-cell responses, yet how VACV modulates neutrophil recruitment and its significance in the immune response are unknown. We generated an attenuated VACV strain that expresses HIV-1 clade C antigens but lacks three specific viral genes (A52R, K7R, and B15R). We found that these genes act together to inhibit the NFκB signaling pathway.

Prophylactic oral nifedipine to reduce preterm delivery: a randomized controlled trial in women at high risk.

Objective: To establish the efficacy of prophylactic nifedipine vs. placebo in reducing spontaneous preterm delivery in asymptomatic women at high risk for preterm delivery.

Design: Prospective multicentric randomized double-blind study.

High-resolution live-cell imaging reveals novel cyclin A2 degradation foci involving autophagy.

Cyclin A2 is a key player in the regulation of the cell cycle. Its degradation in mid-mitosis relies on the ubiquitin-proteasome system (UPS). Using high-resolution microscopic imaging, we find that cyclin A2 persists beyond metaphase.

Enhanced stem cell pluripotency in surface-modified electrospun fibrous matrices.

A previously screened "hit chemistry" (N-[3-(dimethylamino)propyl] methacrylamide) that supports strong attachment and long-term self-renewal of ES cells is selected and grafted to poly(ether sulfone) (PES) fibrous matrices through plasma-induced graft polymerization. The 3D modified fibers exhibit higher cell proliferation and greater expression of pluripotency markers of mouse ES cells than 2D membranes. It is the first demonstration of scaling up an optimal synthetic surface chemistry in 2D using a high throughput synthesis, screening, and selection method to 3D that strongly influences pluripotent stem cell growth.

High-throughput screening of substrate chemistry for embryonic stem cell attachment, expansion, and maintaining pluripotency.

Appropriate surface attachment is essential for growing embryonic stem (ES) cells in an undifferentiated state. It is challenging to identify the optimal surface chemistry of the substrata for ES cell attachment and maintenance. Using a rapid, high-throughput polymerization and screening platform with a comprehensive library of 66 monomer-grafted membrane surfaces, the optimal substrate, N-[3-(dimethylamino)propyl] methacrylamide (DMAPMA) has been identified to support strong attachment, high expansion capacity, and long-term self-renewal of ES cells (up to 7 passages).

Education-service partnership to promote best practices in a latent tuberculosis infection program.

The education-service partnership described addresses the challenges presented to local health departments and public health nurses in completing required latent tuberculosis (LTBI) follow-up in population groups. A service learning partnership between the local health department and a Midwestern university school of nursing resulted in the development of an LTBI follow-up program that completed contacts with 193 subjects. Populations served by the program included immigrants to the community and workers from several occupational settings.

APRIL and BAFF proteins increase proliferation of human adipose-derived stem cells through activation of Erk1/2 MAP kinase.

Human adipose-derived stem cells (hASC) are mesenchymal stem cells with reduced immunogenicity and the ability to modulate immune responses. APRIL and BAFF proteins are overexpressed in inflammatory and autoimmune diseases for which allogeneic hASC therapy is currently under clinical investigation. Modification of hASC properties by the tissue microenvironment could be a critical factor in patient outcome and is still not well understood.

[Vitamin intake and pregnancy].

A suitable intake of vitamins and minerals both during preconceptional period and pregnancy is essential in reducing the incidence of adverse maternal and perinatal outcomes. This is more evident in developing countries, particularly during periods of famine, when women suffer from an inadequate intake of vitamins and minerals. Even in developed countries, however, most women's diet does not meet their increased needs for micronutrients.

Naproxen sodium in short-term prophylaxis of pure menstrual migraine: pathophysiological and clinical considerations.

We investigated the biological and clinical effects of naproxen sodium (NxS) in the short-term prophylaxis of pure menstrual migraine (PMM) in 25 women suffering from migraine without aura, occurring exclusively from 2 days before to 5 days after menstruation onset. Daily oral NxS (550 mg) from 7 days before menstruation to 7 days after menstruation onset was given for 3 menstrual cycles, and 5 days before menstruation to 5 days after menstruation onset over the next 3 menstrual cycles. In the month before initiation of treatment and in the third month of treatment, 6-keto-PGF1(alpha), TXB(2) and PGE(2) were measured in plasma before menstruation (day -2) and on the second day (day +2) after bleeding onset.

Changes of dimeric inhibin B levels in maternal serum throughout healthy gestation and in women with gestational diseases.

Human placenta expresses subunit messenger RNAs for synthesizing inhibin A and B. Experimental studies have shown an effect of inhibins on placental hormone secretion, but an endocrine function is suggested by the high levels in maternal circulation. Although information is available on the changes of inhibin A in serum of healthy pregnant women, data on inhibin B levels are limited to early gestation.

24-hour blood pressure monitoring to evaluate the effects of nifedipine in pre-eclampsia and in chronic hypertension in pregnancy.

Objective: To investigate the effect of 7 to 14 days of therapy with nifedipine (sustained-release preparation) on the 24-hour blood pressure patterns of pregnant women with pre-eclampsia or chronic hypertension, and to test the utility of blood pressure monitoring in modulating the timing and dosage of the drug.

Design: 24-hour automatic blood pressure monitoring of pregnant women with pre-eclampsia or chronic hypertension before and after nifedipine treatment.

Setting: Centre for Prevention, Diagnosis and Treatment of Hypertension in Pregnancy, University of Turin, Italy.

Blood pressure patterns in normal pregnancy and in pregnancy-induced hypertension, preeclampsia, and chronic hypertension.

Objective: To compare the 24-hour blood pressure (BP) pattern in physiologic pregnancy, pregnancy-induced hypertension, preeclampsia, and chronic hypertension.

Methods: We investigated four groups of women with singleton pregnancy: 73 controls, 48 patients with pregnancy-induced hypertension, 38 with preeclampsia, and 53 with mild to moderate chronic hypertension. The 24-hour BP monitoring was performed longitudinally in controls and in patients with chronic hypertension, and at the time of diagnosis in those with pregnancy-induced hypertension or preeclampsia.

Hypertension in pregnancy: changes in activin A maternal serum concentration.

Human placenta is the major source of activin A in maternal circulation. The aim of the present study was to evaluate maternal activin A serum concentration in pregnant women with chronic hypertension (n = 14), pregnancy-induced hypertension (n = 10) or pre-eclampsia (n = 16). In the group of pregnant women with chronic hypertension and of healthy pregnant women (n = 10) activin A was measured in samples collected longitudinally throughout gestation.

Measurement of shoulder related disability: results of a validation study.

Objective: To develop and validate a questionnaire to quantify disability associated with shoulder symptoms.

Methods: A set of questions relevant to shoulder symptoms from a general disability interview was developed and the questionnaire applied to a cross-sectional population survey and a prospective study of general practice attenders. Subjects included adults who reported current shoulder pain in a population survey and patients from three general practices who attended with shoulder symptoms during a six month period.