Dual-Antigen COVID-19 Vaccine Subcutaneous Prime Delivery With Oral Boosts Protects NHP Against SARS-CoV-2 Challenge.

We have developed a dual-antigen COVID-19 vaccine incorporating genes for a modified SARS-CoV-2 spike protein (S-Fusion) and the viral nucleocapsid (N) protein with an Enhanced T-cell Stimulation Domain (N-ETSD) to increase the potential for MHC class II responses. The vaccine antigens are delivered by a human adenovirus serotype 5 platform, hAd5 [E1-, E2b-, E3-], previously demonstrated to be effective in the presence of Ad immunity. Vaccination of rhesus macaques with the hAd5 S-Fusion + N-ETSD vaccine by subcutaneous prime injection followed by two oral boosts elicited neutralizing anti-S IgG and T helper cell 1-biased T-cell responses to both S and N that protected the upper and lower respiratory tracts from high titer (1 x 10 TCID) SARS-CoV-2 challenge.

Susceptibility to Neutralization by Broadly Neutralizing Antibodies Generally Correlates with Infected Cell Binding for a Panel of Clade B HIV Reactivated from Latent Reservoirs.

Efforts to cure human immunodeficiency virus (HIV) infection are obstructed by reservoirs of latently infected CD4 T cells that can reestablish viremia. HIV-specific broadly neutralizing antibodies (bNAbs), defined by unusually wide neutralization breadths against globally diverse viruses, may contribute to the elimination of these reservoirs by binding to reactivated cells, thus targeting them for immune clearance. However, the relationship between neutralization of reservoir isolates and binding to corresponding infected primary CD4 T cells has not been determined.

CAD/POLD2 gene expression is associated with poor overall survival and chemoresistance in bladder urothelial carcinoma.

Somatic mutations in DNA repair genes have been clinically associated with chemosensitivity, although few studies have interrogated the nucleotide synthesis pathways that supply DNA repair processes. Previous work suggests that bladder urothelial carcinoma is uniquely enriched for mutations in nucleotide excision repair genes, and that these mutations are associated with response to platinum-based therapy and favorable survival. Conversely, the pyrimidine synthesis pathway has recently emerged as a putative clinical target.

Identification of an immune gene expression signature associated with favorable clinical features in Treg-enriched patient tumor samples.

Immune heterogeneity within the tumor microenvironment undoubtedly adds several layers of complexity to our understanding of drug sensitivity and patient prognosis across various cancer types. Within the tumor microenvironment, immunogenicity is a favorable clinical feature in part driven by the antitumor activity of CD8+ T cells. However, tumors often inhibit this antitumor activity by exploiting the suppressive function of regulatory T cells (Tregs), thus suppressing the adaptive immune response.

G2A Attenuates Induction of Inflammatory Cytokines in Human Monocytes.

Background: Acne vulgaris is a disease of the pilosebaceous unit characterized by increased sebum production, hyperkeratinization, and immune responses to (PA). Here, we explore a possible mechanism by which a lipid receptor, G2A, regulates immune responses to a commensal bacterium.

Objective: To elucidate the inflammatory properties of G2A in monocytes in response to PA stimulation.

Overexpression of RKIP and its cross-talk with several regulatory gene products in multiple myeloma.

Multiple myeloma (MM) is a clonal plasma-cell neoplastic disorder arising from an indolent premalignant disease known as monoclonal gammopathy of undetermined significance (MGUS). MM is a biologically complex heterogeneous disease reflected by its variable clinical responses of patients receiving the same treatment. Therefore, a molecular identification of stage-specific biomarkers will support a more individualized precise diagnostic/prognostic approach, an effective therapeutic regime, and will assist in the identification of novel therapeutic molecular targets.

Δ9 desaturase from Trypanosoma cruzi: Key enzyme in the parasite metabolism. Cloning and overexpression.

Desaturases, key enzymes in the metabolism of fatty acids, regulate the physical and biochemical properties of membranes. They adjust the composition of saturated and unsaturated fatty acids in response to changes in the environmental. We demonstrated the existence of Δ9 desaturase activity in epimastigotes of the Trypanosoma cruzi Tulahuen strain.

Yin Yang 1 is associated with cancer stem cell transcription factors (SOX2, OCT4, BMI1) and clinical implication.

The transcription factor Yin Yang 1 (YY1) is frequently overexpressed in cancerous tissues compared to normal tissues and has regulatory roles in cell proliferation, cell viability, epithelial-mesenchymal transition, metastasis and drug/immune resistance. YY1 shares many properties with cancer stem cells (CSCs) that drive tumorigenesis, metastasis and drug resistance and are regulated by overexpression of certain transcription factors, including SOX2, OCT4 (POU5F1), BMI1 and NANOG. Based on these similarities, it was expected that YY1 expression would be associated with SOX2, OCT4, BMI1, and NANOG's expressions and activities.

Nitric oxide-mediated sensitization of resistant tumor cells to apoptosis by chemo-immunotherapeutics.

The generation of NO by the various NO synthases in normal and malignant tissues is manifested by various biological effects that are involved in the regulation of cell survival, differentiation and cell death. The role of NO in the cytotoxic immune response was first revealed by demonstrating the induction of iNOS in target cells by immune cytokines (e.g.

Biologic roles of estrogen receptor-β and insulin-like growth factor-2 in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) occurs in 10-15% of patients yet accounts for almost half of all breast cancer deaths. TNBCs lack expression of estrogen and progesterone receptors and HER-2 overexpression and cannot be treated with current targeted therapies. TNBCs often occur in African American and younger women.

Immune response to intrathecal enzyme replacement therapy in mucopolysaccharidosis I patients.

Background: Intrathecal (IT) enzyme replacement therapy with recombinant human α-L-iduronidase (rhIDU) has been studied to treat glycosaminoglycan storage in the central nervous system of mucopolysaccharidosis (MPS) I dogs and is currently being studied in MPS I patients.

Methods: We studied the immune response to IT rhIDU in MPS I subjects with spinal cord compression who had been previously treated with intravenous rhIDU. We measured the concentrations of specific antibodies and cytokines in serum and cerebrospinal fluid (CSF) collected before monthly IT rhIDU infusions and compared the serologic findings with clinical adverse event (AE) reports to establish temporal correlations with clinical symptoms.

Propionibacterium acnes Induces an IL-17 Response in Acne Vulgaris that Is Regulated by Vitamin A and Vitamin D.

Acne vulgaris is the most common skin disorder affecting millions of people worldwide and inflammation resulting from the immune response targeting Propionibacterium acnes has a significant role in its pathogenesis. In this study, we have demonstrated that P. acnes is a potent inducer of T helper 17 (Th17) and Th1, but not Th2 responses in human peripheral blood mononuclear cells (PBMCs).

Propionibacterium acnes Induces IL-1β secretion via the NLRP3 inflammasome in human monocytes.

Propionibacterium acnes induction of inflammatory responses is a major etiological factor contributing to the pathogenesis of acne vulgaris. In particular, the IL-1 family of cytokines has a critical role in both initiation of acne lesions and in the inflammatory response in acne. In this study, we demonstrated that human monocytes respond to P.

Transcription regulator Yin-yang 1: from silence to cancer.

Yin Yang (YY) 1 represents the epitome of what is considered to be a "Swiss army knife" transcription factor and regulator. YY1 is a ubiquitous and multifunctional zinc-finger transcription factor member of the Polycomb group protein family, a group of homeobox gene receptors that can act as activators or repressors of transcriptional activity. Furthermore, YY1 can act as a redox sensor, adaptor molecule, and chromatin structure and function regulator.

CXCR4/YY1 inhibition impairs VEGF network and angiogenesis during malignancy.

Tumor growth requires neoangiogenesis. VEGF is the most potent proangiogenic factor. Dysregulation of hypoxia-inducible factor (HIF) or cytokine stimuli such as those involving the chemokine receptor 4/stromal-derived cell factor 1 (CXCR4/SDF-1) axis are the major cause of ectopic overexpression of VEGF in tumors.

Enhanced antitumor activity induced by adoptive T-cell transfer and adjunctive use of the histone deacetylase inhibitor LAQ824.

Tumors grow in the presence of antigen-specific T cells, suggesting the existence of intrinsic cancer cell escape mechanisms. We hypothesized that a histone deacetylase (HDAC) inhibitor could sensitize tumor cells to immunotherapy because this class of agents has been reported to increase tumor antigen expression and shift gene expression to a proapoptotic milieu in cancer cells. To test this question, we treated B16 murine melanoma with the combination of the HDAC inhibitor LAQ824 and the adoptive transfer of gp100 melanoma antigen-specific pmel-1 T cells.

Immunosensitization with a Bcl-2 small molecule inhibitor.

Several tumor immunotherapy approaches result in a low percentage of durable responses in selected cancers. We hypothesized that the insensitivity of cancer cells to immunotherapy may be related to an anti-apoptotic cancer cell milieu, which could be pharmacologically reverted through the inhibition of antiapoptotic Bcl-2 family proteins in cancer cells. ABT-737, a small molecule inhibitor of the antiapoptotic proteins Bcl-2, Bcl-w and Bcl-x(L), was tested for the ability to increase antitumor immune responses in two tumor immunotherapy animal models.

Regulation of apoptosis-related genes by nitric oxide in cancer.

Nitric oxide (NO) is a simple molecule with a complex and pleiotropic biological activity. NO or related species have been implicated in the regulation of many genes that participate in many diverse biological functions including programmed cell death or apoptosis. Apoptosis is a process that may potentially be disrupted in cancer cells conferring a survival advantage.

Therapeutic potential of nitric oxide in cancer.

In recent years, several novel approaches have been developed to overcome tumor cell resistance to conventional therapeutics. Such approaches include genetic manipulations, vaccine development and exploitation of the anti-tumor host immune response. The overall development of tumor cell resistance to therapeutics is, in large part, the result of the ability of tumor cells to develop specific mechanisms to overcome cell death or apoptosis.

Involvement of the TNF-alpha autocrine-paracrine loop, via NF-kappaB and YY1, in the regulation of tumor cell resistance to Fas-induced apoptosis.

Many tumors are resistant to Fas ligand (FasL)-induced apoptosis. This study examined the role of tumor-derived TNF-alpha, via an autocrine/paracrine loop, in the regulation of tumor-cell resistance to FasL-induced apoptosis. We have reported that Fas expression and sensitivity to FasL is negatively regulated by the transcription repressor factor Yin Yang 1 (YY1).

Immunosensitization of tumor cells to dendritic cell-activated immune responses with the proteasome inhibitor bortezomib (PS-341, Velcade).

Proteasome inhibition results in proapoptotic changes in cancer cells, which may make them more sensitive to immune effector cells. We established a murine model to test whether the proteasome inhibitor bortezomib could sensitize established B16 melanoma tumors to dendritic cell (DC)-activated immune effector cells. Day 3-established s.

Aromatase inhibitors in human lung cancer therapy.

Lung cancer is the most common cancer in the world. It is a highly lethal disease in women and men, and new treatments are urgently needed. Previous studies implicated a role of estrogens and estrogen receptors in lung cancer progression, and this steroidal growth-stimulatory pathway may be promoted by tumor expression and activity of aromatase, an estrogen synthase.

Inhibition of the transcription factor Yin Yang 1 activity by S-nitrosation.

Treatment of several prostate cancer (CaP) cell lines (PC-3, CL-1, and DU-145) with the nitric oxide (NO) donor DETA/NONOate upregulated Fas expression and sensitized the CaP cells to the Fas ligand CH-11 agonist monoclonal antibody-induced apoptosis. Previous findings demonstrated that the transcription repressor Yin Yang 1 (YY1), which is inhibited by NO, negatively regulates Fas transcription [H.J.