Lentiviral vectors for precise expression to treat X-linked lymphoproliferative disease.

X-linked lymphoproliferative disease (XLP1) results from gene mutations affecting the SLAM-associated protein (SAP). A regulated lentiviral vector (LV), XLP-SMART LV, designed to express SAP at therapeutic levels in T, NK, and NKT cells, is crucial for effective gene therapy. We experimentally identified 34 genomic regulatory elements of the gene and designed XLP-SMART LVs to emulate the lineage and stage-specific control of SAP.

A novel high-titer, bifunctional lentiviral vector for autologous hematopoietic stem cell gene therapy of sickle cell disease.

A major limitation of gene therapy for sickle cell disease (SCD) is the availability and access to a potentially curative one-time treatment, due to high treatment costs. We have developed a high-titer bifunctional lentiviral vector (LVV) in a vector backbone that has reduced size, high vector yields, and efficient gene transfer to human CD34 hematopoietic stem and progenitor cells (HSPCs). This LVV contains locus control region cores expressing an anti-sickling β-globin gene and two microRNA-adapted short hairpin RNA simultaneously targeting and transcripts to maximally induce fetal hemoglobin (HbF) expression.

Clinically-observed FOXA1 mutations upregulate SEMA3C through transcriptional derepression in prostate cancer.

FOXA1 is a pioneer transcription factor that is frequently mutated in prostate, breast, bladder, and salivary gland malignancies. Indeed, metastatic castration-resistant prostate cancer (mCRPC) commonly harbour FOXA1 mutations with a prevalence of 35%. However, despite the frequent recurrence of FOXA1 mutations in prostate cancer, the mechanisms by which FOXA1 variants drive its oncogenic effects are still unclear.

Semaphorin 3C promotes de novo steroidogenesis in prostate cancer cells.

Intratumoral androgen biosynthesis contributes to castration-resistant prostate cancer progression in patients treated with androgen deprivation therapy. The molecular mechanisms by which castration-resistant prostate cancer acquires the capacity for androgen biosynthesis to bypass androgen deprivation therapy are not entirely known. Here, we show that semaphorin 3C, a secreted signaling protein that is highly expressed in castration-resistant prostate cancer, can promote steroidogenesis by altering the expression profile of key steroidogenic enzymes.

Beyond the Surface: A Deeper Look at the Psychosocial Impacts of Acne Scarring.

Post-acne scarring is a common consequence of acne vulgaris with no universal cure. Although there have been many recent advances to address acne scars physically, there is still a lack of research that investigates their psychosocial impacts. Our comprehensive PubMed search presents an overview of existing information to highlight known sources of mental distress caused by post-acne scarring, both related to and independent of the psychosocial detriments caused early on by active acne.

Subcision for Atrophic Acne Scarring: A Comprehensive Review of Surgical Instruments and Combinatorial Treatments.

Subcutaneous incisionless surgery, also known as subcision, is a minimally invasive procedure that is commonly indicated for the treatment of atrophic acne scars. In recent years, many new techniques have been developed to maximize results from this procedure. This review article aims to identify an updated list of instruments and combinatorial treatments available for atrophic acne scar patients undergoing subcision.

A Comprehensive Review of Non-Energy-Based Treatments for Atrophic Acne Scarring.

Scarring is a dire consequence of acne vulgaris. Particularly, atrophic acne scarring is highly prevalent among young adults, and its physical and psychological effects can persist throughout their lives if left untreated. This literature review will analyze various non-energy-based approaches to treating atrophic acne scarring, emphasizing recent advances within the last 5 to 10 years.

Improved lentiviral vector titers from a multi-gene knockout packaging line.

Lentiviral vectors (LVs) are robust delivery vehicles for gene therapy as they can efficiently integrate transgenes into host cell genomes. However, LVs with lengthy or complex expression cassettes typically are produced at low titers and have reduced gene transfer capacity, creating barriers for clinical and commercial applications. Modifications of the packaging cell line and methods may be able to produce complex vectors at higher titer and infectivity and may improve production of many different LVs.

Does GD2 synthase (GD2S) detect cancer stem cells in blood samples of breast carcinomas?

Introduction: Cancer stem cells (CSCs) are a theorized subset of cells within the tumor that is thought to drive disease recurrence and metastatic spread. The aim of this study is to investigate mRNA and protein levels of ganglioside GD2 synthase (GD2S), in breast cancer (BC) patients.

Methods: 65 PBMCs of preoperative BC patients without chemotherapy were compared to PBMCs after chemotherapy and controls.

β-Globin Lentiviral Vectors Have Reduced Titers due to Incomplete Vector RNA Genomes and Lowered Virion Production.

Lentiviral vectors (LVs) commonly used for the treatment of hemoglobinopathies often have low titers and sub-optimal gene transfer efficiency for human hematopoietic stem and progenitor cells (HSPCs), hindering clinical translation and commercialization for ex vivo gene therapy. We observed that a high percentage of β-globin LV viral genomic RNAs were incomplete toward the 3' end in packaging cells and in released vector particles. The incomplete vector genomes impeded reverse transcription in target cells, limiting stable gene transfer to HSPCs.

DCLK1, a promising colorectal cancer stem cell marker, regulates tumor progression and invasion through miR-137 and miR-15a dependent manner.

Cancer stem cells (CSCs) are thought to be a major player in tumor initiation, progression, and metastasis. Targeting CSCs for elimination presents a promising therapeutic strategy; however, this approach will require a stronger understanding of CSC biology and identification of CSC-specific markers. The present study was conducted to examine the correlation between DCLK1 and miR-137 and miR-15a levels in colorectal cancer.

Interaction of oxidative stress and neurotrauma in ALDH2 mice causes significant and persistent behavioral and pro-inflammatory effects in a tractable model of mild traumatic brain injury.

Oxidative stress induced by lipid peroxidation products (LPP) accompanies aging and has been hypothesized to exacerbate the secondary cascade in traumatic brain injury (TBI). Increased oxidative stress is a contributor to loss of neural reserve that defines the ability to maintain healthy cognitive function despite the accumulation of neuropathology. ALDH2 mice are unable to clear aldehyde LPP by mitochondrial aldehyde dehydrogenase-2 (Aldh2) detoxification and provide a model to study mild TBI (mTBI), therapeutic interventions, and underlying mechanisms.

Spheroid-Derived Cells From Renal Adenocarcinoma Have Low Telomerase Activity and High Stem-Like and Invasive Characteristics.

Cancer stem cells (CSCs) are a theorized small subpopulation of cells within tumors thought to be responsible for metastasis, tumor development, disease progression, treatment-resistance, and recurrence. The identification, isolation, and biological characterization of CSCs may therefore facilitate the development of efficient therapeutic strategies targeting CSCs. This study aims to compare the biology and telomerase activity of CSCs to parental cells (PCs) in renal cancer.

Stationary and dynamical properties of pure-quartic solitons.

We numerically solve a generalized nonlinear Schrödinger equation and find a family of pure-quartic solitons (PQSs), existing through a balance of positive Kerr nonlinearity and negative quartic dispersion. These solitons have oscillatory tails, which can be understood analytically from the properties of linear waves with quartic dispersion. By computing the linear eigenspectrum of the solitons, we show that they are stable, but that they possess a nontrivial internal mode close to the radiation continuum.

Dendrimer-Based Platform for Effective Capture of Tumor Cells after TGFβ-Induced Epithelial-Mesenchymal Transition.

Detection of circulating tumor cells (CTCs) relying on their expression of epithelial cell markers, such as epithelial cell adhesion molecule (EpCAM), has been commonly used. However, this approach unlikely captures CTCs that have undergone the process of epithelial-mesenchymal transition (EMT). In this study, we have induced EMT of in vitro prostate (PCa) and breast cancer (BCa) cell lines by treatment of transforming growth factor β 1 (TGFβ), a pleiotropic cytokine with transition-regulating activities.

Semaphorin 3C as a Therapeutic Target in Prostate and Other Cancers.

The semaphorins represent a large family of signaling molecules with crucial roles in neuronal and cardiac development. While normal semaphorin function pertains largely to development, their involvement in malignancy is becoming increasingly evident. One member, Semaphorin 3C (SEMA3C), has been shown to drive a number of oncogenic programs, correlate inversely with cancer prognosis, and promote the progression of multiple different cancer types.

Targeting Semaphorin 3C in Prostate Cancer With Small Molecules.

Despite the amenability of early-stage prostate cancer to surgery and radiation therapy, locally advanced and metastatic prostate cancer is clinically problematic. Chemical castration is often used as a first-line therapy for advanced disease, but progression to the castration-resistant prostate cancer phase occurs with dependable frequency, largely through mutations to the androgen receptor (AR), aberrant AR signaling, and AR-independent mechanisms, among other causes. Semaphorin 3C (SEMA3C) is a secreted signaling protein that is essential for cardiac and neuronal development and has been shown to be regulated by the AR, to drive epithelial-to-mesenchymal transition and stem features in prostate cells, to activate receptor tyrosine kinases, and to promote cancer progression.

Small molecule-induced degradation of the full length and V7 truncated variant forms of human androgen receptor.

The androgen receptor (AR) is a hormone-activated transcription factor that regulates the development and progression of prostate cancer (PCa) and represents one of the most well-established drug targets. Currently clinically approved small molecule inhibitors of AR, such as enzalutamide, are built upon a common chemical scaffold that interacts with the AR by the same mechanism of action. These inhibitors eventually fail due to the emergence of drug-resistance in the form of AR mutations and expression of truncated AR splice variants (e.

Selectively targeting the dimerization interface of human androgen receptor with small-molecules to treat castration-resistant prostate cancer.

Prostate cancer (PCa) is a leading cause of death for men in North America. The androgen receptor (AR) - a hormone inducible transcription factor - drives expression of tumor promoting genes and represents an important therapeutic target in PCa. The AR is activated by steroid recruitment to its ligand binding domain (LBD), followed by receptor nuclear translocation and dimerization via the DNA binding domain (DBD).

Multivalent Binding and Biomimetic Cell Rolling Improves the Sensitivity and Specificity of Circulating Tumor Cell Capture.

We aimed to examine the effects of multivalent binding and biomimetic cell rolling on the sensitivity and specificity of circulating tumor cell (CTC) capture. We also investigated the clinical significance of CTCs and their kinetic profiles in patients with cancer undergoing radiotherapy treatment. Patients with histologically confirmed primary carcinoma undergoing radiotherapy, with or without chemotherapy, were eligible for enrollment.

SEMA3C drives cancer growth by transactivating multiple receptor tyrosine kinases via Plexin B1.

Growth factor receptor tyrosine kinase (RTK) pathway activation is a key mechanism for mediating cancer growth, survival, and treatment resistance. Cognate ligands play crucial roles in autocrine or paracrine stimulation of these RTK pathways. Here, we show SEMA3C drives activation of multiple RTKs including EGFR, ErbB2, and MET in a cognate ligand-independent manner via Plexin B1.

Semaphorin 3 C drives epithelial-to-mesenchymal transition, invasiveness, and stem-like characteristics in prostate cells.

Prostate cancer (PCa) is among the most commonly-occurring cancers worldwide and a leader in cancer-related deaths. Local non-invasive PCa is highly treatable but limited treatment options exist for those with locally-advanced and metastatic forms of the disease underscoring the need to identify mechanisms mediating PCa progression. The semaphorins are a large grouping of membrane-associated or secreted signalling proteins whose normal roles reside in embryogenesis and neuronal development.

Bypassing Drug Resistance Mechanisms of Prostate Cancer with Small Molecules that Target Androgen Receptor-Chromatin Interactions.

Human androgen receptor (AR) is a hormone-activated transcription factor that is an important drug target in the treatment of prostate cancer. Current small-molecule AR antagonists, such as enzalutamide, compete with androgens that bind to the steroid-binding pocket of the AR ligand-binding domain (LBD). In castration-resistant prostate cancer (CRPC), drug resistance can manifest through AR-LBD mutations that convert AR antagonists into agonists, or by expression of AR variants lacking the LBD.

Androgen receptor transcriptionally regulates semaphorin 3C in a GATA2-dependent manner.

The androgen receptor (AR) is a member of the nuclear receptor superfamily of transcription factors and is central to prostate cancer (PCa) progression. Ligand-activated AR engages androgen response elements (AREs) at androgen-responsive genes to drive the expression of gene batteries involved in cell proliferation and cell fate. Understanding the transcriptional targets of the AR has become critical in apprehending the mechanisms driving treatment-resistant stages of PCa.

Chemical Structure and Surface Modification of Dendritic Nanomaterials Tailored for Therapeutic and Diagnostic Applications.

Dendritic nanomaterials have attracted a great deal of scientific interest due to their high capacity for multifunctionalization and potential in various biomedical applications, such as drug/gene delivery and diagnostic systems. Depending on the molecular structure and starting monomers, several different types of dendrimers have been developed, including poly(amidoamine) (PAMAM), poly(propylenimine) (PPI), and poly(L-lysine) (PLL) dendrimers, in addition to modified dendritic nanomaterials, such as Janus dendrimers and dendritic block copolymers. The chemical structure and surface modification of dendritic nanomaterials have been found to play a critical role in governing their biological behaviors.