CD4CCR5 T cells and CCL3+ mast cells are increased in the skin of patients with chronic spontaneous urticaria.

Background: The proximity of activated T cells and mast cells in the lesional skin of patients with chronic spontaneous urticaria (CSU) is held to contribute to the development of wheals and angioedema. In a previous study, we demonstrated that increased IL-17 expression in T cells and mast cells in skin lesions of patients with CSU is associated with T/mast cell proximity, but the mechanisms that drive T cell/mast cell co-localization remain unknown.

Objectives: To assess if chemokines expressed in lesional CSU skin contribute to T cell/mast cell proximity.

Aligning tumor mutational burden (TMB) quantification across diagnostic platforms: phase II of the Friends of Cancer Research TMB Harmonization Project.

Background: Tumor mutational burden (TMB) measurements aid in identifying patients who are likely to benefit from immunotherapy; however, there is empirical variability across panel assays and factors contributing to this variability have not been comprehensively investigated. Identifying sources of variability can help facilitate comparability across different panel assays, which may aid in broader adoption of panel assays and development of clinical applications.

Materials And Methods: Twenty-nine tumor samples and 10 human-derived cell lines were processed and distributed to 16 laboratories; each used their own bioinformatics pipelines to calculate TMB and compare to whole exome results.

A Population-Based Study of Genes Previously Implicated in Breast Cancer.

Background: Population-based estimates of the risk of breast cancer associated with germline pathogenic variants in cancer-predisposition genes are critically needed for risk assessment and management in women with inherited pathogenic variants.

Methods: In a population-based case-control study, we performed sequencing using a custom multigene amplicon-based panel to identify germline pathogenic variants in 28 cancer-predisposition genes among 32,247 women with breast cancer (case patients) and 32,544 unaffected women (controls) from population-based studies in the Cancer Risk Estimates Related to Susceptibility (CARRIERS) consortium. Associations between pathogenic variants in each gene and the risk of breast cancer were assessed.

Relationship between Hyperlipidemia, Cardiovascular Disease and Stroke: A Systematic Review.

Background: Globally, dyslipidemia has been shown to be an independent predictor of many cardiovascular and cerebrovascular events, which led to recent advocacy towards dyslipidemia prevention and control as a key risk factor and its prognostic significance to reduce the burden of stroke and myocardial infarction (MI).

Aims: This study aimed to evaluate hyperlipidemia as a risk factor connected with stroke and CVD. Moreover, having identified this risk factor, the study evaluates how hyperlipidemia has been examined earlier and what can be done in the future.

Assessment of the effects of novel insecticides on green peach aphid (Myzus persicae) feeding and transmission of Turnip mosaic virus (TuMV).

Background: Laboratory bioassays using treated leaf disks of peach were conducted to determine the efficacy of nine insecticides against the green peach aphid (GPA), Myzus persicae (Sulzer). The effects of these insecticides on aphid feeding behaviors and rates of transmission of Turnip mosaic virus (TuMV) to potted rutabaga plants were also determined.

Results: Median lethal concentration (LC ) values after 48 h feeding varied considerably, ranging from lows of 1.

Pathogenic Variants in Cancer Predisposition Genes and Prostate Cancer Risk in Men of African Ancestry.

Purpose: In studies of men of European ancestry, rare pathogenic variants in DNA repair pathway genes have been shown to be associated with risk of aggressive prostate cancer. The contribution of rare coding variation to prostate cancer risk in men of African ancestry has not been established.

Methods: We sequenced a panel of 19 DNA repair and cancer predisposition genes in 2,453 African American and 1,151 Ugandan prostate cancer cases and controls.

Relationship between Vitamin D Deficiency, Diabetes, and Obesity.

Aim: This study aimed to assess the prevalence of VDD in Saudi Arabia, revealing the lifestyle and nutritional habits; and assesses the association between VDD, Diabetes Mellitus, and obesity.

Methods: A descriptive, cross-sectional, and correlational design was used in this study. A convenience sampling method of 350 participants participated in the study.

Association Between Inherited Germline Mutations in Cancer Predisposition Genes and Risk of Pancreatic Cancer.

Importance: Individuals genetically predisposed to pancreatic cancer may benefit from early detection. Genes that predispose to pancreatic cancer and the risks of pancreatic cancer associated with mutations in these genes are not well defined.

Objective: To determine whether inherited germline mutations in cancer predisposition genes are associated with increased risks of pancreatic cancer.

Plant growth regulator-mediated anti-herbivore responses of cabbage (Brassica oleracea) against cabbage looper Trichoplusia ni Hübner (Lepidoptera: Noctuidae).

Plant elicitors can be biological or chemical-derived stimulators of jasmonic acid (JA) or salicylic acid (SA) pathways shown to prime the defenses in many crops. Examples of chemical elicitors of the JA and SA pathways include methyl-jasmonate and 1,2,3-benzothiadiazole-7-carbothioate (BTH or the commercial plant activator Actigard 50WG, respectively). The use of specific elicitors has been observed to affect the normal interaction between JA and SA pathways causing one to be upregulated and the other to be suppressed, often, but not always, at the expense of the plant's herbivore or pathogen defenses.

Differential PI3Kδ Signaling in CD4 T-cell Subsets Enables Selective Targeting of T Regulatory Cells to Enhance Cancer Immunotherapy.

To modulate T-cell function for cancer therapy, one challenge is to selectively attenuate regulatory but not conventional CD4 T-cell subsets [regulatory T cell (Treg) and conventional T cell (Tconv)]. In this study, we show how a functional dichotomy in Class IA PI3K isoforms in these two subsets of CD4 T cells can be exploited to target Treg while leaving Tconv intact. Studies employing isoform-specific PI3K inhibitors and a PI3Kδ-deficient mouse strain revealed that PI3Kα and PI3Kβ were functionally redundant with PI3Kδ in Tconv.

A SNP panel for identity and kinship testing using massive parallel sequencing.

Within forensic genetics, there is still a need for supplementary DNA marker typing in order to increase the power to solve cases for both identity testing and complex kinship issues. One major disadvantage with current capillary electrophoresis (CE) methods is the limitation in DNA marker multiplex capability. By utilizing massive parallel sequencing (MPS) technology, this capability can, however, be increased.

Selective inhibition of regulatory T cells by targeting the PI3K-Akt pathway.

Despite the strides that immunotherapy has made in mediating tumor regression, the clinical effects are often transient, and therefore more durable responses are still needed. The temporary nature of the therapy-induced immune response can be attributed to tumor immune evasion mechanisms, mainly the effect of suppressive immune cells and, in particular, regulatory T cells (Treg). Although the depletion of Tregs has been shown to be effective in enhancing immune responses, selective depletion of these suppressive cells without affecting other immune cells has not been very successful, and new agents are sought.

Using templated agarose scaffolds to promote axon regeneration through sites of spinal cord injury.

The past 30 years of research in spinal cord injury (SCI) have revealed that, under certain conditions, some types of axons are able to regenerate. To aid these axons in bridging the lesion site, many experimenters place cellular grafts at the lesion. However, to increase the potential for functional recovery, it is likely advantageous to maximize the number of axons that reach the intact spinal cord on the other side of the lesion.

Motor axonal regeneration after partial and complete spinal cord transection.

We subjected rats to either partial midcervical or complete upper thoracic spinal cord transections and examined whether combinatorial treatments support motor axonal regeneration into and beyond the lesion. Subjects received cAMP injections into brainstem reticular motor neurons to stimulate their endogenous growth state, bone marrow stromal cell grafts in lesion sites to provide permissive matrices for axonal growth, and brain-derived neurotrophic factor gradients beyond the lesion to stimulate distal growth of motor axons. Findings were compared with several control groups.

Anti-PD-1 synergizes with cyclophosphamide to induce potent anti-tumor vaccine effects through novel mechanisms.

Programmed death-1 receptor (PD-1) is expressed on T cells following TCR activation. Binding of this receptor to its cognate ligands, programmed death ligand (PDL)-1 and PDL-2, down-regulates signals by the TCR, promoting T-cell anergy and apoptosis, thus leading to immune suppression. Here, we find that using an anti-PD-1 antibody (CT-011) with Treg-cell depletion by low-dose cyclophosphamide (CPM), combined with a tumor vaccine, induces synergistic antigen-specific immune responses and reveals novel activities of each agent in this combination.

PTEN deletion enhances the regenerative ability of adult corticospinal neurons.

Despite the essential role of the corticospinal tract (CST) in controlling voluntary movements, successful regeneration of large numbers of injured CST axons beyond a spinal cord lesion has never been achieved. We found that PTEN/mTOR are critical for controlling the regenerative capacity of mouse corticospinal neurons. After development, the regrowth potential of CST axons was lost and this was accompanied by a downregulation of mTOR activity in corticospinal neurons.

HPV as a model for the development of prophylactic and therapeutic cancer vaccines.

HPV has been linked to many human malignancies and, as such, represents a major public health crisis. The understanding of HPV biology, however, has helped tremendously in developing prophylactic vaccines, which should help in decreasing mortality due to HPV infections. Understanding HPV biology has allowed researchers to use the virus as a model for the development of not only prophylactic vaccines, but also therapeutic ones.

Matrix metalloproteinase-7 facilitates immune access to the CNS in experimental autoimmune encephalomyelitis.

Background: Metalloproteinase inhibitors can protect mice against experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis (MS). Matrix metalloproteinase-9 (MMP-9) has been implicated, but it is not clear if other MMPs are also involved, including matrilysin/MMP-7 - an enzyme capable of cleaving proteins that are essential for blood brain barrier integrity and immune suppression.

Results: Here we report that MMP-7-deficient (mmp7-/-) mice on the C57Bl/6 background are resistant to EAE induced by myelin oligodendrocyte glycoprotein (MOG).

Electrically evoked locomotor activity in the turtle spinal cord hemi-enlargement preparation.

We assessed the locomotor capacity of the left half of the spinal cord hindlimb enlargement in low-spinal turtles. Forward swimming was evoked in the left hindlimb by electrical stimulation of the right dorsolateral funiculus (DLF) at the anterior end of the third postcervical spinal segment (D3). Animals were held by a band-clamp in a water-filled tank so that hindlimb movements could be recorded from below with a digital video camera.

Location of spinal cord pathways that control hindlimb movement amplitude and interlimb coordination during voluntary swimming in turtles.

We performed mechanical lesions of the midbody (D2-D3; second to third postcervical spinal segments) spinal cord in otherwise intact turtles to locate spinal cord pathways that 1) activate and control the amplitude of voluntary hindlimb swimming movements and 2) coordinate hindlimb swimming with the movement of other limbs. Pre- and postlesion turtles were held by a band clamp around the carapace just beneath the water surface in a clear Plexiglas tank and videotaped from below so that kinematic measurements could be made of voluntary forward swimming with motion analysis software. Movements of the forelimbs (wrists) and hindlimbs (knees and ankles) were tracked relative to stationary reference points on the plastron to obtain bilateral measurements of hip and forelimb angles as functions of time along with foot trajectories.

DR5 receptor mediates anoikis in human colorectal carcinoma cell lines.

As human colorectal cancer (CRC) cells metastasize to distant sites, they are susceptible to detachment-induced cell death or anoikis - a form of apoptosis that occurs when anchorage-dependent CRC cells go into suspension. Our goal was to identify whether tumor necrosis factor receptor apoptosis-inducing ligand (TRAIL) receptors mediate anoikis in human CRC cells. First, we assessed whether caspases of the extrinsic (caspase-8) or intrinsic (caspase-9) death pathways were involved.

Crossed commissural pathways in the spinal hindlimb enlargement are not necessary for right left hindlimb alternation during turtle swimming.

We examined the coordination between right and left hindlimbs during voluntary forward swimming in adult red-eared turtles, before and after midsagittal section of the spinal cord hindlimb enlargement (segments D8-S2) or the enlargement plus the first preenlargement segment (D7-S2). Our purpose was to assess the role of crossed commissural axons in these segments for right-left hindlimb alternation during voluntary locomotion. Midsagittal splitting severed commissural fibers and separated the right and left halves of the posterior spinal cord.

Carcinoembryonic antigen inhibits anoikis in colorectal carcinoma cells by interfering with TRAIL-R2 (DR5) signaling.

Carcinoembryonic antigen (CEA) is a tumor marker that is associated with metastasis, poor response to chemotherapy of colorectal cancer (CRC), and anoikis, a form of apoptosis caused by cell detachment from matrix that is dependent on TRAIL-R2 (DR5) and caspase-8 activation in CRC. Although CEA is a homophilic binding protein that may provide survival signals through homotypical cell aggregation, we now report that CEA binds TRAIL-R2 (DR5) directly in two-hybrid assays to decrease anoikis through the extrinsic pathway. Deletion of the PELPK sequence (delPELPK) of CEA (delPELPK CEA) restores sensitivity to anoikis while it maintains its cell aggregation function.

Carcinoembryonic antigen promotes tumor cell survival in liver through an IL-10-dependent pathway.

Most circulating tumor cells die within 24 h of entering the hepatic microvasculature because their arrest initiates an ischemia-reperfusion (I/R) injury that is cytotoxic. Human colorectal carcinomas (CRC) produce the glycoprotein Carcinoembryonic Antigen (CEA) that increases experimental liver metastasis in nude mice. Since CEA induces release of IL-6 and IL-10, we hypothesized that CEA inhibits the I/R injury through a Kupffer cell-mediated cytokine-dependent pathway.