Immunotherapy-activated T cells recruit and skew late-stage activated M1-like macrophages that are critical for therapeutic efficacy.

Total tumor clearance through immunotherapy is associated with a fully coordinated innate and adaptive immune response, but knowledge on the exact contribution of each immune cell subset is limited. We show that therapy-induced intratumoral CD8 T cells recruited and skewed late-stage activated M1-like macrophages, which were critical for effective tumor control in two different murine models of cancer immunotherapy. The activated CD8 T cells summon these macrophages into the tumor and their close vicinity via CCR5 signaling.

Neutralizing Antibodies Impair the Oncolytic Efficacy of Reovirus but Permit Effective Combination with T cell-Based Immunotherapies.

Reovirus type 3 Dearing (Reo), manufactured for clinical application as pelareorep, is an attractive anticancer agent under evaluation in multiple phase 2 clinical trials for the treatment of solid tumors. It elicits its anticancer efficacy by inducing both oncolysis and intratumoral T-cell influx. Because most people have been preexposed to Reo, neutralizing antibodies (NAb) are prevalent in patients with cancer and might present a barrier to effective Reo therapy.

Invasive margin tissue-resident macrophages of high CD163 expression impede responses to T cell-based immunotherapy.

Background: Primary and secondary resistance is a major hurdle in cancer immunotherapy. Therefore, a better understanding of the underlying mechanisms involved in immunotherapy resistance is of pivotal importance to improve therapy outcome.

Method: Here, two mouse models with resistance against therapeutic vaccine-induced tumor regression were studied.

Intertumoral Differences Dictate the Outcome of TGF-β Blockade on the Efficacy of Viro-Immunotherapy.

Unlabelled: The absence of T cells in the tumor microenvironment of solid tumors is a major barrier to cancer immunotherapy efficacy. Oncolytic viruses, including reovirus type 3 Dearing (Reo), can recruit CD8 T cells to the tumor and thereby enhance the efficacy of immunotherapeutic strategies that depend on high T-cell density, such as CD3-bispecific antibody (bsAb) therapy. TGF-β signaling might represent another barrier to effective Reo&CD3-bsAb therapy due to its immunoinhibitory characteristics.

Preinduced reovirus-specific T-cell immunity enhances the anticancer efficacy of reovirus therapy.

Background: Many solid tumors do not respond to immunotherapy due to their immunologically cold tumor microenvironment (TME). We and others found that oncolytic viruses (OVs), including reovirus type 3 Dearing, can enhance the efficacy of immunotherapy by recruiting CD8 T cells to the TME. A significant part of the incoming CD8 T cells is directed toward reovirus itself, which may be detrimental to the efficacy of OVs.

Impact and benefit-cost ratio of a program for the management of latent tuberculosis infection among refugees in a region of Canada.

Introduction: The identification and treatment of latent tuberculosis infection (LTBI) among immigrants from high-incidence regions who move to low-incidence countries is generally considered an ineffective strategy because only ≈14% of them comply with the multiple steps of the 'cascade of care' and complete treatment. In the Estrie region of Canada, a refugee clinic was opened in 2009. One of its goals is LTBI management.

IL-6 signaling in macrophages is required for immunotherapy-driven regression of tumors.

Background: High serum interleukin (IL-6) levels may cause resistance to immunotherapy by modulation of myeloid cells in the tumor microenvironment. IL-6 signaling blockade is tested in cancer, but as this inflammatory cytokine has pleiotropic effects, this treatment is not always effective.

Methods: IL-6 and IL-6R blockade was applied in an IL-6-mediated immunotherapy-resistant TC-1 tumor model (TC-1.

Interleukin-6-mediated resistance to immunotherapy is linked to impaired myeloid cell function.

High serum levels of interleukin-6 (IL-6) correlate with poor prognosis and chemotherapy resistance in several cancers. The underlying mechanisms and its effects on immunotherapy are largely unknown. To address this, we developed a human papillomavirus type 16 (HPV16)-associated tumor model expressing IL-6 to investigate the impact of tumor-expressed IL-6 during cisplatin chemotherapy and HPV16 synthetic long peptide vaccination as immunotherapy.

Lack of myeloid cell infiltration as an acquired resistance strategy to immunotherapy.

Background: Immunotherapy of cancer is successful but tumor regression often is incomplete and followed by escape. Understanding the mechanisms underlying this acquired resistance will aid the development of more effective treatments.

Methods: We exploited a mouse model where tumor-specific therapeutic vaccination results in tumor regression, followed by local recurrence and resistance.

Modulation of the Tomato Fruit Metabolome by LED Light.

Metabolic profiles of tomatoes change during ripening and light can modulate the activity of relevant biochemical pathways. We investigated the effects of light directly supplied to the fruits on the metabolome of the fruit pericarp during ripening. Mature green tomatoes were exposed to well-controlled conditions with light as the only varying factor; control fruits were kept in darkness.

The genetic and functional analysis of flavor in commercial tomato: the FLORAL4 gene underlies a QTL for floral aroma volatiles in tomato fruit.

Tomato (Solanum lycopersicum L.) has become a popular model for genetic studies of fruit flavor in the last two decades. In this article we present a study of tomato fruit flavor, including an analysis of the genetic, metabolic and sensorial variation of a collection of contemporary commercial glasshouse tomato cultivars, followed by a validation of the associations found by quantitative trait locus (QTL) analysis of representative biparental segregating populations.

Light-Induced Vitamin C Accumulation in Tomato Fruits is Independent of Carbohydrate Availability.

L-ascorbate (ASC) is essential for human health. Therefore, there is interest in increasing the ASC content of crops like tomato. High irradiance induces accumulation of ASC in green tomato fruits.

Regulatory oversight of human pathogens and toxins in Canada.

From 1994 to 2009, federal oversight of human pathogens and toxins was limited to facilities importing human pathogens and toxins into Canada under the (HPIR). This narrow focus of authority restricted the Government of Canada's ability to regulate and monitor a full range of activities, including those involving human pathogens and toxins acquired from domestic sources. In 2009, the (the Act) received Royal Assent to establish a national safety and security regime and expand oversight through a national, standardized process to verify safe and secure use of human pathogens and toxins in Canada.

Prasterone has parallel beneficial effects on the main symptoms of vulvovaginal atrophy: 52-week open-label study.

Objective: An objective was to analyze the time course of efficacy of daily intravaginal administration of 0.5% (6.5mg) DHEA (prasterone) for 52 weeks on the moderate to severe (MS) symptoms and signs of vulvovaginal atrophy (VVA).

Treatment of pain at sexual activity (dyspareunia) with intravaginal dehydroepiandrosterone (prasterone).

Objective: This study aims to confirm the local effects of intravaginal prasterone on moderate to severe dyspareunia, a symptom of vulvovaginal atrophy (VVA) associated with menopause.

Methods: In a prospective, randomized, double-blind, placebo-controlled phase III clinical trial, we examined the effects of daily intravaginal prasterone (6.5 mg) on four co-primary objectives, namely, percentage of vaginal parabasal cells, percentage of vaginal superficial cells, vaginal pH, and moderate to severe dyspareunia identified by women as the most bothersome VVA symptom.

Decreased efficacy of twice-weekly intravaginal dehydroepiandrosterone on vulvovaginal atrophy.

Objective: While daily intravaginal administration of 0.50% (6.5 mg) dehydroepiandrosterone (DHEA, prasterone) for 12 weeks has shown clinically and statistically significant effects on moderate to severe (MS) dyspareunia as the most bothersome symptom (MBS), the present study analyzes the effect of a reduced dosing regimen on MBS vaginal dryness.

Lack of influence of dyspareunia on the beneficial effect of intravaginal prasterone (dehydroepiandrosterone, DHEA) on sexual dysfunction in postmenopausal women.

Introduction: We have previously observed that intravaginal prasterone (dehydroepiandrosterone, DHEA) improved all domains of female sexual dysfunction (FSD).

Aim: Investigate the influence of moderate/severe pain at sexual activity (dyspareunia) (MSD) at baseline on FSD following prasterone administration.

Methods: The effect of daily administration of prasterone (0, 3.

The co-chaperone DNAJC12 binds to Hsc70 and is upregulated by endoplasmic reticulum stress.

Human DNAJC12 is a J domain-containing protein whose regulation, subcellular localization, and function are currently unknown. We show here that the abundance of DNAJC12 in human LNCaP prostate cancer cells is upregulated by the stress-inducing drug A23187 and by the stressregulated transcription factor AIbZIP/CREB3L4. The DNAJC12 gene encodes two isoforms, only one of which (isoform a) is expressed in these cells.

Non-smoky glycosyltransferase1 prevents the release of smoky aroma from tomato fruit.

Phenylpropanoid volatiles are responsible for the key tomato fruit (Solanum lycopersicum) aroma attribute termed "smoky." Release of these volatiles from their glycosylated precursors, rather than their biosynthesis, is the major determinant of smoky aroma in cultivated tomato. using a combinatorial omics approach, we identified the non-smoky glycosyltransferase1 (NSGT1) gene.

Intravaginal prasterone (DHEA) provides local action without clinically significant changes in serum concentrations of estrogens or androgens.

In order to avoid the risks of non-physiological systemic exposure, serum concentrations of estradiol (E2) and testosterone (as measured by mass spectrometry-based assays) should remain below the 95th centiles measured at 9.3pg/ml and 0.26ng/ml for these respective sex steroids in normal postmenopausal women.

DHEA and intracrinology at menopause, a positive choice for evolution of the human species.

Menopause has been chosen by evolution as the convergence of three factors, namely cessation of ovarian function (reproduction and estrogen secretion), high circulating dehydroepiandrosterone (DHEA), and intracrine enzymes able to convert DHEA into active sex steroids in peripheral tissues. The arrest of estrogen secretion by the ovaries at menopause causes a decrease of circulating estradiol below the threshold of biological activity, thus eliminating stimulation of the endometrium and risk of endometrial cancer. As much as the arrest of secretion of estradiol by the ovaries is essential to protect the uterus, it is of major importance that sex steroids continue to be made available in most other tissues which need estrogens and/or androgens for their normal functioning.

Intravaginal dehydroepiandrosterone (prasterone), a highly efficient treatment of dyspareunia.

Objective: To examine the effect of intravaginal dehydroepiandrosterone (DHEA) on pain at sexual activity (dyspareunia) identified as the most bothersome symptom of vaginal atrophy in postmenopausal women at both screening and day 1.

Methods: This prospective, randomized, double-blind and placebo-controlled phase III clinical trial studied the effect of prasterone (DHEA) applied locally in the vagina on the severity of dyspareunia in 114 postmenopausal women who had identified dyspareunia as their most bothersome symptom of vaginal atrophy, while meeting the criteria for superficial cells ≤ 5% and pH > 5.0 at both screening and day 1.

High internal consistency and efficacy of intravaginal DHEA for vaginal atrophy.

Following the compelling data obtained in a pivotal phase III clinical trial performed in 218 postmenopausal women suffering from vaginal atrophy who received daily intravaginal 0.25, 0.5 or 1.

Serum steroid levels during 12-week intravaginal dehydroepiandrosterone administration.

Objective: Because a previous 1-week study has shown no or minimal changes in the serum levels of dehydroepiandrosterone (DHEA) and its metabolites after up to daily 1.8% (23.4 mg) intravaginal DHEA, the objective of the present study was to investigate the serum steroid levels during a 12-week daily intravaginal administration of 0%, 0.