Retinoblastoma (Rb) is the most common primary intraocular tumor in children. Local treatment of the intraocular disease is usually effective if diagnosed early; however advanced Rb can metastasize ...through routes that involve invasion of the choroid, sclera and optic nerve or more broadly via the ocular vasculature. Metastatic Rb patients have very high mortality rates. While current therapy for Rb is directed toward blocking tumor cell division and tumor growth, there are no specific treatments targeted to block Rb metastasis. Two such targets are matrix metalloproteinases-2 and -9 (MMP-2, -9), which degrade extracellular matrix as a prerequisite for cellular invasion and have been shown to be involved in other types of cancer metastasis. Cancer Clinical Trials with an anti-MMP-9 therapeutic antibody were recently initiated, prompting us to investigate the role of MMP-2, -9 in Rb metastasis.
We compare MMP-2, -9 activity in two well-studied Rb cell lines: Y79, which exhibits high metastatic potential and Weri-1, which has low metastatic potential. The effects of inhibitors of MMP-2 (ARP100) and MMP-9 (AG-L-66085) on migration, angiogenesis, and production of immunomodulatory cytokines were determined in both cell lines using qPCR, and ELISA. Cellular migration and potential for invasion were evaluated by the classic wound-healing assay and a Boyden Chamber assay.
Our results showed that both inhibitors had differential effects on the two cell lines, significantly reducing migration in the metastatic Y79 cell line and greatly affecting the viability of Weri-1 cells. The MMP-9 inhibitor (MMP9I) AG-L-66085, diminished the Y79 angiogenic response. In Weri-1 cells, VEGF was significantly reduced and cell viability was decreased by both MMP-2 and MMP-9 inhibitors. Furthermore, inhibition of MMP-2 significantly reduced secretion of TGF-β1 in both Rb models.
Collectively, our data indicates MMP-2 and MMP-9 drive metastatic pathways, including migration, viability and secretion of angiogenic factors in Rb cells. These two subtypes of matrix metalloproteinases represent new potential candidates for targeted anti-metastatic therapy for Rb.
Depression is a public health problem. Despite the availability of treatment options, its prevalence is increasing. A high rate of treatment failure is often reported, along with considerable side ...effects associated with synthetic antidepressants. Therefore, developing effective and safe antidepressants from traditional herbs or natural products as an alternative strategy is warranted to avoid side effects and increase drug efficacy. In traditional medicine, cardamom has traditionally been used to treat conditions like asthma, tooth and gum infections, cataracts, nausea, diarrhea, and even depression and anxiety as well as some problems with the heart, kidneys, and digestive system.
The current study aimed to evaluate the antidepressant activity of cardamom oil in a rat model of depression induced by reserpine and compare it with the activity of the antidepressant drug fluoxetine.
Depression-like symptoms were induced in male rats by daily i. p. injection of reserpine (0.2 mg/kg/d for 15 d followed by 0.1 mg/kg/d for 21 d to maintain the depressive state), and the rats were treated with cardamom oil (oral dose = 200 mg/kg/d) for 21 d along with the maintenance dose of reserpine. We performed behavioral tests (forced swimming test and open-field test) and evaluated biochemical markers of depression.
Our findings revealed that cardamom oil attenuated depression-like symptoms in reserpine-injected rats by improving the behavioral changes measured by the forced swimming test and the locomotor activities measured by the open-field test. In reserpine-injected rats, cardamom oil exerted antidepressant-like effects by modulating lower levels of brain monoamine neurotransmitters (serotonin, norepinephrine, and dopamine), GSH, and higher oxido-nitrosative stress parameters (malondialdehyde and nitric oxide). Moreover, cardamom oil alleviated depression-like behaviors by lowering monoamine oxidase activity and raising the activities of Na+/K+-ATPase and acetylcholinesterase and levels of a brain-derived neurotrophic factor in the cortex and hippocampus.
We recommend the use of cardamom oil as a safe and reliable treatment or an adjuvant for preventing depression-like symptoms in patients suffering from depression.
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•Depression symptoms were induced in rats by injection of reserpine and the rats were treated with cardamom oil for 21 days.•Cardamom oil attenuates depression-like symptoms in a rat model by improving behavioral changes and locomotor activities.•The antidepressant-like effects of cardamom oil are mediated by increasing levels of 5-HT, NA, and DA.•Cardamom oil reduces MAO activity and increases Na+/K+-ATPase and AChE and BDNF levels in the brain cortex and hippocampus.
Social intelligence (SI) is of great importance in the success of the counseling and psychotherapy, whether for the psychologist or for the artificial intelligence systems that help the psychologist, ...as it is the ability to understand the feelings, emotions, and needs of people during the counseling process. Therefore, this study aims to identify the Social Intelligence (SI) of artificial intelligence represented by its large linguistic models, "ChatGPT; Google Bard; and Bing" compared to psychologists.
A stratified random manner sample of 180 students of counseling psychology from the bachelor's and doctoral stages at King Khalid University was selected, while the large linguistic models included ChatGPT-4, Google Bard, and Bing. They (the psychologists and the AI models) responded to the social intelligence scale.
There were significant differences in SI between psychologists and AI's ChatGPT-4 and Bing. ChatGPT-4 exceeded 100% of all the psychologists, and Bing outperformed 50% of PhD holders and 90% of bachelor's holders. The differences in SI between Google Bard and bachelor students were not significant, whereas the differences with PhDs were significant; Where 90% of PhD holders excel on Google Bird.
We explored the possibility of using human measures on AI entities, especially language models, and the results indicate that the development of AI in understanding emotions and social behavior related to social intelligence is very rapid. AI will help the psychotherapist a great deal in new ways. The psychotherapist needs to be aware of possible areas of further development of AI given their benefits in counseling and psychotherapy. Studies using humanistic and non-humanistic criteria with large linguistic models are needed.
Inhibition of the PI3K/mTOR pathway suppresses breast cancer (BC) growth, enhances anti-tumor immune responses, and works synergistically with immune checkpoint inhibitors (ICI). The objective here ...was to identify a subclass of PI3K inhibitors that, when combined with paclitaxel, is effective in enhancing response to ICI.
C57BL/6 mice were orthotopically implanted with syngeneic luminal/triple-negative-like PyMT cells exhibiting high endogenous PI3K activity. Tumor growth in response to treatment with anti-PD-1 + anti-CTLA-4 (ICI), paclitaxel (PTX), and either the PI3Kα-specific inhibitor alpelisib, the pan-PI3K inhibitor copanlisib, or the broad spectrum PI3K/mTOR inhibitor gedatolisib was evaluated in reference to monotherapy or combinations of these therapies. Effects of these therapeutics on intratumoral immune populations were determined by multicolor FACS.
Treatment with alpelisib + PTX inhibited PyMT tumor growth and increased tumor-infiltrating granulocytes but did not significantly affect the number of tumor-infiltrating CD8
T cells and did not synergize with ICI. Copanlisib + PTX + ICI significantly inhibited PyMT growth and increased activation of intratumoral CD8
T cells as compared to ICI alone, yet did not inhibit tumor growth more than ICI alone. In contrast, gedatolisib + ICI resulted in significantly greater inhibition of tumor growth compared to ICI alone and induced durable dendritic-cell, CD8
T-cell, and NK-cell responses. Adding PTX to this regimen yielded complete regression in 60% of tumors.
PI3K/mTOR inhibition plus PTX heightens response to ICI and may provide a viable therapeutic approach for treatment of metastatic BC.
Inhibitors of cyclin-dependent kinases 4 and 6 (CDK4/6i) delay progression of metastatic breast cancer. However, complete responses are uncommon and tumors eventually relapse. Here, we show that ...CDK4/6i can enhance efficacy of T cell-based therapies, such as adoptive T cell transfer or T cell-activating antibodies anti-OX40/anti-4-1BB, in murine breast cancer models. This effect is driven by the induction of chemokines CCL5, CXCL9, and CXCL10 in CDK4/6i-treated tumor cells facilitating recruitment of activated CD8+ T cells, but not Tregs, into the tumor. Mechanistically, chemokine induction is associated with metabolic stress that CDK4/6i treatment induces in breast cancer cells. Despite the cell cycle arrest, CDK4/6i-treated cells retain high metabolic activity driven by deregulated PI3K/mTOR pathway. This causes cell hypertrophy and increases mitochondrial content/activity associated with oxidative stress and inflammatory stress response. Our findings uncover a link between tumor metabolic vulnerabilities and anti-tumor immunity and support further development of CDK4/6i and immunotherapy combinations.
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•Breast cancer cells treated with CDK4/6 inhibitor secrete chemokines CCL5 and CXCL10•Chemokine induction is associated with deregulated mTOR, metabolic stress, and ROS•Chemokines induced by CDK4/6 inhibitor facilitate T cell infiltration into tumors•Chemokines induced by CDK4/6 inhibitor augment adoptive T cell therapy
Inhibitors of cell cycle kinases CDK4/6 delay progression of metastatic breast cancer; however, they do not eliminate tumors. Uzhachenko et al. report that metabolic changes in CDK4/6 inhibitor-treated cancer cells make them vulnerable to T cell therapies. These data highlight potential utility of CDK4/6 inhibitors to overcome immunotherapy resistance.
While immune checkpoint blockade (ICB) is the current first-line treatment for metastatic melanoma, it is effective for ~ 52% of patients and has dangerous side effects. The objective here was to ...identify the feasibility and mechanism of RAS/RAF/PI3K pathway inhibition in melanoma to sensitize tumors to ICB therapy.
Rigosertib (RGS) is a non-ATP-competitive small molecule RAS mimetic. RGS monotherapy or in combination therapy with ICB were investigated using immunocompetent mouse models of BRAF
and BRAF
melanoma and analyzed in reference to patient data.
RGS treatment (300 mg/kg) was well tolerated in mice and resulted in ~ 50% inhibition of tumor growth as monotherapy and ~ 70% inhibition in combination with αPD1 + αCTLA4. RGS-induced tumor growth inhibition depends on CD40 upregulation in melanoma cells followed by immunogenic cell death, leading to enriched dendritic cells and activated T cells in the tumor microenvironment. The RGS-initiated tumor suppression was partially reversed by either knockdown of CD40 expression in melanoma cells or depletion of CD8
cytotoxic T cells. Treatment with either dabrafenib and trametinib or with RGS, increased CD40
SOX10
melanoma cells in the tumors of melanoma patients and patient-derived xenografts. High CD40 expression level correlates with beneficial T-cell responses and better survival in a TCGA dataset from melanoma patients. Expression of CD40 by melanoma cells is associated with therapeutic response to RAF/MEK inhibition and ICB.
Our data support the therapeutic use of RGS + αPD1 + αCTLA4 in RAS/RAF/PI3K pathway-activated melanomas and point to the need for clinical trials of RGS + ICB for melanoma patients who do not respond to ICB alone.
NCT01205815 (Sept 17, 2010).
Current methodologies for developing PDX in humanized mice in preclinical trials with immune-based therapies are limited by GVHD. Here, we compared two approaches for establishing PDX tumors in ...humanized mice: (1) PDX are first established in immune-deficient mice; or (2) PDX are initially established in humanized mice; then established PDX are transplanted to a larger cohort of humanized mice for preclinical trials. With the first approach, there was rapid wasting of PDX-bearing humanized mice with high levels of activated T cells in the circulation and organs, indicating immune-mediated toxicity. In contrast, with the second approach, toxicity was less of an issue and long-term human melanoma tumor growth and maintenance of human chimerism was achieved. Preclinical trials from the second approach revealed that rigosertib, but not anti-PD-1, increased CD8/CD4 T cell ratios in spleen and blood and inhibited PDX tumor growth. Resistance to anti-PD-1 was associated with PDX tumors established from tumors with limited CD8+ T cell content. Our findings suggest that it is essential to carefully manage immune editing by first establishing PDX tumors in humanized mice before expanding PDX tumors into a larger cohort of humanized mice to evaluate therapy response.
BackgroundCyclin-dependent kinase 4/6 inhibitors (CDK4/6i) combined with endocrine therapy are a mainstay treatment for hormone receptor-positive breast cancer. While their principal mechanism is ...inhibition of cancer cell proliferation, preclinical and clinical evidence suggests that CDK4/6i can also promote antitumor T-cell responses. However, this pro-immunogenic property is yet to be successfully harnessed in the clinic, as combining CDK4/6i with immune checkpoint blockade (ICB) has not shown a definitive benefit in patients.MethodWe performed an in-depth analysis of the changes in the tumor immune microenvironment and systemic immune modulation associated with CDK4/6i treatment in muring breast cancer models and in patients with breast cancer using high dimensional flow cytometry and RNA sequencing. Gain and loss of function in vivo experiments employing cell transfer and depletion antibody were performed to uncover immune cell populations critical for CDK4/6i-mediated stimulation of antitumor immunity.ResultsWe found that loss of dendritic cells (DCs) within the tumor microenvironment resulting from CDK4/6 inhibition in bone marrow progenitors is a major factor limiting antitumor immunity after CDK4/6i and ICB. Consequently, restoration of DC compartment by adoptively transferring ex vivo differentiated DCs to mice treated with CDK4/6i and ICB therapy enabled robust tumor inhibition. Mechanistically, the addition of DCs promoted the induction of tumor-localized and systemic CD4 T-cell responses in mice receiving CDK4/6i-ICB-DC combination therapy, as characterized by enrichment of programmed cell death protein-1-negative T helper (Th)1 and Th2 cells with an activated phenotype. CD4 T-cell depletion abrogated the antitumor benefit of CDK4/6i-ICB-DC combination, with outgrowing tumors displaying an increased proportion of terminally exhausted CD8 T cells.ConclusionsOur findings suggest that CDK4/6i-mediated DC suppression limits CD4 T-cell responses essential for the sustained activity of CD8 T cells and tumor inhibition. Furthermore, they imply that restoring DC-CD4 T-cell crosstalk via DC transfer enables effective breast cancer immunity in response to CDK4/6i and ICB treatment.
Objective:
Lebanon has historically maintained high immunization coverage rates for most routine vaccines. However, an increase in poverty rates coupled with an influx of over a million refugees ...posed significant challenges to the national immunization program. In response, an accelerated immunization activities (AIA) program, encompassing community-based outreach and referral activities, was launched to increase the demand for childhood vaccination through the public healthcare system. Despite this effort, uptake among refugee and host community households remained low, resulting in pockets of low immunization coverage rates. This study investigates the barriers that prevent households in low coverage areas from vaccinating their children, and evaluates a behavior change intervention designed to overcome the identified social, perceptual, and cognitive barriers.
Methods:
Households with un- or under-vaccinated children were recruited from seven cadastres with low immunization coverage rates. A mixed methods approach, including stakeholder interviews and field observations, was employed to identify the main barriers to vaccination. Thereafter, a cluster randomized trial was conducted to evaluate the impact of a visual planning aid comprising five behavior change techniques (nudges) on vaccine uptake.
Results:
A total of 12,332 un- or under-vaccinated children from 6160 households (3045 (49.4%) control households; 3115 (50.6%) treated households) were reached during the trial. The observed vaccination rates were 13.5% and 20.2% for control and treated households, respectively. This represents a 6.7 percentage points increase in the likelihood of a treated household to vaccinate at least one child, compared to the control group. At least 390 additional children benefited from life-saving vaccines due to the behavioral intervention.
Conclusions:
This study highlights the importance of integrating behavioral insights into vaccination campaigns and programs, especially in low resource settings, to ensure that more children can benefit from life-saving vaccines.
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