Low-dose all-trans retinoic acid enhances cytotoxicity of cisplatin and 5-fluorouracil on CD44+ cancer stem cells

Cis-diamminedichloridoplatinum(II)(CDDP)-based combination chemotherapy is frequently used in gastrointestinal cancer. The synergistic mechanism of all-trans retinoic acid (ATRA), cisplatin (CDDP) and 5-fluorouracil (5-FU) in combination remains unclear. Despite their potent antitumor properties, resistance to CDDP and 5-FU develops frequently in tumors. To clarify this mechanism, we determined the sensitivity to each drug and their combination in two gastrointestinal cancer stem cells (CSCs) subpopulation.Here, we report the identification and separation of CD44⁺ cells from human gastric carcinoma (AGS) and human esophageal squamous cell carcinoma (KYSE-30) cancer cell lines by magnetic activated cell sorting (MACS). We allowed the CD44^± cells to grow 6 days at a subtoxic concentration of ATRA and then treated with different concentration of CDDP and 5-FU for 24 h. The cytotoxicity was examined by cell proliferation MTT assay. Additionally, AO/EB staining was used for detection of apoptotic cells. In order to determine whether the growth inhibition was also associated with changes in cell cycle distribution, cell cycle analysis was performed using flow cytometry.Low concentration of ATRA (1 μM, 6days) followed by 5-FU and CDDP was found to be more effective than either drugs alone, thus resulting in synergistic cytotoxicity in Kyse-30 and AGSCD44^± cells. Furthermore, there was an indication that the combination of ATRA with 5FU and CDDP caused an increase in cell cycle arrest in G2/M and G0/G1.We conclude that low concentration of ATRA enhances the cytotoxicity of CDDP and 5FU by facilitating apoptosis and cell cycle arrest in gastrointestinal CSCs and provide a rational basis for the design of novel, well-tolerated CDDP- and 5FU-based chemotherapy in human gastrointestinal carcinoma.     

A DNA vaccine expressing an optimized secreted FAPα induces enhanced anti-tumor activity by altering the tumor microenvironment in a murine model of breast cancer

Cancer-associated fibroblasts (CAFs), major components of the tumor microenvironment (TME), promote tumor growth and metastasis and inhibit the anti-tumor immune response. We previously constructed a DNA vaccine expressing human FAPα, which is highly expressed by CAFs, to target these cells in the TME, and observed limited anti-tumor effects in the 4T1 breast cancer model. When the treatment time was delayed until tumor nodes formed, the anti-tumor effect of the vaccine completely disappeared. In this study, to improve the safety and efficacy, we constructed a new FAPα-targeted vaccine containing only the extracellular domain of human FAPα with a tissue plasminogen activator signal sequence for enhanced antigen secretion and immunogenicity. The number of CAFs was more effectively reduced by CD8⁺ T cells induced by the new vaccine. This resulted in decreases in CCL2 and CXCL12 expression, leading to a significant decrease in the ratio of myeloid-derived suppressor cells in the TME. Moreover, when mice were treated after the establishment of tumors, the vaccine could still delay tumor growth. To facilitate the future application of the vaccine in clinical trials, we further optimized the gene codons and reduced the homology between the vaccine and the original sequence, which may be convenient for evaluating the vaccine distribution in the human body. These results indicated that the new FAPα-targeted vaccine expressing an optimized secreted human FAPα induced enhanced anti-tumor activity by reducing the number of FAPα⁺ CAFs and enhancing the recruitment of effector T cells in the 4T1 tumor model mice.     

Age-related variations in gene expression patterns of renal cell carcinoma

Background

Clear cell renal cell carcinoma (ccRCC) is known to occur across the adult lifetime traversing the spectrum of age-related organismal changes. Little is known as to how the aging process may affect the course of renal cell carcinoma (RCC) and the repertoire of genes involved.

Le syndrome de Lazare: une problématique de la rémission. Réflexions autour de la maladie cancéreuse chez l’adulte

Résumé: La rémission du cancer peut être l’occasion pour certains patients d’une réelle détresse émotionnelle ainsi que d’une désadaptation psychologique appelées: syndrome de Lazare. Nous émettons trois hypothèses explicatives quant à la survenue de tels troubles. La première confronte l’issue du cancer aux concepts psychanalytiques de dette et de masochisme. La deuxième envisage les symptômes sous l’angle d’une réaction de sevrage. Et la dernière évoque le contrecoup traumatique des traitements.Dossier: «Cliniques du cancer»     

妇女叶酸增补中需要关注的问题

妇女围孕期增补叶酸能够有效预防神经管缺陷等疾病的发生。随着对叶酸研究的不断深入，叶酸补充中出现了诸多问题。本文简要综述了叶酸在服用方式以及基础和临床研究中出现的值得讨论、已经引起关注和需要进一步研究探讨的问题，并提出了深入研究叶酸可能的发展趋势。     

Amisulpride in the short-term treatment of depressive and physical symptoms in cancer patients during chemotherapies

Introduction Amisulpride is a substituted benzamide that, at low doses, selectively blocks D2 and D3 presynaptic dopamine receptors, enhancing dopaminergic transmission in frontal cortex and limbic areas. Many clinical studies versus placebo, tricyclic antidepressants and selective serotonin reuptake inhibitors showed amisulpride antidepressant effect, supporting its safety and rapid onset of action. In oncological population, depression is quite frequent and difficult to treat because of the particular sensitivity of cancer patients to the antidepressants’ side effects. Goals of work The aims of this study were to evaluate efficacy, safety and tolerability of low doses of amisulpride (50 mg) in oncological, depressed patients during chemotheraphy. Materials and methods One hundred six consecutive cancer outpatients with depressive symptoms were treated in a prospective, intention to treat, 4-week study, and were evaluated in single-blind with Montgomery Asberg rating scale for depression (MADRS), clinical global impression (CGI) and dosage record treatment emergent symptom scale (DOTES) to assess side effects of treatment. Main results After 4 weeks of treatment, scores of MADRS and CGI significantly improved (p < 0.002; p < 0.001, respectively), with a reduction of depressive symptoms concerning both emotional (such as apparent sadness, reported sadness, inner tension, etc.) and physical cluster (such as lack of appetite, reduction in weight, tiredness and insomnia) with good tolerability (only two patients dropped out). Conclusions This study is the first trial on the use of amisulpride in a cohort of oncological, depressed patients during chemotherapy. Amisulpride demonstrated high efficacy and safety. Controlled studies are needed to confirm these preliminary data.     

Short term correlates of the Neuro Emotional Technique for cancer-related traumatic stress symptoms: A pilot case series

Introduction As many as one quarter of all cancer survivors report traumatic stress symptoms from cancer-related experiences. While the majority of these patients do not meet the criteria for posttraumatic stress disorder (PTSD), there is growing evidence that subsyndromal symptoms can significantly contribute to functional impairment and negative health outcomes. Treatment options for the hallmark symptoms of traumatic stress—unpleasant, intrusive thoughts and avoidant behaviors—have not been well investigated for the cancer survivorship population. Materials and methods Seven female cancer survivors with traumatic stress symptoms from cancer-related experiences and no other major psychopathology, were enrolled to receive three sessions of Neuro-Emotional Technique (NET), a brief, targeted treatment that combines traditional desensitization principles with complementary modalities. Results Psychological outcome measures (Impact of Event Scale (IES) and Subjective Units of Distress (SUD) and physiological measures (Heart Rate (HR) and Skin Conductance Level (SCL) demonstrated the following changes: 71% on IES, 88% SUD, 74% on HR, and 65% on SCL following the intervention. Statistically significant changes were observed for all four parameters, and effect size g for proportion improved were 0.50 each for IES, SUD, and HR, and 0.20 for SCL. Conclusions These cases suggest feasibility of the NET intervention for cancer-related traumatic stress and the potential for change in symptoms and physiological reactivity. Further investigation is needed to determine the specific and long-term effects of such an approach. Implications for cancer survivors Traumatic stress from cancer-related experiences might represent a constellation of symptoms that are amenable to brief, targeted interventions. This study was supported by the O.N.E. Research Foundation     

Identifying patients at risk for,and treatment of major psychiatric complications of cancer

A critically important aspect of supportive care in cancer is the prompt recognition and effective treatment of psychiatric complications. Psychiatric disorders such as depression, anxiety and delirium occur in a signifcant percentage of cancer patients, particularly as disease advances and as cancer treatments become more aggressive. This paper reviews factors that can be utilized to identify patients who are at increased risk for developing psychiatric complications, such as those with advanced disease, certain cancer treatments, uncontrolled physical symptoms, functional limitations, lack of social support, and past history of psychiatric disorder. Methods of diagnostic assessment and strategies for managing depression, anxiety, delirium and suicidal ideation are also reviewed.Presented as an invited lecture at the 6th International Symposium: Supportive Care in Cancer, New Orleans, La., USA, 2–5 March 1994