Programmable and multi-targeted CARs: a new breakthrough in cancer CAR-T cell therapy

CAR-T cell therapy, as a novel immunotherapy approach, has indicated successful results in the treatment of hematological malignancies; however, distinct results have been achieved regarding solid tumors. Tumor immunosuppressive microenvironment has been identified as the most critical barrier in CAR-T cell therapy of solid tumors. Developing novel strategies to augment the safety and efficacy of CAR-T cells could be useful to overcome the solid tumor hurdles. Similar to other cancer treatments, CAR-T cell therapy can cause some side effects, which can disturb the healthy tissues. In the current review, we will discuss the practical breakthroughs in CAR-T cell therapy using the multi-targeted and programmable CARs instead of conventional types. These superior types of CAR-T cells have been developed to increase the function and safety of T cells in a controllable manner, which would diminish the incidence of relevant side effects. Moreover, we will describe the capability of these powerful CARs in targeting multiple tumor antigens, redirecting the CAR-T cells to specific target cells, incrementing the safety of CARs, and other advantages that lead to promising outcomes in cancer CAR-T cell therapy (AU)

Programmable and multi-targeted CARs: a new breakthrough in cancer CAR-T cell therapy.

CAR-T cell therapy, as a novel immunotherapy approach, has indicated successful results in the treatment of hematological malignancies; however, distinct results have been achieved regarding solid tumors. Tumor immunosuppressive microenvironment has been identified as the most critical barrier in CAR-T cell therapy of solid tumors. Developing novel strategies to augment the safety and efficacy of CAR-T cells could be useful to overcome the solid tumor hurdles. Similar to other cancer treatments, CAR-T cell therapy can cause some side effects, which can disturb the healthy tissues. In the current review, we will discuss the practical breakthroughs in CAR-T cell therapy using the multi-targeted and programmable CARs instead of conventional types. These superior types of CAR-T cells have been developed to increase the function and safety of T cells in a controllable manner, which would diminish the incidence of relevant side effects. Moreover, we will describe the capability of these powerful CARs in targeting multiple tumor antigens, redirecting the CAR-T cells to specific target cells, incrementing the safety of CARs, and other advantages that lead to promising outcomes in cancer CAR-T cell therapy.

Effects of Nigella sativa on heat-induced testis damage in mouse.

BACKGROUND: Infertility is one of the major health problems. OBJECTIVES: The aim of this study was to evaluate the effects of Nigella sativa on heat-induced testicular damage. METHODS: Forty male mice were randomly divided into the four equal groups as Control, Heat stressed and, Heated and treated with Nigella sativa 10 % and 20 % in diet. The scrotum of mice except to the control mice were immersed for 15 min in a water bath at 43 °C. Animals in the control group were treated identically except that the water bath was maintained at 23 °C. Fifty days after the heating, blood samples were collected for testosterone levels. Testes were removed for the measurement of seminiferous tubules diameter and percentage of spermatogenesis and oxidant/antioxidant status. RESULTS: Heating stress significantly reduced blood testosterone level and increased lipid peroxidation product and decreased antioxidant activities of superoxide dismutase, catalase and glutathione peroxidase (p < 0.01). Nigella sativa treatment significantly increased blood testosterone level and decreased testis malondialdehyde level and increased antioxidant enzymes activities (p < 0.05). In the mice treated with Nigella sativa, testes illustrated normal spermatogenesis and structure. CONCLUSION: The results indicated that supplementation of Nigella sativa in diet improves spermatogenesis and antioxidant status after a short exposure of the mouse testis to heat (Tab. 1, Fig. 4, Ref. 45).

Selective quantification of cardiac sympathetic and parasympathetic nervous function from non-invasive measurements.

Power spectral analysis of spontaneous heart rate (HR) variability is a popular and convenient technique for quantifying cardiac autonomic nervous function. While this technique can provide an effective index of parasympathetic nervous function, it cannot provide a pure index of A -sympathetic nervous function. We have developed a non-invasive technique for selectively quantifying cardiac sympathetic and parasympathetic nervous function by employing a multi-signal approach in conjunction with prior physiologic knowledge. We have tested the technique in 14 human subjects under pharmacological autonomic blockade, and our results show that the technique can substantially outperform traditional HR power spectral indices in terms of predicting the known drug effects.

Results of a phase II concurrent chemoradiotherapy study using three-dimensional conformal radiotherapy with cisplatin and oral etoposide in stage III nonsmall-cell lung cancer.

This phase II study was designed to utilize conformal radiation therapy with cisplatin and oral etoposide in patients with stage III or locally recurrent non-small-cell lung cancer to determine tolerance and toxicity of therapy. From April 1992-February 1996, 18 patients with pathologically confirmed stage IIIA, IIIB, or locally recurrent non-small-cell lung cancer (NSCLC) were entered on study. Metastatic workup included a CT scan of the thorax and upper abdomen as well as a bone scan. Chemotherapy consisted of IV cisplatin (100 mg/m2) with IV etoposide (25 mg/m2) on day 1; oral etoposide was given (50 mg/m2) days 2-14. Using three-dimensional planning, 40-45 Gy were delivered to the clinical target volume, followed by a boost to the gross tumor volume for a total of 70 Gy. Patients with recurrent disease received 40-50 Gy in total. Eighteen patients were enrolled: 16 patients were treated with curative intent and were evaluable for outcome. Two patients were treated for locally recurrent NSCLC and were not included in the outcome analysis. Stages included IIIA (44%) and stage IIIB (54%). Forty-four percent had T3/4 tumors, and 69% had N2/3 disease. Overall survival at 1 year was 64%, while 2-year overall survival was 50%. Distant metastasis-free survival at 1 year was 67%, and at 2 years 60%. The 1-year chest progression-free survival was 57%, and at 2 years 50%. Sixty-three percent required hospitalization for dehydration or neutropenia. Fifty-six percent developed leukopenia (<1,000 cells/microl) sometime during the therapy. We conclude that concurrent cisplatin and oral etoposide with conformal radiation therapy provide encouraging results in stage III lung cancer. The major toxicities of this therapy included leukopenia, thrombocytopenia, and mucosal esophagitis. Local progression of disease continues to be a problem with the current doses given. Future studies should evaluate dose escalation of radiation therapy with limited volumes, utilizing conformal radiation and chemotherapy to improve local control and potentially impact upon distant metastases.

Alterations in GABAA receptor binding in the prefrontal cortex following exposure to chronic stress.

The present study was designed to examine the effects of chronic stress on GABAA receptor binding. Animals were randomly assigned to either a control, acute, or chronic stress condition and changes in specific binding were assessed using the GABAA receptor antagonist [3H]SR 95531. Exposure to chronic restraint stress led to a significant reduction in GABAA receptor binding in the prefrontal cortex. Alterations in specific binding were not observed in the cerebellum, caudate-putamen, hippocampus, or cingulate cortex however, suggesting that the effects of chronic stress may be regionally specific. Exposure to acute restraint did not lead to a significant alteration in [3H]SR 95531 binding in any brain region examined.

GABA receptor binding site "induction" in rabbit retina after nipecotic acid treatment: changes during postnatal development.

The development of the GABA system in the rabbit retina was studied. The number of high- and low-affinity GABA receptor binding sites increased in a sigmoidal manner, with the curve for the low-affinity sites lagging 2-3 days behind that for the high-affinity sites. The KD for both high- (17.5 nM) and low-affinity (138.0 nM) sites remained constant during development. Treatment of isolated eyecups with the uptake blocker nipecotic acid resulted in an increase in the Bmax for high-affinity sites in developing tissue with the maximum sensitivity around eye opening; mature tissue exhibited a decrease in Bmax. In contrast, a gradual decrease in sensitivity to stimulation of the low-affinity sites occurred. These data indicate that the "trophic" action of GABA is limited to the time when the tissue is developing.

Maximal GABA and muscimol binding to high-affinity sites differ in physiological and in non-physiological buffers.

The sensitivity of [(3)H]GABA and [(3)H]muscimol high-affinity binding sites to physiological (Krebs-Ringer's bicarbonate) and non-physiological (Tris-citrate) buffers was examined using synaptosomal membranes from bovine retinas. The maximum number of sites (B(max)) for [(3)H]GABA was present when the tissue was assayed in KRB. With only one exception, this effect was independent of the washing conditions used or a small change in pH. In contrast, [(3)H]muscimol binding sites were maximally present when the tissue was washed in Tris, regardless of the assaying conditions or the small change in pH. Neither [(3)H]GABA nor [(3)H]muscimol was displaced by ( - )baclofen. The apparent dissociation constants (K(d)) of the ligands did not change under any of the conditions tested. These findings demonstrate a fundamental difference between GABA and muscimol binding sites.

Clinical trial of levamisole in the treatment of ascariasis in Khorasan, Iran.

This paper identifies the parasitic infections and their incidence in 246 people aged between 10--20 years living in a semi-rural Iranian village. 64 patients with ascariasis were treated with levamisole ('Ketrax' ICI) in accordance with the manufacturer's instructions. Most were followed up 1 and 2 weeks after treatment, with cure rate of 97.7% and 98.4% respectively, as assessed by negative egg findings in faeces. No side effects were reported. Levamisole meets the requirements of individual and mass treatment of ascariasis.

A survey of intestinal parasitic infestation in Khorasan Province, Iran.

The prevalance of various intestinal parasites has been determined from a study of 40, 267 people from both urban and rural areas of Khorasan province, Iran. Except for G. lamblia, T. hominis, and H. nana, the prevalence of intestinal parasites seems to be lower in this province than in other areas of Iran. The incidence of infestation in village females was higher than in village males, but was similar in the two sexes in the towns and cities. Of those infested, more than 20% from urban areas and 35% from rural areas had multiple infestations.