Theranostic chimeric antigen receptor (CAR)-T cells: Insight into recent trends and challenges in solid tumors.

Cell therapy has reached significant milestones in various life-threatening diseases, including cancer. Cell therapy using fluorescent and radiolabeled chimeric antigen receptor (CAR)-T cell is a successful strategy for diagnosing or treating malignancies. Since cell therapy approaches have different results in cancers, the success of hematological cancers has yet to transfer to solid tumor therapy, leading to more casualties. Therefore, there are many areas for improvement in the cell therapy platform. Understanding the therapeutic barriers associated with solid cancers through cell tracking and molecular imaging may provide a platform for effectively delivering CAR-T cells into solid tumors. This review describes CAR-T cells' role in treating solid and non-solid tumors and recent advances. Furthermore, we discuss the main obstacles, mechanism of action, novel strategies and solutions to overcome the challenges from molecular imaging and cell tracking perspectives.

Inducing apoptosis by using microRNA in radio-resistant prostate cancer: an in-silico study with an in-vitro validation.

BACKGROUND: One of the problems with radiation therapy (RT) is that prostate tumor cells are often radio-resistant, which results in treatment failure. This study aimed to determine the procedure involved in radio-resistant prostate cancer apoptosis. For a deeper insight, we devoted a novel bioinformatics approach to analyze the targeting between microRNAs and radio-resistant prostate cancer genes. METHOD: This study uses the Tarbase, and the Mirtarbase databases as validated experimental databases and mirDIP as a predicted database to identify microRNAs that target radio-resistant anti-apoptotic genes. These genes are used to construct the radio-resistant prostate cancer genes network using the online tool STRING. The validation of causing apoptosis by using microRNA was confirmed with flow cytometry of Annexin V. RESULTS: The anti-apoptotic gene of radio-resistant prostate cancer included BCL-2, MCL1, XIAP, STAT3, NOTCH1, REL, REL B, BIRC3, and AKT1 genes. These genes were identified as anti-apoptotic genes for radio-resistant prostate cancer. The crucial microRNA that knockdown all of these genes was hsa-miR-7-5p. The highest rate of apoptotic cells in a cell transfected with hsa-miR-7-5p was (32.90 ± 1.49), plenti III (21.99 ± 3.72), and the control group (5.08 ± 0.88) in 0 Gy (P < 0.001); also, this rate was in miR-7-5p (47.01 ± 2.48), plenti III (33.79 ± 3.40), and the control group (16.98 ± 3.11) (P < 0.001) for 4 Gy. CONCLUSION: The use of this new treatment such as gene therapy to suppress genes involved in apoptosis can help to improve the treatment results and increase the quality of life of patients with prostate cancer.

Carotid artery stenting prior to coronary artery bypass grafting in patients with carotid stenosis: Clinical outcomes.

OBJECTIVES: Management of patients undergoing coronary artery bypass grafting (CABG) with obstructive disease of the carotid arteries is still a matter of debate. We compared the results of staged carotid artery stenting (CAS) before CABG in patients with carotid lesions. MATERIALS AND METHOD: Patients with significant carotid artery disease who were deemed to simultaneously suffer from an obstructive coronary artery disease requiring CABG from 2008 to 2018 were screened and enrolled in this study. We performed a staged CAS in cases with ≥60% stenosis and neurological symptoms or asymptomatic patients with ≥80% carotid artery stenosis. Patients with bilateral carotid lesions received sequential CAS within three weeks. Six weeks after the CAS procedure, all patients underwent CABG. RESULTS: A total of 142 patients were included. Eighty-five of these had neurological symptoms, while the remaining 40% were asymptomatic. Thirty-one patients underwent sequential CAS for bilateral lesions. The cerebrovascular event (CVE) following CAS (3 patients) and CABG (3 patients) was 4.2%. There was only a single case of mortality in this cohort. Although it was not statistically significant, CVE after CABG was more frequent in patients with bilateral carotid disease. CONCLUSIONS: Our results showed that staged CAS could be performed with minimal adverse outcomes in patients suffering from a simultaneous occlusive disease of carotids and coronary arteries before CABG. Bilateral CAS will further decrease cerebrovascular events and could be performed consequently or concomitantly.

Recent Trends in Diagnostic Biomarkers of Tumor Microenvironment.

The tumor microenvironment (TME) play critical roles in tumor survival, progression, and metastasis and can be considered potential targets for molecular imaging of cancer. The targeting agents for imaging of TME components (e.g., fibroblasts, mesenchymal stromal cells, immune cells, extracellular matrix, blood vessels) provide a promising strategy to target these biomarkers for the early diagnosis of cancers. Moreover, various cancer types have similar tumor immune microenvironment (TIME) features that targeting those biomarkers and offer clinically translatable molecular imaging of cancers. In this review, we categorize and summarize the components in TME which have been targeted for molecular imaging. Moreover, this review updated the recent progress in targeted imaging of TIME biological molecules by various modalities for the early detection of cancer.

Targeting mitochondria in cancer therapy: Insight into photodynamic and photothermal therapies.

Mitochondria are critical multifunctional organelles in cells that generate power, produce reactive oxygen species, and regulate cell survival. Mitochondria that are dysfunctional are eliminated via mitophagy as a way to protect cells under moderate stress and physiological conditions. However, mitophagy is a double-edged sword and can trigger cell death under severe stresses. By targeting mitochondria, photodynamic (PD) and photothermal (PT) therapies may play a role in treating cancer. These therapeutic modalities alter mitochondrial membrane potential, thereby affecting respiratory chain function and generation of reactive oxygen species promotes signaling pathways for cell death. In this regard, PDT, PTT, various mitochondrion-targeting agents and therapeutic methods could have exploited the vital role of mitochondria as the doorway to regulated cell death. Targeted mitochondrial therapies would provide an excellent opportunity for effective mitochondrial injury and accurate tumor erosion. Herein, we summarize the recent progress on the roles of PD and PT treatments in regulating cancerous cell death in relation to mitochondrial targeting and the signaling pathways involved.

Multifunctional magnetic nanoparticles for MRI-guided co-delivery of erlotinib and L-asparaginase to ovarian cancer.

The use of magnetic nanoparticles (MNPs) in biomedical applications has been wildly opted due to their unique properties. Here, we designed MNPs loaded with erlotinib (ERL/SPION-Val-PEG) and conjugated them with anti-mucin16 (MUC16) aptamer to introduce new image-guided nanoparticles (NPs) for targeted drug delivery as well as non-invasive magnetic resonance imaging (MRI) contrast agents. Also, the combination of our nanosystem (NS) along with L-Asparaginase (L-ASPN) led to synergistic effects in terms of reducing cell viability in ovarian cancer cells, which could suggest a novel combination therapy. The mean size of our NS was about 63.4 ± 3.4 nm evaluated by DLS analysis and its morphology was confirmed using TEM. Moreover, the functional groups, as well as magnetic properties of our NS, were examined by FT-IR and VSM tests, respectively. The loading efficacy of erlotinib on MNPs was about 80% and its release reached 70.85% over 7 days in the pH value of 5.4. The MR images and flow cytometry results revealed that the cellular uptake of ERL/SPION-Val-PEG-MUC16 NPs in cells with MUC16 overexpression was considerably higher than unarmed NPs. In addition, T2-weight MR images of ovarian cancer-bearing mice indicated significant signal intensity changes at the tumour site 4 h after intravenous injection compared to the non-target MNPs. Our data suggest ERL/SPION-Val-PEG NPs as an image-guided co-drug delivery system for ovarian cancer.

Photothermal therapy-mediated autophagy in breast cancer treatment: Progress and trends.

Breast cancer (BC) has different clinical manifestations due to its diverse mechanism of action that has created many challenges to choosing appropriate treatment. Recent findings of the biology of breast cancer including the mechanisms of survival and metastasis, understanding the effective signaling pathways in tumor formation and modeling of cancer cell responses to the therapeutic approaches provided significant advances in BC treatment. In this regard, the use of phototherapy-based approaches such as photothermal therapy (PTT) would be an encouraging alternative for tumor suppression through activating autophagy or suppressing cell signaling that influences the cell cycle to induce cell death. Since autophagy has a dual opposite role consisting of pro-survival and growth inhibition in breast cancer microenvironments, the regulation of autophagy would be playing promising roles in the treatment of BC using PTT. This review updates the molecular mechanisms that PTT could evoke autophagic cell death in breast cancer. Moreover, this article provides insights into the biological effects of autophagy-targeted-PTT as a promising strategy for breast cancer therapy.

A review on targeting tumor microenvironment: The main paradigm shift in the mAb-based immunotherapy of solid tumors.

Monoclonal antibodies (mAbs) as biological macromolecules have been remarked the large and growing pipline of the pharmaceutical market and also the most promising tool in modern medicine for cancer therapy. These therapeutic entities, which consist of whole mAbs, armed mAbs (i.e., antibody-toxin conjugates, antibody-drug conjugates, and antibody-radionuclide conjugates), and antibody fragments, mostly target tumor cells. However, due to intrinsic heterogeneity of cancer diseases, tumor cells targeting mAb have been encountered with difficulties in their unpredictable efficacy as well as variability in remission and durable clinical benefits among cancer patients. To address these pitfalls, the area has undergone two major evolutions with the intent of minimizing anti-drug responses and addressing limitations experienced with tumor cell-targeted therapies. As a novel hallmark of cancer, the tumor microenvironment (TME) is becoming the great importance of attention to develop innovative strategies based on therapeutic mAbs. Here, we underscore innovative strategies targeting TME by mAbs which destroy tumor cells indirectly through targeting vasculature system (e.g., anti-angiogenesis), immune system modulation (i.e., stimulation, suppression, and depletion), the targeting and blocking of stroma-based growth signals (e.g., cancer-associated fibroblasts), and targeting cancer stem cells, as well as, their effector mechanisms, clinical uses, and relevant mechanisms of resistance.

Recent advances and trends in nanoparticles based photothermal and photodynamic therapy.

Light-mediated therapies, including photodynamic therapy (PDT) and photothermal therapy (PTT) have been exploited as minimally invasive techniques for ablation of various tumors., Both modalities may eradicate tumors with minimal side effects to normal tissues and organs. Moreover, developments of light-mediated approaches using nanoparticles (NPs) and photosensitizer (PS) as diagnostic and therapeutic agents may have a crucial role in achieving successful cancer treatment. In recent years, novel nanoplatforms and strategies have been investigated to boost the therapeutic effect.. In this regard, gold, iron oxide, graphene oxide nanoparticles and hybrid nanocomposites have attracted attention.. Moreover, the combination of these materials with PS, in the form of hybrid NPs, reduces in vitro and in vivo normal tissue cytotoxicity, improves their solubility property in the biological environment and enhances the therapeutic effects. In this review, we look into the basic principles of PTT and PDT with their strengths and limitations to treat cancers. We also will discuss light-based nanoparticles and their PTT and PDT applications in the preclinical and clinical translation. Also, recent advances and trends in this field will be discussed along with the clinical challenges of PTT and PDT.

Evaluating the radioprotective effect of Cimetidine, IMOD, and hybrid radioprotectors agents: An in-vitro study.

INTRODUCTION: There are various radioprotective agents with different mechanisms that help to decrease ionizing radiation side effects. The radioprotective effect of Cimetidine and IMOD was assessed individually and compared with the hybrid radioprotectors agents (HRPAs-IMOD and Cimetidine) on human lymphocyte cells. METHODS: Twenty healthy volunteers (ten men and ten women) participated in the present study. About 75 mL peripheral blood lymphocytes from each individual were collected, and they were divided into 36 groups. Briefly, the blood samples were treated with different concentrations of Cimetidine (12.6 and 25.2 µg/mL) and IMOD (0.04, 0.08, and 0.12 mg/mL), and also a combination of these agents, namely hybrid radioprotectors agents (HRPAs). Besides, the irradiated groups were exposed to 2 and 4 Gy of Co-60 gamma irradiation. The amount of cellular damage was assessed using the micronucleus assay. The repeated measurements and paired T-test statistical analysis were used to compare the micronucleus frequencies in different groups. RESULTS: The micronucleus frequencies were significantly reduced (p < 0.05) in irradiated groups when the non-toxic concentrations of Cimetidine, IMOD, and HRPAs have been used. The reduction in micronucleus frequency was obtained 5-29% for Cimetidine and 40-51% for IMOD in peripheral blood lymphocytes irradiated with 2 Gy. This reduction in 4 Gy irradiation was 8-17% for Cimetidine and 27-37% for IMOD. The HRPAs resulted in a higher radioprotective effect, in a way that they cause up to 58% and 43% micronucleus frequency reduction in 2 and 4 Gy, respectively. CONCLUSION: In conclusion, the HRPAs showed the highest level of radioprotective. In addition, IMOD was remarkably higher radioprotective than Cimetidine, which may be related to its greater non-toxic concentrations.

IMPACT OF PELVIC AND RAD-BOARD LEAD SHIELDS ON OPERATOR AND PATIENT RADIATION DOSE IN TRANS-RADIAL CORONARY PROCEDURES.

BACKGROUND: Trans-radial approach for cardiac catheterisation procedures has long been associated with high operator and patient radiation dose. The aim of the present study was to determine the effect of pelvic and radial shields on decreasing coronary procedure radiation doses. METHODS: A total of 418 patients randomly underwent diagnostic and therapeutic cardiac procedures with and without the pelvic and rad-board lead shields during the procedures. The operator and patient doses were then determined by means of a personal dosimeter and dose area product (DAP), respectively. RESULTS: The shields decreased the operator radiation dose by 40% in coronary angiography (CA) and by 45% during angioplasty (PCI). These results were achieved at the cost of increased patient radiation dose. CONCLUSION: Pelvic lead shields combined with rad-board shields are highly effective in reducing operator radiation dose in trans-radial approach, but it is only achieved at the cost of increased patient DAP.

AN ANALYSIS OF OPERATING PHYSICIAN AND PATIENT RADIATION EXPOSURE DURING RADIAL CORONARY ANGIOPLASTIES.

The objective of this study was to evaluate radiation exposure levels in conjunction with operator dose implemented, patient vascular characteristics, and other technical angiographic parameters. In total, 756 radial coronary angioplasties were evaluated in a major metropolitan general hospital in Tabriz, Iran. The classification of coronary lesions was based on the ACC/AHA system. One interventional cardiologist performed all of the procedures using a single angiography unit. The mean kerma-area product and mean cumulative dose for all cases was 5081 µGy m2 and 814.44 mGy, respectively. Average times of 26.16 and 9.1 min were recorded for the overall procedure and fluoroscopy, respectively. A strong correlation was demonstrated between types of lesions, number of stents and vessels treated in relation to physician radiation exposure. It was determined that operator radiation exposure levels for percutaneous coronary interventions lesions (complex) were higher than that of simple and moderate lesions. In addition, operator radiation exposure levels increased with the treatment of more coronary vessels and implementation of additional stents.

Vertebrobasilar Artery Stroke as the Heralding Sign of Systemic Lupus Erythematosus.

Cerebral ischemia because of vertebrobasilar insufficiency (VBI) rarely presents as an initial sign within the systemic lupus erythematosus (SLE) population, and there are very few case reports supporting this manifestation. This report details 3 different patients with SLE who experienced VBI as an initial manifestation. Patient 1 was a 24-year-old female who developed a bilateral pontine lesion as a consequence of basilar artery stenosis. Patient 2 was a 34-year-old male with an acute ischemic lesion on the right side of his cerebellum and pons because of significant stenosis in the distal segment of the right vertebral artery. Patient 3 was a 37-year-old female, previously diagnosed with multiple sclerosis, with multiple lesions in her cerebellum and pons bilaterally. Further investigations within this case revealed severe stenosis of the left vertebral artery. The diagnosis of SLE was based on clinical presentations such as myalgia, skin rashes, ulcers, and fatigue along with relevant laboratory findings including positive anti ds-DNA antibody and depressed levels of complement C3 and C4 proteins. In young patients with multifocal ischemic lesions or infarcts in the posterior cerebral circulation system, physicians should investigate for less common etiologies such as SLE.

Beam projections and radiation exposure in transradial and transfemoral approaches during coronary angiography.

OBJECTIVE: We aimed to compare the operator and patient radiation exposure in standard projections during elective diagnostic coronary angiography procedures via transradial (TRA) versus transfemoral (TFA) approaches. METHODS: In this analytical cross-sectional study, a total of 202 consecutive patients who were candidates for diagnostic coronary angiography were randomized to undergo the procedure via TFA or TRA approaches (101 in each group). Patients with abnormal Allen test and history of coronary artery bypass surgery, valvular heart disease, and unsuccessful coronary angiography were excluded from the study. A single operator performed all of the procedures using a single angiography system. Patient and operator radiation exposure were measured using diamentor and an electronic personal dosimeter, respectively. Each procedure comprised a standardized sequence of projections including four standard views for the left coronary system and two standard views for the right coronary system. RESULTS: Left anterior oblique (LAO) caudal (50°/30°) and right anterior oblique RAO (30°) projections were associated with the highest and lowest patient radiation exposure, respectively. The operator received a significantly higher radiation exposure in the TRA approach for LAO cranial (for both left and right coronary systems) and LAO caudal (for left coronary system) projections during coronary angiography compared with the TFA approach. CONCLUSION: Though a similar amount of patient radiation exposure in each projection was observed among TFA and TRA groups; LAO cranial and LAO caudal projections were associated with a significantly higher operator radiation exposure in the TRA group. These findings need to be considered when choosing the optimal arterial approach for patients scheduled for coronary angiography.

Comparison of the patient radiation exposure during coronary angiography and angioplasty procedures using trans-radial and trans-femoral access.

INTRODUCTION: Cardiac catheterization procedure through the trans-radial access (TRA) have shown many clinical advantages over the trans-femoral (TFA), but despite its advantages, there are serious concerns regarding higher possible radiation dose for the patients and operators in TRA. This study was planned to compare the patients' radiation dose associated with TRA and TFA during coronary angiography (CA) and percutaneous transluminal coronary angioplasty (PTCA). METHODS: Of 700 candidates for angiography, 326 patients were entered the study. All the procedures were carried out by one interventional cardiologist employing the same angiography unit in Aalinasab hospital and the patients' dose area product (DAP), air kerma (AK), fluoroscopy time (FT) and cine film time (CFT) were then determined in both access groups (TRA,TFA) in CA, PTCA and CA+PTCA procedures. RESULTS: The mean FT, CFT and AK values in both TRA & TFA groups were the same in all procedures (P>0.05). The mean DAP in CA+PTCA procedures was 6704.01±3243.23 µGym(2) in femoral access compare with 5647.46±2797.74 µGym(2) in radial access, which were significantly less than that in TFA with P= 0.02. CONCLUSION: On the basis of the results obtained in this study, no differences were found in patients' radiation dose in both access groups, therefore with regard to comparatively more clinical advantages associated with the Trans-radial access technique it might be a good substitute for Trans-femoral access.