Sunitinib for the treatment of metastatic gastrointestinal stromal tumors: the effect of TDM-guided dose optimization on clinical outcomes.

BACKGROUND: Sunitinib is an oral anticancer drug approved for the treatment of among others gastrointestinal stromal tumor (GIST). Previous analyses demonstrated an exposure-response relationship at the standard dose, and minimum target levels of drug exposure have been defined above which better treatment outcomes are observed. Therapeutic drug monitoring (TDM) could be used as a tool to optimize the individual dose, aiming at sunitinib trough concentrations ≥37.5 ng/ml for continuous dosing. Nonetheless, data on the added value of TDM-guided dosing on clinical endpoints are currently lacking. Therefore, we evaluate the effect of TDM in patients with advanced and metastatic GIST treated with sunitinib in terms of efficacy and toxicity. PATIENTS AND METHODS: A TDM-guided cohort was compared to a non-TDM-guided cohort in terms of median progression-free survival (mPFS) and overall survival (mOS). Also, mPFS between patients with and without dose-limiting toxicities (DLTs) was compared. Patients in the prospective cohort were included in two studies on TDM-guided dosing (the DPOG-TDM study and TUNE study). The retrospective cohort consisted of patients from the Dutch GIST Registry who did not receive TDM-guided dosing. RESULTS: In total, 51 and 106 patients were included in the TDM-guided cohort and non-TDM-guided cohort, respectively. No statistical difference in mPFS was observed between these two cohorts (39.4 versus 46.9 weeks, respectively; P = 0.52). Patients who experienced sunitinib-induced DLTs had longer mPFS compared to those who did not (51.9 versus 28.9 weeks, respectively; P = 0.002). CONCLUSIONS: Our results do not support the routine use of TDM-guided dose optimization of sunitinib in patients with advanced/metastatic GIST to improve survival.

Deep-learning Method for the Prediction of Three-Dimensional Dose Distribution for Left Breast Cancer Conformal Radiation Therapy.

AIMS: An increase in the demand of a new generation of radiotherapy planning systems based on learning approaches has been reported. At this stage, the new approach is able to improve the planning speed while saving a reasonable level of plan quality, compared with available planning systems. We believe that new achievements, such as deep-learning models, will be able to review the issue from a different point of view. MATERIALS AND METHODS: The data of 120 breast cancer patients were used to train and test the three-dimensional U-Res-Net model. The network input was computed tomography images and patients' contouring, while the patients' dose distribution was addressed as the output of the model proposed. The predicted dose distributions, created by the model for 10 test patients, were then compared with corresponding dose distributions calculated by a reliable treatment planning system. In particular, the dice similarity coefficients for different isodose volumes, dose difference and mean absolute errors (MAE) for all voxels inside the body, Dmean, D98%, D50%, D2%, V95% for planning target volume and organs at risk were calculated and were statistically analysed with the paired-samples t-test. RESULTS: The average dose difference for all patients and voxels in body was 0.60 ± 2.81%. The MAE varied from 3.85 ± 6.65% to 8.06 ± 10.00%. The average MAE for test cases was 5.71 ± 1.19%. The average dice similarity coefficients for isodose volumes was 0.91 ± 0.03. The three-dimensional gamma passing rates with 3 mm/3% criteria varied from 78.99% to 97.58% for planning target volume and organs at risk, respectively. CONCLUSIONS: The investigation showed that a deep-learning model can be applied to predict the three-dimensional dose distribution with optimal accuracy and precision for patients with left breast cancer. As further study, the model can be extended to predict dose distribution in other cancers.

Cell Encapsulation and 3D Bioprinting for Therapeutic Cell Transplantation.

The promise of cell therapy has been augmented by introducing biomaterials, where intricate scaffold shapes are fabricated to accommodate the cells within. In this review, we first discuss cell encapsulation and the promising potential of biomaterials to overcome challenges associated with cell therapy, particularly cellular function and longevity. More specifically, cell therapies in the context of autoimmune disorders, neurodegenerative diseases, and cancer are reviewed from the perspectives of preclinical findings as well as available clinical data. Next, techniques to fabricate cell-biomaterials constructs, focusing on emerging 3D bioprinting technologies, will be reviewed. 3D bioprinting is an advancing field that enables fabricating complex, interconnected, and consistent cell-based constructs capable of scaling up highly reproducible cell-biomaterials platforms with high precision. It is expected that 3D bioprinting devices will expand and become more precise, scalable, and appropriate for clinical manufacturing. Rather than one printer fits all, seeing more application-specific printer types, such as a bioprinter for bone tissue fabrication, which would be different from a bioprinter for skin tissue fabrication, is anticipated in the future.

Effects of Fe2+ Nanoparticles on Pain Responses and Neural Oscillation Following Chronic Neuropathic Pain in Rats.

Neuropathic pain, a chronic pain condition caused by nerve damage either of the peripheral or central nervous system, responds poorly to current drug treatments. The present study aimed to investigate the analgesic and anxiolytic effect of Fe2+ nanoparticles on chronic constriction injury of sciatic nerve (CCI)-induced neuropathic pain in rats. We also assessed the effects of Fe2+ nanoparticles on brain rhythmical oscillation in rats with neuropathic pain. The CCI model was induced by four loose ligations of the left sciatic nerve. Male Wistar rats were divided into four groups: control, sham, CCI, and CCI+Fe2+ nanoparticle (1 mg/kg). The Fe2+ nanoparticle was administered by gavage on the day of CCI surgery (day 0) and daily (once a day) for 21 consecutive days after CCI surgery. Behavioral studies were conducted on days -1, 3, 7, 14, and 21 after CCI. An acetone test and elevated plus maze were performed to evaluate cold allodynia and induced anxiety-like responses, respectively. A field test was conducted to evaluate innate anxiety-like behaviors. In addition, an electrophysiological study was carried out on day 21 after CCI to assess the effects of drugs on brain wave power. Application of Fe2+ significantly reduced cold allodynia in all tested days after CCI, compared to the CCI group. The obtained data demonstrated that Fe2+ nanoparticle gavage caused analgesic and anxiolytic effects on all experimental days after CCI, compared to the CCI group. The CCI surgery significantly disturbed theta, alpha, and beta power in the brain. The application of Fe2+ nanoparticles could not significantly change brain wave power. It is suggested that Fe2+ nanoparticle has analgesic and anxiolytic effects during chronic neuropathic pain in rats. Furthermore, the CCI surgery effectively disturbed brain theta, alpha, and beta power. Nonetheless, the application of Fe2+ nanoparticles could not change deregulated brain oscillation in rats.

Sex differences in patients with gastrointestinal stromal tumours: do they exist and does it affect survival?

BACKGROUND: Sex differences in cancer have gained attention in recent years. The role of sex as a prognostic factor in gastrointestinal stromal tumours (GIST) has not been well established. The aim of this research was to elucidate potential sex differences in GIST patients and the influence of sex on disease-specific survival (DSS). METHODS: A review of the literature was carried out to obtain an overview of all literature with sex as a covariate on GIST survival analyses. Furthermore, in the Dutch GIST Registry, GIST characteristics between males and females were compared and the influence of sex on DSS was analysed. RESULTS: A total of 118 articles from the review of the literature met our selection criteria; 58% of the articles found no sex difference in survival and 42% did find a sex difference. All differences favoured female patients, although there was substantial overlap of individual patients in the various reported groups. The Dutch GIST Registry cohort consisted of 1425 patients (46% female). Compared with female patients, male patients had larger tumours (mean 9.0 cm versus 7.9 cm) and higher mitotic rates (34.4% versus 28.0% >5 mitoses/5 mm2). GIST in males was more often metastasized at diagnosis (21.3% versus 13.7%) and incurable (38.5% versus 31.0%). Male patients less often received surgery of the primary tumour (71.7% versus 78.9%), but did experience more tumour ruptures (18.2% versus 13.3%). Male patients had a worse DSS than females. This was not statistically significant when corrected for differences in GIST characteristics. CONCLUSIONS: In case of sex differences in GIST in the literature, male patients have a worse outcome. In our Dutch GIST cohort a similar finding was made, but sex was shown not to be an independent factor. Male patients more often had aggressive GISTs, with larger tumours, higher mitotic rates, more tumour ruptures, and metastases, which could explain the sex differences in DSS.

Dosimetric verification of IMRT and 3D conformal treatment delivery using EPID.

PURPOSE: Electronic portal imaging devices (EPIDs) could potentially be useful for either in-vivo or pre-treatment dosimetric verification of external beam radiation therapy. The accuracy of EPID for dosimetric purposes is highly dependent on the specific method used for the determination of dose-response characteristics. The aim of this study was to develop a simple and time-saving EPID back-projection dosimetry algorithm for 2D dose verification in 3D conformal and intensity-modulated beams. METHODS: The procedure of dose reconstruction includes a first calibration step using ionization chamber measurements to convert the Electronic Portal Image (EPI) pixel values into an absorbed dose in water. Subsequently, several corrections were applied to the Portal Dose Images (PDIs) for the effect of field size, attenuator thickness, scattering radiation, beam hardening and EPID off-axis response. Furthermore, to consider tissue inhomogeneity for accurate dose reconstruction, the patient's water equivalent path length (WEPL) was calculated using a range of digitally reconstructed radiographs (DRRs) obtained at various thicknesses by Plastimatch software. The EPID-derived dose maps accuracy was assessed by comparing with the treatment planning system (TPS) calculated dose in the prostate region of Alderson phantom irradiated with 3D conformal and intensity-modulated beams. RESULTS: The gamma analysis for the dose plane showed agreements of 96.95% and 93.5% for 3D conformal and IMRT fields, respectively, with 3%/3 mm acceptance criteria. CONCLUSION: The presented algorithm can provide accurate absolute 2D dose maps for clinical use in the context of 3DCRT or IMRT Quality Assurance (QA) programs.

Exosome loaded immunomodulatory biomaterials alleviate local immune response in immunocompetent diabetic mice post islet xenotransplantation.

Foreign body response (FBR) to biomaterials compromises the function of implants and leads to medical complications. Here, we report a hybrid alginate microcapsule (AlgXO) that attenuated the immune response after implantation, through releasing exosomes derived from human Umbilical Cord Mesenchymal Stem Cells (XOs). Upon release, XOs suppress the local immune microenvironment, where xenotransplantation of rat islets encapsulated in AlgXO led to >170 days euglycemia in immunocompetent mouse model of Type 1 Diabetes. In vitro analyses revealed that XOs suppressed the proliferation of CD3/CD28 activated splenocytes and CD3+ T cells. Comparing suppressive potency of XOs in purified CD3+ T cells versus splenocytes, we found XOs more profoundly suppressed T cells in the splenocytes co-culture, where a heterogenous cell population is present. XOs also suppressed CD3/CD28 activated human peripheral blood mononuclear cells (PBMCs) and reduced their cytokine secretion including IL-2, IL-6, IL-12p70, IL-22, and TNFα. We further demonstrate that XOs mechanism of action is likely mediated via myeloid cells and XOs suppress both murine and human macrophages partly by interfering with NFκB pathway. We propose that through controlled release of XOs, AlgXO provide a promising new platform that could alleviate the local immune response to implantable biomaterials.

Ocular toxicity assessment of nanoemulsion in-situ gel formulation of fluconazole.

PURPOSE: Fluconazole is an effective anti-fungal drug. Due to the limitations of fluconazole, such as poor water solubility and consequently low ocular bioavailability, an optimized fluconazole nanoemulsion in-situ gel formulation (temperature-sensitive) was developed. METHODS AND MATERIALS: To verify formulation's safety for ophthalmic use, preparation was tested for potential ocular toxicity using a cell viability assay on retinal cells. The hen's egg test-chorioallantoic membrane (HET-CAM), as a borderline test between in vivo and in vitro techniques, was chosen for investigating the irritation potential of the formulation. HET-CAM test was done by adding the formulation directly to the CAM surface and monitoring the vessels visually in terms of irritation reactions. Eye tolerance was determined using the modified Draize test. RESULTS: Viability assay on retinal cells displayed that fluconazole nanoemulsion in-situ gel formulation was non-toxic and can be safely used in the eye at concentrations of 0.1% and 0.5%. HET-CAM and Draize tests revealed that optimized formulation of fluconazole did not result in any irritation and was considered non-irritant and well-tolerated for ocular use. CONCLUSION: Regarding to the findings of the three mentioned methods, fluconazole nanoemulsion in-situ gel formulation is harmless and as a proper and safe alternative, can be considered for ocular delivery of fluconazole in the future.

Preferences of Type 1 Diabetic Patients on Devices for Islet Transplantation.

Transplantation of pancreatic islets within a biomaterial device is currently under investigation in clinical trials for the treatment of patients with type 1 diabetes (T1D). Patients' preferences on such implants could guide the designs of next-generation implantable devices; however, such information is not currently available. We surveyed the preferences of 482 patients with T1D on the size, shape, visibility, and transplantation site of islet containing implants. More than 83% of participants were willing to receive autologous stem cells, and there was no significant association between implant fabricated by one's own stem cell with gender (χ2 (1, n = 468) = 0.28; P = 0.6) or with age (χ2 (4, n = 468) = 2.92; P = 0.6). Preferred location for islet transplantation within devices was under the skin (52.7%). 48.3% preferred microscopic disks, and 32.3% preferred a thin device (like a credit card). Moreover, 58.4% preferred the implant to be as small as possible, 25.4% did not care about visibility, and 16.2% preferred their implants not to be visible. Among female participants, 81% cared about the implant visibility, whereas this number was 64% for male respondents (χ2 test (1, n = 468) = 16.34; P < 0.0001). 22% of those younger than 50 years of age and 30% of those older than 50 did not care about the visibility of implant (χ2 test (4, n = 468) = 23.69; P < 0.0001). These results suggest that subcutaneous sites and micron-sized devices are preferred choices among patients with T1D who participated in our survey.

Performance of a linear accelerator couch positioning quality control task using an electronic portal imaging device.

Short and semi-automated quality assurance (QA) programs are becoming one of the most popular and highly demanding tasks in radiotherapy. The current research investigates the accuracy of a four degrees of freedom (4DoF) medical linear accelerator couch positioning with a fast and accurate method based on images acquired using an electronic portal imaging device (EPID). An accurate EPID QA phantom and a proper in-house code were used. A Siemens medical linear accelerator equipped with an a-Si EPID was used to acquire portal images. For verifying the mechanical performance of the EPID positioning, EPID sensitivity, and accuracy of the code response from the image processing point of view were investigated. To characterize the results, three deviations in the phantom positioning were deliberately created. The translational and rotational displacements of the treatment couch were then evaluated. The loading effect on the treatment couch was then investigated. The results of prerequisite tests, including the mechanical performance of the EPID, and the sensitivity and accuracy of the recognition codes, were assessed. The results were found to be within the tolerance range reported at AAPM TG-142. The mean deviations of the tests between expected and measured displacements by 4DoF treatment couch were found to be 0.13° ± 0.11°, 0.12 ± 0.17 mm, 0.17 ± 0.13 mm, and 0.04 ± 0.09 mm for rotational, longitudinal, lateral, and vertical shifts, respectively. The results showed that the proposed method is a reliable and fast approach to find the uncertainties occurring intreatment couch positioning.

Isolation and characterization of microvesicles from mesenchymal stem cells.

Mesenchymal stem or stromal cells are currently under clinical investigation for multiple diseases. While their mechanism of action is still not fully elucidated, vesicles secreted by MSCs are believed to recapitulate their therapeutic potentials to some extent. Microvesicles (MVs), also called as microparticles or ectosome, are among secreted vesicles that could transfer cytoplasmic cargo, including RNA and proteins, from emitting (source) cells to recipient cells. Given the importance of MVs, we here attempted to establish a method to isolate and characterize MVs secreted from unmodified human bone marrow derived MSCs (referred to as native MSCs, and their microvesicles as Native-MVs) and IFNγ stimulated MSCs (referred to as IFNγ-MSCs, and their microvesicles as IFNγ-MVs). We first describe an ultracentrifugation technique to isolate MVs from the conditioned cell culture media of MSCs. Next, we describe characterization and quality control steps to analyze the protein and RNA content of MVs. Finally, we examined the potential of MVs to exert immunomodulatory effects through induction of regulatory T cells (Tregs). Secretory vesicles from MSCs are promising alternatives for cell therapy with applications in drug delivery, regenerative medicine, and immunotherapy.

Smart electrospun nanofibers containing PCL/gelatin/graphene oxide for application in nerve tissue engineering.

Currently graphene-doped electrospun scaffolds have been a matter of great interest to be exploited in biomedical fields such as tissue engineering and drug delivery applications. The main objective of this paper is to evaluate the effect of graphene on biological properties of PCL/gelatin nanofibrous mats. SEM analysis was conducted to investigate the morphology of the electrospun nanofibers. The in-vitro cellular proliferation of PC12 cells on nanofibrous web was also investigated. Electrospun PCL/gelatin/graphene nanofibrous mats exhibited 99% antibacterial properties against gram-positive and gram-negative bacteria. Drug release studies indicated that the π-π stacking interaction between TCH and graphene has led to the far better controlled release of TCH from electrospun PCL/gelatin/graphene compared to PCL/gelatin nanofibrous scaffolds. These superior properties along with an improvement in hydrophilicity and biodegradation features has made the nanofibers a promising candidate to be used as electrically conductive scaffolds in neural tissue engineering as well as controlled drug delivery.

Evaluation of Breast Cancer Radiation Therapy Techniques in Outfield Organs of Rando Phantom with Thermoluminescence Dosimeter.

BACKGROUND: Given the importance of scattered and low doses in secondary cancer caused by radiation treatment, the point dose of critical organs, which were not subjected to radiation treatment in breast cancer radiotherapy, was measured. OBJECTIVE: The purpose of this study is to evaluate the peripheral dose in two techniques of breast cancer radiotherapy with two energies. MATERIAL AND METHODS: Eight different plans in two techniques (conventional and conformal) and two photon energies (6 and 15 MeV) were applied to Rando Alderson Phantom's DICOM images. Nine organs were contoured in the treatment planning system and specified on the phantom. To measure the photon dose, forty-eight thermoluminescence dosimeters (MTS700) were positioned in special places on the above nine organs and plans were applied to Rando phantom with Elekta presice linac. To obtain approximately the same dose distribution in the clinical organ volume, a wedge was used on planes with an energy of 6 MeV photon. RESULTS: Point doses in critical organs with 8 different plans demonstrated that scattering in low-energy photon is greater than high-energy photon. In contrast, neutron contamination in high-energy photon is not negligible. Using the wedge and shield impose greater scattering and neutron contamination on patients with low-and high-energy photon, respectively. CONCLUSION: Deciding on techniques and energies required for preparing an acceptable treatment plan in terms of scattering and neutron contamination is a key issue that may affect the probability of secondary cancer in a patient.

Biohybrid Nanoparticles to Negotiate with Biological Barriers.

Incapability of effective cross-talk with biological environments has partly impaired the in vivo functionality of nanoparticles (NPs). Homing, biodistribution, and function of NPs could be engineered through regulating their interactions with in vivo niches. Inspired by communications in biological systems, endowing a "biological identity" to synthetic NPs is one approach to control their biodistribution, and immunonegotiation profiles. This synthetic-biological combination is referred to as biohybrid NPs, which comprise both i) engineerable, readily producible, and trackable synthetic NPs as well as ii) biological moieties with the capability to cross-talk with immunological barriers. Here, the latest understanding on the in vivo interactions of NPs, biological barriers they face, and emerging methods for quantitative measurements of NPs' biodistribution are reviewed. Some key biomolecules that have emerged as negotiators with the immune system in the context of cancer and autoimmunity, and their inspirations on biohybrid NPs are introduced. Critical design considerations for efficient cross-talk between NPs and innate and adaptive immunity followed by hybridization methods are also discussed. Finally, clinical translation challenges and future perspectives regarding biohybrid NPs are discussed.

Stem Cell-Derived Exosomes as Nanotherapeutics for Autoimmune and Neurodegenerative Disorders.

To dissect therapeutic mechanisms of transplanted stem cells and develop exosome-based nanotherapeutics in treating autoimmune and neurodegenerative diseases, we assessed the effect of exosomes secreted from human mesenchymal stem cells (MSCs) in treating multiple sclerosis using an experimental autoimmune encephalomyelitis (EAE) mouse model. We found that intravenous administration of exosomes produced by MSCs stimulated by IFNγ (IFNγ-Exo) (i) reduced the mean clinical score of EAE mice compared to PBS control, (ii) reduced demyelination, (iii) decreased neuroinflammation, and (iv) upregulated the number of CD4+CD25+FOXP3+ regulatory T cells (Tregs) within the spinal cords of EAE mice. Co-culture of IFNγ-Exo with activated peripheral blood mononuclear cells (PBMCs) cells in vitro reduced PBMC proliferation and levels of pro-inflammatory Th1 and Th17 cytokines including IL-6, IL-12p70, IL-17AF, and IL-22 yet increased levels of immunosuppressive cytokine indoleamine 2,3-dioxygenase. IFNγ-Exo could also induce Tregs in vitro in a murine splenocyte culture, likely mediated by a third-party accessory cell type. Further, IFNγ-Exo characterization by deep RNA sequencing suggested that IFNγ-Exo contains anti-inflammatory RNAs, where their inactivation partially hindered the exosomes potential to induce Tregs. Furthermore, we found that IFNγ-Exo harbors multiple anti-inflammatory and neuroprotective proteins. These results not only shed light on stem cell therapeutic mechanisms but also provide evidence that MSC-derived exosomes can potentially serve as cell-free therapies in creating a tolerogenic immune response to treat autoimmune and central nervous system disorders.

Impact of comorbidity on disease characteristics, treatment intent and outcome in diffuse large B-cell lymphoma: a Swedish lymphoma register study.

BACKGROUND: Comorbidity impacts overall survival amongst patients with diffuse large B-cell lymphoma (DLBCL). However, associations of comorbidity with lymphoma characteristics, treatment selection and lymphoma-specific mortality are less well known. OBJECTIVE: To examine the impact of comorbidity on DLBCL characteristics, treatment intent and cause of death. METHODS: We identified 3905 adult patients diagnosed with DLBCL 2007-2013 through the Swedish Lymphoma Register. We assessed comorbid disease history according to the Charlson comorbidity index (CCI). Comorbidity data and causes of death were collected through register linkage. Associations were estimated using multinomial regression and flexible parametric survival models. RESULTS: Overall, 45% of the patients (n = 1737) had a history of at least one comorbidity at DLBCL diagnosis (cardiovascular disease, diabetes and solid cancer were most frequent), and 997 (26%) had a CCI score of ≥2. The relative probability of presenting with poor performance status (PS > 2) was higher amongst comorbid patients [Relative Risk Ratio (RRR)PS>2 : 2.02, 95% CI: 1.63-2.51]. Comorbid patients had a substantially lower relative probability of receiving curative treatment (RRR: 0.48, 95% CI: 0.38-0.61). Amongst all patients, CCI ≥ 1 was associated with a significantly increased risk of all-cause and lymphoma-specific death after adjustments. Amongst patients selected for curative treatment, comorbidity was associated with an increased risk of all-cause death (HRCCI>1 : 1.54, 95% CI: 1.32-1.80), but not with lymphoma-specific death (HRCCI>1 : 1.05, 95% CI: 0.86-1.28). CONCLUSION: Comorbidity is associated with inferior DLBCL outcome, mainly due to a lower likelihood of receiving treatment with curative intent. Possibly, more comorbid DLBCL patients could be treated with curative intent if comorbid conditions were optimized in parallel.

Cytokines as therapeutic agents and targets in heart disease.

Cytokine therapies have emerged during the past decade as promising noninvasive treatments for heart disease. In general, current drug treatments are directed towards symptom control and prevention of disease progression; however, many agents also produce cause side effects that alter quality of life. Cytokine based therapies have the potential to reduce post-infarct heart failure and chronic ischemia by stimulating the proliferation and differentiation of endothelial cells and bone marrow hematopoietic stem cells and mobilizing these cells toward ischemic tissue. In turn, these mobilized cell populations contribute to myocardial regeneration. In contrast, over-expression of several cytokines has been linked to a variety of heart diseases; thus, therapies targeting and monitoring these cytokines are of great interest. Here we summarize results from clinical studies on cytokines as therapeutic agents or therapeutic targets in the treatment for heart disease as well as cytokines involved in the evolution of heart disease.

Approaches in Immunotherapy, Regenerative Medicine, and Bioengineering for Type 1 Diabetes.

Recent advances on using immune and stem cells as two-pronged approaches for type 1 diabetes mellitus (T1DM) treatment show promise for advancement into clinical practice. As T1DM is thought to arise from autoimmune attack destroying pancreatic ß-cells, increasing treatments that use biologics and cells to manipulate the immune system are achieving better results in pre-clinical and clinical studies. Increasingly, focus has shifted from small molecule drugs that suppress the immune system nonspecifically to more complex biologics that show enhanced efficacy due to their selectivity for specific types of immune cells. Approaches that seek to inhibit only autoreactive effector T cells or enhance the suppressive regulatory T cell subset are showing remarkable promise. These modern immune interventions are also enabling the transplantation of pancreatic islets or ß-like cells derived from stem cells. While complete immune tolerance and body acceptance of grafted islets and cells is still challenging, bioengineering approaches that shield the implanted cells are also advancing. Integrating immunotherapy, stem cell-mediated ß-cell or islet production and bioengineering to interface with the patient is expected to lead to a durable cure or pave the way for a clinical solution for T1DM.

Strategies for directing cells into building functional hearts and parts.

The increasing population of patients with heart disease and the limited availability of organs for transplantation have encouraged multiple strategies to fabricate healthy implantable cardiac tissues. One of the main challenges in cardiac tissue engineering is to direct cell behaviors to form functional three-dimensional (3D) biomimetic constructs. This article provides a brief review on various cell sources used in cardiac tissue engineering and highlights the effect of scaffold-based signals such as topographical and biochemical cues and stiffness. Then, conventional and novel micro-engineered bioreactors for the development of functional cardiac tissues will be explained. Bioreactor-based signals including mechanical and electrical cues to control cardiac cell behavior will also be elaborated in detail. Finally, the application of computational fluid dynamics to design suitable bioreactors will be discussed. This review presents the current state-of-the-art, emerging directions and future trends that critically appraise the concepts involved in various approaches to direct cells for building functional hearts and heart parts.

Protective Effects of IMOD and Cimetidine against Radiation-induced Cellular Damage.

Radiation damage is to a large extent caused by overproduction of reactive oxygen species (ROS). Radioprotectors are agents or substances that reduce the effects of radiation in healthy normal tissues while maintaining the sensitivity to radiation damage in tumor cells. Radioprotectors are agents or substances that reduce the effects of radiation in healthy normal tissues while maintaining the sensitivity to radiation damage in tumor cells Cimetidine was found more effective when used in vivo; this effect might be due to the augmentation of the presence of Sulphur atom in the compound which is ýimportant for their scavenging activity. Recently, a new herbal-based medicine with immunomodulatory capacities, Setarud (IMOD), was introduced as an additional therapy in various inflammatory diseases and HIV infection. IMOD is a mixture of herbal extracts enriched with selenium. Selenium confers protection by inducing or activating cellular free-radical scavenging systems and by enhancing peroxide breakdown. This article suggests that nontoxic amount of IMOD and cimetidine have radioprotective properties and could reduce cytotoxic effects of radiation.