Clinical and echocardiographic characteristics after six months of sacubitril/valsartan in Chagas heart disease - A case series.

Chagas cardiomyopathy is the most prevalent non-ischaemic cardiomyopathy in Latin America, with high morbidity and mortality even today. Treatment of these patients is based on the use of medications for heart failure. This study evaluated a case series of patients with Chagas heart disease who used sacubitril/valsartan at a referral hospital for this disease in Brazil. After 6 months, there was a symptomatic improvement in these individuals assessed by the New York Heart Association (NYHA) functional class, with a 44.3% reduction in the absolute number of patients classified as III-IV in the period (P = 0.035), but without changes in the parameters on the echocardiogram for reverse ventricular remodelling. There was a high mortality rate and number of hospitalizations. These results emphasize the importance of studying the use of sacubitril/valsartan in Chagas heart disease to better describe its effectiveness considering the particularities of these individuals.

Circulating miRNAs as Potential Biomarkers Associated with Cardiac Remodeling and Fibrosis in Chagas Disease Cardiomyopathy.

Chagas disease (CD) affects approximately 6-7 million people worldwide, from which 30% develop chronic Chagas cardiomyopathy (CCC), usually after being asymptomatic for years. Currently available diagnostic methods are capable of adequately identifying infected patients, but do not provide information regarding the individual risk of developing the most severe form of the disease. The identification of biomarkers that predict the progression from asymptomatic or indeterminate form to CCC, may guide early implementation of pharmacological therapy. Here, six circulating microRNAs (miR-19a-3p, miR-21-5p, miR-29b-3p, miR-30a-5p, miR-199b-5p and miR-208a-3p) were evaluated and compared among patients with CCC (n = 28), CD indeterminate form (n = 10) and healthy controls (n = 10). MiR-19a-3p, miR-21-5p, and miR-29b-3p were differentially expressed in CCC patients when compared to indeterminate form, showing a positive correlation with cardiac dysfunction, functional class, and fibrosis, and a negative correlation with ejection fraction and left ventricular strain. Cardiac tissue analysis confirmed increased expression of microRNAs in CCC patients. In vitro studies using human cells indicated the involvement of these microRNAs in the processes of cardiac hypertrophy and fibrosis. Our study suggests that miRNAs are involved in the process of cardiac fibrosis and remodeling presented in CD and indicate a group of miRNAs as potential biomarkers of disease progression in CCC.

Bone marrow-derived mesenchymal stem/stromal cells reverse the sensorial diabetic neuropathy via modulation of spinal neuroinflammatory cascades.

BACKGROUND: Diabetic neuropathy (DN) is a frequent and debilitating manifestation of diabetes mellitus, to which there are no effective therapeutic approaches. Mesenchymal stem/stromal cells (MSC) have a great potential for the treatment of this syndrome, possibly through regenerative actions on peripheral nerves. Here, we evaluated the therapeutic effects of MSC on spinal neuroinflammation, as well as on ultrastructural aspects of the peripheral nerve in DN-associated sensorial dysfunction. METHODS: C57Bl/6 mice were treated with bone marrow-derived MSC (1 × 106), conditioned medium from MSC cultures (CM-MSC) or vehicle by endovenous route following the onset of streptozotocin (STZ)-induced diabetes. Paw mechanical and thermal nociceptive thresholds were evaluated by using von Frey filaments and Hargreaves test, respectively. Morphological and morphometric analysis of the sciatic nerve was performed by light microscopy and transmission electron microscopy. Mediators and markers of neuroinflammation in the spinal cord were measured by radioimmunoassay, real-time PCR, and immunofluorescence analyses. RESULTS: Diabetic mice presented behavioral signs of sensory neuropathy, mechanical allodynia, and heat hypoalgesia, which were completely reversed by a single administration of MSC or CM-MSC. The ultrastructural analysis of the sciatic nerve showed that diabetic mice exhibited morphological and morphometric alterations, considered hallmarks of DN, such as degenerative changes in axons and myelin sheath, and reduced area and density of unmyelinated fibers. In MSC-treated mice, these structural alterations were markedly less commonly observed and/or less pronounced. Moreover, MSC transplantation inhibited multiple parameters of spinal neuroinflammation found in diabetic mice, causing the reduction of activated astrocytes and microglia, oxidative stress signals, galectin-3, IL-1ß, and TNF-α production. Conversely, MSC increased the levels of anti-inflammatory cytokines, IL-10, and TGF-ß. CONCLUSIONS: The present study described the modulatory effects of MSC on spinal cord neuroinflammation in diabetic mice, suggesting new mechanisms by which MSC can improve DN.

Association of Cardiac Galectin-3 Expression, Myocarditis, and Fibrosis in Chronic Chagas Disease Cardiomyopathy.

Chronic Chagas disease cardiomyopathy, caused by Trypanosoma cruzi infection, is a major cause of heart failure in Latin America. Galectin-3 (Gal-3) has been linked to cardiac remodeling and poor prognosis in heart failure of different etiologies. Herein, we investigated the involvement of Gal-3 in the disease pathogenesis and its role as a target for disease intervention. Gal-3 expression in mouse hearts was evaluated during T. cruzi infection by confocal microscopy and flow cytometry analysis, showing a high expression in macrophages, T cells, and fibroblasts. In vitro studies using Gal-3 knockdown in cardiac fibroblasts demonstrated that Gal-3 regulates cell survival, proliferation, and type I collagen synthesis. In vivo blockade of Gal-3 with N-acetyl-d-lactosamine in T. cruzi-infected mice led to a significant reduction of cardiac fibrosis and inflammation in the heart. Moreover, a modulation in the expression of proinflammatory genes in the heart was observed. Finally, histological analysis in human heart samples obtained from subjects with Chagas disease who underwent heart transplantation showed the expression of Gal-3 in areas of inflammation, similar to the mouse model. Our results indicate that Gal-3 plays a role in the pathogenesis of experimental chronic Chagas disease, favoring inflammation and fibrogenesis. Moreover, by demonstrating Gal-3 expression in human hearts, our finding reinforces that this protein could be a novel target for drug development for Chagas cardiomyopathy.

Effect of GaAlAs low-level laser therapy on mouth opening after orthognathic surgery.

To evaluate low-level laser therapy (LLLT) as an adjunct to enhance postoperative mouth opening after orthognathic surgery. Prospective clinical trial of 82 patients allocated into an intervention group (laser, LG) and a control group (no laser, CG) and subgroups according to the procedure type : (1) surgically assisted rapid maxillary expansion (SARME); (2) maxillary surgery; (3) mandibular surgery; or (4) bimaxillary surgery. LG patients received LLLT immediately after surgery and every 24 h thereafter for 3 days, using a gallium-aluminum-arsenide (GaAlAs) diode laser (780 nm, 28 spots, 14 on each side of the face, output power 2 J/spot). Maximum mouth opening was measured using digital calipers at five time points: preoperative baseline and postoperative days 2, 7, 14, and 21. ANOVA was used to evaluate difference in mouth opening across groups. Significance was accepted at P ≤ 0.05. Final average mouth opening differed between women (GL1 = 94.24%, GC1 = 89.54%, GL2 = 69.39%; GC2 = 68.46%; GL3 = 65.11%; GC3 = 58.64%; GL4 = 61.85%; GC4 = 57.11%) and men (GL1 = 86.92%, GC1 = 102.44%, GL2 = 77.56%; GC2 = 81.65%; GL3 = 80.29%; GC3 = 67.63%; GL4 = 66.93%; GC4 = 55.31%). There were no significant differences between the SARME and isolated maxillary/mandibular surgery groups. In the bimaxillary groups, average mouth opening was increased in all patients who received LLLT, significantly so in male patients. LLLT with a GaAlAs diode laser (780 nm) did not affect postoperative mouth opening after SARME, isolated maxillary surgery, or isolated mandibular surgery. However, it improved mouth opening in men who had undergone bimaxillary orthognathic surgery.

Image-guided percutaneous intralesional administration of mesenchymal stromal cells in subjects with chronic complete spinal cord injury: a pilot study.

BACKGROUND AIMS: The potential of cell therapies to improve neurological function in subjects with spinal cord injury (SCI) is currently under investigation. In this context, the choice of cell type, dose, route and administration regimen are key factors. Mesenchymal stromal cells (MSCs) can be easily obtained, expanded and are suitable for autologous transplantation. Here we conducted a pilot study that evaluated safety, feasibility and potential efficacy of intralesional MSCs transplantation performed through image-guided percutaneous injection, in subjects with chronic complete SCI. METHODS: Five subjects with chronic traumatic SCI (>6 months), at thoracic level, classified as American Spinal Cord Injury Association impairment scale (AIS) grade A, complete injury, were included. Somatosensory evoked potentials (SSEP), spinal magnetic resonance imaging (MRI) and urodynamics were assessed before and after treatment. Autologous MSCs were injected directly into the lesion site through percutaneous injection guided by computerized tomography (CT). RESULTS: Tomography-guided percutaneous cell transplantation was a safe procedure without adverse effects. All subjects displayed improvements in spinal cord independence measure (SCIM) scores and functional independence measure (FIM), mainly due to improvements in bowel movements and regularity. Three subjects showed improved sensitivity to tactile stimulation. Two subjects improved AIS grade to B, incomplete injury, although this was sustained in only one of them during the study follow-up. CONCLUSION: Autologous bone marrow MSC transplantation, performed through CT-guided percutaneous injection, was shown to be safe and feasible. Further studies are required to demonstrate efficacy of this therapeutic scheme.

Evaluation of two formulations containing mineral trioxide aggregate on delayed tooth replantation: relevance of RANKL/RANK/OPG system.

This study aimed to evaluate the effects of White MTA (WMTA) and MTA Fillapex(®) on root resorption, when used for root canal filling, in a rat model of delayed tooth replantation, with special focus on the RANKL/RANK/OPG system. Maxillary right central incisors of male rats were extracted (total N = 48), and exposed to dry environment for 30 min. The animals were allocated into four groups: (1) WMTA; (2) MTA Fillapex; (3) Calcium hydroxide; (4) Negative control. After periodontal ligament removal, root canals were filled with the corresponding material and replanted. After 10 and 60 days, qualitative and semi-quantitative histological and immunohistochemical analyses were carried out. Analysis of variance (ANOVA) with Tukey's post hoc adjustment was used, at 10 and 60 days, to compare the experimental groups in terms of the inflammatory scores and in terms of the changes in OPG, RANK and RANKL. Both WMTA and MTA Fillapex groups displayed inflammatory and replacement resorption, with the presence of dento-alveolar ankylosis, similarly to that observed for calcium hydroxide, in either 10 or 60 days. Notably, a slight increase of the inflammatory process was observed in both MTA groups. Quantitatively, inflammation score analysis showed a significant difference between the calcium hydroxide and the control group at 10 days. On 60 days, dento-alveolar ankylosis was found significantly increased in the MTA Fillapex, in comparison to the control group (p < 0.05). For immunohistochemical analysis, the expression of both RANK and RANKL was reduced in calcium hydroxide and WMTA groups, from 10 to 60 days of evaluation, an effect that was accompanied by increased OPG immunolabelling. Otherwise, the MTA Fillapex group presented a general increase of RANKL immunopositivity, similarly to that observed in the negative control group. Our data showed that none of tested materials was able to fully prevent the root resorption, although the white MTA cement presented an outcome comparable to that seen for calcium hydroxide. MTA cements might present some advantages when considering no need of frequent changes, although the effects of MTA cements in dental avulsion still require further investigation.

Peripheral osteoma bilateral of the mandible without association with Gardner syndrome.

Periosteal osteoma is a rare benign pathologic lesion in the jaws and the mandible is the anatomic region most frequently involved. Elective treatment consists of surgical excision. The aim of this report was to report a rare case of bilateral periosteal osteoma involving the mandible--a painless, firm, and well-circumscribed lesion, with more bony prominence on the left than on the right side. The patient had no history of facial trauma or systemic changes that could intervene with the progression of the lesion. It was diagnosed as a periosteal osteoma, and surgical excision was performed. No recurrence after 4 years of follow-up was demonstrated. Surgical excision of the periosteal osteoma was demonstrated to be a useful technical strategy that simplifies and accelerates the surgical procedures and probably contributes to establish harmony of the jaws. Periodical clinical and radiographic follow-ups after surgery are advised.

Process Development for Adoptive Cell Therapy in Academia: A Pipeline for Clinical-Scale Manufacturing of Multiple TCR-T Cell Products.

Cellular immunotherapies based on T cell receptor (TCR) transfer are promising approaches for the treatment of cancer and chronic viral infections. The discovery of novel receptors is expanding considerably; however, the clinical development of TCR-T cell therapies still lags. Here we provide a pipeline for process development and clinical-scale manufacturing of TCR-T cells in academia. We utilized two TCRs specific for hepatitis C virus (HCV) as models because of their marked differences in avidity and functional profile in TCR-redirected cells. With our clinical-scale pipeline, we reproduced the functional profile associated with each TCR. Moreover, the two TCR-T cell products demonstrated similar yield, purity, transduction efficiency as well as phenotype. The TCR-T cell products had a highly reproducible yield of over 1.4 × 109 cells, with an average viability of 93%; 97.8-99% of cells were CD3+, of which 47.66 ± 2.02% were CD8+ T cells; the phenotype was markedly associated with central memory (CD62L+CD45RO+) for CD4+ (93.70 ± 5.23%) and CD8+ (94.26 ± 4.04%). The functional assessments in 2D and 3D cell culture assays showed that TCR-T cells mounted a polyfunctional response to the cognate HCV peptide target in tumor cell lines, including killing. Collectively, we report a solid strategy for the efficient large-scale manufacturing of TCR-T cells.

Current Status of Mesenchymal Stem/Stromal Cells for Treatment of Neurological Diseases.

Neurological disorders include a wide spectrum of clinical conditions affecting the central and peripheral nervous systems. For these conditions, which affect hundreds of millions of people worldwide, generally limited or no treatments are available, and cell-based therapies have been intensively investigated in preclinical and clinical studies. Among the available cell types, mesenchymal stem/stromal cells (MSCs) have been widely studied but as yet no cell-based treatment exists for neurological disease. We review current knowledge of the therapeutic potential of MSC-based therapies for neurological diseases, as well as possible mechanisms of action that may be explored to hasten the development of new and effective treatments. We also discuss the challenges for culture conditions, quality control, and the development of potency tests, aiming to generate more efficient cell therapy products for neurological disorders.

Clinical Trials Using Mesenchymal Stem Cells for Spinal Cord Injury: Challenges in Generating Evidence.

Spinal cord injury (SCI) remains an important public health problem which often causes permanent loss of muscle strength, sensation, and function below the site of the injury, generating physical, psychological, and social impacts throughout the lives of the affected individuals, since there are no effective treatments available. The use of stem cells has been investigated as a therapeutic approach for the treatment of SCI. Although a significant number of studies have been conducted in pre-clinical and clinical settings, so far there is no established cell therapy for the treatment of SCI. One aspect that makes it difficult to evaluate the efficacy is the heterogeneity of experimental designs in the clinical trials that have been published. Cell transplantation methods vary widely among the trials, and there are still no standardized protocols or recommendations for the therapeutic use of stem cells in SCI. Among the different cell types, mesenchymal stem/stromal cells (MSCs) are the most frequently tested in clinical trials for SCI treatment. This study reviews the clinical applications of MSCs for SCI, focusing on the critical analysis of 17 clinical trials published thus far, with emphasis on their design and quality. Moreover, it highlights the need for more evidence-based studies designed as randomized controlled trials and potential challenges to be addressed in context of stem cell therapies for SCI.

Enucleation and liquid nitrogen cryotherapy in the treatment of keratocystic odontogenic tumors: a case series.

PURPOSE: This study describes the technique of lesion enucleation without capsule disruption combined with liquid nitrogen cryotherapy in the surgical treatment of keratocystic odontogenic tumors (KOTs). PATIENTS AND METHODS: Eight patients (9 KOTs) were included in the study. After enucleation, liquid nitrogen was applied twice for 1 minute, with 5-minute intervals between applications. The patients were followed up for 3 to 9 years. RESULTS: There were no recurrences during the follow-up of 9 KOTs for up to 9 years. Only 1 patient had temporary reversible loss of lip sensation after treatment. There were no pathologic fractures. In all cases bone height at the surgical site was restored, and no patients needed bone reconstruction for post-treatment rehabilitation. CONCLUSIONS: This study confirmed the efficiency of KOT treatment enucleation without fragmentation combined with liquid nitrogen cryotherapy at the surgical site.

Liquid Biopsy in Hepatocellular Carcinoma: Opportunities and Challenges for Immunotherapy.

Hepatocellular carcinoma (HCC) is one of the deadliest cancer types worldwide. HCC is often diagnosed at a late stage when the therapeutic options are very limited. However, even at the earlier stages, the best treatment is liver transplantation, surgical resection or ablation. Surgical resection and ablation may carry a high risk of tumor recurrence. The recent introduction of immunotherapies resulted in clinical responses for a subgroup of patients, but there were still no effective predictive markers for response to immunotherapy or for recurrence after surgical therapy. The identification of biomarkers that could correlate and predict response or recurrence would require close monitoring of the patients throughout and after the completion of treatment. However, this would not be performed efficiently by repeated and invasive tissue biopsies. A better approach would be to use liquid biopsies including circulating tumor DNA (ctDNA), circulating RNA (e.g., microRNAs), circulating tumor cells (CTC) and extracellular vesicles (EVs) (e.g., exosomes) for disease monitoring in a non-invasive manner. In this review, we discuss the currently available technology that can enable the use of liquid biopsy as a diagnostic and prognostic tool. Moreover, we discuss the opportunities and challenges of the clinical application of liquid biopsy for immunotherapy of HCC.

Mesenchymal stem cells reduce the oxaliplatin-induced sensory neuropathy through the reestablishment of redox homeostasis in the spinal cord.

AIMS: The present study was designed to investigate whether the antinociceptive effect of bone marrow-derived mesenchymal stem/stromal cells (MSC) during oxaliplatin (OXL)-induced sensory neuropathy is related to antioxidant properties. MAIN METHODS: Male mice C57BL/6 were submitted to repeated intravenous administration of OXL (1 mg/kg, 9 administrations). After the establishment of sensory neuropathy, mice were treated with a single intravenous administration of MSC (1 × 106), vehicle or gabapentin. Paw mechanical and thermal nociceptive thresholds were evaluated through von Frey filaments and cold plate test, respectively. Motor performance was evaluated in the rota-rod test. Gene expression profile, cytokine levels, and oxidative stress markers in the spinal cord were evaluated by real-time PCR, ELISA and biochemical assays, respectively. KEY FINDINGS: OXL-treated mice presented behavioral signs of sensory neuropathy, such as mechanical allodynia and thermal hyperalgesia, which were completely reverted by a single administration of MSC. Repeated oral treatment with gabapentin (70 mg/kg) induced only transient antinociception. The IL-1ß and TNF-α spinal levels did not differ between mice with or without sensory neuropathy. MSC increased the levels of anti-inflammatory cytokines, IL-10 and TGF-ß, in the spinal cord of neuropathic mice, in addition to increasing the gene expression of antioxidant factors SOD and Nrf-2. Additionally, nitrite and MDA spinal levels were reduced by the MSC treatment. SIGNIFICANCE: MSC induce reversion of sensory neuropathy induced by OXL possibly by activation of anti-inflammatory and antioxidant pathways, leading to reestablishment of redox homeostasis in the spinal cord.

A Novel High-Content Screening-Based Method for Anti-Trypanosoma cruzi Drug Discovery Using Human-Induced Pluripotent Stem Cell-Derived Cardiomyocytes.

Chagas disease is caused by Trypanosoma cruzi infection and remains a relevant cause of chronic heart failure in Latin America. The pharmacological arsenal for Chagas disease is limited, and the available anti-T. cruzi drugs are not effective when administered during the chronic phase. Cardiomyocytes derived from human-induced pluripotent stem cells (hiPSC-CMs) have the potential to accelerate the process of drug discovery for Chagas disease, through predictive preclinical assays in target human cells. Here, we aimed to establish a novel high-content screening- (HCS-) based method using hiPSC-CMs to simultaneously evaluate anti-T. cruzi activity and cardiotoxicity of chemical compounds. To provide proof-of-concept data, the reference drug benznidazole and three compounds with known anti-T. cruzi activity (a betulinic acid derivative named BA5 and two thiazolidinone compounds named GT5A and GT5B) were evaluated in the assay. hiPSC-CMs were infected with T. cruzi and incubated for 48 h with serial dilutions of the compounds for determination of EC50 and CC50 values. Automated multiparametric analyses were performed using an automated high-content imaging system. Sublethal toxicity measurements were evaluated through morphological measurements related to the integrity of the cytoskeleton by phalloidin staining, nuclear score by Hoechst 33342 staining, mitochondria score following MitoTracker staining, and quantification of NT-pro-BNP, a peptide released upon mechanical myocardial stress. The compounds showed EC50 values for anti-T. cruzi activity similar to those previously described for other cell types, and GT5B showed a pronounced trypanocidal activity in hiPSC-CMs. Sublethal changes in cytoskeletal and nucleus scores correlated with NT-pro-BNP levels in the culture supernatant. Mitochondrial score changes were associated with increased cytotoxicity. The assay was feasible and allowed rapid assessment of anti-T. cruzi action of the compounds, in addition to cardiotoxicity parameters. The utilization of hiPSC-CMs in the drug development workflow for Chagas disease may help in the identification of novel compounds.

Leukemia Inhibitory Factor (LIF) Overexpression Increases the Angiogenic Potential of Bone Marrow Mesenchymal Stem/Stromal Cells.

Mesenchymal stem/stromal cells (MSCs) have the ability to secrete bioactive molecules, exerting multiple biological effects, such as tissue regeneration, reduction of inflammation, and neovascularization. The therapeutic potential of MSCs can be increased by genetic modification to overexpress cytokines and growth factors. Here we produced mouse MSCs overexpressing human leukemia inhibitory factor (LIF) to assess their proangiogenic potential in vitro and in vivo. Mouse bone marrow-derived MSCs were transduced by using a second-generation lentiviral system to express human LIF. Leukemia inhibitory factor expression was confirmed by RT-qPCR and by ELISA, allowing the quantification of the transcript and secreted protein, respectively. Flow cytometry analysis and trilineage differentiation assay showed that the MSC_LIF cell line maintained the immunophenotype and a multipotency characteristic of MSCs. The immunosuppressive activity of MSC_LIF was confirmed using a lymphoproliferation assay. Moreover, gene expression analysis demonstrated upregulation of genes coding for strategic factors in the neovascularization process, such as angiogenin, IL-8, MCP-1, and VEGF, and for the perivascular cell markers αSMA, Col4a1, SM22, and NG2. To evaluate the pro-angiogenic potential of MSC_LIF, we first tested its effects on endothelial cells obtained from umbilical vein in a scratch wound healing assay. Conditioned medium (CM) from MSC_LIF promoted a significant increase in cell migration compared to CM from control MSC. Additionally, in vitro tube formation of endothelial cells was increased by the presence of MSC_LIF, as shown in microvessel sprouting in aortic ring cultures. Finally, an in vivo Matrigel plug assay was performed, showing that MSC_LIF were more potent in promoting in vivo angiogenesis and tissue vascularization than control MSCs. In conclusion, LIF overexpression is a promising strategy to increase the proangiogenic potential of MSCs and sets precedents for future investigations of their potential applications for the treatment of ischemic diseases and tissue repair.

Two Decades of Global Progress in Authorized Advanced Therapy Medicinal Products: An Emerging Revolution in Therapeutic Strategies.

The introduction of advanced therapy medicinal products (ATMPs) to the global pharma market has been revolutionizing the pharmaceutical industry and has opened new routes for treating various types of cancers and incurable diseases. In the past two decades, a noticeable part of clinical practices has been devoting progressively to these products. The first step to develop such an ATMP product is to be familiar with other approved products to obtain a general view about this industry trend. The present paper depicts an overall perspective of approved ATMPs in different countries, while reflecting the degree of their success in a clinical point of view and highlighting their main safety issues and also related market size as a whole. In this regard, published articles regarding safety, efficacy, and market size of approved ATMPs were reviewed using the search engines PubMed, Scopus, and Google Scholar. For some products which the related papers were not available, data on the relevant company website were referenced. In this descriptive study, we have introduced and classified approved cell, gene, and tissue engineering-based products by different regulatory agencies, along with their characteristics, manufacturer, indication, approval date, related regulatory agency, dosage, product description, price and published data about their safety and efficacy. In addition, to gain insights about the commercial situation of each product, we have gathered accessible sale reports and market size information that pertain to some of these products.

Arming Mesenchymal Stromal/Stem Cells Against Cancer: Has the Time Come?

Since mesenchymal stromal/stem cells (MSCs) were discovered, researchers have been drawn to study their peculiar biological features, including their immune privileged status and their capacity to selectively migrate into inflammatory areas, including tumors. These properties make MSCs promising cellular vehicles for the delivery of therapeutic molecules in the clinical setting. In recent decades, the engineering of MSCs into biological vehicles carrying anticancer compounds has been achieved in different ways, including the loading of MSCs with chemotherapeutics or drug functionalized nanoparticles (NPs), genetic modifications to force the production of anticancer proteins, and the use of oncolytic viruses. Recently, it has been demonstrated that wild-type and engineered MSCs can release extracellular vesicles (EVs) that contain therapeutic agents. Despite the enthusiasm for MSCs as cyto-pharmaceutical agents, many challenges, including controlling the fate of MSCs after administration, must still be considered. Preclinical results demonstrated that MSCs accumulate in lung, liver, and spleen, which could prevent their engraftment into tumor sites. For this reason, physical, physiological, and biological methods have been implemented to increase MSC concentration in the target tumors. Currently, there are more than 900 registered clinical trials using MSCs. Only a small fraction of these are investigating MSC-based therapies for cancer, but the number of these clinical trials is expected to increase as technology and our understanding of MSCs improve. This review will summarize MSC-based antitumor therapies to generate an increasing awareness of their potential and limits to accelerate their clinical translation.

A primary cutaneous anaplastic large cell lymphoma mimicking labial herpes.

INTRODUCTION: A primary cutaneous CD-30 positive T -cell lymphoproliferative disorders are rare and heterogeneous group of primary skin tumors, which include primary cutaneous anaplastic large cell lymphoma (PCALCL) and lymphomatoid papulois. CASE REPORT: We report a rare an atypical case of PCALCL with an aggressive and refractory behavior that occurred in the lip vermilion, and that had been initially diagnosed as aggressive herpes. The lesion was recurrent and refractory to the CHOEP chemotherapy protocol followed by radiotherapy, but after hyper CVAD (acronym) + brentuximab with a considerable improvement. After 4 cycles of hyper CVAD plus brentuximab, the patient underwent 100% compatible sibling bone marrow transplantation, with success in the procedure. CONCLUSION: Primary cutaneous anaplastic large cell lymphoma is a rare disease of difficult diagnosis and may be confused with chronic infectious diseases, postponing treatment.

Genetic Engineering as a Strategy to Improve the Therapeutic Efficacy of Mesenchymal Stem/Stromal Cells in Regenerative Medicine.

Mesenchymal stem/stromal cells (MSCs) have been widely studied in the field of regenerative medicine for applications in the treatment of several disease settings. The therapeutic potential of MSCs has been evaluated in studies in vitro and in vivo, especially based on their anti-inflammatory and pro-regenerative action, through the secretion of soluble mediators. In many cases, however, insufficient engraftment and limited beneficial effects of MSCs indicate the need of approaches to enhance their survival, migration and therapeutic potential. Genetic engineering emerges as a means to induce the expression of different proteins and soluble factors with a wide range of applications, such as growth factors, cytokines, chemokines, transcription factors, enzymes and microRNAs. Distinct strategies have been applied to induce genetic modifications with the goal to enhance the potential of MCSs. This review aims to contribute to the update of the different genetically engineered tools employed for MSCs modification, as well as the factors investigated in different fields in which genetically engineered MSCs have been tested.