Acute and Post-Acute COVID-19 Cardiovascular Complications: A Comprehensive Review.

PURPOSE OF REVIEW: The risk of cardiovascular complications due to SARS-CoV-2 are significantly increased within the first 6 months of the infection. Patients with COVID-19 have an increased risk of death, and there is evidence that many may experience a wide range of post-acute cardiovascular complications. Our work aims to provide an update on current clinical aspects of diagnosis and treatment of cardiovascular manifestations during acute and long-term COVID-19. RECENT FINDINGS: SARS-CoV-2 has been shown to be associated with increased incidence of cardiovascular complications such as myocardial injury, heart failure, and dysrhythmias, as well as coagulation abnormalities not only during the acute phase but also beyond the first 30 days of the infection, associated with high mortality and poor outcomes. Cardiovascular complications during long-COVID-19 were found regardless of comorbidities such as age, hypertension, and diabetes; nevertheless, these populations remain at high risk for the worst outcomes during post-acute COVID-19. Emphasis should be given to the management of these patients. Treatment with low-dose oral propranolol, a beta blocker, for heart rate management may be considered, since it was found to significantly attenuate tachycardia and improve symptoms in postural tachycardia syndrome, while for patients on ACE inhibitors or angiotensin-receptor blockers (ARBs), under no circumstances should these medications be withdrawn. In addition, in patients at high risk after hospitalization due to COVID-19, thromboprophylaxis with rivaroxaban 10 mg/day for 35 days improved clinical outcomes compared with no extended thromboprophylaxis. In this work we provide a comprehensive review on acute and post-acute COVID-19 cardiovascular complications, symptomatology, and pathophysiology mechanisms. We also discuss therapeutic strategies for these patients during acute and long-term care and highlight populations at risk. Our findings suggest that older patients with risk factors such as hypertension, diabetes, and medical history of vascular disease have worse outcomes during acute SARS-CoV-2 infection and are more likely to develop cardiovascular complications during long-COVID-19.

Cerebrovascular Manifestations of SARS-CoV-2: A Comprehensive Review.

Purpose of review: The risks of cerebrovascular manifestations due to SARS-CoV-2 infection are significantly increased within the first 6 months of the infection. Our work aims to give an update on current clinical aspects of diagnosis and treatment of cerebrovascular manifestations during acute and long-term SARS-CoV-2 infection. Recent findings: The incidence of acute ischemic stroke and haemorrhagic stroke during acute SARS-CoV-2 patients is estimated at 0.9 to 4.6% and 0.5-0.9%, respectively, and were associated with increased mortality. The majority presented with hemiparesis, dysarthria, sensory deficits, and a NIHSS score within 5-15. In addition, beyond the first 30 days of infection people with COVID-19 exhibited increased risk of stroke. During acute phase, age, hypertension, diabetes, and medical history of vascular disease were increased in patients with COVID-19 with new onset of cerebrovascular manifestations, while during long-COVID-19, the risk of cerebrovascular manifestations were found increased regardless of these factors. The management of patients with large-vessel ischemic stroke fulfilling the intravenous thrombolysis criteria are successfully treated according to the guidelines, while hyperosmolar therapy is typically administered in 4- to 6-h intervals. In addition, prophylaxis of anticoagulation therapy is associated with a better prognosis and low mortality during acute and post hospital discharge of patients with COVID-19. Summary: In this work, we provide a comprehensive review of the current literature on acute and post-acute COVID-19 cerebrovascular sequelae, symptomatology, and its pathophysiology mechanisms. Moreover, we discuss therapeutic strategies for these patients during acute and long-term care and point populations at risk. Our findings suggest that older patients with risk factors such as hypertension, diabetes, and medical history of vascular disease are more likely to develop cerebrovascular complications.

Hereditary Diffuse Gastric Cancer: A 2022 Update.

Gastric cancer is ranked fifth among the most commonly diagnosed cancers, and is the fourth leading cause of cancer-related deaths worldwide. The majority of gastric cancers are sporadic, while only a small percentage, less than 1%, are hereditary. Hereditary diffuse gastric cancer (HDGC) is a rare malignancy, characterized by early-onset, highly-penetrant autosomal dominant inheritance mainly of the germline alterations in the E-cadherin gene (CDH1) and ß-catenin (CTNNA1). In the present study, we provide an overview on the molecular basis of HDGC and outline the essential elements of genetic counseling and surveillance. We further provide a practical summary of current guidelines on clinical management and treatment of individuals at risk and patients with early disease.

Advances in stem cell therapy in Alzheimer's disease: a comprehensive clinical trial review.

Alzheimer's disease (AD) is the most common type of dementia responsible for more than 121,499 deaths from AD in 2019 making AD the sixth-leading cause in the United States. AD is a progressive neurodegenerative disorder characterized by decline of memory, behavioral impairments that affects a person's ability to function independently ultimately leading to death. The current pressing need for a treatment for (AD) and advances in the field of cell therapy, has rendered stem cell therapeutics a promising field of research. Despite advancements in stem cell technology, confirmed by encouraging pre-clinical utilization of stem cells in AD animal models, the number of clinical trials evaluating the efficacy of stem cell therapy is limited, with the results of many ongoing clinical trials on cell therapy for AD still pending. Mesenchymal stem cells (MSCs) have been the main focus in these studies, reporting encouraging results concerning safety profile, however their efficacy remains unproven. In the current article we review the latest advances regarding different sources of stem cell therapy and present a comprehensive list of every available clinical trial in national and international registries. Finally, we discuss drawbacks arising from AD pathology and technical limitations that hinder the transition of stem cell technology from bench to bedside. Our findings emphasize the need to increase clinical trials towards uncovering the mode of action and the underlying therapeutic mechanisms of transplanted cells as well as the molecular mechanisms controlling regeneration and neuronal microenvironment.

Immunotherapy in Combination with Well-Established Treatment Strategies in Pancreatic Cancer: Current Insights.

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and fourth most common cause of death in developed countries. Despite improved survival rates after resection combined with adjuvant chemotherapy or neoadjuvant chemotherapy, recurrence still occurs in a high percentage of patients within the first 2 years after resection. Immunotherapy aims to improve antitumor immune responses and reduce toxicity providing a more specific, targeted therapy compared to chemotherapy and has been proved an efficient therapeutic tool for many solid tumors. In this work, we present the latest advances in PDAC treatment using a combination of immunotherapy with other interventions such as chemotherapy and/or radiation both at neoadjuvant and adjuvant setting. Moreover, we outline the role of the tumor microenvironment as a key barrier to immunotherapy efficacy and examine how immunotherapy biomarkers may be used to detect immunotherapy's response.

Immunotherapy for gastroenteropancreatic neuroendocrine neoplasms (GEP-NENs): a 2021 update.

Neuroendocrine neoplasms (NENs) are a group of heterogeneous malignancies, arising from the neuroendocrine system. These neoplasms are divided into two distinct groups, the low-proliferating, well-differentiated neuroendocrine tumors (NETs), and the highly-proliferating, poorly-differentiated neuroendocrine carcinomas (NECs). Recent data demonstrate that the incidence of gastroenteropancreatic (GEP) neuroendocrine neoplasms, GEP-NETs and GEP-NECs, has increased exponentially over the last three decades. Although surgical resection is considered the best treatment modality, patients with GEP-NETs often present with advanced disease at diagnosis associated with a 5-year survival rate of 57% for well-differentiated tumors, and only 5.2% for small-cell tumors. Immunotherapy is a novel treatment approach, which has demonstrated effective and promising therapeutic results against several types of cancers. In the present study, we review the current ongoing clinical trials and to evaluate the efficacy of immunotherapy in GEP-NENs. Furthermore, we analyze the importance of tumor genetic profiling and its clinical implications in immunotherapy response.

Immunotherapy for gastric cancer: a 2021 update.

Gastric cancer, the fifth most frequent cancer and the fourth leading cause of cancer deaths, accounts for a devastating death rate worldwide. Since the majority of patients with gastric cancer are diagnosed at advanced stages, they are not suitable for surgery and present with locally advanced or metastatic disease. Recent advances in immunotherapy have elicited a considerable amount of attention as viable therapeutic options for several cancer types. This work presents a summary of the currently ongoing clinical trials and critically addresses the efficacy of a large spectrum of immunotherapy approaches in the general population for gastric cancer as well as in relation to tumor genetic profiling.

Immunotherapy for cholangiocarcinoma: a 2021 update.

Cholangiocarcinoma (CCA) is a rare malignancy with generally dismal prognosis. Immunotherapy has revolutionized the management of cancer patients during the last decade, offering durable responses with an acceptable safety profile, but there are still no significant advances regarding CCA. Novel immunotherapeutic methods, such as cancer vaccines, oncolytic viruses, adoptive cell therapy and combinations of immune checkpoint inhibitors with other agents are currently under investigation and may improve prognosis. Efforts to find robust biomarkers for response are also ongoing. In this review, we discuss the rationale for the use of immunotherapy in CCA and available clinical data. Ongoing trials will also be presented, as well as key findings from each study.

Immunotherapy for Hepatocellular Carcinoma: A 2021 Update.

Hepatocellular carcinoma (HCC) is one of one of the most frequent liver cancers and the fourth leading cause of cancer-related mortality worldwide. Current treatment options such as surgery, neoadjuvant chemoradiotherapy, liver transplantation, and radiofrequency ablation will benefit only a very small percentage of patients. Immunotherapy is a novel treatment approach representing an effective and promising option against several types of cancer. The aim of our study is to present the currently ongoing clinical trials and to evaluate the efficacy of immunotherapy in HCC. In this paper, we demonstrate that combination of different immunotherapies or immunotherapy with other modalities results in better overall survival (OS) and progression-free survival (PFS) compared to single immunotherapy agent. Another objective of this paper is to demonstrate and highlight the importance of tumor microenvironment as a predictive and prognostic marker and its clinical implications in immunotherapy response.

Assessment of Synergistic Contribution of Histone Deacetylases in Prognosis and Therapeutic Management of Sarcoma.

Sarcomas are a rare group of neoplasms with a mesenchymal origin that are mainly characterized by the abnormal growth of connective tissue cells. The standard treatment for local control of sarcomas includes surgery and radiation, while for adjuvant and palliative therapy, chemotherapy has been strongly recommended. Despite the availability of multimodal therapies, the survival rate for patients with sarcoma is still not satisfactory. In recent decades, there has been a considerable effort to overcome chemotherapy resistance in sarcoma cells. This has led to the investigation of more cellular compounds implicated in gene expression and transcription processes. Furthermore, it has been discovered that histone acetylation/deacetylation equilibrium is affected in carcinogenesis, leading to a modified chromatin structure and therefore changes in gene expression. In addition, histone deacetylase inhibition is found to play a key role in limiting the tumor burden in sarcomas, as histone deacetylase inhibitors act on well-described oncogenic signaling pathways. Histone deacetylase inhibitors disrupt the increased cell motility and invasiveness of sarcoma cells, undermining their metastatic potential. Moreover, their activity on evoking cell arrest has been extensively described, with histone deacetylase inhibitors regulating the reactivation of tumor suppressor genes and induction of apoptosis. Promoting autophagy and increasing cellular reactive oxygen species are also included in the antitumor activity of histone deacetylase inhibitors. It should be noted that many studies revealed the synergy between histone deacetylase inhibitors and other drugs, leading to the enhancement of an antitumor effect in sarcomas. Therefore, there is an urgent need for therapeutic interventions modulated according to the distinct clinical and molecular characteristics of each sarcoma subtype. It is concluded that a better understanding of histone deacetylase and histone deacetylase inhibitors could provide patients with sarcoma with more targeted and efficient therapies, which may contribute to significant improvement of their survival potential.

Viral delivery of multiple miRNAs promotes retinal ganglion cell survival and functional preservation after optic nerve crush injury.

Bone marrow mesenchymal stem cell (BMSC)-derived small extracellular vesicles (sEV) but not fibroblast sEV provide retinal ganglion cell (RGC) neuroprotection both in vitro and in vivo, with miRNAs playing an essential role. More than 40 miRNAs were more abundant in BMSC-sEV than in fibroblast-sEV. The purpose of this study was to test the in vitro and in vivo neuroprotective and axogenic properties of six candidate miRNAs (miR-26a, miR-17, miR-30c-2, miR-92a, miR-292, and miR-182) that were more abundant in BMSC-sEV than in fibroblast-sEV. Adeno-associated virus 2 (AAV2) expressing a combination of three of the above candidate miRNAs were added to heterogenous adult rat retinal cultures or intravitreally injected into rat eyes one week before optic nerve crush (ONC) injury. Survival and neuritogenesis of ßIII-tubulin+ RGCs was assessed in vitro, as well as the survival of RBPMS+ RGCs and regeneration of their axons in vivo. Retinal nerve fiber layer thickness (RNFL) was measured to assess axonal density whereas positive scotopic threshold response electroretinography amplitudes provided a readout of RGC function. Qualitative retinal expression of PTEN, a target of several of the above miRNAs, was used to confirm successful miRNA activity. AAV2 reliably transduced RGCs in vitro and in vivo. Viral delivery of miRNAs in vitro showed a trend towards neuroprotection but remained insignificant. Delivery of selected combinations of miRNAs (miR-17-5p, miR-30c-2 and miR-92a; miR-92a, miR-292 and miR-182) before ONC provided significant therapeutic benefits according to the above measurable endpoints. However, no single miRNA appeared to be responsible for the effects observed, whilst positive effects observed appeared to coincide with successful qualitative reduction in PTEN immunofluorescence in the retina. Viral delivery of miRNAs provides a possible neuroprotective strategy for injured RGCs that is conducive to therapeutic manipulation.

Immunotherapy for pancreatic cancer: A 2020 update.

Pancreatic adenocarcinoma (PAC) is associated with extremely poor prognosis and remains a lethal malignancy. The main cure for PAC is surgical resection. Further treatment modalities, such as surgery, chemotherapy, radiotherapy and other locoregional therapies provide low survival rates. Currently, many clinical trials seek to assess the efficacy of immunotherapeutic strategies in PAC, including immune checkpoint inhibitors, cancer vaccines, adoptive cell transfer, combinations with other immunotherapeutic agents, chemoradiotherapy or other molecularly targeted agents; however, none of these studies have shown practice changing results. There seems to be a synergistic effect with increased response rates when a combinatorial approach of immunotherapy in conjunction with other modalities is being exploited. In this review, we illustrate the current role of immunotherapy in PAC.

Immunotherapy for esophageal cancer: a 2019 update.

Esophageal cancer remains a global health concern with a dismal prognosis and an estimated 5-year survival rate of approximately 10-15%. Immunotherapy is a novel treatment approach representing an effective and promising option against several types of cancer. The development of new and efficacious immunotherapeutic strategies, such as adoptive cell therapy-based, antibody-based and vaccine-based therapies, aims to prevent immunological escape and modify immunological responses. In this review, we discuss the theoretical background and current status of immunotherapy for patients with esophageal cancer. We also present ongoing clinical trials and summarize key findings concerning survival and safety analyses.

Activating Transcription Factor 3 (ATF3) Protects Retinal Ganglion Cells and Promotes Functional Preservation After Optic Nerve Crush.

Purpose: To investigate the possible role of activating transcription factor 3 (ATF3) in retinal ganglion cell (RGC) neuroprotection and optic nerve regeneration after optic nerve crush (ONC). Methods: Overexpression of proteins of interest (ATF3, phosphatase and tensin homolog [PTEN], placental alkaline phosphatase, green fluorescent protein) in the retina was achieved by intravitreal injections of recombinant adenovirus-associated viruses (rAAVs) expressing corresponding proteins. The number of RGCs and αRGCs was evaluated by immunostaining retinal sections and whole-mount retinas with antibodies against RNA binding protein with multiple splicing (RBPMS) and osteopontin, respectively. Axonal regeneration was assessed via fluorophore-coupled cholera toxin subunit B labeling. RGC function was evaluated by recording positive scotopic threshold response. Results: The level of ATF3 is preferentially elevated in osteopontin+/RBPMS+ αRGCs following ONC. Overexpression of ATF3 by intravitreal injection of rAAV 2 weeks before ONC promoted RBPMS+ RGC survival and preserved RGC function as assessed by positive scotopic threshold response recordings 2 weeks after ONC. However, overexpression of ATF3 and simultaneous downregulation of PTEN, a negative regulator of the mTOR pathway, combined with ONC, only moderately promoted short distance RGC axon regeneration (200 µm from the lesion site) but did not provide additional RGC neuroprotection compared with PTEN downregulation alone. Conclusions: These results reveal a neuroprotective effect of ATF3 in the retina following injury and identify ATF3 as a promising agent for potential treatments of optic neuropathies.

Otx2-Genetically Modified Retinal Pigment Epithelial Cells Rescue Photoreceptors after Transplantation.

Inherited retinal degenerations are blinding diseases characterized by the loss of photoreceptors. Their extreme genetic heterogeneity complicates treatment by gene therapy. This has motivated broader strategies for transplantation of healthy retinal pigmented epithelium to protect photoreceptors independently of the gene causing the disease. The limited clinical benefit for visual function reported up to now is mainly due to dedifferentiation of the transplanted cells that undergo an epithelial-mesenchymal transition. We have studied this mechanism in vitro and revealed the role of the homeogene OTX2 in preventing dedifferentiation through the regulation of target genes. We have overexpressed OTX2 in retinal pigmented epithelial cells before their transplantation in the eye of a model of retinitis pigmentosa carrying a mutation in Mertk, a gene specifically expressed by retinal pigmented epithelial cells. OTX2 increases significantly the protection of photoreceptors as seen by histological and functional analyses. We observed that the beneficial effect of OTX2 is non-cell autonomous, and it is at least partly mediated by unidentified trophic factors. Transplantation of OTX2-genetically modified cells may be medically effective for other retinal diseases involving the retinal pigmented epithelium as age-related macular degeneration.

The Thioredoxin Encoded by the Rod-Derived Cone Viability Factor Gene Protects Cone Photoreceptors Against Oxidative Stress.

AIMS: Rod-derived cone viability factor long (RdCVFL) is an enzymatically active thioredoxin encoded by the nucleoredoxin-like-1 (Nxnl1) gene. The second product of the gene, RdCVF, made by alternative splicing is a novel trophic factor secreted by rods that protects cones in rodent models of retinitis pigmentosa, the most prevalent inherited retinal disease. It acts on cones by stimulating aerobic glycolysis through its interaction with a complex containing basigin-1 and the glucose transporter GLUT1. We studied the role of Nxnl1 in cones after its homologous recombination using a transgenic line expressing Cre recombinase under the control of a cone opsin promoter. RESULTS: We show that the cones of these mice are dysfunctional and degenerate by 8 months of age. The age-related deficit in cones is exacerbated in young animals by exposure to high level of oxygen. In agreement with this phenotype, we found that the cones express only one of the two Nxnl1 gene products, the thioredoxin RdCVFL. Administration of RdCVFL to the mouse carrying a deletion of the Nxnl1 gene in cones reduces the damage produced by oxidative stress. Silencing the expression of RdCVFL in cone-enriched culture reduces cell viability, showing that RdCVFL is a cell-autonomous mechanism of protection. INNOVATION: This novel mode of action is certainly relevant for the therapy of retinitis pigmentosa since the delivery into cones of the rd10 mouse, a recessive model of the disease, rescues cones. CONCLUSION: Our work highlights the duality of the Nxnl1 gene, which protects the cones by two distinct mechanisms. Antioxid. Redox Signal. 24, 909-923.

Identification of an Alternative Splicing Product of the Otx2 Gene Expressed in the Neural Retina and Retinal Pigmented Epithelial Cells.

To investigate the complexity of alternative splicing in the retina, we sequenced and analyzed a total of 115,706 clones from normalized cDNA libraries from mouse neural retina (66,217) and rat retinal pigmented epithelium (49,489). Based upon clustering the cDNAs and mapping them with their respective genomes, the estimated numbers of genes were 9,134 for the mouse neural retina and 12,050 for the rat retinal pigmented epithelium libraries. This unique collection of retinal of messenger RNAs is maintained and accessible through a web-base server to the whole community of retinal biologists for further functional characterization. The analysis revealed 3,248 and 3,202 alternative splice events for mouse neural retina and rat retinal pigmented epithelium, respectively. We focused on transcription factors involved in vision. Among the six candidates suitable for functional analysis, we selected Otx2S, a novel variant of the Otx2 gene with a deletion within the homeodomain sequence. Otx2S is expressed in both the neural retina and retinal pigmented epithelium, and encodes a protein that is targeted to the nucleus. OTX2S exerts transdominant activity on the tyrosinase promoter when tested in the physiological environment of primary RPE cells. By overexpressing OTX2S in primary RPE cells using an adeno associated viral vector, we identified 10 genes whose expression is positively regulated by OTX2S. We find that OTX2S is able to bind to the chromatin at the promoter of the retinal dehydrogenase 10 (RDH10) gene.