scholarly journals Retinal organoids as models for development and diseases

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Xiao Zhang ◽  
Wen Wang ◽  
Zi-Bing Jin
Keyword(s):  
Disease Model ◽  
Three Dimensional ◽  
Treatment Strategies ◽  
Disease Process ◽  
Retinal Disease ◽  
Current Treatment ◽  
Clear Understanding ◽  
Retinal Diseases ◽  
Developmental Studies ◽  
Novel Treatment Strategies

AbstractThe evolution of pluripotent stem cell-derived retinal organoids (ROs) has brought remarkable opportunities for developmental studies while also presenting new therapeutic avenues for retinal diseases. With a clear understanding of how well these models mimic native retinas, such preclinical models may be crucial tools that are widely used for the more efficient translation of studies into novel treatment strategies for retinal diseases. Genetic modifications or patient-derived ROs can allow these models to simulate the physical microenvironments of the actual disease process. However, we are currently at the beginning of the three-dimensional (3D) RO era, and a general quantitative technology for analyzing ROs derived from numerous differentiation protocols is still missing. Continued efforts to improve the efficiency and stability of differentiation, as well as understanding the disparity between the artificial retina and the native retina and advancing the current treatment strategies, will be essential in ensuring that these scientific advances can benefit patients with retinal disease. Herein, we briefly discuss RO differentiation protocols, the current applications of RO as a disease model and the treatments for retinal diseases by using RO modeling, to have a clear view of the role of current ROs in retinal development and diseases.

scholarly journals Unique Genomic Landscape of High-Grade Neuroendocrine Cervical Carcinoma: Implications for Rethinking Current Treatment Paradigms

2020 ◽  
pp. 972-987
Author(s):  
Ramez N. Eskander ◽  
Julia Elvin ◽  
Laurie Gay ◽  
Jeffrey S. Ross ◽  
Vincent A. Miller ◽  
...  
Keyword(s):  
Treatment Strategies ◽  
Current Treatment ◽  
High Grade ◽  
Novel Treatment ◽  
Sample Average ◽  
Genomic Landscape ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Sample Range ◽  
Novel Treatment Strategies

PURPOSE High-grade neuroendocrine cervical cancer (HGNECC) is an uncommon malignancy with limited therapeutic options; treatment is patterned after the histologically similar small-cell lung cancer (SCLC). To better understand HGNECC biology, we report its genomic landscape. PATIENTS AND METHODS Ninety-seven patients with HGNECC underwent comprehensive genomic profiling (182-315 genes). These results were subsequently compared with a cohort of 1,800 SCLCs. RESULTS The median age of patients with HGNECC was 40.5 years; 83 patients (85.6%) harbored high-risk human papillomavirus (HPV). Overall, 294 genomic alterations (GAs) were identified (median, 2 GAs/sample; average, 3.0 GAs/sample, range, 0-25 GAs/sample) in 109 distinct genes. The most frequently altered genes were PIK3CA (19.6% of cohort), MYC (15.5%), TP53 (15.5%), and PTEN (14.4%). RB1 GAs occurred in 4% versus 32% of HPV-positive versus HPV-negative tumors ( P < .0001). GAs in HGNECC involved the following pathways: PI3K/AKT/mTOR (41.2%); RAS/MEK (11.3%); homologous recombination (9.3%); and ERBB (7.2%). Two tumors (2.1%) had high tumor mutational burden (TMB; both with MSH2 alterations); 16 (16.5%) had intermediate TMB. Seventy-one patients (73%) had ≥ 1 alteration that was theoretically druggable. Comparing HGNECC with SCLC, significant differences in TMB, microsatellite instability, HPV-positive status, and in PIK3CA, MYC, PTEN, TP53, ARID1A, and RB1 alteration rates were found. CONCLUSION This large cohort of patients with HGNECC demonstrated a genomic landscape distinct from SCLC, calling into question the biologic and therapeutic relevance of the histologic similarities between the entities. Furthermore, 73% of HGNECC tumors had potentially actionable alterations, suggesting novel treatment strategies for this aggressive malignancy.

scholarly journals A Comparison of Two-Dimensional and Three-Dimensional Techniques for Kinematic Analysis of the Sagittal Motion of Sheep Hindlimbs During Walking on a Treadmill

2021 ◽  
Vol 8 ◽  
Author(s):  
Camila Cardoso Diogo ◽  
José Arthur Camassa ◽  
Bárbara Fonseca ◽  
Luís Maltez da Costa ◽  
José Eduardo Pereira ◽  
...  
Keyword(s):  
Objective Assessment ◽  
Three Dimensional ◽  
Treatment Strategies ◽  
Metatarsophalangeal Joint ◽  
Treadmill Walking ◽  
Two Dimensional ◽  
Ovine Model ◽  
Surgical Interventions ◽  
Novel Treatment ◽  
Novel Treatment Strategies

Compared to rodents, sheep offer several attractive features as an experimental model for testing different medical and surgical interventions related to pathological gait caused by neurological diseases and injuries. To use sheep for development of novel treatment strategies in the field of neuroscience, it is key to establish the relevant kinematic features of locomotion in this species. To use sheep for development of novel treatment strategies in the field of neuroscience, it is crucial to understand fundamental baseline characteristics of locomotion in this species. Despite their relevance for medical research, little is known about the locomotion in the ovine model, and next to nothing about the three-dimensional (3D) kinematics of the hindlimb. This study is the first to perform and compare two-dimensional (2D) and 3D hindlimb kinematics of the sagittal motion during treadmill walking in the ovine model. Our results show that the most significant differences took place throughout the swing phase of the gait cycle were for the distal joints, ankle and metatarsophalangeal joint, whereas the hip and knee joints were much less affected. The results provide evidence of the inadequacy of a 2D approach to the computation of joint kinematics in clinically normal sheep during treadmill walking when the interest is centered on the hoof's joints. The findings from the present investigation are likely to be useful for an accurate, quantitative and objective assessment of functionally altered gait and its underlying neuronal mechanisms and biomechanical consequences.

scholarly journals Novel Therapies for Relapsed and Refractory Neuroblastoma

Children ◽  
2018 ◽  
Vol 5 (11) ◽  
pp. 148 ◽  
Author(s):  
Peter Zage
Keyword(s):  
Clinical Trials ◽  
Treatment Strategies ◽  
Current Treatment ◽  
Disease Relapse ◽  
Therapeutic Modalities ◽  
Treatment Regimens ◽  
Novel Treatment ◽  
Improved Outcomes ◽  
Outcomes For Children ◽  
Novel Treatment Strategies

While recent increases in our understanding of the biology of neuroblastoma have allowed for more precise risk stratification and improved outcomes for many patients, children with high-risk neuroblastoma continue to suffer from frequent disease relapse, and despite recent advances in our understanding of neuroblastoma pathogenesis, the outcomes for children with relapsed neuroblastoma remain poor. These children with relapsed neuroblastoma, therefore, continue to need novel treatment strategies based on a better understanding of neuroblastoma biology to improve outcomes. The discovery of new tumor targets and the development of novel antibody- and cell-mediated immunotherapy agents have led to a large number of clinical trials for children with relapsed neuroblastoma, and additional clinical trials using molecular and genetic tumor profiling to target tumor-specific aberrations are ongoing. Combinations of these new therapeutic modalities with current treatment regimens will likely be needed to improve the outcomes of children with relapsed and refractory neuroblastoma.

scholarly journals The Role of Estrogen Receptors and Their Signaling across Psychiatric Disorders

2020 ◽  
Vol 22 (1) ◽  
pp. 373
Author(s):  
Wu Jeong Hwang ◽  
Tae Young Lee ◽  
Nahrie Suk Kim ◽  
Jun Soo Kwon
Keyword(s):  
Estrogen Receptors ◽  
Psychiatric Disorders ◽  
Treatment Strategies ◽  
Current Treatment ◽  
Estrogen Signaling ◽  
Brain Functions ◽  
Wide Range ◽  
Novel Treatment Strategies ◽  
Future Direction ◽  
Preclinical And Clinical Studies

Increasing evidence suggests estrogen and estrogen signaling pathway disturbances across psychiatric disorders. Estrogens are not only crucial in sexual maturation and reproduction but are also highly involved in a wide range of brain functions, such as cognition, memory, neurodevelopment, and neuroplasticity. To add more, the recent findings of its neuroprotective and anti-inflammatory effects have grown interested in investigating its potential therapeutic use to psychiatric disorders. In this review, we analyze the emerging literature on estrogen receptors and psychiatric disorders in cellular, preclinical, and clinical studies. Specifically, we discuss the contribution of estrogen receptor and estrogen signaling to cognition and neuroprotection via mediating multiple neural systems, such as dopaminergic, serotonergic, and glutamatergic systems. Then, we assess their disruptions and their potential implications for pathophysiologies in psychiatric disorders. Further, in this review, current treatment strategies involving estrogen and estrogen signaling are evaluated to suggest a future direction in identifying novel treatment strategies in psychiatric disorders.

scholarly journals SAAP-148 Eradicates MRSA Persisters Within Mature Biofilm Models Simulating Prosthetic Joint Infection

2021 ◽  
Vol 12 ◽  
Author(s):  
Henk Scheper ◽  
Julia M. Wubbolts ◽  
Joanne A. M. Verhagen ◽  
Adriëtte W. de Visser ◽  
Robert J. P. van der Wal ◽  
...  
Keyword(s):  
Prosthetic Joint Infection ◽  
Joint Infection ◽  
Treatment Strategies ◽  
Antibacterial Activities ◽  
Current Treatment ◽  
Log Reduction ◽  
Prosthetic Joint ◽  
Novel Treatment Strategies ◽  
Titanium Aluminium

Prosthetic joint infection (PJI) is a severe complication of arthroplasty. Due to biofilm and persister formation current treatment strategies often fail. Therefore, innovative anti-biofilm and anti-persister agents are urgently needed. Antimicrobial peptides with their broad antibacterial activities may be such candidates. An in vitro model simulating PJI comprising of rifampicin/ciprofloxacin-exposed, mature methicillin-resistant Staphylococcus aureus (MRSA) biofilms on polystyrene plates, titanium/aluminium/niobium disks, and prosthetic joint liners were developed. Bacteria obtained from and residing within these biofilms were exposed to SAAP-148, acyldepsipeptide-4, LL-37, and pexiganan. Microcalorimetry was used to monitor the heat flow by the bacteria in these models. Daily exposure of mature biofilms to rifampicin/ciprofloxacin for 3 days resulted in a 4-log reduction of MRSA. Prolonged antibiotic exposure did not further reduce bacterial counts. Microcalorimetry confirmed the low metabolic activity of these persisters. SAAP-148 and pexiganan, but not LL-37, eliminated the persisters while ADEP4 reduced the number of persisters. SAAP-148 further eradicated persisters within antibiotics-exposed, mature biofilms on the various surfaces. To conclude, antibiotic-exposed, mature MRSA biofilms on various surfaces have been developed as in vitro models for PJI. SAAP-148 is highly effective against persisters obtained from the biofilms as well as within these models. Antibiotics-exposed, mature biofilms on relevant surfaces can be instrumental in the search for novel treatment strategies to combat biofilm-associated infections.

scholarly journals Targeting Aging Pathways in Chronic Obstructive Pulmonary Disease

2020 ◽  
Vol 21 (18) ◽  
pp. 6924
Author(s):  
Molly Easter ◽  
Seth Bollenbecker ◽  
Jarrod W. Barnes ◽  
Stefanie Krick
Keyword(s):  
Chronic Obstructive Pulmonary Disease ◽  
Pulmonary Disease ◽  
Treatment Strategies ◽  
Current Treatment ◽  
Nutrient Sensing ◽  
Chronic Obstructive ◽  
Obstructive Pulmonary Disease ◽  
Telomere Attrition ◽  
Global Epidemic ◽  
Novel Treatment Strategies

Chronic obstructive pulmonary disease (COPD) has become a global epidemic and is the third leading cause of death worldwide. COPD is characterized by chronic airway inflammation, loss of alveolar-capillary units, and progressive decline in lung function. Major risk factors for COPD are cigarette smoking and aging. COPD-associated pathomechanisms include multiple aging pathways such as telomere attrition, epigenetic alterations, altered nutrient sensing, mitochondrial dysfunction, cell senescence, stem cell exhaustion and chronic inflammation. In this review, we will highlight the current literature that focuses on the role of age and aging-associated signaling pathways as well as their impact on current treatment strategies in the pathogenesis of COPD. Furthermore, we will discuss established and experimental COPD treatments including senolytic and anti-aging therapies and their potential use as novel treatment strategies in COPD.

scholarly journals RVG-functionalized reduction sensitive micelles for the effective accumulation of doxorubicin in brain

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Jiangkang Xu ◽  
Xiaoye Yang ◽  
Jianbo Ji ◽  
Yuan Gao ◽  
Na Qiu ◽  
...  
Keyword(s):  
Treatment Strategies ◽  
Glioma Cells ◽  
Current Treatment ◽  
Chemotherapeutic Agents ◽  
Brain Targeting ◽  
Hydrophobic Core ◽  
Rat Glioma ◽  
Novel Treatment Strategies ◽  
The Brain

Abstract Background Glioblastoma is a lethal neoplasm with few effective therapy options. As a mainstay in the current treatment of glioma at present, chemotherapeutic agents usually show inadequate therapeutic efficiency due to their low blood brain barrier traversal and brain targeting, together with tumor multidrug resistance. Novel treatment strategies are thus urgently needed to improve chemotherapy outcomes. Results Here, we report that nanomedicines developed by functionalizing the neurotropic rabies virus-derived polypeptide, RVG, and loading reduction-sensitive nanomicelles (polymer and doxorubicin) enable a highly specific and efficacious drug accumulation in the brain. Interestingly, curcumin serves as the hydrophobic core of the polymer, while suppressing the major efflux proteins in doxorubicin-resistant glioma cells. Studies on doxorubicin-resistant rat glioma cells demonstrate that the RVG-modified micelles exhibit superior cell entry and antitumor activity. In vivo research further showed that RVG modified nanomicelles significantly enhanced brain accumulation and tumor inhibition rate in mice, leading to a higher survival rate with negligible systemic toxicity. Moreover, effective suppression of recurrence and pulmonary metastatic nodules were also determined after the RVG-modified nanomicelles treatment. Conclusions The potential of RVG-modified nanomicelles for glioma was demonstrated. Brain accumulation was markedly enhanced after intravenous administration. This unique drug delivery nanoplatform to the brain provides a novel and powerful therapeutic strategy for the treatment of central nervous system disorders including glioma. Graphic abstract

scholarly journals Low-dose Radiotherapy for Unstageable Pressure Ulcer:A Case Report

2021 ◽  
Author(s):  
YuPing Lin ◽  
MiaoBin Mao ◽  
BingJie Guan ◽  
ShengHong Shi ◽  
GuiQing Shi ◽  
...  
Keyword(s):  
Scale Score ◽  
Pressure Ulcer ◽  
Three Dimensional ◽  
Treatment Strategies ◽  
Conformal Radiotherapy ◽  
Current Treatment ◽  
Low Dose Radiotherapy ◽  
Promising Treatment ◽  
Three Dimensional Conformal Radiotherapy

Abstract Background：Pressure ulcer is a common complication of long-term bedridden patients, but current treatment strategies have limited efficacy for pressure ulcer. Case presentation：We present a 17-year-old man with unstageable pressure ulcer treated with three-dimensional conformal radiotherapy. We irradiate the posterior lumbosacral pressure ulcer with 3D-CRT using a 6 MV photon beam. The patient was placed in a prone position and a total dose of 50cGy was administered. Then, the healing was evaluated using PUSH scale score on days 8，12 and 3 months after radiotherapy. After radiotherapy, beefy red tissue with a shiny, moist, granular appearance tissue are present in the wound bed, exudate amount was decreased, the depth of the pressure ulcer became significantly shallower and the wound surface area was reduced. PUSH scale score descreased from15 to 7.Conclusion: Radiotherapy could be a promising treatment strategy of unstageable pressure ulcer.

scholarly journals Entry of Human Coronavirus NL63 into the Cell

2017 ◽  
Vol 92 (3) ◽  
Author(s):  
Aleksandra Milewska ◽  
Paulina Nowak ◽  
Katarzyna Owczarek ◽  
Artur Szczepanski ◽  
Miroslaw Zarebski ◽  
...  
Keyword(s):  
Ex Vivo ◽  
Three Dimensional ◽  
Treatment Strategies ◽  
Infection Process ◽  
Target Cells ◽  
Human Coronavirus ◽  
Actin Cortex ◽  
Undifferentiated Cells ◽  
Novel Treatment Strategies ◽  
Immortalized Cell

ABSTRACT The first steps of human coronavirus NL63 (HCoV-NL63) infection were previously described. The virus binds to target cells by use of heparan sulfate proteoglycans and interacts with the ACE2 protein. Subsequent events, including virus internalization and trafficking, remain to be elucidated. In this study, we mapped the process of HCoV-NL63 entry into the LLC-Mk2 cell line and ex vivo three-dimensional (3D) tracheobronchial tissue. Using a variety of techniques, we have shown that HCoV-NL63 virions require endocytosis for successful entry into the LLC-MK2 cells, and interaction between the virus and the ACE2 molecule triggers recruitment of clathrin. Subsequent vesicle scission by dynamin results in virus internalization, and the newly formed vesicle passes the actin cortex, which requires active cytoskeleton rearrangement. Finally, acidification of the endosomal microenvironment is required for successful fusion and release of the viral genome into the cytoplasm. For 3D tracheobronchial tissue cultures, we also observed that the virus enters the cell by clathrin-mediated endocytosis, but we obtained results suggesting that this pathway may be bypassed. IMPORTANCE Available data on coronavirus entry frequently originate from studies employing immortalized cell lines or undifferentiated cells. Here, using the most advanced 3D tissue culture system mimicking the epithelium of conductive airways, we systematically mapped HCoV-NL63 entry into susceptible cells. The data obtained allow for a better understanding of the infection process and may support development of novel treatment strategies.

scholarly journals Cardiomyocyte Remodeling in Atrial Fibrillation and Hibernating Myocardium: Shared Pathophysiologic Traits Identify Novel Treatment Strategies?

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Brian R. Weil ◽  
Cevher Ozcan
Keyword(s):  
Atrial Fibrillation ◽  
Molecular Mechanisms ◽  
Disease Onset ◽  
Treatment Strategies ◽  
Disease Process ◽  
Hibernating Myocardium ◽  
Atrial Remodeling ◽  
Therapeutic Implications ◽  
Atrial Myocyte ◽  
Novel Treatment Strategies

Atrial fibrillation (AF) is the most common arrhythmia and is associated with a high risk of morbidity and mortality. However, there are limited treatment strategies for prevention of disease onset and progression. Development of novel therapies for primary and secondary prevention of AF is critical and requires improved understanding of the cellular and molecular mechanisms underlying the AF disease process. Translational and clinical studies conducted over the past twenty years have revealed that atrial remodeling in AF shares several important pathophysiologic traits with the remodeling processes exhibited by hibernating myocardium that develop in response to chronic ischemia. These shared features, which include an array of structural, metabolic, and electrophysiologic changes, appear to represent a conserved adaptive myocyte response to chronic stress that involves dedifferentiation towards a fetal phenotype to promote survival. In this review, we discuss the pathophysiology of AF, summarize studies supporting a common remodeling program in AF and hibernating myocardium, and propose future therapeutic implications of this emerging paradigm. Ultimately, better understanding of the molecular mechanisms of atrial myocyte remodeling during the onset of AF and the transition from paroxysmal to persistent stages of the disease may facilitate discovery of new therapeutic targets.

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