Therapeutic Entity Research Articles

Sequential Release of Ibuprofen and the Gasotransmitter Hydrogen sulfide using Oxanorbornane-Based Synthetic Lipids as Carriers.

After understanding the biological signaling roles of hydrogen sulfide and its involvement in various physiological processes, there has been enormous interest in exploring its therapeutic utility in areas such as cancer, inflammation, cardiovascular diseases, etc. There is also growing interest in using suitable H2S donors in combination with other drugs to improve the treatment outcome through the modulation of multiple pathways. The premature release of H2S from small molecule donors and the difficulty in controlling its spatio-temporal distribution are the major challenges during these efforts. Hence the development of appropriate carriers that can release this gasotransmitter along with the therapeutic entity of interest in a controlled manner has high significance. In this regard, this report presents a novel drug delivery system from oxanorbornane-based synthetic lipids that carries a H2S-releasing 1,2-dithiole-3-thione moiety as part of the head group. Nanoaggregates of the resulting conjugate are not only capable of efficiently entrapping a non-steroidal anti-inflammatory drug such as ibuprofen, but also release this drug and H2S in a controlled and sequential manner.

A top-down approach for studying the in-silico effect of the novel phytocompound tribulusamide B on the inhibition of Nipah virus transmission through targeting fusion glycoprotein and matrix protein

The proteins of Nipah virus ascribe to its lifecycle and are crucial to infections caused by the virus. In the absence of approved therapeutics, these proteins can be considered as drug targets. This study examined the potential of fifty-three (53) natural compounds to inhibit Nipah virus fusion glycoprotein (NiV F) and matrix protein (NiV M) in silico. The molecular docking experiment, supported by the principal component analysis (PCA), showed that out of all the phytochemicals considered, Tribulusamide B had the highest inhibitory potential against the target proteins NiV F and NiV M (-9.21 and −8.66 kcal mol−1, respectively), when compared to the control drug, Ribavirin (-7.01 and −6.52 kcal mol−1, respectively). Furthermore, it was found that Tribulusamide B pharmacophores, namely, hydrogen donors, acceptors, aromatic and hydrophobic groups, contributed towards the effective residual interactions with the target proteins. The molecular dynamic simulation further validated the results of the docking studies and concluded that Tribulusamide B formed a stable complex with the target proteins. The data obtained from MM-PBSA study further explained that the phytochemical could strongly bind with NiV F (-31.26 kJ mol−1) and NiV M (-40.26 kJ mol−1) proteins in comparison with the control drug Ribavirin (-13.12 and −13.94 kJ mol−1, respectively). Finally, the results indicated that Tribulusamide B, a common inhibitor effective against multiple proteins, can be considered a potential therapeutic entity in treating the Nipah virus infection.

The fulfilled promise and unmet potential of umbilical cord blood.

Here, we review classic and emerging uses of umbilical cord blood and highlight strategies to improve its utility, focusing on selection of the appropriate units and cell types for the intended applications. Recent studies have shown advancements in cord blood cell utility in a variety of cellular therapies and have made strides in elucidating manners to select the best units for therapy and target new ways to improve the various cell subpopulations for their respective applications. Umbilical cord blood is a proven source of cells for hematopoietic cell transplantation and research and is an important potential source for additional cellular therapies. However, cord blood utility is limited by low "doses" of potent cells that can be obtained from individual units, a limitation that is specific to cord blood as a donor source. In addition to traditional CD34 + progenitor cells, cord blood lymphocytes are being pursued as therapeutic entities with their own unique properties and characteristics. Thus, selection of ideal units depends on the intended therapeutic entity and target, and identification of differential potency parameters is critical to drive effective banking strategies accommodating successful clinical use of cord blood in broader cell therapy settings.

Emerging therapies for childhood-onset movement disorders.

We highlight novel and emerging therapies in the treatment of childhood-onset movement disorders. We structured this review by therapeutic entity (small molecule drugs, RNA-targeted therapeutics, gene replacement therapy, and neuromodulation), recognizing that there are two main approaches to treatment: symptomatic (based on phenomenology) and molecular mechanism-based therapy or 'precision medicine' (which is disease-modifying). We highlight reports of new small molecule drugs for Tourette syndrome, Friedreich's ataxia and Rett syndrome. We also discuss developments in gene therapy for aromatic l-amino acid decarboxylase deficiency and hereditary spastic paraplegia, as well as current work exploring optimization of deep brain stimulation and lesioning with focused ultrasound. Childhood-onset movement disorders have traditionally been treated symptomatically based on phenomenology, but focus has recently shifted toward targeted molecular mechanism-based therapeutics. The development of precision therapies is driven by increasing capabilities for genetic testing and a better delineation of the underlying disease mechanisms. We highlight novel and exciting approaches to the treatment of genetic childhood-onset movement disorders while also discussing general challenges in therapy development for rare diseases. We provide a framework for molecular mechanism-based treatment approaches, a summary of specific treatments for various movement disorders, and a clinical trial readiness framework.

The Role of the Proteasome in Limiting Cellular Stress Associated with Protein Accumulation

AbstractThe proteasome is comprised of multiple subunits that catalyze the degradation of proteins to maintain cellular homeostasis. The proteasome targets protein substrates by two different pathways. The ubiquitin‐dependent pathway requires proteins to be labeled with a ubiquitin tag to signal for degradation by the 26S isoform of the proteasome. Protein degradation through this pathway declines during age progression. The ubiquitin‐independent pathway utilizes the 20S proteasome isoform. It can degrade misfolded and intrinsically disordered proteins to decrease cellular stress. Age‐related protein accumulation and aggregation can occur due to the decreased activity and expression of the proteasome. Protein accumulation causes increased cellular stress which can contribute to disease progression. Increasing proteasome activity could serve as a solution to eliminating and preventing protein accumulation. Studies have shown the value of the proteasome as a therapeutic entity to mitigate cellular stress. This perspective explores the link between proteasome activity and cellular stress caused by age‐related misfolded protein accumulation.

Critical Decision-Making: Technical Aspects of Performing POEM

Achalasia has become increasingly diagnosed in the last decade and has become an important therapeutic entity for advanced endoscopists since the advent of PerOral Endoscopic Myotomy (POEM). This treatment now provides a highly successful minimally-invasive approach which, for most patients, is an outpatient procedure. Consistent success depends on patient selection, sound technique and management of infrequent adverse events . This article focusses on these three areas and hopes to assist referring gastroenterologists in understanding the appropriateness of POEM for achalasia and to guide those endoscopists embarking on a POEM program in making decisons.

Oncolytic Virotherapy for High-Grade Glioma and Current Evidence and Factors to Consider for Incorporation into Clinical Practice.

Brain tumor incidence is on the rise, and glioblastoma comprises the majority of primary tumors. Despite maximal safe resection and adjuvant chemoradiation, median survival for high-grade glioma remains poor. For this reason, it is important to develop and incorporate new treatment strategies. Oncolytic virotherapy has emerged as a viable new therapeutic entity to fill this gap. Preclinical research has shown oncolytic virotherapy to be a robust and effective treatment option for brain tumors, and clinical trials for both adult and pediatric high-grade glioma are underway. The unique and protected environment of the nervous system, in part due to the blood-brain barrier, prevents traditional systemic therapies from achieving adequate penetration. Brain tumors are also heterogenous in nature due to their diverse molecular profiles, further complicating systemic treatment efforts. Oncolytic viruses may serve to fill this gap in brain tumor treatment given their amenability to genetic modification and ability to target unique tumor epitopes. In addition, direct inoculation of the oncolytic virus agent to the tumor bed following surgical resection absolves risk of systemic side effects and ensures adequate delivery. As virotherapy transitions from bench to bedside, it is important to discuss factors to make this transition more seamless. In this article, we describe the current clinical evidence as it pertains to oncolytic virotherapy and the treatment of brain tumors as well as factors to consider for its incorporation into neurosurgical workflow.

Effect of multi-targeting bacterial gene therapy on tumour regression and survival in mouse models of ovarian and intraperitoneal cancer.

e17550 Background: With a prevalence of more than 2 million cases, a 5-year survival below 20% in stage 3 and 4, and limited treatment options, ovarian cancer represents a significant unmet medical need. We assessed the efficacy of AUP-55, a genetically engineered Lactococcus cremoris for the treatment of ovarian cancer and peritoneal carcinomatosis. We evaluated the efficacy of two AUP-55 leads producing human therapeutic proteins in situ; namely interleukin 18 (IL-18), granulocyte-macrophage colony stimulating factor (GM-CSF), interleukin-12 (IL-12) and interferon alpha (IFN-A) in syngeneic intraperitoneal ID8 ovarian cancer and B16F1 melanoma models in mice. Methods: ID8-Luc-mCherry-Puro ovarian cancer model was used for survival and tumor burden by bioluminescent imaging with post-mortem pathology for all animals, whereas the B16F1 melanoma model was used solely for survival. Animals were treated daily or every other day with i.p injections of the AUP-55 leads (1e8 CFU/dose for 12-22 times). Results: In the ID8 model treatment was started 14 days after tumor implantation. Most untreated mice were terminated due to the disease progress. Treatment with AUP-55 resulted in 91.3 % survival and lower tumor load during the study duration of 81 days compared to the 0 % survival and massively increased tumor load in untreated mice. When compared to the available data from the CRO, the survival advantage was superior to, for example anti-PD1 and cisplatin treatments in the same model. In the B16F1 model, treatment with AUP-55 led to 90 % survival in comparison to 10 % untreated mice. All AUP-55 treatments were well tolerated. In the pathology post-mortem, all untreated animals had typical findings for ovarian cancer, such as ascites and high number of tumor nodules present in abdominal cavity, liver, spleen, kidney and pancreas. In the group treated with AUP-55 there were no macroscopic tumor deposits detected. Conclusions: Cytokine armed Lactococcus cremoris AUP-55 enables multimodal action. Treatment with AUP-55 suggests anti-tumor activity as a single therapeutic entity for the treatment of ovarian cancer and peritoneal carcinomatosis.

Abstract P4-07-30: Features and survival outcomes of HER2-low patients from a prospective registry of unresectable locally advanced or metastatic breast cancer: GEICAM/2014-03 (RegistEM)

Abstract Background: HER2-low breast cancer (BC) is a new therapeutic entity, but it is uncertain if this subgroup of BC differs from HER2-negative tumors in clinical characteristics, prognosis, and response to therapy. The objective is to describe the clinical characteristics and outcomes of 422 patients (pts) with HER2-low BC documented before 1st line, having been diagnosed with advanced BC (ABC) before 2019 and included in the RegistEM study (n=1,663). Methods: In this analysis (cut-off date 08/April/2022; database is ongoing), two subgroups of pts have been considered based on HER2 results: HER2-low (n=422) (immunohistochemistry [IHC] 1+ or IHC 2+ and in situ hybridization [ISH] negative) and HER2-IHC 0 (n=590), as reference. Hormone Receptor (HR) expression has also been considered for subgroup analysis. Results: At first ABC diagnosis, < 1% pts had unresectable locally advanced BC (ULABC) in both groups, 31% de novo metastatic BC in HER2-low and 20% in HER2-IHC0 groups. Less than 1% were male, 99% Caucasian and ~71% postmenopausal. Median age was 60 years, being similar between both groups (range 26-96). Family history of BC and/or ovarian cancer was reported in 32% pts in HER2-low and 29% in HER2-IHC0. Germline BRCA1/2 mutation was higher in HER2-low (14/40=35%) in reference to HER2-IHC0 (14/64=22%) (p=0.14). Relevant information summarized by HR expression and HER2 status are detailed in the table below. Visceral disease was similar in both total groups (58% in HER2-low vs HER2-IHC0 56%), but slightly higher in HR- HER2-low pts (81% vs 64%), and 84% and 90% pts had ≤3 metastatic locations, in HER2-low and HER2-IHC0 groups, respectively. Distribution of 1st-line therapies was also similar between both groups, being endocrine therapy (ET) plus biological therapy (BT) (HER2-low 39% vs HER2-IHC0 36%) and ET (HER2-low 30% vs HER2-IHC0 28%), while chemotherapy (CT) (HER2-low 13% vs HER2-IHC0 16%) and CT plus BT (HER2-low 9% vs HER2-IHC0 10%) were more frequent in HR- pts. A 2nd-line therapy was reported in 70% HER2-low pts and 67% HER2-IHC0 pts. The median time to progression (TTP) at 1st-line therapy in HER2-low pts was 11 mo (0-66), being similar in HER2-IHC0 pts, but the higher difference was observed in relation to HR expression. Treatments in 2nd-line were similar in both groups, CT and ET/BT were the most frequent totally. Median duration of 2nd-line therapy was ~6 mo; progressive disease (PD) was reported in 85% pts. A 3rd-line therapy was reported in 74% HER2-low and 69% HER2-IHC0 pts. The median time to progression (TTP) to 3rd-line therapy was 6 mo, being similar in HER2-low and HER2-IHC0 pts .The most frequent 3rd-line therapies were CT and ET/BT in both groups, as in 2nd-line. Median duration of 3rd-line therapy was 4 mo; PD was reported in 84% HER2-low pts and 82% HER2-IHC0 pts. Median (95% confidence interval [CI]) PFS at 1st, 2nd and 3rd lines (mo) were 14 (12-16), 6 (5-7) and 6 (5-6) in HER2-low pts, being similar in HER2-IHC0. OS was comparable in all soubgroups analyzed, however, differences were observed regarding HR status. Conclusions: Our results show that HER2-low BC pts have similar characteristics than HER2-IHC0 BC pts. There are differences in therapy outcomes in terms of survival and prognosis, particularly in HR- tumors, being better in HER2-low BC pts. It could be related to the fact that these tumors have a specific biology, but more evidence is needed. Citation Format: Isabel Álvarez, Angel Guerrero-Zotano, Ariadna Tibau, Catalina Falo, María Hernández, Ana Miguel, Raquel Andrés, Álvaro Rodríguez-Lescure, Miguel Corbellas, Sara López-Tarruella, Purificación Martínez, Cesar A Rodríguez, Diego Malón, María Marin, Mª José Echarri, Antonio Antón, Josefina Cruz, Diana Moreno, J. Ignacio Chacón, Ruth Campo, Andrea Blasco, Susana Bezares, Federico Rojo, Silvia Antolin. Features and survival outcomes of HER2-low patients from a prospective registry of unresectable locally advanced or metastatic breast cancer: GEICAM/2014-03 (RegistEM) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-07-30.

Contemporary Interpretation of Congenital Vascular Malformations: Extratruncular or Truncular lesions

Due to the wide range of clinical presentations, degree of severity and its location, together with unpredictable clinical course and erratic response to treatment with high recurrence by its nature/pathogenesis, congenital vascular malformation (CVM) remains a most challenging and confusing diagnostic and therapeutic clinical entity. Indeed, old definition of the CVMs based on only the clinical findings and also the classification with name-based eponyms through the last century added more confusion and failed to provide proper information necessary for its advanced management. But Hamburg Classification and ISSVA Classification have been established to meet its mandate for the contemporary management through last two decades as new classifications. The role of old classification became obsolete, no longer needed for contemporary management of the CVMs since both new classifications were based on advanced knowledge of the anatomy, embryology and pathophysiology involved to the CVM pathogenesis as birth defects affecting entire vascular system: artery, vein, and lymphatics. Hamburg Classification can provide more safer clinical guide with its subclassification based on embryological characteristics of the CVM lesions depending upon the stage of embryogenesis when the developmental arrest occurs: 'extratruncular' type for the lesions originated from the 'early' classified with the potential for growth and proliferation to cause the recurrence and subsequent morbidity while 'truncular' type for the lesion from the 'late' stage with more serious hemodynamic impacts. This subclassification would give a role as the clinical histopathological classification to bridge to the future genetic classification till available. ISSVA Classification also provides a clear guideline for the differentiation between the vascular tumor, known as hemangioma, and vascular malformation which was further subgrouped based on the flow characteristics. Further, ‘updated’ ISSVA classification of 2014-2016 is a hybrid classification matching the anatomical and the genetic characteristics of many pathologies. Hence, correct understanding on these two classifications will be critical for proper management of every CVM lesion based on correct identification and confirmation of each CVM lesion on this embryological subtype.

Aneurysm of The Superior Mesenteric Artery Associated With A Cardio-Renal Syndrome About A Case in Mali

The authors report a rare association of superior mesenteric artery aneurysm and cardio-renal syndrome is a complex clinical and therapeutic entity of cardiovascular and renal pathology whose prognosis depends on the precocity of management. We report a case of superior mesenteric artery aneurysm in a 36-year-old hypertensive patient, suffering from terminal renal failure complicating with stage 2 cardiorenal syndrome who underwent a hemodialysis session and a literature review.

Natural product preferentially targets redox and metabolic adaptations and aberrantly active STAT3 to inhibit breast tumor growth in vivo

Dysregulated gene expression programs and redox and metabolic adaptations allow cancer cells to survive under high oxidative burden. These mechanisms also represent therapeutic vulnerabilities. Using triple-negative breast cancer (TNBC) as a model, we show that compared to normal human breast epithelial cells, the TNBC cells, MDA-MB-231 and MDA-MB-468 that harbor constitutively active STAT3 also express higher glucose-6-phosphate dehydrogenase (G6PD), thioredoxin reductase (TrxR)1, NADPH, and GSH levels for survival. Present studies discover that the natural product, R001, targets these adaptation mechanisms. Treatment of TNBC cells with R001 inhibited constitutively active STAT3, STAT3-regulated gene expression, and the functions of G6PD and TrxR1. Consequently, in the TNBC, but not normal cells, R001 suppressed GSH levels, but raised NADPH levels, reflective of a loss of mitochondrial respiration and which led to reactive oxygen species (ROS) induction, all of which led to loss of viable cells and inhibition of anchorage-dependent and independent growth. R001 treatment further led to early pyroptosis and late DNA damage, cell cycle arrest, and apoptosis only in the TNBC cells. Oral administration of 5 mg/kg R001 inhibited MDA-MB-468 xenografts growth in mice, with reduced pY705-STAT3, G6PD, TrxR1, and GSH levels. R001 serves as a therapeutic entity that targets the vulnerabilities of TNBC cells to inhibit tumor growth in vivo.

Potential Reversal of Alzheimer’s Disease pathology by Antibody TB006 Targeting Galectin‐3, the Root Cause of Oligomerization of Amyloid Proteins

AbstractBackgroundAlzheimer’s disease (AD) is a chronic progressive neurodegenerative disorder caused by multiple pathogenic factors including Amyloid‐β (Aβ), phospho‐Tau (pTau), alpha‐synuclein, and ApoE4, etc. It is widely accepted that intermediate oligomeric forms, rather than monomers or mature fibrils, are more neurotoxic. Galectin‐3 (Gal‐3) was reported to be involved in Aβ oligomerization. Here, we show that Gal‐3 promotes oligomerization of Aβ and other pathogenic factors, and TB006, a monoclonal antibody targeting Gal‐3, acts as a possible treatment for AD by degrading neurotoxic oligomers.MethodWe used two anti‐Gal‐3 antibodies, our clinical lead TB006 and a mouse cross‐reactive surrogate, mTB001, to establish the benefits of Gal‐3 neutralization in AD in vitro and in vivo. The effects of mTB001 were tested in three AD mouse models (two transgenic mouse models (APPSwe, 5xFAD) and an Aβ42‐injected mouse model). After two‐week treatment, a spatial memory function test was conducted, followed by biochemical and immunohistochemical characterizations.ResultAmyloid aggregation is a hallmark of several neurodegenerative diseases (AD, PD and ALS) affecting the brain or peripheral tissues, whose intermediates (oligomers, protofibrils) and final mature fibrils display different toxicity. In vitro, Gal‐3 intrinsically and selectively promotes, while mTB001 and TB006 degrade, oligomerization of only pathogenic proteins like Aβ42/40, α‐synuclein, pTau and ApoE4, but not of normal proteins like normal Tau and ApoE2/3. Gal‐3 enhanced, while mTB001 blocked, Aβ42‐induced microglia activation. Additionally, Aβ42 and Gal‐3 synergistically induced, while mTB001 reversed, neuronal death. In vivo, in three mouse models of AD, cognitive deficits were strongly attenuated after just two weeks of mTB001 treatment. Mechanistically, Gal‐3 antibody blocked the initiating events in AD (Aβ aggregates), reduced inflammation and rescued neuronal damage. Furthermore, microhemorrhages, a potential safety liability seen in clinical stage drugs, were reduced.ConclusionPre‐clinical studies show that TB006 is an efficacious therapeutic entity through degradation of toxic oligomers and blocking or even reversing AD progression. Clinically, TB006 has shown a superior safety profile without any drug‐related adverse events in a nearly finished healthy volunteer trial. Promising efficacious data are expected in Q2/2022 from the ongoing phase I/II AD trial.

Complement-regulatory biomaterial coatings: Activity and selectivity profile of the factor H-binding peptide 5C6

The use of biomaterials in modern medicine has enabled advanced drug delivery strategies and led to reduced morbidity and mortality in a variety of interventions such as transplantation or hemodialysis. However, immune-mediated reactions still present a serious complication of these applications. One of the drivers of such reactions is the complement system, a central part of humoral innate immunity that acts as a first-in-line defense system in its own right but also coordinates other host defense responses. A major regulator of the complement system is the abundant plasma protein factor H (FH), which impairs the amplification of complement responses. Previously, we could show that it is possible to recruit FH to biomedical surfaces using the phage display-derived cyclic peptide 5C6 and, consequently, reduce deposition of C3b, an activation product of the complement system. However, the optimal orientation of 5C6 on surfaces, structural determinants within the peptide for the binding, and the exact binding region on FH remained unknown. Here, we show that the cyclic core and C-terminal region of 5C6 are essential for its interaction with FH and that coating through its N-terminus strongly increases FH recruitment and reduces C3-mediated opsonization in a microparticle-based assay. Furthermore, we could demonstrate that 5C6 selectively binds to FH but not to related proteins. The observation that 5C6 also binds murine FH raises the potential for translational evaluation in animal models. This work provides important insight for the future development of 5C6 as a probe or therapeutic entity to reduce complement activation on biomaterials. Statement of significanceBiomaterials have evolved into core technologies critical to biomedical and drug delivery applications alike, yet their safe and efficient use may be adversely impacted by immune responses to the foreign materials. Taking inspiration from microbial immune evasion strategies, our group developed a peptide-based surface coating that recruits factor H (FH), a host regulator of the complement system, from plasma to the material surface and prevents unwanted activation of this innate immunity pathway. In this study, we identified the molecular determinants that define the interaction between FH and the coated peptide, developed tethering strategies with largely enhanced binding capacity and provided important insight into the target selectivity and species specificity of the FH-binding peptide, thereby paving the way for preclinical development steps.

Oral sorafenib-loaded microemulsion for breast cancer: evidences from the in-vitro evaluations and pharmacokinetic studies

Sorafenib tosylate (SFB) is a multikinase inhibitor that inhibits tumour growth and proliferation for the management of breast cancer but is also associated with issues like toxicity and drug resistance. Also, being a biopharmaceutical class II (BCS II) drug, its oral bioavailability is the other challenge. Henceforth, this report intended to encapsulate SFB into a biocompatible carrier with biodegradable components, i.e., phospholipid. The microemulsion of the SFB was prepared and characterized for the surface charge, morphology, micromeritics and drug release studies. The cell viability assay was performed on 4T1 cell lines and inferred that the IC50 value of sorafenib-loaded microemulsion (SFB-loaded ME) was enhanced compared to the naïve SFB at the concentrations of about 0.75 µM. More drug was available for the pharmacological response, as the protein binding was notably decreased, and the drug from the developed carriers was released in a controlled manner. Furthermore, the pharmacokinetic studies established that the developed nanocarrier was suitable for the oral administration of a drug by substantially enhancing the bioavailability of the drug to that of the free SFB. The results bring forth the preliminary evidence for the future scope of SFB as a successful therapeutic entity in its nano-form for effective and safer cancer chemotherapy via the oral route.

MicroRNA-124-3p-enriched small extracellular vesicles as a therapeutic approach for Parkinson’s disease

Parkinson's disease is a neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra with no effective cure available. MicroRNA-124 has been regarded as a promising therapeutic entity for Parkinson's disease due to its pro-neurogenic and neuroprotective roles. However, its efficient delivery to the brain remains challenging. Here, we used umbilical cord blood mononuclear cell-derived extracellular vesicles as a biological vehicle to deliver microRNA (miR)-124-3p and evaluate its therapeutic effects in a mouse model of Parkinson's disease. Invitro, miR-124-3p-loaded small extracellular vesicles induced neuronal differentiation in subventricular zone neural stem cell cultures and protected N27 dopaminergic cells against 6-hydroxydopamine-induced toxicity. Invivo, intracerebroventricularly administered small extracellular vesicles were detected in the subventricular zone lining the lateral ventricles and in the striatum and substantia nigra, the brain regions most affected by the disease. Most importantly, although miR-124-3p-loaded small extracellular vesicles did not increase the number of new neurons in the 6-hydroxydopamine-lesioned striatum, the formulation protected dopaminergic neurons in the substantia nigra and striatal fibers, which fully counteracted motor behavior symptoms. Our findings reveal a novel promising therapeutic application of small extracellular vesicles as delivery agents for miR-124-3p in the context of Parkinson's disease.

Plants with Therapeutic Potential for Ischemic Acute Kidney Injury: A Systematic Review.

Acute kidney injury (AKI) is a complex condition which has an intricate pathology mostly involving hemodynamic, inflammatory, and direct toxic effects at the cellular level with high morbidity and mortality ratios. Renal ischemic reperfusion injury (RIRI) is the main factor responsible for AKI, most often observed in different types of shock, kidney transplantation, sepsis, and postoperative procedures. The RIRI-induced AKI is accompanied by increased reactive oxygen species generation together with the activation of various inflammatory pathways. In this context, plant-derived medicines have shown encouraging nephroprotective properties. Evidence provided in this systemic review leads to the conclusion that plant-derived extracts and compounds exhibit nephroprotective action against renal ischemic reperfusion induced-AKI by increasing endogenous antioxidants and decreasing anti-inflammatory cytokines. However, there is no defined biomarker or target which can be used for treating AKI completely. These plant-derived extracts and compounds are only tested in selected transgenic animal models. To develop the results obtained into a therapeutic entity, one should apply them in proper vertebrate multitransgenic animal models prior to further validation in humans.

Do Patients' and Physicians' Perspectives Differ on Preferences for Irritable Bowel Syndrome Treatment?

Irritable bowel syndrome (IBS) is a highly prevalent disorder of gut-brain interaction and poses a significant burden to patients. Pharmacotherapy, diet, and psychotherapy all have largely comparable clinical efficacy. Therefore, factors outside efficacy can have an important impact in determining preferences for a specific therapeutic entity. The aim of this study was to compare the patient and physician perspectives and identify important treatment characteristics regarding the management of IBS. Semistructured interviews were performed among IBS patients (n = 8), fulfilling the Rome IV criteria, and surveys were sent to physicians involved in IBS care (n = 15). Nine important treatment characteristics were revealed: effectiveness, time until response, cessation of response, side effects, location, waiting period, treatment burden, frequency of healthcare appointments, and willingness to pay. Time to response, location, and waiting time were less important for patients compared to physicians. This study assessed important IBS treatment characteristics and provided context to preferences from a patient and physician perspective. These data could be relevant during shared decision-making in clinical practice.

Choledochal cyst: A challenging diagnostic and therapeutic entity in low-resource settings.

BackgroundCholedochal cyst is an uncommon congenital biliary tract abnormality of unknown etiology. Its classical symptoms are jaundice, abdominal pain, and right upper quadrant mass. However, the disease may present with a vague and non-specific chronic abdominal discomfort. Delay in diagnosis and management may increase the risk of complications particularly the malignancy, which can directly affect the prognosis and outcome. Complete excision of the extra-hepatic duct, cholecystectomy, and Roux-en-Y hepaticojejeunostomy through the open surgical intervention or laparoscopic procedure is the mainstay of treatment.Case PresentationA 14-year-old male was presented to our hospital complaining of vague abdominal pain for 5 years. The radiologic imaging showed the features of a type IVa choledochal cyst. He underwent complete excision of the extra-hepatic duct, cholecystectomy, and Roux-en-Y hepaticojejeunostomy. Although the bile leakage occurred as a complication of the procedure, our team best managed the patient in the post-operative period until full recovery.DiscussionThe Choledochal cyst was first described by Vater, which is a congenital anomaly that sometimes may remain asymptomatic till adulthood. Surgical intervention is the mainstay of treatment. However, postoperative complications including bile leakage need a close follow-up of the patient.ConclusionDiagnostic delay (antenatal and postnatal) and non-specific symptoms will mask the real feature of the disease, especially in low-resource settings. Technical facilities and professional care of the patient may preclude complications.

Isolated Ruptured Paravisceral Penetrating Aortic Ulcers

The goal of this study is to investigate the clinical presentation, treatment options, and outcomes of the patients with isolated ruptured paravisceral penetrating aortic ulcers (PV-PAU). All patients presenting with acute aortic syndrome from 2015 to 2020 were screened, of which patients with isolated ruptured PV-PAU were included in this retrospective study. Study endpoints were the assessment of treatment options, technical success, and clinical outcome. Outcome measures included major perioperative complications and mortality. Sixteen patients (11 men; median age 68; IQR 60 - 75 years) presented with isolated ruptured PV-PAU were included in this study. The median follow-up was 25 months (range 1 - 51). Ruptured PV-PAUs represented 12.3% of the ruptured aortic aneurysms in all locations. PV-PAUs were found in segment A (n=8, 50%), segment B (n=5, 31%), and segment C (n=3, 19%). PV-PAUs showed a mean protrusion distance of 27±10 mm, a mean neck diameter of 21 ± 7 mm, and maximal aortic diameter of 50 ± 11 mm. Five patients (31%) showed hemodynamic instability on admission and needed intense fluid resuscitation. Of those, 2 patients needed urgent laparotomy with a fast transabdominal supraceliac aortic clamping, one needed an aortic balloon occlusion to obtain rapid aortic control. The open aortic repair was the most frequently performed surgery (11/16, 69%), followed by hybrid procedures (3/16) and parallel graft chimney technique (2/16). Two patients died during the follow-up, calculating for in-hospital and 1-year mortality rates of 6 - 12%, respectively. The postoperative morbidity rate was 31%. Postoperative complications included acute renal failure (31%), pneumonia (25%), and 1case of ischemic colitis (6%). No spinal cord ischemia was reported. Ruptured PV-PAU is a rare and challenging diagnostic and therapeutic entity. Open aortic repair seems to be a reliable option in treating patients with isolated ruptured PV-PAUs. Hybrid procedures and parallel stent-graft techniques can only be used in selected patients.