Therapeutic Spectrum Research Articles

Ascending Aorta and Aortic Arch - Endovascular Therapy Today and in the Future

Pathologies in the region of the aortic arch may occur in isolation, but adjacent segments of the thoracic aorta - the ascending or descending aorta - are much more commonly affected. The first surgical procedures to treat the aortic arch were performed nearly six decades ago. Despite numerous improvements and innovations in the 20th and early 21st centuries, these procedures are still associated with relevant operative mortality and neurological complication rates. Endovascular techniques and modern hybrid procedures are increasingly expanding the therapeutic spectrum in the aortic arch, although the open surgical approach is currently still the gold standard. Endovascular treatment of aortic aneurysm was first performed in the early 1990s in the infrarenal abdominal aorta. It was not long before the first attempts at endovascular therapy were made for the treatment of the aortic arch. In 1996, Inoue et al. reported the use of the first commonly used endoprosthesis to treat aneurysms in the aortic arch. Continuous improvements and refinements in implantation techniques and also implanted material have resulted in endovascular therapy now being an increasingly important option compared to open surgical procedures in the descending thoracic and abdominal aorta and has partially replaced them as the gold standard. This review article aims to provide an overview of the prerequisites, results, but also limitations of endovascular surgery of the aortic arch.

The Osculating Circles Gastroplasty: A Novel Endoscopic Submucosal Resection Enhanced Endoluminal Suturing for Obesity

Endoscopic bariatric therapies have emerged as minimally invasive alternatives to bariatric surgery that augment the therapeutic spectrum as primary and revisional interventions.1 Endoscopic sleeve gastroplasty (ESG) is a primary endoscopic bariatric therapy and involves transoral endoscopic reduction of the gastric reservoir.2 Transoral outlet reduction (TORe) is a minimally invasive option for management of weight regain after Roux-en-Y gastric bypass secondary to dilation of the gastrojejunal anastomosis.

Low-Valent Calix[4]arene Glycoconjugates Based on Hydroxamic Acid Bearing Linkers as Potent Inhibitors in a Model of Ebola Virus Cis-Infection and HCMV-gB-Recombinant Glycoprotein Interaction with MDDC Cells by Blocking DC-SIGN.

In addition to a variety of viral-glycoprotein receptors (e.g., heparan sulfate, Niemann-Pick C1, etc.), dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN), from the C-type lectin receptor family, plays one of the most important pathogenic functions for a wide range of viruses (e.g., Ebola, human cytomegalovirus (HCMV), HIV-1, severe acute respiratory syndrome coronavirus 2, etc.) that invade host cells before replication; thus, its inhibition represents a relevant extracellular antiviral therapy. We report two novel p-tBu-calixarene glycoclusters 1 and 2, bearing tetrahydroxamic acid groups, which exhibit micromolar inhibition of soluble DC-SIGN binding and provide nanomolar IC50 inhibition of both DC-SIGN-dependent Jurkat cis-cell infection by viral particle pseudotyped with Ebola virus glycoprotein and the HCMV-gB-recombinant glycoprotein interaction with monocyte-derived dendritic cells expressing DC-SIGN. A unique cooperative involvement of sugar, linker, and calixarene core is likely behind the strong avidity of DC-SIGN for these low-valent systems. We claim herein new promising candidates for the rational development of a large spectrum of antiviral therapeutics.

Classical View on Bhasma as Chief Formulation of Rasashastra: An Ayurveda Review

Minerals and metals based drugs possess important therapeutic potential and preparation of such medicines described in Rasashastra which deals with minerals and metals based formulations. The processing techniques related to the preparation of these medicines are very specific to make these drugs nontoxic and efficacious. Shodhana means purification and Marana means incineration/calcinations are main procedures associated with the preparation of Rasa- Aushdhis. Bhasmas are important preparation of this category which is considered as herbo-metallic preparation and description of Bhasma Kalpana is found in Ayurveda Samhitas during Arsha Sampradaya. These herbo-mineral/metallic formulations (Bhasma) mainly prepared by various steps of purification, grinding, mixing, heating, incineration and size reduction, etc. These drugs possess advantages of palatability, low dosing frequency, high potency, good bioavailability, optimum absorption and wide range of therapeutic spectrum. Bhasma not only used for therapeutic purpose but also advised for promoting general health and rejuvenating effects. Makshika bhasma, Swarna bhasma, Abhrak bhasma, Louha bhasma and Tamra bhasma, etc. are commonly used Bhasma preparation indicated for many pathological conditions including skin diseases, digestive ailments, sexual disorders, asthma and infections, etc.

A SARS-CoV-2 antibody broadly neutralizes SARS-related coronaviruses and variants by coordinated recognition of a virus-vulnerable site

Potent neutralizing SARS-CoV-2 antibodies often target the spike protein receptor-binding site (RBS), but the variability of RBS epitopes hampers broad neutralization of multiple sarbecoviruses and drifted viruses. Here, using humanized mice, we identified an RBS antibody with a germline VH gene that potently neutralized SARS-related coronaviruses, including SARS-CoV and SARS-CoV-2 variants. X-ray crystallography revealed coordinated recognition by the heavy chain of non-RBS conserved sites and the light chain of RBS with a binding angle mimicking the angiotensin-converting enzyme 2 (ACE2) receptor. The minimum footprints in the hypervariable region of RBS contributed to the breadth of neutralization, which was enhanced by immunoglobulin G3 (IgG3) class switching. The coordinated binding resulted in broad neutralization of SARS-CoV and emerging SARS-CoV-2 variants of concern. Low-dose therapeutic antibody treatment in hamsters reduced the virus titers and morbidity during SARS-CoV-2 challenge. The structural basis for broad neutralizing activity may inform the design of a broad spectrum of therapeutics and vaccines.

Neuropharmacology of Antiseizure Drugs.

BackgroundAntiseizure drugs (ASDs) are the primary therapy for epilepsy, with more than 20 drugs introduced into clinical practice to date. These drugs are typically grouped by their mechanisms of action and therapeutic spectrum. This article aims to educate non‐neurologists and medical students about the new frontiers in the pharmacology of ASDs and presents the current state of the literature on the efficacy and tolerability of these agents.MethodsRandomized controlled trials, observational studies, and evidence‐based meta‐analyses of ASD efficacy and tolerability as initial monotherapy for epileptic seizures and syndromes were identified in PubMed, EMBASE, the Cochrane Library, and Elsevier Clinical Pharmacology.ResultsThe choice of ASD varies primarily according to the seizure type. Practical guidelines for ASD selection in patients with new‐onset and drug‐resistant epilepsy were recently published. The guidelines have shown that the newer‐generation drugs, which have unique mechanistic and pharmacokinetic properties, are better tolerated but have similar efficacy compared with the older drugs. Several ASDs are effective as first‐line monotherapy in focal seizures, including lamotrigine, carbamazepine, phenytoin, levetiracetam, and zonisamide. Valproate remains the first‐line drug for many patients with generalized and unclassified epilepsies. However, valproate should be avoided, if possible, in women of childbearing potential because of teratogenicity. Toxicity profile precludes several drugs from use as first‐line treatment, for example, vigabatrin, felbamate, and rufinamide.ConclusionsAntiseizure drugs have different pharmacologic profiles that should be considered when selecting and prescribing these agents for epilepsy. These include pharmacokinetic properties, propensity for drug‐drug interactions, and adverse effects.

Need for real-world data studies on hidradenitis suppurativa/acne inversa treatment

Publication of real world data on the results of treatment with (approved) drugs is important to allow for areasonable judgement about the efficacy of amedication, especially since due to the nature of controlled clinical studies certain patient groups, who in daily clinical routine would best benefit from such new treatments, are excluded from study inclusions. In the present review, real-world data on the treatment of hidradenitis suppurativa (HS) are summarized. It appears that adalimumab, as the only approved biological treatment so far, represents acost-efficient and effective therapy. Patient education is important to increase treatment adherence and efficacy. The baseline IHS4 score has proven to be ameaningful predictor for recurrences during adalimumab therapy. Additional publications on real-world data including high numbers of patients with different risk factors are required to meaningly evaluate the evolving therapeutic spectrum of treatment options for HS in clinical practice.

From discovery to approval: A brief history of the compstatin family of complement C3 inhibitors

The FDA approval of pegcetacoplan (Empaveli), a PEGylated compstatin-based C3 therapeutic, as a new treatment for paroxysmal nocturnal hemoglobinuria (PNH) marks a milestone in the history of complement drug discovery. Almost 15 years after the approval of the first complement-specific drug for PNH, the anti-C5 antibody eculizumab, a novel class of complement inhibitors with a distinct mechanism of action finally enters the clinic. This landmark decision broadens the spectrum of available complement therapeutics, offering patients with unmet clinical needs or insufficient responses to anti-C5 therapy an alternative treatment option with a broad activity profile. Here we present a brief historical account of this newly approved complement drug, consolidating its approval within the long research record of the compstatin family of peptidic C3 inhibitors.

Appraisals of the Bangladeshi Medicinal Plant Calotropis gigantea Used by Folk Medicine Practitioners in the Management of COVID-19: A Biochemical and Computational Approach.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was first recognized in Wuhan in late 2019 and, since then, had spread globally, eventually culminating in the ongoing pandemic. As there is a lack of targeted therapeutics, there is certain opportunity for the scientific community to develop new drugs or vaccines against COVID-19 and so many synthetic bioactive compounds are undergoing clinical trials. In most of the countries, due to the broad therapeutic spectrum and minimal side effects, medicinal plants have been used widely throughout history as traditional healing remedy. Because of the unavailability of synthetic bioactive antiviral drugs, hence all possible efforts have been focused on the search for new drugs and alternative medicines from different herbal formulations. In recent times, it has been assured that the Mpro, also called 3CLpro, is the SARS-CoV-2 main protease enzyme responsible for viral reproduction and thereby impeding the host’s immune response. As such, Mpro represents a highly specified target for drugs capable of inhibitory action against coronavirus disease 2019 (COVID-19). As there continue to be no clear options for the treatment of COVID-19, the identification of potential candidates has become a necessity. The present investigation focuses on the in silico pharmacological activity of Calotropis gigantea, a large shrub, as a potential option for COVID-19 Mpro inhibition and includes an ADME/T profile analysis of that ligand. For this study, with the help of gas chromatography–mass spectrometry analysis of C. gigantea methanolic leaf extract, a total of 30 bioactive compounds were selected. Our analyses unveiled the top four options that might turn out to be prospective anti–SARS-CoV-2 lead molecules; these warrant further exploration as well as possible application in processes of drug development to combat COVID-19.

Xiaoyaosan Improves Antibiotic-Induced Depressive-Like and Anxiety-Like Behavior in Mice Through Modulating the Gut Microbiota and Regulating the NLRP3 Inflammasome in the Colon.

Disturbance of the gut microbiota plays an essential role in mental disorders such as depression and anxiety. Xiaoyaosan, a traditional Chinese medicine formula, has a wide therapeutic spectrum and is used especially in the management of depression and anxiety. In this study, we used an antibiotic-induced microbiome-depleted (AIMD) mouse model to determine the possible relationship between imbalance of the intestinal flora and behavioral abnormalities in rodents. We explored the regulatory effect of Xiaoyaosan on the intestinal flora and attempted to elucidate the potential mechanism of behavioral improvement. We screened NLRP3, ASC, and CASPASE-1 as target genes based on the changes in gut microbiota and explored the effect of Xiaoyaosan on the colonic NLRP3 pathway. After Xiaoyaosan intervention, AIMD mice showed a change in body weight and an improvement in depressive and anxious behaviors. Moreover, the gut flora diversity was significantly improved. Xiaoyaosan increased the abundance of Lachnospiraceae in AIMD mice and decreased that of Bacteroidaceae, the main lipopolysaccharide (LPS)-producing bacteria, resulting in decreased levels of LPS in feces, blood, and colon tissue. Moreover, serum levels of the inflammatory factor, IL-1β, and the levels of NLRP3, ASC, and CASPASE-1 mRNA and DNA in the colon were significantly reduced. Therefore, Xiaoyaosan may alleviate anxiety and depression by modulating the gut microbiota, correcting excessive LPS release, and inhibiting the immoderate activation of the NLRP3 inflammasome in the colon.

Tyloxapol inhibits RANKL-stimulated osteoclastogenesis and ovariectomized-induced bone loss by restraining NF-κB and MAPK activation.

ObjectiveTyloxapol is a non-ionic surfactant with diverse pharmacological effects including anti-inflammatory, anti-malignant tumor and antioxidant activities. However, the effect of tyloxapol on osteoclastogenesis has not been elucidated. In this study, we intended to clarify the effect of tyloxapol on RANKL-stimulated osteoclastogenesis and the molecular mechanism both ex vivo and in vivo.MethodsIn vitro osteoclastogenesis assay was performed in BMMs and Raw 264.7 cells. The mature osteoclasts were visualized by TRAP staining. The osteoblsats were visualized by alkaline phosphatase (ALP) staining and Von Kossa staining. To assess whether tyloxapol inhibited the function of mature osteoclasts, F-actin belts and pit formation assays were carried out in BMMs. To evaluate the effect of tyloxapol on post-menopausal osteoporosis, the OVX mouse model were utilized. The bone tissue TRAP staining was used to evaluate the osteoclast activity in vivo. The von kossa staining and micro computed tomography were used to evaluate the histomorphometric parameters. The Goldner's staining was used to evaluate the osteoblast activity. The expression of osteoclastogenesis-associated markers were evaluated by Real-time PCR. The NF-κB and NFATc1 transcriptional activities were illustrated utilizing the assay of luciferase reporter. The effect of tyloxapol pretreatment on IκBa degradation and p65 phosphorylation was evaluated using Western bloting assay. The effect of tyloxapol pretreatment on p65 nuclear translocation was evaluated utilizing immunofluorescence. The effect of tyloxapol pretreatment on the phosphorylatio of ERK, p38 and JNK was examined utilizing Western bloting assay.ResultsIn our research, we found that tyloxapol suppresses RANKL-stimulated osteoclastogenesis in a dose dependent manner and in the initial stage of osteoclastogenesis. Through F-actin belts and pit formation assays, we found that tyloxapol had the ability to inhibit the function of mature osteoclasts in vitro. The results of animal experiments demonstrated that tyloxapol inhibits OVX-induced bone mass loss by inhibiting the activity of osteoclasts but had a limited effect on osteoblastic differentiation and mineralization. Molecularly, we found that tyloxapol suppresses RANKL-stimulated NF-κB activation through suppressing degradation of IκBα, phosphorylation and nuclear translocation of p65. At last, MAPK signaling pathway was also suppressed by tyloxapol in dose and time-dependent manners.ConclusionOur research illustrated that tyloxapol was able to suppress osteoclastogenesis in vitro and ovariectomized-induced bone loss in vivo by restraining NF-κB and MAPK activation. This is pioneer research could pave the way for the development of tyloxapol as a potential therapeutic treatment for osteoporosis.The translational potential of this articleThis study explores that tyloxapol, also known as Triton WR-1339, may be a drug candidate for osteoclastogenic sicknesses like osteoporosis. Our study may also extend the clinical therapeutic spectrum of tyloxapol.

Broad Neutralization Activity of SARS-CoV-2 Antibody is Achieved by Coordinated Recognition of Virus Vulnerable Site

Potently neutralizing SARS-CoV-2 antibodies often target the receptor binding site (RBS) of spike protein but the variability of RBS epitopes hampers broad neutralization of different clades of coronaviruses and emerging drifted viruses. Here, we identified a human RBS antibody that potently neutralizes SARS-CoV and SARS-CoV-2 variants that belong to clade 1 SARS-related coronavirus. X-ray crystallography revealed coordinated recognition by the heavy chain to conserved sites and the light chain to RBS, allowing for the mimicry of ACE2 binding mode. The minimum footprints in the hypervariable region of RBS contributed to the breadth of neutralization, and the activity was further enhanced by IgG3 switching. Eventually, the coordinated binding resulted in broad neutralization of SARS-CoV and emerging SARS-CoV-2 variants of concern. Furthermore, therapeutic treatment in a hamster model provided protection at low dosage. The structural basis for broadly neutralizing activity informs the design of broad spectrum of therapeutics and vaccines.Funding: This work was supported by Japan Agency for Medical Research and Development grant JP19fk0108111 (TH, YT), JP20fk0108298 (TK, TH, KM, YT), JP20am0101093 (KM), JP20ae0101047 (KM), JP20fk0108251 (HS), and JP20am0101124 (YK), by Ministry of Education, Culture, Sports, Science and Technology grant JPMXS0420100119 (KM) and 20H05773 (TH), by The Naito Foundation (TH), and by Joint Usage/Research Center program of Institute for Frontier Life and Medical Sciences, Kyoto University (KM).Conflict of Interest: AS is an employee of Shionogi & Co., Ltd. MO is a CEO, employee, and shareholder of Trans Chromosomics, Inc. These authors acknowledge a potential conflict of interest and attest that the work contained in this report is free of any bias that might be associated with the commercial goals of the company. TO, YA, MO, TH, KM, and YT declare that an intellectual property application has been filed using the data presented in this paper. The other authors declare that they have no competing interests.Ethical Approval: Animal procedures were approved by the Animal Ethics Committee of the National Institute of Infectious Diseases, Japan, and performed in accordance with the guidelines of the Institutional Animal Care and Use Committee. In vitro escape mutation screening experiments for SARSCoV-2 were performed at the Biosafety Level-3 facility of the Research Center for ZoonosisControl, Hokkaido University, and the National Institute of Infectious Diseases following the institutional guidelines.

Personalized Image-Guided Therapies for Local Malignencies: Interdisciplinary Options for Interventional Radiology and Interventional Radiotherapy.

Minimal-invasive interventions considerably extend the therapeutic spectrum in oncology and open new dimensions in terms of survival, tolerability and patient-friendliness. Through the influence of image-guided interventions, many interdisciplinary therapy concepts have significantly evolved, and this process is by far not yet over. The rapid progression of minimal-invasive technologies offers hope for new therapeutic concepts in the short, medium and long term. Image-guided hybrid-technologies complement and even replace in selected cases classic surgery. In this newly begun era of immune-oncology, interdisciplinary collaboration and the focus on individualized and patient-friendly therapies are crucial.

In Translation: FcRn across the Therapeutic Spectrum.

As an essential modulator of IgG disposition, the neonatal Fc receptor (FcRn) governs the pharmacokinetics and functions many therapeutic modalities. In this review, we thoroughly reexamine the hitherto elucidated biological and thermodynamic properties of FcRn to provide context for our assessment of more recent advances, which covers antigen-binding fragment (Fab) determinants of FcRn affinity, transgenic preclinical models, and FcRn targeting as an immune-complex (IC)-clearing strategy. We further comment on therapeutic antibodies authorized for treating SARS-CoV-2 (bamlanivimab, casirivimab, and imdevimab) and evaluate their potential to saturate FcRn-mediated recycling. Finally, we discuss modeling and simulation studies that probe the quantitative relationship between in vivo IgG persistence and in vitro FcRn binding, emphasizing the importance of endosomal transit parameters.

Therapeutic wavelengths of ultraviolet B radiation activate apoptotic, circadian rhythm, redox signalling and key canonical pathways in psoriatic epidermis

Ultraviolet B radiation (UVB) exerts pleiotropic effects on human skin. DNA damage response and repair pathways are activated by UVB; if damage cannot be repaired, apoptosis ensues. Although cumulative UVB exposure predisposes to skin cancer, UVB phototherapy is widely used as an effective treatment for psoriasis. Previous studies defined the therapeutic action spectrum of UVB and showed that psoriasis is resistant to apoptosis. This study aimed to investigate early molecular responses within psoriasis plaques following irradiation with single equi-erythemogenic doses of clinically-effective (311 nm, narrow-band) compared to clinically-ineffective (290 nm) UVB. Forty-eight micro-dissected epidermal samples from 20 psoriatic patients were analyzed using microarrays. Our bioinformatic analysis compared gene expression between 311 nm irradiated, 290 nm irradiated and control psoriasis epidermis to specifically identify 311 nm UVB differentially expressed genes (DEGs) and their upstream regulatory pathways. Key DEGs and pathways were validated by immunohistochemical analysis.There was a dynamic induction and repression of 311 nm UVB DEGs between 6 h and 18 h, only a limited number of DEGs maintained their designated expression status between time-points. Key disease and function pathways included apoptosis, cell death, cell migration and leucocyte chemotaxis. DNA damage response pathways, NRF2-mediated oxidative stress response and P53 signalling were key nodes, interconnecting apoptosis and cell cycle arrest. Interferon signalling, dendritic cell maturation, granulocyte adhesion and atherosclerotic pathways were also differentially regulated. Consistent with these findings, top transcriptional regulators of 311 nm UVB DEGs related to: a) apoptosis, DNA damage response and cell cycle control; b) innate/acquired immune regulation and inflammation; c) hypoxia/redox response and angiogenesis; d) circadian rhythmicity; f) EGR/AP1 signalling and keratinocyte differentiation; and g) mitochondrial biogenesis.This research provides important insights into the molecular targets of 311 nm UVB, underscoring key roles for apoptosis and cell death. These and the other key pathways delineated may be central to the therapeutic effects of 311 nm in psoriasis.

NOSE-TO-BRAIN DRUG DELIVERY: AN UPDATE TO THE ALTERNATIVE PATH TO SUCCESSFUL TARGETED ANTI-MIGRAINE DRUGS

The Blood-Brain Barrier (BBB) limits transportation to the brain of possible treatment moieties. Specific stimulation of the brain through olfactory and trigeminal neural pathways by BBB has been taken into consideration for the development of a wide spectrum of brain therapeutics. The intranasal delivery path delivers the drugs through the brain, eliminating any side effects and increasing neurotherapeutics performance. Diverse drug delivery systems (DDDss) for reaching the brain via the nasal route have been researched over the past few decades. Large-scale molecular biologics, such as Deoxyribonucleic acid (DNA), gene vectors, and stem cells, can be administered intranasally, as a method for the management of a range of CNS illnesses, including stroke, Parkinson's diseases, multiple sclerosis, Migraine, Alzheimer's diseases, epilepsy, and mental disorders. New DDSs, including nanoparticles, liposomes, and polymeric micelles, have acquired potentials in the nasal mucosa and central nervous system (CNS), as effective means of concentrating the brain without toxicity. Differential nasal cavity structures posed a significant obstacle in ineffective drugs beyond the nasal valve. Pharmaceutical firms have increasingly used emerging techniques for the production of new nasal pharmaceutical drugs to overcome these obstacles. This review aims to identify the new advances in the nasal administration of brain-based DDSs for Migraines.

Testicular sperm extraction in male infertility : Indications, success rates, practical implementation, and possible complications

Unwanted childlessness is aburden on acouple's relationship. The therapeutic spectrum of male infertility has increased significantly in recent years so that even azoospermia patients can be given biological paternity by testicular sperm extraction (TESE). The indications, success rates, practical implementation, and possible complications of conventional and microscopic TESE in male infertility are presented in this review. Anonsystematic search of the relevant literature was carried out. In obstructive azoospermia (OA), primarily desobstructive surgical procedures are used, while TESE is the surgical procedure of choice in nonobstructive azoospermia (NOA). In the latter, sperm extraction can be performed conventionally or microscopically (mTESE) assisted, whereby the latter offers an advantage in terms of sperm detection rate in the case of small testicular volumes (<12 ml), chemotherapy, Klinefelter's disease and AZFc microdeletions. The sperm detection rate of TESE is about 50%. Postoperative controls are useful because of the possible induction of symptomatic hypogonadism. Before performing TESE, determining the hormone status and human genetic clarification are necessary. Any costs incurred and the possibility of missing sperm proof must be discussed. Close cooperation between andrologists, gynecologists, reproductive physicians, and human geneticists is necessary. All in all, TESE is asafe surgical procedure with a low complication rate.

Sialolithiasis: retrospective analysis of the effect of an escalating treatment algorithm on patient-perceived health-related quality of life

BackgroundGland preserving techniques in the treatment of sialolithiasis have continuously replaced radical surgery. The aim of this study was to evaluate a multimodal treatment algorithm in the therapy of sialolithiasis and assess improvement of HRQoL perceived by patients.MethodsPatients with sialolithiasis were treated by a multimodal treatment algorithm based on multiplicity of stones, stone size, affected gland, and stone position. The therapeutic spectrum ranged from conservative measures, extracorporeal shockwave lithotripsy, interventional sialendoscopy, combined endoscopic-surgical procedures to surgical gland removal as ultima ratio. Outcomes were evaluated by surgeons by means of the electronic patient record and by patients themselves using a standardized questionnaire.Results87 patients treated for sialolithiasis were comprised in this study. The submandibular gland (SMG) was affected in 58.6% and the parotid gland (PG) in 41.4% of cases. Mean patient age was 41.67 years for SMG and 48.91 years for PG. In over 80% of cases sialolithiasis was associated with classic meal-related pain and swelling. Type and intensity of symptomatic sialolithiasis were not dependent on patient age or gender, nor could a relation between the affected gland and the occurrence of symptoms be demonstrated. Overall, 86.2% of cases were reported as cured using the multimodal step-by-step treatment algorithm. Resection of the affected gland could be dispensed in 98.9% of cases. According to patients pain could be reduced in 94.3% of cases.ConclusionsThe analyzed treatment algorithm of increasing invasiveness is a favorable and effective tool to successfully treat sialolithiasis in > 86% of cases. For the first time, the present study shows that patient-perceived improvement of HRQoL due to ease of symptoms has an even higher success rate of > 94%.

Ursolic Acid and Its Nanoparticles Are Potentiators of Oncolytic Measles Virotherapy against Breast Cancer Cells.

Simple SummaryDespite the advancing treatments, female breast cancer is one of the most common cancers and a leading cause of cancer deaths in women. To help broaden the therapeutic spectrum of breast cancer, we identified the natural compound ursolic acid (UA) as a potentiator that enhances the oncolytic activity of measles virus (MV) against breast cancer cells through the induction of apoptosis. In addition, to increase clinical applicability, we further generated UA nanoparticles that achieved improved solubility. UA nanoparticles similarly synergized with MV in killing breast cancer cells by triggering apoptosis, and this synergistic anticancer effect was also observed in various breast cancer cell types. This study demonstrates for the first time that UA and its nanoparticles enhance MV’s oncolytic activity in breast cancer cells, suggesting that such combinations may be worth further exploring as an anticancer strategy against breast cancer.Oncolytic viruses (OVs) and phytochemical ursolic acid (UA) are two efficacious therapeutic candidates in development against breast cancer, the deadliest women’s cancer worldwide. However, as single agents, OVs and UA have limited clinical efficacies. As a common strategy of enhancing monotherapeutic anticancer efficacy, we explored the combinatorial chemovirotherapeutic approach of combining oncolytic measles virus (MV), which targets the breast tumor marker Nectin-4, and the anticancer UA against breast adenocarcinoma. Our findings revealed that in vitro co-treatment with UA synergistically potentiated the killing of human breast cancer cells by oncolytic MV, without UA interfering the various steps of the viral infection. Mechanistic studies revealed that the synergistic outcome from the combined treatment was mediated through UA’s potentiation of apoptotic killing by MV. To circumvent UA’s poor solubility and bioavailability and strengthen its clinical applicability, we further developed UA nanoparticles (UA-NP) by nanoemulsification. Compared to the non-formulated UA, UA-NP exhibited improved drug dissolution property and similarly synergized with oncolytic MV in inducing apoptotic breast cancer cell death. This oncolytic potentiation was partly attributed to the enhanced autophagic flux induced by the UA-NP and MV combined treatment. Finally, the synergistic effect from the UA-NP and MV combination was also observed in BT-474 and MDA-MB-468 breast cancer cells. Our study thus highlights the potential value of oncolytic MV and UA-based chemovirotherapy for further development as a treatment strategy against breast cancer, and the feasibility of employing nanoformulation to enhance UA’s applicability.

Challenges in the treatment of psoriasis in childhood

Psoriasis is a chronic, immune-mediated, inflammatory skin disease that affects up to 1.2% of children and adolescents. The treatment possibilities for pediatric psoriasis are usually based on the same principles as in adults. Most information on safety and efficacy has been derived from adult studies, but only some of the frequently used treatments have approval for use in children. Treatment options for psoriasis in children and adolescents are mostly off-label, with little available data on efficacy and safety, and so the treatment of pediatric psoriasis remains a challenge. In the future, new pediatric clinical trials should be undertaken to expand the therapeutic spectrum for psoriasis in children and adolescents.