Current Treatment Options Research Articles

Patient-Reported Outcomes in Chinese Patients with Locally Advanced or Recurrent Colorectal Cancer After Pelvic Exenteration.

Pelvic exenteration (PE) is often the only curative treatment option for selected locally advanced and locally recurrent colorectal cancer associated with significant morbidity. Open and laparoscopic approaches were accepted for this procedure. This study aimed to examine the Chinese patient-reported outcomes (PROs) and health-related quality of life (HRQoL) after PE. A total of 122 enrolled participants were asked to complete PROs at baseline and 1, 3, 6, 9 and 12 months after PE. PROs included seven symptoms from the National Cancer Institute's Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE). The HRQoL was assessed using the Functional Assessment of Cancer Therapy-Colorectal (FACT-C). The overall postoperative complication rate was 41.0%. Patients experienced lower physical and functional well-being and FACT-C 1month after surgery, then gradually recovered. The FACT-C score returned to baseline 9 months after surgery. Social and emotional well-being did not show signs of recovery until 6 months after the surgical procedure, and did not fully return to baseline until 12 months post-surgery. Symptom rates of insomnia, anxiety, discouragement, and sadness (composite score >0) did not improve significantly from baseline until 12 months after surgery. PE is a feasible treatment choice for locally advanced primary and recurrent colorectal cancer. Social, psychological, and emotional recovery in the Chinese population after PE tends to be slower compared with the physical condition.

Patient preferences for preventive migraine treatments among Canadian adults: A discrete choice experiment.

To evaluate preferences for key attributes of injected or infused preventive migraine treatments and assess heterogeneity in preferences among Canadian participants with migraine. Current treatment options for migraine prevention differ in their attributes, including mode of administration, efficacy, and dosing frequency; preferences for such attributes can vary among patients. With the advent of new therapies, evidence demonstrating patient preferences for injected or infused preventive migraine treatments is necessary. Canadian adults self-reporting a diagnosis of migraine completed a cross-sectional, internet-based survey that included a discrete choice experiment. Participants were presented with attributes of preventive migraine treatments, including speed of onset, durability of efficacy, mode of administration, administration setting, and dosing frequency. Latent class analysis (LCA) was used to identify subgroups of patients who differed in their treatment preferences. In total, 200 participants completed the survey. Participants' treatment preferences were most sensitive to improvements in the durability of effectiveness from "wears off 2 weeks before next dose" to "does not wear off before the next dose" (absolute difference in weights = |-0.95 to 1.07| = 2.02) and improvements from "cranial injections" to "intravenous infusions" (|-1.04 to 0.58| = 1.62); participants equally preferred self-injection and intravenous infusion from a health-care provider (mean weight = 0.58 and 0.47, respectively) as a route of administration over cranial injections (mean weight = -1.04). Three subgroups were identified with LCA: group one (n = 103) prioritized fast-acting and durable therapies, group two (n = 54) expressed aversion to cranial injections, and group three (n = 43) favored treatments administered in a health-care provider setting. In this sample of Canadian adults with migraine, we showed that durability of effectiveness and mode of administration are key attributes influencing patient preferences for preventive migraine treatments; however, certain groups of patients may differ in their treatment priorities. Our results highlight the need for patient-provider discussions regarding treatment attributes and consideration of patients' preferences when selecting a preventive migraine treatment.

Neuropathy and pain in Fabry disease

Fabry disease (FD) is a multiorgan lysosomal storage disorder caused by mutations in the alfa-galactosidase A (GLA ) gene. Pathogenic GLA mutations lead to impaired or even lost enzyme activity, which causes the accumulation of sphingolipids, e.g., globotriaosylceramide, in cells and tissues. The majority of FD patients experience triggerable pain, mainly acral and burning, which often begins in early childhood. While small fiber pathology is assumed to be the basis of FD pain, the underlying molecular mechanisms are not well understood. This review summarizes the clinical characteristics of neuropathy and neuropathic pain in FD, presents current treatment options, and gives an overview of the latest findings from experimental and human model systems on the pathomechanisms contributing to small fiber pathology and FD-associated pain.

Liposomal quercetin: A promising strategy to combat hepatic insulin resistance and inflammation in type 2 diabetes mellitus

In type 2 diabetes mellitus, hepatic insulin resistance is intricately associated with oxidative stress and inflammation. Nonetheless, the lack of therapeutic interventions directly targeting hepatic dysfunction represents a notable gap in current treatment options. Flavonoids have been explored due to their potential anti-diabetic effects. However, these compounds are associated with low bioavailability and high metabolization. In the present study, four flavonoids, kaempferol, quercetin, kaempferol-7-O-glucoside and quercetin-7-O-glucoside, were studied in a cellular model of hepatic insulin resistance using HepG2 cells. Quercetin was selected as the most promising flavonoid and incorporated into liposomes to enhance its therapeutic effect. Quercetin liposomes had a mean size of 0.12 µm, with an incorporation efficiency of 93 %. Quercetin liposomes exhibited increased efficacy in modulating insulin resistance. This was achieved through the modulation of Akt expression and the attenuation of inflammation, particularly via the NF-κB pathway, as well as the regulation of PGE2 and COX-2 expression. Furthermore, quercetin liposomes displayed a significant advantage over free quercetin in attenuating the production of reactive pro-oxidant species. These findings open new avenues for developing innovative therapeutic strategies to manage diabetes, emphasizing the potential of quercetin liposomes as a promising approach for targeting both hepatic insulin resistance and associated inflammation.

A Case-based Guide for World Health Organization (WHO) Grade 2 Meningioma Radiosurgery and Radiation Therapy from The Radiosurgery Society

Meningiomas represent the most common primary tumor of the central nervous system. Current treatment options include surgical resection with or without adjuvant radiation therapy (RT), definitive RT, and observation. However, the radiation dose, fractionation, and margins used to treat patients with WHO grade 2 meningiomas, which account for approximately 20% of all meningiomas, are not clearly defined, and deciding on the optimal treatment modality can be challenging owing to the lack of randomized data. In this manuscript, 3 cases of patients with WHO grade 2 meningiomas are presented with descriptions of treatment options after gross total resection, subtotal resection, and recurrent tumors within a prior irradiated field. Treatment recommendations were compiled from 9 central nervous system radiation oncology and neurosurgery experts from The Radiosurgery Society, and the majority consensus of treatment guidelines are reported. Both conventional and stereotactic RT are treatment options for WHO grade 2 meningiomas. The majority of prospective data in the setting of WHO grade 2 meningiomas involve larger margins. Stereotactic radiosurgery/hypofractionated stereotactic RT are less appropriate in this setting. Conventionally fractionated RT to at least 59.4 Gy is considered standard of care with utilization of preoperative and postoperative imaging to evaluate the extent of disease and possible osseous involvement. After careful discussion, stereotactic radiosurgery/hypofractionated stereotactic RT may play a role for the subset of patients who are unable to tolerate the standard lengthy conventionally fractionated treatment course, for those with prior RT, or for small residual tumors. However, more studies are needed to determine the optimal approach. This case-based evaluation of the current literature seeks to provide examples for the management of grade 2 meningiomas and give examples of both conventional and stereotactic RT.

Case report of a child with nephronophthisis from South Africa

BackgroundNephronophthisis (NPHP) is an autosomal recessive disorder with a subset of patients presenting with extrarenal manifestations such as retinal degeneration, cerebella ataxia, liver fibrosis, skeletal abnormalities, cardiac malformations, and lung bronchiectasis. However, the involvement of other organ systems has also been documented. Extrarenal manifestations occur in approximately 10–20% of patients. In developed countries, it has been reported as one of the most common causes of monogenic chronic kidney failure (CKF) during the first three decades of life, with more than 25 genes associated with this condition. The current treatment options for managing NPHP include supportive care, management of complications, and kidney replacement therapy when necessary.The index patient is a 10-year-old Caucasian female who presented with recurrent attacks of abdominal pain. Her elder sister, TN, who was 17 years old, was diagnosed with CKF and noted to have persistently elevated liver enzymes (gamma-glutamyl transferase, alanine, and aspartate transaminases). Following genetic testing, her elder sister was shown to have Nephronophthisis Type 3, and a liver biopsy showed early fibrotic changes. Subsequent genetic testing confirmed the index patient as having NPHP Type 3. A kidney biopsy showed focal sclerosed glomeruli with patchy areas of tubular atrophy and related tubulointerstitial changes in keeping with NPHP. We present the first confirmatory case of NPHP from South Africa based on histopathology and genetic testing in a 10-year-old Caucasian female who presented with recurrent attacks of abdominal pain, whose elder sister also presented with CKF and early liver fibrosis, confirmed on biopsy and genetic testing.ConclusionIn low-middle-income countries, genetic testing should be undertaken whenever possible to confirm the diagnosis of NPHP, especially in those with a suggestive biopsy or if there is CKF of unknown aetiology with or without extra-renal manifestations.

In silico exploration of anti-prostate cancer compounds from differential expressed genes

Prostate cancer (PCa) is a complex and biologically diverse disease with no curative treatment options at present. This study aims to utilize computational methods to explore potential anti-PCa compounds based on differentially expressed genes (DEGs), with the goal of identifying novel therapeutic indications or repurposing existing drugs. The methods employed in this study include DEGs-to-drug prediction, pharmacokinetics prediction, target prediction, network analysis, and molecular docking. The findings revealed a total of 79 upregulated DEGs and 110 downregulated DEGs in PCa, which were used to identify drug compounds capable of reversing the dysregulated conditions (dexverapamil, emetine, parthenolide, dobutamine, terfenadine, pimozide, mefloquine, ellipticine, and trifluoperazine) at a threshold probability of 20% on several molecular targets, such as serotonin receptors 2a/2b/2c, HERG protein, adrenergic receptors alpha-1a/2a, dopamine D3 receptor, inducible nitric oxide synthase (iNOS), epidermal growth factor receptor erbB1 (EGFR), tyrosine-protein kinases, and C-C chemokine receptor type 5 (CCR5). Molecular docking analysis revealed that terfenadine binding to inducible nitric oxide synthase (-7.833 kcal.mol−1) and pimozide binding to HERG (-7.636 kcal.mol−1). Overall, binding energy ΔGbind (Total) at 0 ns was lower than that of 100 ns for both the Terfenadine-iNOS complex (-101.707 to -103.302 kcal.mol−1) and Ellipticine-TOPIIα complex (-42.229 to -58.780 kcal.mol−1). In conclusion, this study provides insight on molecular targets that could possibly contribute to the molecular mechanisms underlying PCa. Further preclinical and clinical studies are required to validate the therapeutic effectiveness of these identified drugs in PCa disease.

Comparative Clinical Trial of Dermapen Microneedling and Platelet-Rich Plasma versus Dermapen Microneedling Alone in the Treatment of Stretch Marks in Egyptian Adults

Abstract Background Striae distensae are common skin lesions affecting up to 90% of pregnant women, and many adolescents and men. They pose a psychological burden to many people and no known treatment is completely effective for them. The current treatment options are limited by significant side effects, operator skill, cost, prolonged treatment period, or a combination thereof. Platelet-rich plasma (PRP), along with microneedling (MN), are promising dermatologic procedures with a wide range of applications, excellent safety profiles, yet only partially understood mechanisms of action. Aim of the Work to evaluate the effectiveness and side effects of MN with PRP versus MN alone in the treatment of striae distensae. This work included 40 patients who were divided into left-side lesions (MN alone) versus right-side lesions (PRP + MN). PRP was prepared using single-spin technique, and applied topically just before MN on right-side lesions. An automated MN pen device was used on both sides. Patients and Methods This was a prospective case control study with a split-body design which included 40 adult patients with striae distensae. The patients were recruited from the outpatient dermatology clinic in Ain Shams University hospitals, Cairo. Miravex Antera TM 3D Camera system measured the efficacy by indentation and roughness indices, and patients’ subjective improvement and reported side effects were recorded and analysed. Results A significant improvement was illustrated in both MN and MN + PRP sides in both the indentation and roughness indices measured by the Antera 3D camera system, and most patients reported subjective improvement in color (62.5%), smoothness (97.5%), size (82.5% vs 85%), and general appearance (92.5% vs 90%). Side effects including pain and erythema affected virtually all cases, while pruritis, edema, bleeding, and tram-tracking were less common and short-lasting. Post-inflammatory hyperpigmentation affected about 20% of patients and lasted more than one month in about half of those affected. No significant difference was found between MN and MN + PRP in efficacy or side effects. Conclusion Microneedling offers an effective, cheap, and relatively safe treatment option for striae distensae. Miravex Antera TM 3D Camera system is a powerful objective method of documenting lesions and following up the treatment process. Platelet-rich plasma did not offer additional benefit over microneedling alone.

O-057 Newly identified female mutations causing failed fertilization

Abstract Over the past decade, advancements in next-generation sequencing technology, alongside reduced costs, and the rising demand for infertility medical care, have resulted in the discovery of new genes and genetic variants linked to infertility conditions. Phenotypes of ICSI failure, such as oocyte maturation arrest (OMA), fertilization failure (FF) and embryo developmental arrest (EDA), can now be attributed to male or female genetic causes. This represents a transformative shift in patient treatment, allowing the identification of some cases previously classified as unexplained infertility, thereby reducing patient stress. Moreover, it facilitates personalized treatment recommendations, as well as paves the way for the exploration of novel treatment options, thus expanding research opportunities. This talk will review the genetic causes of FF following ICSI, with the main focus on the newly identified female causes, as well as give an update on current diagnostic tests and treatment options for this infertility condition. FF after ICSI still occurs in 1-3% of ICSI cycles, primarily due to oocyte activation deficiency (OAD). Defects in the male PLCζ protein, responsible of inducing calcium oscillations during oocyte activation, have long been known as the leading cause of OAD. Recent discoveries have identified genetic variants in the male genes ACTL7A, ACTL9 and IQCN, which also reduce PLCζ protein content in sperm cells and thus, contribute to FF after ICSI. Additionally, for the first time in 2018, mutations in a female gene (WEE2) crucial for oocyte activation were identified. WEE2 is an oocyte kinase that acts downstream the calcium release during fertilization. Interestingly, genetic variants in other female genes, such as PATL2, TUBB8 and CDC20 associated mainly to OMA and TLE6 and NLRP5 associated mainly to EDA, have also been described to cause failed fertilization in some patients. Determining whether the deficiency lies in sperm- or oocyte-related genes is crucial for tailoring the most effective treatment for FF after ICSI. For sperm-related factors, assisted oocyte activation (AOA), which consists in the artificial induction of calcium oscillations using calcium ionophores, has proven highly beneficial. However, most patients with oocyte-factors do not benefit from AOA (e.g. patients with WEE2 variants). In this regard, wild-type cRNA injection of the defected protein has been shown to rescue fertilization. A more generalist approach, such as maternal spindle transfer, which consists in replacing poor-quality oocyte cytoplasm with healthy cytoplasm from a donor oocyte, represents a potential treatment for these patients, as recently demonstrated in infertile females with repeated IVF failures. Nevertheless, further research into the safety of these procedures is needed before clinical application, and for now, gamete donation should be considered when facing female-related FF.

Eteplirsen Treatment for Duchenne Muscular Dystrophy: A Qualitative Patient Experience Study.

Duchenne muscular dystrophy (DMD) is characterized by rapid functional decline. Current available treatment options aim to delay disease progression or stabilize physical function. To aid in healthcare providers' understanding of the symptoms of disease that impact patients' experience, this study explored children's physical functioning, activities of daily living (ADLs), and health-related quality of life (HRQoL) after receiving eteplirsen, a weekly infusion indicated for individuals with DMD with exon51 skip-amenable mutations. Fifteen caregivers of male individuals with DMD participated in a 60-min, semi-structured interview. Open-ended questioning explored changes in the children's condition or maintenance in abilities since eteplirsen initiation. Children with DMD (age 7-15years [mean 10.9]; steroid treatment at interview, n = 8; time since eteplirsen initiation 3-24months [mean 14.9]) were described by caregivers as ambulatory (n = 9) and non-ambulatory (n = 6). Caregivers of ambulatory children reported improvements or maintenance of walking ability (n = 7/9), running (n = 6/9), and using stairs (n = 4/9). Continued decline in using stairs was reported by two caregivers. In upper-limb functioning, improvements or maintenances in fine-motor movements were reported by nearly half of all caregivers (n = 7/15), with one caregiver noting a continued decline. Subsequent improvements or maintenances in ADLs were described. Improvements or maintenances in fatigue (n = 9/15), muscle weakness (n = 7/15), and pain (n = 6/15) were reported, although some caregivers described a continued decline (n = 3/15 fatigue, n = 1/15 muscle weakness, n = 2/15 pain). Importantly, most caregivers who reported maintenances in ability perceived this as a positive outcome (n = 6/9). This exploratory study indicated that most caregivers perceived improvements or maintenances in aspects of their child's physical functioning, ADLs, and HRQoL since eteplirsen initiation, which they perceived to be a positive outcome.

531 Research Priorities for Oesophageal Cancer : Results from a Priority Setting Partnership

Abstract Aim Oesophageal cancer is the seventh most common cancer worldwide and the sixth leading cause of cancer-related deaths, and it remains one of the hardest cancers to treat. Despite advances in the last decade, oesophageal cancer still has high morbidity and mortality burdens, and further research is needed to improve those outcomes. The aim of the Priority Setting Partnership was to bring together patients, family, caregivers, and the multidisciplinary healthcare team to identify and prioritise the most important unanswered questions for future research. Method Following the James Lind Alliance methodology, different stakeholders were asked to list their uncertainties about oesophageal cancer, which were then checked against existing evidence, categorised, and formed into questions. These then went through a survey for interim ranking, and those shortlisted were discussed at a final workshop to identify the Top 10 unanswered research questions. Results 230 responders to the initial survey, two-thirds of which were patients, revealed 365 uncertainties. After removing duplicates and previously answered questions, sixty-three remained for interim ranking, and twenty-five were shortlisted for the workshop. Participants agreed on their Top 10 priorities, which covered topics such as prevention, current and novel treatment options, nutrition, survivorship concerns, and risk factors for developing oesophageal cancer, particularly at a young age. Conclusions Patients, family members, carers, and healthcare professionals collaborated to identify the most important questions for oesophageal cancer research. The results can help direct funding and attention to the shared priorities of those with personal experiences living with and providing care for oesophageal cancer.

Evidence of Perivascular Mesenchymal Bone Marrow Microenvironment Affection in Poor Graft Function Post Allogenic Stem Cell Transplantation

Abstract Allogeneic hematopoietic stem cell transplantation (HSCT) is regarded as a curative treatment option for a variety of hematological disorders. The prognosis of allogenic (HSCT) patients is dependent on a variety of factors that affect the bone marrow microenvironment. One of these factors is the number and function of CD146+ perivascular mesenchymal cells that support the hematopoietic stem cells in the bone marrow and help their proliferation. Aim of the Study The aim of this study was to assess how the bone marrow microenvironment is being affected in patients with poor graft function post allogenic stem cell transplantation targeting the perivascular mesenchymal cells using multiparameter flow cytometric analysis of CD146 antibody. Patients and Methods Forty patients were enrolled in this study with both benign and malignant hematological diseases who underwent allogenic HSCT from matched related donors. Patients were divided into 2 equal groups: poor graft function (PGF) group and good graft function group (GGF). Patients were subjected to full history recording, clinical examination, full laboratory and radiological work-up, tissue typing and chemotherapeutic conditioning before transplantation. After transplant, bone marrow aspirate was obtained and analyzed for CD146+ perivascular mesenchymal cells using Quantitative tri-color Flow cytometric assay. Results PGF group showed significantly lower counts of WBCs, platelets and hemoglobin concentration compared to GGF group. In addition, CD34 dose showed significantly lower concentration in PGF group compared to GGF group. CD146 expression intensity on non-stem cells was significantly higher in PGF group compared to the GGF group to increase the function of these cells in supporting the proliferation of stem cells in the bone marrow. Conclusion CD146 can have a potential therapeutic role if CD146+ selected mesenchymal cells are infused in patients with refractory poor graft function to enhance the proliferation of stem cells and help in recovery of patients with PGF however further studies are warranted to document its suggested therapeutic role.

Dual-Drug Nanomedicine Assembly with Synergistic Anti-Aneurysmal Effects via Inflammation Suppression and Extracellular Matrix Stabilization.

Abdominal aortic aneurysm (AAA) represents a critical cardiovascular condition characterized by localized dilation of the abdominal aorta, carrying a significant risk of rupture and mortality. Current treatment options are limited, necessitating novel therapeutic approaches. This study investigates the potential of a pioneering nanodrug delivery system, RAP@PFB, in mitigating AAA progression. RAP@PFB integrates pentagalloyl glucose (PGG) and rapamycin (RAP) within a metal-organic-framework (MOF) structure through a facile assembly process, ensuring remarkable drug loading capacity and colloidal stability. The synergistic effects of PGG, a polyphenolic antioxidant, and RAP, an mTOR inhibitor, collectively regulate key players in AAA pathogenesis, such as macrophages and smooth muscle cells (SMCs). In macrophages, RAP@PFB efficiently scavenges various free radicals, suppresses inflammation, and promotes M1-to-M2 phenotype repolarization. In SMCs, it inhibits apoptosis and calcification, thereby stabilizing the extracellular matrix and reducing the risk of AAA rupture. Administered intravenously, RAP@PFB exhibits effective accumulation at the AAA site, demonstrating robust efficacy in reducing AAA progression through multiple mechanisms. Moreover, RAP@PFB demonstrates favorable biosafety profiles, supporting its potential translation into clinical applications for AAA therapy.

Timed fetal inflammation and postnatal hypoxia cause cortical white matter injury, interneuron imbalances, and behavioral deficits in a double-hit rat model of encephalopathy of prematurity

Extreme preterm birth-associated adversities are a major risk factor for aberrant brain development, known as encephalopathy of prematurity (EoP), which can lead to long-term neurodevelopmental impairments. Although progress in clinical care for preterm infants has markedly improved perinatal outcomes, there are currently no curative treatment options available to combat EoP. EoP has a multifactorial etiology, including but not limited to pre- or postnatal immune activation and oxygen fluctuations. Elucidating the underlying mechanisms of EoP and determining the efficacy of potential therapies relies on valid, clinically translatable experimental models that reflect the neurodevelopmental and pathophysiological hallmarks of EoP. Here, we expand on our double-hit rat model that can be used to study EoP disease mechanisms and therapeutic options in a preclinical setting. Pregnant Wistar dams were intraperitoneally injected with 10μg/kg LPS on embryonic day (E)20 and offspring was subjected to hypoxia (140 min, 8% O2) at postnatal day 4. Rats exposed to fetal inflammation and postnatal hypoxia (FIPH) showed neurodevelopmental impairments, such as reduced nest-seeking ability, ultrasonic vocalizations, social engagement, and working memory, and increased anxiety and sensitivity. Impairments in myelination, oligodendrocyte maturation and interneuron development were examined as hallmarks for EoP, in different layers and coordinates of the cortex using histological and molecular techniques. Myelin density and complexity was decreased in the cortex, which partially coincided with a decrease in mature oligodendrocytes. Furthermore, interneuron populations (GAD67+ and PVALB+) were affected. To determine if the timing of inducing fetal inflammation affected the severity of EoP hallmarks in the cortex, multiple timepoints of fetal inflammation were compared. Inflammation at E20 combined with postnatal hypoxia gave the most severe EoP phenotype in the cortex. In conclusion, we present a double-hit rat model which displays various behavioral, anatomical and molecular hallmarks of EoP, including diffuse white matter injury. This double-hit model can be used to investigate pathophysiological mechanisms and potential therapies for EoP.

Laccase/caffeic acid-catalyzed crosslinking coupled with galactomannan alters the conformational structure of ovalbumin and alleviates Th2-mediated allergic asthma

Ovalbumin (OVA) is the major allergenic protein that can induce T helper 2 (Th2)-allergic reactions, for which current treatment options are inadequate. In this study, we developed a polymerized hypoallergenic OVA product via laccase/caffeic acid (Lac/CA)-catalyzed crosslinking in conjunction with galactomannan (Man). The formation of high molecular weight crosslinked polymers and the IgG-binding were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting. The study indicated that Lac/CA-catalyzed crosslinking plus Man conjugation substantially altered secondary and tertiary structures of OVA along with the variation in surface hydrophobicity. Gastrointestinal digestion stability assay indicated that crosslinked OVA exhibited less resistance in simulated gastric fluid (SGF) and simulated intestinal fluid (SIF). Mouse model study indicated that Lac-Man/OVA ameliorated eosinophilic airway inflammatory response and efficiently downregulated the expression of Th2-related cytokines (interleukin (IL)-4, IL-5, and IL-13), and upregulated IFN-γ and IL-10 expression. Stimulation of bone marrow-derived dendritic cells with Lac-Man/OVA suppressed the expression of phenotypic maturation markers (CD80 and CD86) and MHC class II molecules, and suppressed the expression levels of proinflammatory cytokines. The knowledge obtained in the present study offers an effective way to acquire a hypoallergenic OVA product that can have a therapeutic effect in alleviating OVA-induced allergic asthma.

Cold atmospheric plasma therapy for Malassezia folliculitis: Laboratory investigations and a randomized clinical trial.

Current treatment options for Malassezia folliculitis (MF) are limited. Recent research has demonstrated the inhibitory effect of cold atmospheric plasma (CAP) on the growth of Malassezia pachydermatis in vitro, suggesting CAP as a potential therapeutic approach for managing MF. The objective of our study is to assess the in vitro antifungal susceptibility of Malassezia yeasts to CAP. Additionally, we aim to evaluate the efficacy and tolerability of CAP in treating patients with MF. We initially studied the antifungal effect of CAP on planktonic and biofilm forms of Malassezia yeasts, using well-established techniques such as zone of inhibition, transmission electron microscopy, colony count assay and 2,3-bis(2-methoxy-4-nitro-5-sulfophenyl)-2H-tetrazolium-5-carboxanilide salt assay. Subsequently, a randomized (1:1 ratio), active comparator-controlled, observer-blind study was conducted comparing daily CAP therapy versus itraconazole 200mg/day for 2weeks in 50 patients with MF. Efficacy outcomes were measured by success rate, negative microscopy rate and changes in Dermatology Life Quality Index (DLQI) and Global Aesthetic Improvement Scale (GAIS) scores. Safety was assessed by monitoring adverse events (AEs) and local tolerability. In laboratory investigations, CAP time-dependently inhibited the growth of Malassezia yeasts in both planktonic and biofilm forms. Forty-nine patients completed the clinical study. At week 2, success was achieved by 40.0% of subjects in the CAP group versus 58.3% in the itraconazole group (p=0.199). The negative direct microscopy rates of follicular samples were 56.0% in the CAP group versus 66.7% in the itraconazole group (p=0.444). No significant differences were found in the proportion of subjects achieving DLQI scores of 0/1 (p=0.456) or in the GAIS responder rates (p=0.588) between the two groups. Three patients in the CAP group and one patient in the itraconazole group reported mild AEs. CAP demonstrated significant antifungal activity against Malassezia yeasts in vitro and exhibited comparable efficacy to itraconazole in treating MF patients. Without the associated adverse effects of oral antifungal drugs, CAP can be considered a promising and safe treatment modality for MF.

A brief review of current treatment options for osteoarthritis including disease-modifying osteoarthritis drugs (DMOADs) and novel therapeutics.

Osteoarthritis (OA) is a chronic disorder caused by degenerative changes in articular cartilage, which are mainly manifests as degeneration of cartilage, subchondral bone remodeling, as well as synovial inflammation. Over the next few decades, OA and its burden will continue to increase worldwide, posing a major public health challenge for the foreseeable future. Treatment for OA includes non-pharmacological, pharmacological, and surgical treatments. Existing conservative treatments and joint surgery can only alleviate the symptoms and cannot be cured, so new therapies for OA are urgently needed. Since advances in the understanding of OA pathophysiology, researchers have identified some potential therapeutic targets against degeneration of cartilage, subchondral bone remodeling and synovial inflammation, enabling development of the disease-modifying OA drugs (DMOADs). Additionally, a number of new technologies are also being investigated for treating OA, such as RNA interference (RNAi), CRISPR/Cas9 and PROTAC. The goal of this review is to describe the current development status of DMOADs and to discuss the potential of emerging therapeutic approaches for treating OA, thus providing a reference for OA treatments.

Development of an Ex Vivo Functional Assay for Prediction of Irradiation Related Toxicity in Healthy Oral Mucosa Tissue

Radiotherapy in the head-and-neck area is one of the main curative treatment options. However, this comes at the cost of varying levels of normal tissue toxicity, affecting up to 80% of patients. Mucositis can cause pain, weight loss and treatment delays, leading to worse outcomes and a decreased quality of life. Therefore, there is an urgent need for an approach to predicting normal mucosal responses in patients prior to treatment. We here describe an assay to detect irradiation responses in healthy oral mucosa tissue. Mucosa specimens from the oral cavity were obtained after surgical resection, cut into thin slices, irradiated and cultured for three days. Seven samples were irradiated with X-rays, and three additional samples were irradiated with both X-rays and protons. Healthy oral mucosa tissue slices maintained normal morphology and viability for three days. We measured a dose-dependent response to X-ray irradiation and compared X-ray and proton irradiation in the same mucosa sample using standardized automated image analysis. Furthermore, increased levels of inflammation-inducing factors—major drivers of mucositis development—could be detected after irradiation. This model can be utilized for investigating mechanistic aspects of mucositis development and can be developed into an assay to predict radiation-induced toxicity in normal mucosa.

S-(N,N-diethyldithiocarbamoyl)-N-acetyl-L-cysteine for the Treatment of Non-Small Cell Lung Cancer through Regulating NF-κB Signaling Pathway without Neurotoxicity

The discovery of novel targeted agents for non-small cell lung cancer (NSCLC) remains an important research landscape due to the limited efficacy, side effects and drug resistance of current treatment options. Among many repurposed drugs, disulfiram (DSF) has shown the potential to target tumors. However, its unpleasant neurotoxicity greatly limits its use. A DSF derivative, S-(N,N-diethyldithiocarbamoyl)-N-acetyl-L-cysteine (DS-NAC), was synthesized against NSCLC. The therapeutic effects, mechanism, and toxicities of DS-NAC were evaluated in A549 and H460 cells and the mouse model of in-situ lung cancer. The in-vitro results exhibited that DS-NAC had potent anti-proliferation, apoptotic, anti-metastasis, and epithelial-mesenchymal transition (EMT) inhibition effects. In the orthotopic lung cancer mouse model, therapeutic effects of DS-NAC were better than that of DSF and were similar to docetaxel (DTX). Also, results from western blot and immunohistochemistry showed that DS-NAC in combination with copper exerted the therapeutic effects via regulating NF-κB signaling pathway and ROS-related proteins such as HIF-1α, Nrf2, and PKC-δ rather than regulating ROS level directly. Moreover, the safety evaluation study showed that DS-NAC had low hematologic and hepatic toxicities in comparision with DTX as well as low neurological toxicity compared with DSF. DS-NAC could be a promising anti-lung cancer agent with a favorable safety profile.

MicroRNA miR-20a-5p targets CYCS to inhibit apoptosis in hepatocellular carcinoma

Hepatocellular carcinoma is a primary liver cancer, characterised by diverse etiology, late diagnoses, and poor prognosis. Hepatocellular carcinoma is mostly resistant to current treatment options, therefore, identification of more effective druggable therapeutic targets is needed. We found microRNA miR-20a-5p is upregulated during mouse liver tumor progression and in human hepatocellular carcinoma patients. In this study, we elucidated the therapeutic potential of targeting oncogenic miR-20a-5p, in vivo, in a xenograft model and in two transgenic hepatocellular carcinoma mouse models via adeno-associated virus-mediated miR-20a-Tough-Decoy treatment. In vivo knockdown of miR-20a-5p attenuates tumor burden and prolongs survival in the two independent hepatocellular carcinoma mouse models. We identified and validated cytochrome c as a novel target of miR-20a-5p. Cytochrome c plays a key role in initiation of the apoptotic cascade and in the electron transport chain. We show for the first time, that miR-20a modulation affects both these key functions of cytochrome c during HCC development. Our study thus demonstrates the promising ‘two birds with one stone’ approach of therapeutic in vivo targeting of an oncogenic miRNA, whereby more than one key deregulated cellular process is affected, and unequivocally leads to more effective attenuation of HCC progression and significantly longer overall survival.