Side Effects Of Current Treatments Research Articles

Bioprospecting, Synergistic Antifungal and Toxicological Aspects of the Hydroxychalcones and Their Association with Azole Derivates against Candida spp. for Treating Vulvovaginal Candidiasis.

Vulvovaginal candidiasis (VVC) remains a prevalent fungal disease, characterized by challenges, such as increased fungal resistance, side effects of current treatments, and the rising prevalence of non-albicans Candida spp. naturally more resistant. This study aimed to propose a novel therapeutic approach by investigating the antifungal properties and toxicity of 2-hydroxychalcone (2-HC) and 3'-hydroxychalcone (3'-HC), both alone and in combination with fluconazole (FCZ) and clotrimazole (CTZ). A lipid carrier (LC) was also developed to deliver these molecules. The study evaluated in vitro anti-Candida activity against five Candida species and assessed cytotoxicity in the C33-A cell line. The safety and therapeutic efficacy of in vivo were tested using an alternative animal model, Galleria mellonella. The results showed antifungal activity of 2-HC and 3'-HC, ranging from 7.8 to 31.2 as fungistatic and 15.6 to 125.0 mg/L as fungicide effect, with cell viability above 80% from a concentration of 9.3 mg/L (2-HC). Synergistic and partially synergistic interactions of these chalcones with FCZ and CTZ demonstrated significant improvement in antifungal activity, with MIC values ranging from 0.06 to 62.5 mg/L. Some combinations reduced cytotoxicity, achieving 100% cell viability in many interactions. Additionally, two LCs with suitable properties for intravaginal application were developed. These formulations demonstrated promising therapeutic efficacy and low toxicity in Galleria mellonella assays. These results suggest the potential of this approach in developing new therapies for VVC.

Unlocking new avenues for neuropsychiatric disease therapy: the emerging potential of Peroxisome proliferator-activated receptors as promising therapeutic targets.

Peroxisome proliferator-activated receptors (PPARs) are transcription factors that regulate variousphysiological processes such as inflammation, lipid metabolism, and glucose homeostasis. Recent studies suggestthat targeting PPARs could be beneficial in treating neuropsychiatric disorders by modulating neuronal function andsignaling pathways in the brain. PPAR-α, PPAR-δ, and PPAR-γ have been found to play important roles incognitive function, neuroinflammation, and neuroprotection. Dysregulation of PPARs has been associated withneuropsychiatric disorders like bipolar disorder, schizophrenia, major depression disorder, and autism spectrumdisorder. The limitations and side effects of current treatments have prompted research to target PPARs as apromising novel therapeutic strategy. Preclinical and clinical studies have shown the potential of PPAR agonistsand antagonists to improve symptoms associated with these disorders. This review aims to provide an overview of the current understanding of PPARs in neuropsychiatricdisorders, their potential as therapeutic targets, and the challenges and future directions for developingPPAR-basedtherapies. An extensive literature review of various search engines like PubMed, Medline, Bentham, Scopus, andEMBASE (Elsevier) databases was carried out with the keywords "PPAR, Neuropsychiatric disorders, Oxidativestress, Inflammation, Bipolar Disorder, Schizophrenia, Major depression disorder, Autism spectrum disorder,molecular pathway". Although PPARs present a hopeful direction for innovative therapeutic approaches inneuropsychiatric conditions, additional research is required to address obstacles and convert this potential intoclinically viable and individualized treatments.

Piperine, quercetin, and curcumin identified as promising natural products for topical treatment of cutaneous leishmaniasis

Leishmania braziliensis (L. braziliensis) causes cutaneous leishmaniasis (CL) in the New World. The costs and the side effects of current treatments render imperative the development of new therapies that are affordable and easy to administer. Topical treatment would be the ideal option for the treatment of CL. This underscores the urgent need for affordable and effective treatments, with natural compounds being explored as potential solutions. The alkaloid piperine (PIP), the polyphenol curcumin (CUR), and the flavonoid quercetin (QUE), known for their diverse biological properties, are promising candidates to address these parasitic diseases. Initially, the in vitro cytotoxicity activity of the compounds was evaluated using U-937 cells, followed by the assessment of the leishmanicidal activity of these compounds against amastigotes of L. braziliensis. Subsequently, a golden hamster model with stationary-phase L. braziliensis promastigote infections was employed. Once the ulcer appeared, hamsters were treated with QUE, PIP, or CUR formulations and compared to the control group treated with meglumine antimoniate administered intralesionally. We observed that the three organic compounds showed high in vitro leishmanicidal activity with effective concentrations of less than 50 mM, with PIP having the highest activity at a concentration of 8 mM. None of the compounds showed cytotoxic activity for U937 macrophages with values between 500 and 700 mM. In vivo, topical treatment with QUE daily for 15 days produced cured in 100% of hamsters while the effectiveness of CUR and PIP was 83% and 67%, respectively. No failures were observed with QUE. Collectively, our data suggest that topical formulations mainly for QUE but also for CUR and PIP could be a promising topical treatment for CL. Not only the ease of obtaining or synthesizing the organic compounds evaluated in this work but also their commercial availability eliminates one of the most important barriers or bottlenecks in drug development, thus facilitating the roadmap for the development of a topical drug for the management of CL caused by L. braziliensis.

The acyl-CoA synthetase TgACS1 allows neutral lipid metabolism and extracellular motility in Toxoplasma gondii through relocation via its peroxisomal targeting sequence (PTS) under low nutrient conditions.

Apicomplexa parasites cause major diseases such as toxoplasmosis and malaria that have major health and economic burdens. These unicellular pathogens are obligate intracellular parasites that heavily depend on lipid metabolism for the survival within their hosts. Their lipid synthesis relies on an essential combination of fatty acids (FAs) obtained from both de novo synthesis and scavenging from the host. The constant flux of scavenged FA needs to be channeled toward parasite lipid storage, and these FA storages are timely mobilized during parasite division. In eukaryotes, the utilization of FA relies on their obligate metabolic activation mediated by acyl-co-enzyme A (CoA) synthases (ACSs), which catalyze the thioesterification of FA to a CoA. Besides the essential functions of FA for parasite survival, the presence and roles of ACS are yet to be determined in Apicomplexa. Here, we identified TgACS1 as a Toxoplasma gondii cytosolic ACS that is involved in FA mobilization in the parasite specifically during low host nutrient conditions, especially in extracellular stages where it adopts a different localization. Heterologous complementation of yeast ACS mutants confirmed TgACS1 as being an Acyl-CoA synthetase of the bubble gum family that is most likely involved in β-oxidation processes. We further demonstrate that TgACS1 is critical for gliding motility of extracellular parasite facing low nutrient conditions, by relocating to peroxisomal-like area.IMPORTANCEToxoplasma gondii, causing human toxoplasmosis, is an Apicomplexa parasite and model within this phylum that hosts major infectious agents, such as Plasmodium spp., responsible for malaria. The diseases caused by apicomplexans are responsible for major social and economic burdens affecting hundreds of millions of people, like toxoplasmosis chronically present in about one-third of the world's population. Lack of efficient vaccines, rapid emergence of resistance to existing treatments, and toxic side effects of current treatments all argue for the urgent need to develop new therapeutic tools to combat these diseases. Understanding the key metabolic pathways sustaining host-intracellular parasite interactions is pivotal to develop new efficient ways to kill these parasites. Current consensus supports parasite lipid synthesis and trafficking as pertinent target for novel treatments. Many processes of this essential lipid metabolism in the parasite are not fully understood. The capacity for the parasites to sense and metabolically adapt to the host physiological conditions has only recently been unraveled. Our results clearly indicate the role of acyl-co-enzyme A (CoA) synthetases for the essential metabolic activation of fatty acid (FA) used to maintain parasite propagation and survival. The significance of our research is (i) the identification of seven of these enzymes that localize at different cellular areas in T. gondii parasites; (ii) using lipidomic approaches, we show that TgACS1 mobilizes FA under low host nutrient content; (iii) yeast complementation showed that acyl-CoA synthase 1 (ACS1) is an ACS that is likely involved in peroxisomal β-oxidation; (iv) the importance of the peroxisomal targeting sequence for correct localization of TgACS1 to a peroxisomal-like compartment in extracellular parasites; and lastly, (v) that TgACS1 has a crucial role in energy production and extracellular parasite motility.

Nanotechnologies for the detection and treatment of endometriosis.

Endometriosis is an incurable gynecologic disease characterized by endometrial-like tissue growth outside of the uterine cavity. It affects approximately 10% of reproductive age women, who endure pelvic pain during periods and/or sexual intercourse and who suffer from reduced fertility and diminished quality of life due to the side effects of current treatments. To improve the management and prognosis of endometriosis patients, researchers have recently begun to develop nanoparticle-based diagnostics and treatments that are more effective and less invasive than existing approaches. This review discusses the current state of the field and highlights considerations for the continued development of nanotechnologies for the diagnosis and treatment of endometriosis.

In Vitro Approaches to Explore the Anticancer Potential of One Natural Flavanone and Four Derivatives Loaded in Biopolymeric Nanoparticles for Application in Topical Delivery Treatments.

The increasing number of skin cancer cases worldwide and the adverse side effects of current treatments have led to the search for new anticancer agents. In this present work, the anticancer potential of the natural flavanone 1, extracted from Eysenhardtia platycarpa, and four flavanone derivatives 1a-d obtained by different reactions from 1 was investigated by an in silico study and through cytotoxicity assays in melanoma (M21), cervical cancer (HeLa) cell lines and in a non-tumor cell line (HEK-293). The free compounds and compounds loaded in biopolymeric nanoparticles (PLGA NPs 1, 1a-d) were assayed. A structure-activity study (SAR) was performed to establish the main physicochemical characteristics that most contribute to cytotoxicity. Finally, ex vivo permeation studies were performed to assess the suitability of the flavanones for topical administration. Results revealed that most of the studied flavanones and their respective PLGA NPs inhibited cell growth depending on the concentration; 1b should be highlighted. The descriptors of the energetic factor were those that played a more important role in cellular activity. PLGA NPs demonstrated their ability to penetrate (Qp of 17.84-118.29 µg) and be retained (Qr of 0.01-1.44 g/gskin/cm2) in the skin and to exert their action for longer. The results of the study suggest that flavanones could offer many opportunities as a future anticancer topical adjuvant treatment.

Conventional and new proposals of GnRH therapy for ovarian, breast, and prostatic cancers.

For many years, luteinizing hormone-releasing hormone or gonadotropin-releasing hormone (GnRH) analogs have been used to treat androgen or estrogen-dependent tumors. However, emerging evidence shows that the GnRH receptor (GnRH-R) is overexpressed in several cancer cells, including ovarian, endometrial, and prostate cancer cells, suggesting that GnRH analogs could exert direct antitumoral actions in tumoral tissues that express GnRH-R. Another recent approach based on this knowledge was the use of GnRH peptides for developing specific targeted therapies, improving the delivery and accumulation of drugs in tumoral cells, and decreasing most side effects of current treatments. In this review, we discuss the conventional uses of GnRH analogs, together with the recent advances in GnRH-based drug delivery for ovarian, breast, and prostatic cancer cells.

In vitro high-content tissue models to address precision medicine challenges.

The field of precision medicine allows for tailor-made treatments specific to a patient and thereby improve the efficiency and accuracy of disease prevention, diagnosis, and treatment and at the same time would reduce the cost, redundant treatment, and side effects of current treatments. Here, the combination of organ-on-a-chip and bioprinting into engineering high-content in vitro tissue models is envisioned to address some precision medicine challenges. This strategy could be employed to tackle the current coronavirus disease 2019 (COVID-19), which has made a significant impact and paradigm shift in our society. Nevertheless, despite that vaccines against COVID-19 have been successfully developed and vaccination programs are already being deployed worldwide, it will likely require some time before it is available to everyone. Furthermore, there are still some uncertainties and lack of a full understanding of the virus as demonstrated in the high number new mutations arising worldwide and reinfections of already vaccinated individuals. To this end, efficient diagnostic tools and treatments are still urgently needed. In this context, the convergence of bioprinting and organ-on-a-chip technologies, either used alone or in combination, could possibly function as a prominent tool in addressing the current pandemic. This could enable facile advances of important tools, diagnostics, and better physiologically representative in vitro models specific to individuals allowing for faster and more accurate screening of therapeutics evaluating their efficacy and toxicity. This review will cover such technological advances and highlight what is needed for the field to mature for tackling the various needs for current and future pandemics as well as their relevancy towards precision medicine.

Arylquin 1 (Potent Par-4 Secretagogue) Inhibits Tumor Progression and Induces Apoptosis in Colon Cancer Cells

Colorectal cancer (CRC) is one of the most common gastrointestinal cancers worldwide. Current therapeutic strategies mainly involve surgery and chemoradiotherapy; however, novel antitumor compounds are needed to avoid drug resistance in CRC, as well as the severe side effects of current treatments. In this study, we investigated the anticancer effects and underlying mechanisms of Arylquin 1 in CRC. The MTT assay was used to detect the viability of SW620 and HCT116 cancer cells treated with Arylquin 1 in a dose-dependent manner in vitro. Further, wound-healing and transwell migration assays were used to evaluate the migration and invasion abilities of cultured cells, and Annexin V was used to detect apoptotic cells. Additionally, Western blot was used to identify the expression levels of N-cadherin, caspase-3, cyclin D1, p-extracellular signal-regulated kinase (ERK), p-c-JUN N-terminal kinase (JNK), and phospho-p38, related to key signaling proteins, after administration of Arylquin 1. Xenograft experiments further confirmed the effects of Arylquin 1 on CRC cells in vivo. Arylquin 1 exhibited a dose-dependent reduction in cell viability in cultured CRC cells. It also inhibited cell proliferation, migration, and invasion, and induced apoptosis. Mechanistic analysis demonstrated that Arylquin 1 increased phosphorylation levels of ERK, JNK, and p38. In a mouse xenograft model, Arylquin 1 treatment diminished the growth of colon tumors after injection of cultured cancer cells. Arylquin 1 may have potential anticancer effects and translational significance in the treatment of CRC.

Mechanism of Anosmia Caused by Symptoms of COVID-19 and Emerging Treatments.

The occurrence of anosmia, the loss or change in sense of smell, is one of the most common symptoms of COVID-19 experienced by almost 53% of those affected. Several hypotheses explain the mechanism of anosmia in patients suffering from COVID-19. This study aims to review the related mechanisms and answer the questions regarding COVID-19-related anosmia as well as propose a new strategy for treatment of long-term anosmia as a result of COVID-19 infection. This paper covers all of the studies investigating olfactory disorders following COVID-19 infection and explains the possible reasons for the correlated anosmia, including olfactory cleft syndrome, local inflammation in the nasal epithelium, early apoptosis of olfactory cells, changes in olfactory cilia and odor transmission, damage to microglial cells, effect on olfactory bulbs, epithelial olfactory injury, and impairment of olfactory neurons and stem cells. The key questions that arise in this field have been discussed, such as why prevalent anosmia is varied among the age categories and among sexes and the correlation of anosmia with mild or severe COVID-19 infection. The angiotensin-converting enzyme 2 receptor is a significant player in the mechanism of anosmia in COVID-19 patients. Based on current studies, a novel approach to treat long-COVID-19 with ongoing anosmia has been proposed. The fields of smart drug delivery, tissue engineering, and cell therapy provide a hypothesized strategy that can minimize the side effects of current treatments and support efficient recovery of the olfactory system.

Endocannabinoids in Bladder Sensory Mechanisms in Health and Diseases.

The recent surge in research on cannabinoids may have been fueled by changes in legislation in several jurisdictions, and by approval for the use of cannabinoids for treatment of some chronic diseases. Endocannabinoids act largely, but not exclusively on cannabinoid receptors 1 and 2 (CBR1 and CBR2) which are expressed in the bladder mainly by the urothelium and the axons and endings of motor and sensory neurons. A growing body of evidence suggests that endocannabinoid system constitutively downregulates sensory bladder function during urine storage and micturition, under normal physiological conditions. Similarly, exogenous cannabinoid agonists have potent modulatory effects, as do inhibitors of endocannabinoid inactivation. Results suggest a high potential of cannabinoids to therapeutically ameliorate lower urinary tract symptoms in overactive bladder and painful bladder syndromes. At least part of this may be mediated via effects on sensory nerves, although actions on efferent nerves complicate interpretation. The sensory innervation of bladder is complex with at least eight classes identified. There is a large gap in our knowledge of the effects of endocannabinoids and synthetic agonists on different classes of bladder sensory neurons. Future studies are needed to reveal the action of selective cannabinoid receptor 2 agonists and/or peripherally restricted synthetic cannabinoid receptor 1 agonists on bladder sensory neurons in animal models of bladder diseases. There is significant potential for these novel therapeutics which are devoid of central nervous system psychotropic actions, and which may avoid many of the side effects of current treatments for overactive bladder and painful bladder syndromes.

Naringenin prevents pregnancy-induced hypertension via suppression of JAK/STAT3 signalling pathway in mice.

Pregnancy-induced hypertension (PIH) is characterized by high blood pressure during pregnancy, which causes perinatal and maternal mortality. Inflammation, oxidative stress and the JAK2/STAT3 signalling pathway have been reported to play critical roles in the pathogenies of PIH. Due to the safety and side effects of current treatments for PIH, searching for new therapeutic agents is urgently needed. Naringenin is a flavonoid with anti-inflammation and anti-oxidation activities. In the current study, the effects of naringenin on PIH were investigated. We established the PIH mouse model and administrated naringenin to these mice. The blood pressure, total urine protein, plasma levels of vasodilation converting enzyme (VCE), α-1A adrenergic receptor (α-ADR) and angiotensin, inflammatory cytokines, oxidative stress markers were measured. The protein levels of reactive oxygen species proto-oncogene 1 (ROS1), superoxide dismutase 2 (SOD2), signal transducer and activator of transcription 3 (STAT3), phospho-STAT3, Src homology 2 domain-containing protein tyrosine phosphatase 1 (SHP-1), Janus kinase 2 (JAK2) and phospho-JAK2, in vascular endothelium cells were detected by western blot. Administration of naringenin significantly decreased blood pressure, total urine protein level, plasma levels of VCE, α-ADR and angiotensin in PIH mice. Naringenin decreased serum levels of pro-inflammatory cytokines interleukin (IL)-2, IL-6 and tumour necrosis factor alpha (TNF-α), while increased IL-10. Naringenin decreased serum levels of ROS, endothelin while increased SOD and nitric oxide levels. Western blot analysis showed that naringenin inhibited ROS expression, while increased SOD expression in vascular endothelial cells of mice. In addition, western blot also showed that naringenin inhibited JAK2/STAT3 signalling by suppressing SHP-1 expression in vascular endothelial cells of mice. Naringenin suppressed the activation of JAK2/STAT3 signalling pathway and promoted SHP-1 expression, leading to ameliorated hypertension in pregnancy.

In Vitro and In Vivo Survey of Ethyl Acetate Extract of Acorus calamus (Sweet Flag) Rhizome on Toxoplasma gondii

Background Toxoplasmosis is a zoonosis disease that can cause a variety range of manifestations in human specially fetus duration and immunodeficiency conditions. Due to toxicity and side effects of current treatment, we evaluated in vivo and in vitro effects of ethyl acetate extract of Acorus calamus rhizomes (rootstocks) on Toxoplasma gondii. Methods The plant, Acorus calamus, was collected from Sari, North of Iran in spring season. Ethyl acetate extract was provided from plant rhizomes using Soxhlet apparatus. The total phenolic and flavonoid contents of the extract were measured by the Folin–Ciocalteu method. The mortality effect of different concentrations (1-256 μg/ml) of the extract on Toxoplasma tachyzoites was assessed by flowcytometry and propidium iodide staining. For the therapeutic effect assessment, the tachyzoites were inoculated intraperitoneally to mice, and then these mice were orally and intraperitoneally administered different concentrations (32, 64, 128, and 256 mg/kg) of the extract. Also, an infected group received PBS including DMSO 1% as negative control, and an infected group administered sulfadiazine as positive control. For toxicity evaluation of this extract, a group only received dose 256 mg/kg. Results The plant extract was rich of phenolic compounds (41.27 ± 0.21 mg/g), whereas it contained fewer amounts of flavonoids (4.79 ± 0.01 mg/g). Results of in vitro experiments showed that there is an inverse relationship between the concentrations and the mortality of the parasites (IC50 = 200.01 ± 7.74 μg/ml). The highest percentage (62%) of dead tachyzoites was seen at maximum concentration of the extract. A significant longevity (8.9 days) was belonged to mice orally administered extract dose (256 mg/kg/day).Conclusion The ethyl acetate extract of A. calamus rhizomes had significant anti-Toxoplasma activities either in vitro or in vivo. It may be connected to high amount of phenolic compounds. We suggest that the effects of different fractions and the admin types of the extract will be evaluated on the parasite.

Evaluation of a New Topical Treatment for the Control of Cutaneous Leishmaniasis.

Leishmania major (L. major) causes cutaneous leishmaniasis in the Old World. The infection mostly induces a localized lesion restricted to the sand fly bite. The costs and the side effects of current treatments render imperative the development of new therapies that are affordable and easy to administrate. Topical treatment would be the ideal option for the treatment of cutaneous leishmaniasis. MF29 is a 3-haloacetamidobenzoate that was shown in vitro to inhibit tubulin assembly in Leishmania. Here, we tested a topical cream formulated with MF29. BALB/c mice were infected in the ear dermis with L. major metacyclic promastigotes and once the lesion appeared, mice were treated with different concentrations of MF29 and compared to the control group treated with the cream used as the vehicle. We observed that topical application of MF29 reduced the progression of the infection while control groups developed an unhealing lesion that became necrotic. The treatment decreased the type 2 immune response. Comparison with SinaAmphoLeish, another topical treatment, revealed that MF29 treatment once a day was sufficient to control lesion development, while application SinaAmphoLeish needed applications twice daily. Collectively, our data suggest that MF-29 topical application could be a promising topical treatment for cutaneous leishmaniasis.

Eslicarbazepine acetate interacts in a beneficial manner with standard and alternative analgesics to reduce trigeminal nociception.

Acute pain states in the trigeminal region (headaches, dental pain) fall into the most prevalent painful conditions. Standard analgesics (paracetamol/NSAIDs) represent the cornerstone of their treatment, whereas triptans are primarily used in migraine attacks. Due to limited efficacy and/or side effects of current treatments, identifying favorable combinations of available drugs is justified. Eslicarbazepine acetate (ESL) is a novel antiepileptic drug whose effectiveness against trigeminal pain was recently demonstrated. Here, we examined the interactions between ESL and several standard/alternative analgesics (paracetamol, propyphenazone, naproxen, zolmitriptan, and metoclopramide) in a model of trigeminal pain. The antinociceptive effects of orally administered ESL, standard/alternative analgesics, and two-drug ESL-analgesic combinations were examined in the orofacial formalin test in mice. The type of interaction between drugs was determined by isobolographic analysis. ESL, analgesics, and two-drug ESL-analgesic combinations significantly and dose-dependently reduced nociceptive behaviour in the second, inflammatory phase of the test. Isobolographic analysis revealed that ESL interacted additively with paracetamol/propyphenazone/zolmitriptan and synergistically with naproxen/metoclopramide (with about a 4-fold and 3-fold reduction of doses in the ESL-naproxen and ESL-metoclopramide combination, respectively). ESL interacted in a beneficial manner with several analgesics that are used for trigeminal pain treatment, producing synergistic interactions with naproxen/metoclopramide and additive interactions with paracetamol/propyphenazone/zolmitriptan. Our results suggest that combining ESL with analgesics could theoretically enable the use of lower doses of individual drugs for achieving pain relief.

Single Cell Transcriptomics Predicts Relapse in Infants with Acute Lymphoblastic Leukemia

Care of infants (<1 year of age) diagnosed with MLL (KMT2A)-rearranged acute lymphoblastic leukemia (MLLr-iALL) suffers from two major drawbacks. First, a poor survival rate due to a high rates of early relapse and chemo-resistance. Additionally, the approximately 30-50% of patients that do survive, suffer from life-long, debilitating side-effects of current treatment. While almost all MLLr-iALL patients show an initial promising response to treatment, two-third of the patients relapse, typically within the first year from diagnosis and while still on treatment. Accurate relapse prediction would allow implementation of treatment strategies that take relapse risk into account, with great potential benefit for all patients. Here, we show that Single-cell RNA sequencing (scRNA-seq) can be valuable for risk stratification and that the abundance of chemo-resistant cells within the diagnosis sample might be a powerful indicator of the likelihood of relapse. We have used scRNA-seq to analyze the response to treatment of leukemic cells in bone marrow biopsies of seven MLLr-iALL patients, expressing either the oncogenic MLL-AF4 or MLL-ENL fusion gene, at the time of initial diagnosis. Three of these patients successfully underwent treatment and remained disease-free during 7 years of follow-up, while in the remaining four cases the disease returned within a year from diagnosis. All samples were subjected to scRNA-seq by FACS index sorting with the aim of identifying differences between early relapsers and long-term survivors. Quantification of the proportion of cells classified by single cell transcriptomics, categorized as either chemo-resistant or chemo-sensitive, accurately predicts the occurrence of future relapse in individual patients. Strikingly, the single cell-based classification is even consistent with the order of relapse timing. Additionally, leukemic cells associated with high relapse risk are typified by a small phenotype, which coincides with an apparent quiescent gene expression pattern. This study clearly and, to the best of our knowledge, for the first time shows how disease classification and treatment management can directly benefit from single cell genomics. It demonstrates how classification based on a pivotal functional characteristic of single cells can be performed, despite individual patient variation. Our results shed light on the subpopulation from which leukemic relapse originates, and opens up opportunities for strong, risk-based strategies for future MLLr-iALL treatment regimens. Disclosures Pieters: medac: Consultancy; jazz farmaceuticals: Consultancy.

Psoralen and narrowband UVB combination provides higher efficacy in treating vitiligo compared with narrowband UVB alone: A randomised clinical trial.

Side effects of current treatments and the need for a safe treatment with higher efficiency necessitate seeking new treatment options for vitiligo. Few studies have investigated the combination of psoralen with narrowband ultraviolet B (NBUVB). In this study, we compared the efficacy and safety of psoralen and NBUVB combination (P-NBUVB) with NBUVB alone in treatment of vitiligo. This randomised clinical trial was carried out during 2015-2017 in dermatology clinics of Ghaem and Imam Reza hospitals, Mashhad, Iran on 40 vitiligo patients with 5-60% body involvement. The patients were randomly divided into two groups of NBUVB alone and P-NBUVB. Both groups underwent 60 phototherapy sessions (three sessions per week), and the repigmentation rate was measured using vitiligo area severity index (VASI) score. SPSS v. 16 software and appropriate statistical tests were used to analyse the data. P<0.05 was considered statistically significant. The mean age of patients was 33.9±11.3years. Twenty patients (50%) were females. The P-NBUVB group showed greater VASI improvement in lower extremities (P=0.003) and overall (P=0.026) compared with NBUVB group. Moreover, the treatment response appeared sooner in P-NUVB group. Based on our results, we can conclude that adding psoralen to NBUVB phototherapy can result in increased efficacy. However, more studies are needed to evaluate the long-term effects and side effects of this treatment.

Effect of low intensity ultrasound on cancerous prostate cell viability compared to viability of healthy prostate cells

Cancer continues to be a leading cause of death in the United States. Currently, the most commonly utilized treatment options in radiotherapy and chemotherapy raise serious biocompatibility and toxicity concerns. Given the adverse side effects of current treatment, it is important to explore modalities that can clearly discriminate between healthy and cancerous tissue. This investigation identifies low intensity ultrasound as a candidate for cancer therapy and tests whether it demonstrates a discriminatory response between cancerous prostate cells and healthy prostate cells. Cells were exposed to a 5 MHz, 0.126 W/cm2 wave for 60 minutes via a single element unfocused transducer in a water tank-controlled environment at 33 °C. Cell counts (alive and dead) before and after exposure to ultrasound were performed. On average cancerous prostate cells showed a viability of 53% compared to a viability of 99% for benign prostate cells, indicating a significant difference in observed death between healthy and cancerous prostate cells.Cancer continues to be a leading cause of death in the United States. Currently, the most commonly utilized treatment options in radiotherapy and chemotherapy raise serious biocompatibility and toxicity concerns. Given the adverse side effects of current treatment, it is important to explore modalities that can clearly discriminate between healthy and cancerous tissue. This investigation identifies low intensity ultrasound as a candidate for cancer therapy and tests whether it demonstrates a discriminatory response between cancerous prostate cells and healthy prostate cells. Cells were exposed to a 5 MHz, 0.126 W/cm2 wave for 60 minutes via a single element unfocused transducer in a water tank-controlled environment at 33 °C. Cell counts (alive and dead) before and after exposure to ultrasound were performed. On average cancerous prostate cells showed a viability of 53% compared to a viability of 99% for benign prostate cells, indicating a significant difference in observed death between healthy and canc...

Inhibition of eIF2\u03b1 dephosphorylation accelerates pterostilbene-induced cell death in human hepatocellular carcinoma cells in an ER stress and autophagy-dependent manner

Hepatocellular carcinoma (HCC) is the one of the most common cancers worldwide. Because the side effects of current treatments are severe, new effective therapeutic strategies are urgently required. Pterostilbene (PT), a natural analogue of resveratrol, has diverse pharmacologic activities, including antioxidative, anti-inflammatory and antiproliferative activities. Here we demonstrated that PT inhibits HCC cell growth without the induction of apoptosis in an endoplasmic reticulum (ER) stress- and autophagy-dependent manner. Mechanistic studies indicated that the combination of salubrinal and PT modulates ER stress-related autophagy through the phospho-eukaryotic initiation factor 2α/activating transcription factor-4/LC3 pathway, leading to a further inhibition of eIF2α dephosphorylation and the potentiation of cell death. An in vivo xenograft analysis revealed that PT significantly reduced tumour growth in mice with a SK-Hep-1 tumour xenograft. Taken together, our results yield novel insights into the pivotal roles of PT in ER stress- and autophagy-dependent cell death in HCC cells.

P006 DISCORDANCE OF COMMUNICATION PRIORITIES BETWEEN HEALTHCARE PROFESSIONALS AND PATIENTS WITH ULCERATIVE COLITIS: RESULTS OF A GLOBAL ULCERATIVE COLITIS NARRATIVE SURVEY

The Ulcerative Colitis (UC) Narrative is a global survey of patients (pts) and gastroenterology physicians (GIs) aimed at identifying the impact of the disease and comparing and contrasting perceptions of UC burden and management approaches. We describe the prioritization of topics for discussion at routine appointments from pt and GI perspectives, and examine the potential impact of any discordance. Data are presented from 2100 pts and 1254 GIs in Australia, Canada, Finland, France, Germany, Italy, Japan, Spain, the UK, and the USA. Surveys were conducted online and by phone by The Harris Poll between August 2017 and February 2018. Eligible adult pts with UC (confirmed by endoscopy) were those who had visited a GI in the previous 12 months and had ever received prescription medication for UC. Self-reported medication history was used as a proxy for disease severity, with pts with moderate to severe UC defined as pts who had ever taken immunosuppressants, tumor necrosis factor inhibitors, other biologics, or corticosteroids for >4 of the past 12 months. Pts who had only ever taken 5-aminosalicylates or had a colectomy were excluded. Eligible GIs were those who saw ≥10 UC pts each month (≥5 in Japan), of whom ≥10% were taking a biologic and did not practice in a long-term care facility or hospice. Data are presented from all respondents who consented and completed the survey. Pts were a mean age of 40.8 years (standard deviation [SD] 12.4), 53% were male, and 82% had moderate to severe UC, with 67% considering their UC to be controlled with few to no symptoms. Survey responses showed some overlap between pts and GIs in their priorities for discussion at routine appointments. The top priorities selected for pts were discussions on ‘ability to manage symptoms’ (32%), ‘symptoms/problems experienced since last visit’ (29%), ‘how to control inflammation’ (29%), and ‘cancer risk’ (24%), while GIs’ highest priorities for discussion included ‘symptoms since last visit’ (53%), ‘ability to manage symptoms’ (40%), and ‘side effects of current treatment’ (40%). The greatest discordance between pt and GI prioritization was observed for cancer risk (24% vs 11%), fatigue management (16% vs 5%), emotional impact (13% vs 7%), and new medications (21% vs 15%). Both pts (63%) and GIs (79%) wish they had more time at appointments. Symptom control is a high priority for discussion among pts with UC and GIs, but other topics such as cancer risk, fatigue management, emotional impact, and new medications were viewed as less of a priority for GIs than for pts. GIs need to be mindful of those topics of greatest concern to the pt, and identify ways to discuss topics important to both parties, since shortage of appointment time is a barrier to communication.