Unveiling the potential of ursolic acid modified hyaluronate nanoparticles for combination drug therapy in triple negative breast cancer.

Triple negative breast cancer (TNBC) represents the most aggressive and heterogenous disease, and combination therapy holds promising potential. Here, an enzyme-responsive polymeric prodrug with self-assembly properties was synthesized for targeted co-delivery of paclitaxel (PTX) and ursolic acid (UA). Hyaluronic acid (HA) was conjugated with UA, yielding an amphiphilic prodrug with 13.85 mol% UA and a CMC of 32.3 µg/mL. The HA-UA conjugate exhibited ∼14 % and 47 % hydrolysis at pH 7.4 and in tumor cell lysate. HA-UA/PTX NPs exhibited a spherical structure with 173 nm particle size, and 0.15 PDI. The nanoparticles showed high drug loading (11.58 %) and entrapment efficiency (76.87 %) of PTX. Release experiments revealed accelerated drug release (∼78 %) in the presence of hyaluronidase enzyme. Cellular uptake in MDA-MB-231 cells showed enhanced uptake of HA-UA/PTX NPs through CD44 receptor-mediated endocytosis. In vitro, HA-UA/PTX NPs exhibited higher cytotoxicity, apoptosis, and mitochondrial depolarization compared to PTX alone. In vivo, HA-UA/PTX NPs demonstrated improved pharmacokinetic properties, with 2.18, 2.40, and 2.35-fold higher AUC, t1/2, and MRT compared to free PTX. Notably, HA-UA/PTX NPs exhibited superior antitumor efficacy with a 90 % tumor inhibition rate in 4T1 tumor model and low systemic toxicity, showcasing their significant potential as carriers for TNBC combination therapy.

Systemic Sclerosis in Males-Deciphering the Enigma of Erasmus Syndrome.

Background: Systemic sclerosis is an autoimmune connective tissue disease characterized by fibrosis in skin and internal organs. Chronic exposure to silica may not only lead to silicosis of lungs but also systemic sclerosis. Systemic sclerosis is relatively commoner in females; however, occupational exposure to silica in males makes them vulnerable to silica--associated systemic sclerosis (Erasmus syndrome). Objective: To describe the clinico-epidemiological aspects of systemic sclerosis in males in a retrospective cohort study. Materials and Methods: The data were analysed retrospectively for demographic profile and clinical characteristics including examination findings, laboratory investigations, and treatments of all male patients diagnosed with systemic sclerosis with or without silica exposure, managed from January 2018 to December 2021. Results: Eight out of twelve patients were having silica exposure in the form of stone cutting, cement exposure, and working with concrete. The average age was 55 ± 10.72 years with average smoking exposure of around 24.4 ± 12.8 pack years. Skin thickening was reported by all patients with an average modified Rodnan score of 18.33/51 in diffuse and 7/51 in limited cutaneous systemic sclerosis. Raynaud's phenomenon and sclerodactyly were universal findings, while 9 (75%) patients had digital pitted scars. Antinuclear antibodies were present in all patients and specific antibodies substantiated the clinical assessment in almost all patients. Interstitial lung disease was the most common systemic finding present in 11 (91%) patients and tuberculosis was diagnosed in 2 (25%) cases with silica exposure. Gastrointestinal and cardiac system involvement was seen in 5 (41.6%) and 4 (33.3%) patients, respectively. Conclusion: Systemic sclerosis in males against the gender predilection indicates the role of occupational exposure. Silicosis and systemic sclerosis synergistically add to lung damage, and at the same time, these patients are more prone to infections like tuberculosis.

HYPofractionated Adjuvant RadioTherapy in 1 versus 2 weeks in high-risk patients with breast cancer (HYPART): a non-inferiority, open-label, phase III randomised trial.

BACKGROUND: Breast cancer is the most common cancer in women. Radiotherapy is an important part of breast cancer treatment after surgery. Breast cancer radiotherapy is usually delivered in 3-5 weeks. This is a long duration for women with breast cancer to stay away from the family and work. We wanted to reduce this duration so that the wages loss and the logistics can be minimised for these patients. Hypofractionation, i.e. high dose per fraction, is delivered in a smaller number of days. In this study, we will compare a 1-week schedule of hypofractionated adjuvant whole breast/chest wall and/or regional nodal radiotherapy against 2 weeks for locoregional disease control, toxicities, quality of life (QoL), survival and second cancers after primary surgery in patients with breast cancer. METHODS: Eligible patients with breast cancer after mastectomy or breast conserving surgery (BCS) will be treated with a radiotherapy dose of 26 Gy in 5 fractions over 1 week in the study arm and 34 Gy in 10 fractions over 2 weeks in the control arm. The primary endpoint of this noninferiority study will be locoregional tumour control. Secondary endpoints will be early and late radiation toxicities, quality of life, contralateral primary tumours, regional and distant metastases, survival and second cancers. A total of 1018 patients will be randomised (1:1) to receive 1 week or 2 weeks of radiotherapy. An event-driven analysis will be performed after at least 94 patients have documented locoregional recurrences. Acute radiation toxicity will be assessed and scaled according to the RTOG grading system. Late radiation toxicity will be assessed with the Radiation Therapy Oncology Group and the European Organisation for Research and Treatment of Cancer late radiation morbidity scale. Cosmetic assessment will be done using Harvard/NSABP/RTOG breast cosmesis grading scale at baseline and 3 and 5 years. QoL will be assessed with EORTC QLQ-30 and EORTC QLQ-BR 23 at baseline and 3 and 5 years. DISCUSSION: Hypofractionation reduces treatment time to half while maintaining breast cosmesis and gives control rates equal to conventional fractionation. This is possible because breast tissue can tolerate high dose per fraction. In this study, we presume that 1-week radiotherapy will be non-inferior to 2 week radiotherapy, i.e. disease control will be similar with both the schedules without additional side effects, and QoL of these patients will be maintained. If we are able to achieve these outcomes, then patients will be able to complete their radiotherapy in less duration. There is not much data on regional nodal irradiation with hypofraction in breast cancer. We have used hypofraction for regional nodal irradiation in the past and not encountered any safety issue. If we are able to prove that late-term effects are comparable in the two schedules, it will make the radiation oncologist confident about hypofractionation in breast cancer. As breast cancer is a leading cancer in females and radiation therapy is an integral part of its local management, hypofractionation will help radiation centres worldwide to meet the growing need for radiation treatment in breast cancer, particularly in developing countries where resources are limited. It will also reduce the financial burden on the patient and family. Since we will treat these patients with both simple and complex radiotherapy techniques, it will also be possible for the low-income countries to follow this trial without needing a high-end or expensive radiotherapy equipment as the planning and treatment process will be very simple. TRIAL REGISTRATION: The trial is registered with ClinicalTrials.gov ID NCT04472845 and CTRI with REF/2020/09/037050.

Long-term administration of intravenous Trappsol® Cyclo™ (HP-ß-CD) results in clinical benefits and stabilization or slowing of disease progression in patients with Niemann-Pick disease type C1: Results of an international 48-week Phase I/II trial.

Background: Niemann-Pick disease type C (NPC) is a rare, fatal, pan-ethnic, autosomal recessive lysosomal storage disease characterized by progressive major organ failure and neurodegeneration. Preclinical studies confirmed a critical role of systemically administered hydroxypropyl-ß-cyclodextrin (HP-ß-CD; Trappsol® Cyclo™) in cholesterol metabolism and homeostasis in peripheral tissues of the body, including the liver, and in the central nervous system (CNS). Herein, the pharmacokinetics (PK), safety, and efficacy of HP-ß-CD, and biomarkers of NPC were assessed in pediatric and adult patients with NPC1. Methods: This was a multicenter, Phase I/II, randomized, double-blind, parallel-group, 48-week study (ClinicalTrials.gov identifier NCT02912793) to compare the PK of three different single intravenous (IV) doses of HP-ß-CD in pediatric and adult patients with NPC1 and to evaluate the efficacy and tolerability of three different dosages of HP-ß-CD in patients with NPC1 after long-term treatment. Twelve patients aged at least 2 years (2-39 years of age) with a confirmed diagnosis of NPC1 were randomized to receive one of three IV doses of HP-ß-CD (1500 mg/kg, 2000 mg/kg, or 2500 mg/kg) every 2 weeks for 48 weeks. All patients received HP-ß-CD; there was no placebo or other control. PK testing of plasma and cerebrospinal fluid (CSF) was at set times after the first infusion. Pharmacodynamic assessments included biomarkers of cholesterol metabolism (synthesis and breakdown products), N-palmitoyl-O-phosphocholineserine (PPCS), and specific biomarkers of CSF neurodegeneration (including total Tau), CNS inflammation (glial fibrillary acidic protein [GFAP] and tumor necrosis factor α [TNFα]), CNS cholesterol metabolism (24S-hydroxycholesterol) and inflammatory markers. Efficacy measures included clinical disease severity, neurologic symptoms, and clinical impressions of improvement. Safety assessment included physical examination, vital signs, clinical safety laboratory assessment and adverse events (AEs). Results: Nine patients completed the study, 2 in the 1500 mg/kg group, 4 in the 2000 mg/kg group and 3 in the 2500 mg/kg group. Three patients (all in the 1500 mg/kg group) discontinued the study because of either physician decision/site Principal Investigator (PI) discretion, withdrawal by subject/patient/parent/guardian, or other non-safety reasons. In 5 patients who underwent serial lumbar punctures, HP-ß-CD was detected in the CSF. Of the 9 patients who completed the study, 8 (88.9%) improved in at least two domains of the 17-Domain Niemann-Pick disease Type C-Clinical Severity Scale (17D-NPC-CSS), and 6 of these patients improved in at least one domain viewed by patients and their caregivers to be key to quality of life, namely, speech, swallow, fine and gross motor skills, and cognition. Of the 9 patients who completed the study, 7 were viewed by their treating physicians as having improved to some degree at the end of the study, and 2 remained stable; both outcomes are highly relevant in a progressive neurodegenerative disease. Some patients and families reported improvement in quality of life.All three doses of HP-ß-CD were well tolerated overall, with most treatment-emergent adverse events transient, mild-to-moderate in nature, and considered by the site PIs to be not related to study drug. Interpretation: This 48-week trial is the longest to date to evaluate the safety, tolerability, and efficacy across multiple clinical endpoints of IV administration of Trappsol® Cyclo™ (HP-ß-CD) in NPC1 patients. In pediatric and adult patients with NPC, Trappsol® Cyclo™ IV improved clinical signs and symptoms and was generally well tolerated. The findings presented here demonstrate a favorable benefit-risk profile and support the global pivotal trial now underway to evaluate the long-term treatment benefits and the potential of Trappsol® Cyclo™ as a disease-modifying treatment in this patient population.

Recent advances in lipid-based long-acting injectable depot formulations.

Long-acting injectable (LAIs) delivery systems sustain the drug therapeutic action in the body, resulting in reduced dosage regimen, toxicity, and improved patient compliance. Lipid-based depots are biocompatible, provide extended drug release, and improve drug stability, making them suitable for systemic and localized treatment of various chronic ailments, including psychosis, diabetes, hormonal disorders, arthritis, ocular diseases, and cancer. These depots include oil solutions, suspensions, oleogels, liquid crystalline systems, liposomes, solid lipid nanoparticles, nanostructured lipid carriers, phospholipid phase separation gel, vesicular phospholipid gel etc. This review summarizes recent advancements in lipid-based LAIs for delivering small and macromolecules, and their potential in managing chronic diseases. It also provides an overview of the lipid depots available in market or clinical phase, as well as patents for lipid-based LAIs. Furthermore, this review critically discusses the current scenario of using in vitro release methods to establish IVIVC and highlights the challenges involved in developing lipid-based LAIs.

Randomized Controlled Trial Comparing Ferrous Sulfate and Iron Sucrose in Iron Deficiency Anemia in Pregnancy.

INTRODUCTION:  Anemia among pregnant women is one of the major health concerns for healthcare workers. The management becomes a concern in the pregnancy where the question arises of which is better the intravenous iron sucrose or the oral ferrous sulfate tablets. To answer this, a randomized control trial comparing both the treatment options in a tertiary care government hospital was set up in the hilly terrains of India. This study discusses the effectiveness and practical aspect of using both, which seems to be the better out of both, and why. METHODS:  The study was conducted as a parallel-group, open-label randomized controlled trial (RCT) in the Department of Obstetrics and Gynecology of a tertiary care government hospital in India, with approximately 4,000 delivery loads annually. Ethical clearance was obtained from the institute's ethics committee (IEC), and the trial was registered with the Clinical Trial Registry of India (REF/2022/06/055013). Two hundred sixty-eight pregnant women between 18 and 45 years of age with moderate iron deficiency anemia (IDA) (hemoglobin (Hb) 7-9g/dl, microcytic-hypochromic, and serum ferritin <30ng/ml) were included in the study. Patients were randomly divided into two groups: group 1 with 134 patients to receive intravenous iron sucrose and group 2 with 134 patients to receive oral ferrous sulfate tablets. RESULTS: The intravenous iron sucrose is superior in terms of tolerability and correction of iron deficiency anemia during pregnancy. CONCLUSION: It yields a quicker rise in Hb and serum ferritin with no major side effects. In the difficult terrain of Himachal Pradesh, this makes IV iron sucrose a better option for anemic pregnant women who do not have easy access to health facilities resulting in a large number of them reaching hospitals with moderate to severe anemia at a later gestation.

Improving Delirium Assessment in Palliative Homecare - A Quality Improvement Project at CanSupport.

Objectives: Delirium increases distress in patients and caregivers and often leads to hospitalisation and increased health-care costs. It is early diagnosis and management improves the quality of life (QoL) of advanced cancer patients as well as their families. This quality improvement (QI) project aimed at increasing delirium assessment in poor performance advanced cancer patients receiving palliative homecare. Material and Methods: The A3 methodology for QI was used. Our SMART goal was to increase the assessment of delirium in poor performance advanced cancer patients from 25% to 50%. The Fishbone and Pareto analysis helped to determine the reasons for low assessment rates. A validated screening tool for delirium assessment was selected and the homecare team doctors and nurses were trained to use it. A flier was designed to help educate families about delirium. Results: Regular use of the tool helped to increase delirium assessment from an initial 25-50% at the time of project completion. The homecare teams learnt the importance of early delirium diagnosis and the need for regular delirium screening. Family caregivers were empowered through education and use of fliers. Conclusion: The QI project helped to improve delirium assessment and leading to improved QoL of patients and their caregivers. Regular training and awareness and continued use of a validated screening tool should help to sustain the results.

A New RP-HPLC Method for Simultaneous Determination of Amaroswerin, Amarogentin and Andrographolide in a Herbal Drug "Chirayata".

Chirayata-the whole dried plant of Swertia chirayita-is an important traditional drug of Indian System of Medicines. A novel reverse-phase high performance liquid chromatography (RP-HPLC) method has been developed for the simultaneous determination and quantification of amaroswerin, amarogentin and andrographolide in a herbal drug "Chirayata," which is oftenly adulterated/substituted with herbal drug Kalmegh. The developed method is in accordance with International Council for Harmonization guidelines and is simple, precise, accurate, rapid, reproducible and specific to determine amarogentin, amaroswerin and andrographolide. Reverse-phase column (Water's X-bridge C18, 5 µm, 4.6 mm × 250 mm) with high resolution for all marker compounds was used with binary gradient elution (methanol:water) with a flow rate of 1 mL/min and detection at 235 nm. The developed method showed good linearity (R2 > 0.999) in a relatively wider range of concentration 2.968-95.00 ppm for amarogentin, amaroswerin and 5.625-180 ppm for andrographolide. The method is important for quality control analysis of drug Chirayata.

Enhanced stability and oral bioavailability of erlotinib by solid self nano emulsifying drug delivery systems.

The present investigation demonstrates the preparation of solid self nanoemulsfying drug delivery system (sSNEDDS) to enhance stability and bioavailability of Erlotinib (ERL) via the oral route. Capmul®MCM EP (CPM EP, oil), Cremophor® RH 40 (CMR RH 40, surfactant), and LBF CS (LBF CS, cosurfactant) were chosen as chief components for preparing Liquids SNEDDS (L-ERL-SNEDDS) based on solubility and emulsion forming ability. Pseudo ternary phase diagram and constrained mixture designs were applied to identify the self-emulsifying area and it was found that CPM EP, CMR RH 40, and LBF CS in the ratio of 59:11:30 showed optimized particle size (110.08 nm), with narrow PDI (0.114) and high ERL loading capacity (14.31 mg/g). Adsorption method was implemented for solidification of L-ERL-SNEDDS. Among various solid carriers were studied, Aerosil® 200 (A200) was finalized based on free flowing property and reconstitution ability. DSC and XRD studies revealed that crystallinity of drug was reduced in developed system. The developed formulation (named as, A200-ERL-sSNEDDS) showed increased cytotoxicity and apoptosis in PANC-1 and MIA PaCa-2 cells. Pharmacokinetic studies revealed ∼2.2 times increase in AUC0-∞values in case of A200-ERL-sSNEDDS as compared to free ERL. Thus current strategy can be extrapolated for delivering of poorly soluble drugs via oral route.

Chondroitin Sulfate: Emerging biomaterial for biopharmaceutical purpose and tissue engineering.

Chondroitin Sulfate (CS) is an anionic hetero polysaccharide possessing anti-inflammatory, antioxidant, antitumor, anticoagulant and antithrombogenic activities. It is biodegradable and biocompatible in nature. Further, it inherits the ability of active and subcellular targeting due to its affinity for CD 44 receptors and glycosylation enzymes, which are overexpressed on the surface of tumor cells and intracellular organelles respectively. CS is known to degrade in presence of physiological stimuli, the hyaluronidase (HAase) enzyme and reactive oxygen species (ROS), assisting in site specific drug release. Due to these properties, it serve as a promising biomaterial for drug delivery and tissue engineering. In this review, the fundamental theory of CS, CS-based nanocarriers for the delivery of biopharmaceuticals and stimuli sensitive delivery systems such as HAase and ROS responsive nanocarriers for tumor targeted delivery are discussed critically. In addition, the manuscript describes the application of CS-based tissue constructs in tissue engineering and wound healing.

In-depth phenotyping for clinical stratification of Gaucher disease.

BACKGROUND: The Gaucher Investigative Therapy Evaluation is a national clinical cohort of 250 patients aged 5-87 years with Gaucher disease in the United Kingdom-an ultra-rare genetic disorder. To inform clinical decision-making and improve pathophysiological understanding, we characterized the course of Gaucher disease and explored the influence of costly innovative medication and other interventions. Retrospective and prospective clinical, laboratory and radiological information including molecular analysis of the GBA1 gene and comprising > 2500 variables were collected systematically into a relational database with banking of collated biological samples in a central bioresource. Data for deep phenotyping and life-quality evaluation, including skeletal, visceral, haematological and neurological manifestations were recorded for a median of 17.3 years; the skeletal and neurological manifestations are the main focus of this study. RESULTS: At baseline, 223 of the 250 patients were classified as type 1 Gaucher disease. Skeletal manifestations occurred in most patients in the cohort (131 of 201 specifically reported bone pain). Symptomatic osteonecrosis and fragility fractures occurred respectively in 76 and 37 of all 250 patients and the first osseous events occurred significantly earlier in those with neuronopathic disease. Intensive phenotyping in a subgroup of 40 patients originally considered to have only systemic features, revealed neurological involvement in 18: two had Parkinson disease and 16 had clinical signs compatible with neuronopathic Gaucher disease-indicating a greater than expected prevalence of neurological features. Analysis of longitudinal real-world data enabled Gaucher disease to be stratified with respect to advanced therapies and splenectomy. Splenectomy was associated with an increased hazard of fragility fractures, in addition to osteonecrosis and orthopaedic surgery; there were marked gender differences in fracture risk over time since splenectomy. Skeletal disease was a heavy burden of illness, especially where access to specific therapy was delayed and in patients requiring orthopaedic surgery. CONCLUSION: Gaucher disease has been explored using real-world data obtained in an era of therapeutic transformation. Introduction of advanced therapies and repeated longitudinal measures enabled this heterogeneous condition to be stratified into obvious clinical endotypes. The study reveals diverse and changing phenotypic manifestations with systemic, skeletal and neurological disease as inter-related sources of disability.

Exploring the therapeutic potential of the bioinspired reconstituted high density lipoprotein nanostructures.

Lipoproteins are endogenously present nanocarriers and are the primary commuters of cholesterol within the body. Among lipoproteins, HDL inherits size in nm range with anti-oxidant potential and receptor affinity which makes them an attractive candidate for drug delivery. Hence, in this review, we glance across the biosynthesis, architecture, and methods to prepare rHDL which acts as an endogenously present delivery vehicle. The review critically describes the range of applications possible for targeted delivery in multiple ailments (cancer, atherosclerosis, Alzheimer, age-related macular degeneration and psoriasis) using rHDL. Moreover, the review also expounds on to the case reports where, drug delivery aspect of rHDL is augmented through stimuli sensitivity (ultrasounds, magnetic field, photodynamic therapy) and pH dependent approaches. Further, the role of rHDL in combating the blood brain barrier for efficient delivery of peptides into the brain is also been highlighted. Additionally, the manuscript also expounds on rHDL based formulations which are under clinical review with elaboration on challenges and future prospects pertaining to their clinical translation. Overall, the present article showcases several aspects of rHDL, which are or can be explored for present and future investigations.

Adults with a more extensive body involvement, moderate to extremely severe vitiligo and a prolonged clinical course have an early onset in childhood in addition to other prognostic factors as compared to individuals with later-onset vitiligo.

BACKGROUND: The extent and disease severity, duration and other associated prognostic cofactors in vitiligo in adults may vary with the age of onset (before or after 10 years of age). OBJECTIVES: To compare extent and disease severity, duration and other cofactors in adults with early-onset and late-onset vitiligo. METHODS: The medical records of 408 (M:F 1:1.1) adults aged 20-75 years diagnosed with vitiligo between January 2016 and December 2019 were examined retrospectively. The extent and severity of vitiligo were defined. Characteristics of vitiligo with early onset and late onset were compared statistically and odds ratios calculated for risk assessment. RESULTS: 31 (7.6%, M:F 1:2.4) patients had early-onset vitiligo, and 377 (92.4%, M:F 0.8:1) patients had later-onset vitiligo. Compared to late onset, patients with early-onset vitiligo had a significant number of males (71% vs 45.9%), higher percentages of body surface area involvement and moderate to extremely severe disease (29% vs 10.6%), longer duration of disease (41.9% vs 9%), Koebner's phenomenon (48.4% vs 15.6%) and halo nevus (9.7% vs 1.9%). Differences between the two groups were not significant for types of vitiligo, family history of vitiligo and presence of cutaneous and systemic/autoimmune diseases. CONCLUSION: The adults, males in particular, with generalised vitiligo (>10% BSA involvement) appear to have an early onset and a prolonged clinical course. The presence of Koebner's phenomenon and halo nevus in patients with early-onset vitiligo was other poor prognostic factors compared to patients with late-onset vitiligo. The retrospective, hospital-based cross-sectional design and small sample size for stratification remain major limitations.

The clinico-epidemiological characteristics and therapeutic experience of 152 patients with cutaneous sporotrichosis: a 10-year retrospective study from India.

BACKGROUND: Cutaneous sporotrichosis, a subcutaneous mycosis because of Sporothrix schenckii, is sporadic worldwide with local hyperendemic pockets. OBJECTIVES: To study clinico-epidemiological and therapeutic aspects of sporotrichosis in our clinic. METHODS: We retrospectively analyzed medical records of 152 (M:F 52:100) patients with cutaneous sporotrichosis managed during 2010-2019. RESULTS: All patients were involved in agricultural activities, and 63.2% were aged 21-60 years. Women outnumbered men by nearly two times. Fixed and lymphocutaneous sporotrichosis occurred in 54.6% and 43.4% patients, respectively. Only 2% of patients had multifocal sporotrichosis. Only 48% of patients imputed their disease to prior injuries. Extremities, upper in 53.9% and lower in 21% of patients, were mostly involved. Scrotum involvement in one patient was unusual. A mixed inflammatory infiltrate in 38.7%, chronic granuloma formation in 35%, and presence of spores in 48.9% biopsies was noted. S. schenckii grew on Sabouraud's dextrose agar in 40.2% of cases. Treatment with saturated solution of potassium iodide was curative in 76.8% patients, and lesions healed in 2-9 months (average 5.2 months). Metallic taste was experienced by 42.9% of patients. Itraconazole therapy was safe and effective in seven patients, and the response was better when combined with SSKI compared to either drug used alone. CONCLUSION: Cutaneous sporotrichosis mostly affects persons during active years of life. The injuries predisposing to infection are mostly forgotten. Both fixed and lymphocutaneous sporotrichosis involving extremities remain common forms. SSKI alone or in combination with itraconazole is safe and effective treatment. Itraconazole is preferable in patients having preexisting hypothyroidism or intolerance to SSKI.

Chemo-Geographic Variations in Wild Population of Asteriscus graveolens in Israel Based on Volatile Composition Analyses.

Asteriscus graveolens is an aromatic desert shrub which holds medicinal potential. This species belongs to the Asteraceae family and is endemic to the Mediterranean region. In the present study, wild plants were sampled from eleven locations throughout southern Israel and the volatile profiles from leaves and flowers were analyzed using GC/MS. Three methods for volatile sampling were tested for a representative population: solvent extraction (methyl tert-butyl ether), hydrodistillation of the essential oil and headspace solid-phase microextraction. In all methods, the majority of volatiles were characterized as oxygenated mono- and sesquiterpenes. Only solvent extraction was able to detect asteriscunolides that were previously reported as anticancer molecules. Hence, that method was chosen for further analyses. The leaves were dominated by three asteriscunolide isomers, cis-chrysanthenyl acetate and intermedeol. The flowers were dominated by bisabolone, 6-hydroxybisabol-2-en-1-one, cis-chrysanthenyl acetate, epi-α-cadinol, and germacrene-D. k-Means clustering analysis of these data divided the population into four clusters that significantly differ in their volatile composition as was further demonstrated by MANOVA analysis. Geographically, A. graveolens populations growing in Israel were found to be chemically diverse with unique varieties in the Dead Sea basin and the Arava region. This work demonstrates that chemo-geographic variation of volatile composition exists within A. graveolens population growing in Israel, so future research evaluating the medicinal potential of that plant should take this into consideration.

Sebelipase alfa for lysosomal acid lipase deficiency: 5-year treatment experience from a phase 2 open-label extension study.

BACKGROUND AND AIMS: Lysosomal acid lipase deficiency is characterized by hepatomegaly and dyslipidaemia, which can lead to cirrhosis and premature atherosclerosis. Sebelipase alfa is an approved recombinant human lysosomal acid lipase. In an open-label extension study of adults with lysosomal acid lipase deficiency (LAL-CL04), sebelipase alfa treatment for 1 year reduced serum transaminase levels and liver fat content and improved serum lipid levels. METHODS: Final data from LAL-CL04 are reported herein for patients who received sebelipase alfa infusions (1.0 or 3.0 mg/kg every other week) for up to 5 years. RESULTS: Of 8 patients enrolled, 7 received sebelipase alfa for 224-260 weeks; 1 was lost to follow-up. Median baseline levels of alanine aminotransferase and aspartate aminotransferase (81.5 and 50.0 U/L, respectively) were decreased through the end-of-study visit (54.0 and 34.0 U/L). Median low-density lipoprotein cholesterol decreased from 113 to 78 mg/dL, total cholesterol decreased from 171 to 132 mg/dL, and high-density lipoprotein cholesterol increased from 37 to 42 mg/dL. Most treatment-emergent adverse events were nonserious (99%), mild/moderate (98%) and unrelated to sebelipase alfa (87%); no patient discontinued as a result of treatment-emergent adverse events. One patient had 2 serious treatment-emergent adverse events (cholecystitis and cholelithiasis; assessed as unlikely related to sebelipase alfa). Two patients had 20 nonserious infusion-associated reactions in weeks 6-38; all were manageable. One patient tested positive for antidrug antibodies (single occurrence). CONCLUSIONS: Sebelipase alfa was well tolerated and improved serum transaminase and lipid levels for up to 5 years in adults with lysosomal acid lipase deficiency. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov record NCT01488097.

The dual benefit of a dominant mutation in Arabidopsis IRON DEFICIENCY TOLERANT1 for iron biofortification and heavy metal phytoremediation.

One of the goals of biofortification is to generate iron-enriched crops to combat growth and developmental defects especially iron (Fe) deficiency anaemia. Fe-fortification of food is challenging because soluble Fe is unstable and insoluble Fe is nonbioavailable. Genetic engineering is an alternative approach for Fe-biofortification, but so far strategies to increase Fe content have only encompassed a few genes with limited success. In this study, we demonstrate that the ethyl methanesulfonate (EMS) mutant, iron deficiency tolerant1 (idt1), can accumulate 4-7 times higher amounts of Fe than the wild type in roots, shoots and seeds, and exhibits the metal tolerance and iron accumulation (Metina) phenotype in Arabidopsis. Fe-regulated protein stability and nuclear localisation of the upstream transcriptional regulator bHLH34 were uncovered. The C to T transition mutation resulting in substitution of alanine to valine at amino acid position 320 of bHLH34 (designated as IDT1A320V ) in a conserved motif among mono- and dicots was found to be responsible for a dominant phenotype that possesses constitutive activation of the Fe regulatory pathway. Overexpression of IDT1A320V in Arabidopsis and tobacco led to the Metina phenotype; a phenotype that has escalated specificity towards optimising Fe homeostasis and may be useful in Fe-biofortification. Knowledge of the high tolerance and accumulation of heavy metals of this mutant can aid the development of tools for phytoremediation of contaminants.