Immunomedics (Germany)

<p>Supplementary Table S1. Extraction efficiency for isolation of SN-38 in buffer with or without human serum albumin (HSA) or from the ADC with or without acid hydrolysis followed by extraction; Supplementary Figure S1. Schematic depiction of the conjugation of CL2A-SN-38 to mildly reduced IgG yielding site-specifically coupled SN-38 to 8 well-defined sites; Supplementary Figure S2. CL2A-SN38 amide capped with N-acetylcysteine; Supplementary Figure S3. SDS-Page gels comparing profiles for labetuzumab (unconjugated hMN-14 IgG) and labetuzumab govitecan (CL2A-SN-38 conjugated hMN-14 IgG; IMMU-130); Supplementary Figure S4. In vitro cell binding assay performed on LS174T cells, evaluating the binding of unconjugated hMN-14 IgG and SN-38-conjugated hMN-14 IgG (IMMU-130); Supplementary Figure S5. Stability of IMMU-130 in serum from different sources; Supplementary Figure S6. Evaluation of lactone ring stability of the CL2A-linked SN-38 compared to SN-38 at pH 7.4.</p>

The aim: To study the intensity and depth of carious tooth lesions in rats with experimental juvenile adjuvant-induced arthritis. Materials and methods: An experimental study on a model of juvenile adjuvant arthritis (JAA) in 10 one-month-old rats induced by method of A.M. Bendele was carried out. 10 rats of the same age were intact. Injection of adjutant in rats of experimental group led to the development of acute local reaction and then caused generalized joint reaction of autoimmune origin. The performed basic therapy of JAA promoted transition of acute autoimmune process to chronic. Rats were withdrawn from the experiment in 58 days and the dental-jaw blocks were made, in which the intensity and depth of carious lesions of the masticatory group of teeth were determined. Results: The course of JAA was accompanied by the development of dental caries in 100% of experimental animals. It was found that the intensity of carious teeth lesions in terms of the number of carious teeth and cavities is probably higher than in intact rats (respectively 4.3 ± 0.3 vs. 2.2 ± 0.6 and 4.5 ± 0.3 vs. 2.3 ± 0.7, p <0.001). In rats with JAA, mostly middle and deep carious cavities were revealed, at the same time in intact rats - superficial and middle carious cavities were observed. Conclusions: It has been established that adjuvant arthritis is accompanied by 100% prevalence of dental caries, high intensity of carious process, presence of middle and deep carious cavities, that confirm the negative influence of autoimmune disease on the condition of the hard tooth tissues.

Metabolic reprogramming of the myofibroblast plays a fundamental role in the pathogenesis of fibrosing interstitial lung diseases. Here, we characterized the in vitro and in vivo metabolic and antifibrotic effects of IM156, an oxidative phosphorylation (OXPHOS) modulator that acts by inhibiting protein complex 1. In vitro, IM156 inhibited transforming growth factor β (TGFβ)-dependent increases in mitochondrial oxygen consumption rate and expression of myofibroblast markers in human pulmonary fibroblasts without altering cell viability or adding to TGFβ-induced increases in the extracellular acidification rate. IM156 significantly increased cellular AMP-activated protein kinase (AMPK) phosphorylation and was 60-fold more potent than metformin. In vivo, chronic oral administration of IM156 was highly distributed to major peripheral organs (i.e., lung, liver, kidney, heart) and had significant dose-related effects on the plasma metabolome consistent with OXPHOS modulation and AMPK activation. IM156 increased glycolysis, lipolysis, β-oxidation, and amino acids and decreased free fatty acids, tricarboxylic acid cycle activity, and protein synthesis. In the murine bleomycin model of pulmonary fibrosis, daily oral administration of IM156, administered 7 days after lung injury, attenuated body/lung weight changes and reduced lung fibrosis and inflammatory cell infiltration. The plasma exposures of IM156 were comparable to well tolerated doses in human studies. In conclusion, the metabolic and antifibrotic effects of IM156 suggest that OXPHOS modulation can attenuate myofibroblast metabolic reprogramming and support testing IM156 as a therapy for idiopathic pulmonary fibrosis and other fibrotic diseases. SIGNIFICANCE STATEMENT: Fibrosing interstitial lung diseases have a poor prognosis, and current antifibrotic treatments have significant limitations. This study demonstrates that attenuation of fibrogenic metabolic remodeling, by modulation of oxidative phosphorylation with IM156, prevents myofibroblast phenotype/collagen deposition and is a potentially effective and translational antifibrotic strategy.

High levels of serum alanine aminotransferase (ALT) and gamma-glutamyltransferase (GGT) are associated with increased diabetes risk. In the present study, we investigated the combined effects of ALT and GGT on the development of diabetes in a Korean population. A total of 9405 individuals (4020 women and 5385 men) without diabetes were enrolled in this study. From the baseline health screening to the follow-up examination, the development of diabetes, based on changes in ALT and GGT quartile levels, was analyzed. In addition, we analyzed the quartiles of ALT and GGT together to determine any synergistic effect from the fourth quartile of ALT and GGT on the development of diabetes. The development of diabetes gradually increased with an increase in the circulating levels of ALT and GGT. For the fourth quartile ALT and GGT, the hazard ratios of diabetes compared with the first quartile were 1.892 (95% confidence interval [CI]: 1.26–2.83, P = .002) and 3.526 (95% CI: 2.12–5.85, P < .001) after adjusting for confounders, respectively. Hazard ratios of diabetes after combining both fourth quartiles of ALT and GGT were 3.663 (95% CI: 2.42–5.52, P < .001), as compared with the first and second quartiles. Serum ALT and GGT levels are well associated with diabetes in Koreans after adjusting for confounders, and a combination of ALT and GGT levels can have a synergy in predicting the development of diabetes.

PURPOSEBreast and cervical cancer are the most common cancers among women in East and Southern Africa, where mortality remains high because of late diagnosis and limited access to treatment. We explored local approaches to breast and cervical cancer advocacy to identify the most pressing issues and opportunities for increasing the impact of civil society activities in the region.METHODSFocus group discussions were conducted with participants of the 2016 Women’s Empowerment Cancer Advocacy Network (WE CAN) Summit in Nairobi, Kenya. Discussions were audio-recorded, transcribed, coded, and analyzed for emergent themes. Results were presented to participants of 2019 WE CAN summit for cross-validation.RESULTSFour focus group discussions were conducted with 50 participants. Thirty-six (70%) identified as advocates, 30 (59%) as cancer survivors, 14 (27%) as nongovernmental organization representatives, 13 (25%) as researchers, 4 (8%) as clinicians, and 6 (8%) as policymakers. Although most participants focused on cancer awareness and screening/early detection, some noted that treatment was often unavailable and advocated for a broader strategy to improving access to care. Challenges to designing and implementing such a strategy included knowledge gaps in addressing late diagnosis and access to care, difficulty collaborating with like-minded organizations, approaching policymakers, and addressing treatment financing. Cancer coalitions, although rare, were crucial to building collaborations with ministries of health, policymakers, and international organizations that advanced breast and cervical cancer care.CONCLUSIONParticipants indicated that they would benefit from additional training about resource-appropriate best practices for improving breast and cervical cancer care and outcomes. Coalition-building and collaborations, including with oncologists and other medical professionals involved in cancer care, were crucial to leveraging limited resources, sharing lessons learned, and developing local solutions to common challenges.

A series of nanomedicinized formulations of paclitaxel were made using a variety of combinations of process and polymer. Formulations created with phospholipid as the polymer differ in their characteristics based on the process used to produce the nanoparticles. Cyclic voltammetry, size, polydispersity, drug incorporation and zeta potential were used to characterize the nanoparticles created.

Background: Successful nanoparticles formulations include Abraxane® (an albumin bound nanoparticle paclitaxel), Genexol-PM® (a polymer bound nanoparticle paclitaxel), and Doxil®. At LipoMedics we have developed a unique nanomedicinization process of water insoluble drug for intravenous administration using combination of solvents and polymers. The polymers can be simple phospholipid or synthetic diblock polymer or complex protein such as albumin. Electrochemistry was used to understand the molecular organization of these nanoparticles and biosensor built to support the in process monitoring of this pharmaceutic. Materials and Methods: Nanoparticle synthesis was conducted using a two step method whereby the drug is first emulsified in presence of solvent and then nanofabricated in presence of polymer. Nanoparticle size and zeta potential were measured using a Malvern ZS DLS system. The formulation was subjected to serial filtration using 1.2µm, 0.8µm, 0.45µm and 0.2µm syringe filters. The drug incorporation/loading was measured using ELISA. Electrochemical properties of the formulation were measured using screen printed carbon nanotube (CNT) electrodes from DropSens and a PGSTAT204 Autolab Potentiostat from Metrohm. The drug being evaluated in this study is paclitaxel- a water insoluble drug that can only be solubilized in Cremophor EL for intravenous administration. Only nanomedicinization allowed paclitaxel to be formulated without solvent. Results:A series of stable nanomedicinized paclitaxel formulations were created using chloroform or ethanol as solvent and phospholipid or albumin as polymer. Each formulation exhibited a distinct cyclic voltammetry (CV) scan. The CV scan was highly dependent on the polymer used. Monolayer and bilayer phospholipids behaved similarly as polymer with or without paclitaxel. Increasing the loading of these phospholipid nanoparticles caused a shift from profiles of high capacitance material to profiles of low capacitance material. Discussion: Capacitance of a carbon-based electrode consists of two major components: the electrical double layer capacitance due to the electrostatic attraction of charged carbon surfaces to electrolyte ions and the pseudocapacitance due to the Faradic reactions of electroactive species on the carbon surfaces. During electrochemical evaluations, the nanoparticles were treated as ionic liquid capacitance material. Low capacitance is suggestive of weakened charge accumulation in the electrode - electrolyte interface which depends on the mesoporosity and electrolyte accessibility of the capacitive material.

Erythropoietin (Epo) plays a dual role as an erythropoiesis-stimulating hormone and a locally produced cytoprotectant in various vertebrate tissues. Splice variants and engineered derivatives of Epo that mediate neuroprotection but do not stimulate erythropoiesis suggest that alternative receptors, different from the 'classical' homodimeric receptor involved in haematopoiesis, mediate neuroprotective Epo functions. Previous studies on grasshoppers demonstrated neuroprotective and neuroregenerative effects of Epo that involved similar transduction pathways as in mammals. To advance the characterization of yet unidentified neuroprotective Epo receptors, we studied the neuroprotective potency of the human non-erythropoietic Epo splice variant EV-3 in primary cultured locust brain neurons. We demonstrate that EV-3, like Epo, protects locust neurons from hypoxia-induced apoptotic death through activation of the Janus kinase/signal transducer and activator of transcription transduction pathway. Using the fluorescent dye FM1-43 to quantify endocytotic activity we show that both Epo and EV-3 increase the number of fluorescently labelled endocytotic vesicles. This reveals that binding of Epo to its neuroprotective receptor induces endocytosis, as it has been described for the mammalian homodimeric Epo-receptor expressed by erythroid progenitors. Reduction in Epo-stimulated endocytotic activity following pre-exposure to EV-3 indicated that both Epo and its splice variant bind to the same receptor on locust neurons. The shared neuroprotective potency of Epo and EV-3 in insect and mammalian neurons, in the absence of erythropoietic effects of EV-3 in mammals, suggests a greater similarity of the unidentified nervous Epo receptors (or receptor complexes) across phyla than between mammalian haematopoietic and neuroprotective receptors. Insects may serve as suitable models to evaluate the specific protective mechanisms mediated by Epo and its variants in non-erythropoietic mammalian tissues.

Complementary techniques elucidate water–framework interactions in different states of dehydration, two of which have not been observed before.