Genetic evidence links mutations in the LRRK2 gene with an increased risk of Parkinson's disease, for which no neuroprotective or neurorestorative therapies currently exist. While the role of LRRK2 ...in normal cellular function has yet to be fully described, evidence suggests involvement with immune and kidney functions. A comparative study of LRRK2-deficient and wild type rats investigated the influence that this gene has on the phenotype of these rats. Significant weight gain in the LRRK2 null rats was observed and was accompanied by significant increases in insulin and insulin-like growth factors. Additionally, LRRK2-deficient rats displayed kidney morphological and histopathological alterations in the renal tubule epithelial cells of all animals assessed. These perturbations in renal morphology were accompanied by significant decreases of lipocalin-2, in both the urine and plasma of knockout animals. Significant alterations in the cellular composition of the spleen between LRRK2 knockout and wild type animals were identified by immunophenotyping and were associated with subtle differences in response to dual infection with rat-adapted influenza virus (RAIV) and Streptococcus pneumoniae. Ontological pathway analysis of LRRK2 across metabolic and kidney processes and pathological categories suggested that the thioredoxin network may play a role in perturbing these organ systems. The phenotype of the LRRK2 null rat is suggestive of a complex biology influencing metabolism, immune function and kidney homeostasis. These data need to be extended to better understand the role of the kinase domain or other biological functions of the gene to better inform the development of pharmacological inhibitors.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
There is increasing interest in targeting histone N-methyl-lysine demethylases (KDMs) with small molecules both for the generation of probes for target exploration and for therapeutic purposes. Here ...we update on previous reviews on the inhibition of the lysine-specific demethylases (LSDs or KDM1s) and JmjC families of N-methyl-lysine demethylases (JmjC KDMs, KDM2–7), focusing on the academic and patent literature from 2014 to date. We also highlight recent biochemical, biological, and structural studies which are relevant to KDM inhibitor development.
Altitudinal gradients are characterized by steep changes of the physical and biotic environment that present challenges to plant adaptation throughout large parts of the world. Hybrid zones may form ...where related species inhabit different neighbouring altitudes and can facilitate interspecific gene flow and potentially the breakdown of species barriers. Studies of such hybrid zones can reveal much about the genetic basis of adaptation to environmental differences stemming from changes in altitude and the maintenance of species divergence in the face of gene flow. Furthermore, owing to recombination and transgressive effects, such hybrid zones can be sources of evolutionary novelty. We document plant hybrid zones associated with altitudinal gradients and emphasize similarities and differences in their structure. We then focus on recent studies of a hybrid zone between two Senecio species that occur at high and low altitude on Mount Etna, Sicily, showing how adaptation to local environments and intrinsic selection against hybrids act to maintain it. Finally, we consider the potential of altitudinal hybrid zones for generating evolutionary novelty through adaptive introgression and hybrid speciation. Examples of homoploid hybrid species of Senecio and Pinus that originated from altitudinal hybrid zones are discussed.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
The JmjC histone demethylases (KDMs) are linked to tumour cell proliferation and are current cancer targets; however, very few highly selective inhibitors for these are available. Here we report ...cyclic peptide inhibitors of the KDM4A-C with selectivity over other KDMs/2OG oxygenases, including closely related KDM4D/E isoforms. Crystal structures and biochemical analyses of one of the inhibitors (CP2) with KDM4A reveals that CP2 binds differently to, but competes with, histone substrates in the active site. Substitution of the active site binding arginine of CP2 to N-ɛ-trimethyl-lysine or methylated arginine results in cyclic peptide substrates, indicating that KDM4s may act on non-histone substrates. Targeted modifications to CP2 based on crystallographic and mass spectrometry analyses results in variants with greater proteolytic robustness. Peptide dosing in cells manifests KDM4A target stabilization. Although further development is required to optimize cellular activity, the results reveal the feasibility of highly selective non-metal chelating, substrate-competitive inhibitors of the JmjC KDMs.
Hyperbaric oxygen (HBO) has been advocated in the prevention and treatment of osteoradionecrosis (ORN) of the jaw after head and neck radiation therapy, but supporting evidence is weak. The aim of ...this randomized trial was to establish the benefit of HBO in the prevention of ORN after high-risk surgical procedures to the irradiated mandible.
HOPON was a randomized, controlled, phase 3 trial. Participants who required dental extractions or implant placement in the mandible with prior radiation therapy >50 Gy were recruited. Eligible patients were randomly assigned 1:1 to receive or not receive HBO. All patients received chlorhexidine mouthwash and antibiotics. For patients in the HBO arm, oxygen was administered in 30 daily dives at 100% oxygen to a pressure of 2.4 atmospheres absolute for 80 to 90 minutes. The primary outcome measure was the diagnosis of ORN 6 months after surgery, as determined by a blinded central review of clinical photographs and radiographs. The secondary endpoints included grade of ORN, ORN at other time points, acute symptoms, pain, and quality of life.
A total of 144 patients were randomized, and data from 100 patients were analyzed for the primary endpoint. The incidence of ORN at 6 months was 6.4% and 5.7% for the HBO and control groups, respectively (odds ratio, 1.13; 95% confidence interval, 0.14-8.92; P = 1). Patients in the hyperbaric arm had fewer acute symptoms but no significant differences in late pain or quality of life. Dropout was higher in the HBO arm, but the baseline characteristics of the groups that completed the trial were comparable between the 2 arms.
The low incidence of ORN makes recommending HBO for dental extractions or implant placement in the irradiated mandible unnecessary. These findings are in contrast with a recently published Cochrane review and previous trials reporting rates of ORN (non-HBO) of 14% to 30% and challenge a long-established standard of care.
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GEOZS, IJS, NUK, OILJ, UL, UM, UPUK
An in-depth evaluation of target safety is an invaluable resource throughout drug discovery and development. The goal of a target safety evaluation is to identify potential unintended adverse ...consequences of target modulation, and to propose a risk evaluation and mitigation strategy to shepherd compounds through the discovery and development pipeline, to confirm and characterize unavoidable on-target toxicities in a timely manner to assist in early program advancement decisions, and to anticipate, monitor, and manage potential clinical adverse events. The role of an experienced discovery toxicologist in synthesizing the available information into an actionable set of recommendations for a safety evaluation strategy is critical to its successful application in early discovery programs. This chapter presents a summary of some of the information types and sources that should be investigated, and approaches that can be taken to generate an early assessment of potential safety liabilities.
To document the clinical presentation, treatment, and visual outcome of sarcoid uveitis and to determine the timing and potential risk factors of sarcoidosis progression to symptomatic systemic ...disease from the time of sarcoid uveitis diagnosis.
Retrospective, interventional case series.
Subjects: Patients with dual diagnoses of uveitis and presumed/biopsy-proven sarcoidosis. Procedure: Retrospective review of 143 patient records from the Royal Victorian Eye and Ear Hospital and Eye Surgery Associates in Melbourne, Australia, between October 1990 and April 2014 coded with the dual diagnoses of uveitis and sarcoidosis. Only patients with uveitis and presumed or biopsy-proven sarcoidosis (N = 113) were included. Main Outcome Measures: Ascertainment of rate and time (months) to the development of symptomatic systemic sarcoidosis from uveitis onset; comparison of the patient demographics, characteristics of uveitis, treatment, and visual outcome between those who developed systemic sarcoidosis and those who remained systemically asymptomatic.
Uveitis was the initial presenting complaint of sarcoidosis in 78.8% (n = 89). Twenty-three patients had concurrent undiagnosed systemic disease at presentation and 29 subsequently developed symptomatic sarcoidosis in an organ uninvolved at uveitis onset. The median time to the development of symptomatic systemic sarcoidosis was 12 months. No statistically significant association was ascertained between any particular uveitis characteristic and extraocular sarcoidosis progression.
Uveitis was the initial presentation of sarcoidosis in the vast majority of our subjects. Concurrent undiagnosed systemic sarcoidosis was common at the time of uveitis onset. A high index of suspicion for subsequent systemic progression should also be maintained, especially within the first 5 years of the uveitis diagnosis.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
SYNB1891 is a live, modified strain of the probiotic E. coli Nissle 1917 (EcN) engineered to produce cyclic dinucleotides under hypoxia leading to stimulator of interferon genes (STING)-activation in ...phagocytic antigen-presenting cells in tumors and activating complementary innate immune pathways.
This first-in-human study (NCT04167137) enrolled participants with refractory advanced cancers to receive repeat intratumoral (IT) injections of SYNB1891 either alone or in combination atezolizumab, with the primary objective of evaluating the safety and tolerability of both regimens.
Twenty-four participants received monotherapy across 6 cohorts, and 8 participants received combination therapy in 2 cohorts. Five cytokine release syndrome events occurred with monotherapy, including one that met the criteria for dose-limiting toxicity at the highest dose; no other SYNB1891-related serious adverse events occurred, and no SYNB1891-related infections were observed. SYNB1891 was not detected in the blood at 6 or 24h after the first IT dose or in tumor tissue 7 days following the first dose. Treatment with SYNB1891 resulted in activation of the STING pathway and target engagement as assessed by upregulation of interferon-stimulated genes, chemokines/cytokines, and T-cell response genes in core biopsies obtained pre-dose and 7 days following the third weekly dose. In addition, a dose‑related increase in serum cytokines was observed, as well as stable disease in 4 participants refractory to prior PD-1/L1 antibodies.
Repeat IT injection of SYNB1891 as monotherapy and in combination atezolizumab was safe and well tolerated and evidence of STING pathway target engagement was observed.
Many agents are active in multiple myeloma, but the majority of patients relapse. This clinical pattern suggests most cancer cells are eliminated, but cells with the clonogenic potential to mediate ...tumor regrowth are relatively chemoresistant. Our previous data suggested that CD138(+) multiple myeloma plasma cells cannot undergo long-term proliferation but rather arise from clonogenic CD138(neg) B cells. We compared the relative sensitivity of these distinct cell types to clinical antimyeloma agents and found that dexamethasone, lenadilomide, bortezomib, and 4-hydroxycyclophosphamide inhibited CD138(+) multiple myeloma plasma cells but had little effect on CD138(neg) precursors in vitro. We further characterized clonogenic multiple myeloma cells and stained cell lines using the Hoechst side population and Aldefluor assays. Each assay identified CD138(neg) cells suggesting that they possess high drug efflux capacity and intracellular drug detoxification activity. We also found that multiple myeloma cells expressing the memory B-cell markers CD20 and CD27 could give rise to clonogenic multiple myeloma growth in vitro and engraft immunodeficient nonobese diabetes/severe combined immunodeficient mice during both primary and secondary transplantation. Furthermore, both the side population and Aldefluor assays were capable of identifying circulating clonotypic memory B-cell populations within the peripheral blood of multiple myeloma patients. Our results suggest that circulating clonotypic B-cell populations represent multiple myeloma stem cells, and the relative drug resistance of these cells is mediated by processes that protect normal stem cells from toxic injury.
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