Botulinski nevrotoksin je izredno strupena beljakovina, ki jo tvori anaerobna po Gramu pozitivna bakterija Clostridium botulinum. Zgodba o odkritju botulinskega nevrotoksina se je pričela s ...pojavljanjem nepojasnjenih zastrupitev s klobasami, iz česar tudi izvira njegovo ime. Latinska beseda za klobaso je namreč botulus. Zgodba o tem se je nadaljevala s stoletji raziskav in še poteka z njegovo vedno širšo uporabo v medicini. Botulinski nevrotoksin v aktivni obliki postane proteolitični encim, izključno specifičen za fuzijske beljakovine kompleksa SNARE v presinaptičnih živčnih končičih. Prek kemodenervacije začasno zavre delovanje tarčnega tkiva, na skeletnih in gladkih mišicah povzroči npr. začasno ohlapno paralizo mišic. Botulinski nevrotoksin se uporablja v nevrologiji, za zdravljenje čezmerne aktivnosti sečnega mehurja in tudi v dermatologiji, kjer njegovo uporabo še vedno mnogi povezujejo zgolj z estetiko. Novejša dognanja pa razkrivajo, da botulinski nevrotoksin zmanjšuje bolečino in srbež ter vpliva tudi na nekatere nenevronske celice, kot npr. epidermalne keratinocite, dermalne fibroblaste, vnetne celice, lojnice, žilne endotelne celice in mezenhimske matične celice v podkožnem maščevju. Odkritja napovedujejo tudi možno razširitev nabora indikacij v dermatologiji. Članek predstavi zgodovino razvoja botulinskega nevrotoksina, njegovo sestavo, mehanizem delovanja in trenutne ter obetavne indikacije za uporabo v dermatologiji.
Inhibition of the epidermal growth factor receptor represents one of the most promising strategies in the treatment of lung cancer. Acquired resistance compromises the clinical efficacy of EGFR ...inhibitors during long-term treatment. The recently discovered EGFR-C797S mutation causes resistance against third-generation EGFR inhibitors. Here we present a rational approach based on extending the inhibition profile of a p38 MAP kinase inhibitor toward mutant EGFR inhibition. We used a privileged scaffold with proven cellular potency as well as in vivo efficacy and low toxicity. Guided by molecular modeling, we synthesized and studied the structure–activity relationship of 40 compounds against clinically relevant EGFR mutants. We successfully improved the cellular EGFR inhibition down to the low nanomolar range with covalently binding inhibitors against a gefitinib resistant T790M mutant cell line. We identified additional noncovalent interactions, which allowed us to develop metabolically stable inhibitors with high activities against the osimertinib resistant L858R/T790M/C797S mutant.
Excessive gestational weight gain (GWG) leads to obstetric complications, maternal postpartum weight retention and an increased risk of offspring obesity. The GeliS study examines the effect of a ...lifestyle intervention during pregnancy on the proportion of women with excessive GWG and pregnancy and obstetric complications, as well as the long-term risk of maternal and infant obesity.
The GeliS study is a cluster-randomised multicentre controlled trial including 2286 women with a pre-pregnancy BMI between 18.5 and 40.0 kg/m
recruited from gynaecological and midwifery practices prior to the end of the 12
week of gestation in five Bavarian regions. In the intervention regions, four lifestyle counselling sessions covering a balanced healthy diet, regular physical activity and self-monitoring of weight gain were performed by trained healthcare providers alongside routine pre- and postnatal practice visits. In the control regions, leaflets with general recommendations for a healthy lifestyle during pregnancy were provided.
The intervention did not result in a significant reduction of women showing excessive GWG (adjusted OR 0.95, 95% CI 0.66-1.38, p = 0.789), with 45.1% and 45.7% of women in the intervention and control groups, respectively, gaining weight above the Institute of Medicine recommendations. Gestational diabetes mellitus was diagnosed in 10.8% and 11.1% of women in the intervention and control groups, respectively (p = 0.622). Mean birth weight and length were slightly lower in the intervention group (3313 ± 536 g vs. 3363 ± 498 g, p = 0.020; 51.1 ± 2.7 cm vs. 51.6 ± 2.5 cm, p = 0.001).
In the setting of routine prenatal care, lifestyle advice given by trained healthcare providers was not successful in limiting GWG and pregnancy complications. Nevertheless, the potential long-term effects of the intervention remain to be assessed.
NCT01958307 , ClinicalTrials.gov, retrospectively registered October 9, 2013.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•CH may be associated with broader ill health (worse performance status, increased and potentially novel comorbidities).•Serum interleukin-6 is elevated in people with CH and genetic subtypes, ...providing a view of the human systemic inflammatory landscape of CH.
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Gastrointestinal stromal tumors (GIST) harboring activating mutations of
respond to imatinib, with the notable exception of the most common mutation, D842V. Avapritinib is a novel, potent KIT/PDGFRA ...inhibitor with substantial clinical activity in patients with the D842V genotype. To date, only a minority of
-mutant patients treated with avapritinib have developed secondary resistance. Tumor and plasma biopsies in 6 of 7 patients with
primary mutations who progressed on avapritinib or imatinib had secondary resistance mutations within
exons 13, 14, and 15 that interfere with avapritinib binding. Secondary
mutations causing V658A, N659K, Y676C, and G680R substitutions were found in 2 or more patients each, representing recurrent mechanisms of PDGFRA GIST drug resistance. Notably, most PDGFRA-mutant GISTs refractory to avapritinib remain dependent on the PDGFRA oncogenic signal. Inhibitors that target PDGFRA protein stability or inhibition of PDGFRA-dependent signaling pathways may overcome avapritinib resistance. SIGNIFICANCE: Here, we provide the first description of avapritinib resistance mechanisms in PDGFRA-mutant GIST.
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Intrauterine growth restriction (IUGR) predisposes to chronic kidney disease via activation of proinflammatory pathways, and omega-3 PUFAs (n-3 PUFAs) have anti-inflammatory properties. In female ...rats, we investigated 1) how an elevated dietary n-3/n-6 PUFA ratio (1:1) during postnatal kidney development modifies kidney phospholipid (PL) and arachidonic acid (AA) metabolite content and 2) whether the diet counteracts adverse molecular protein signatures expected in IUGR kidneys. IUGR was induced by bilateral uterine vessel ligation or intrauterine stress through sham operation 3.5 days before term. Control (C) offspring were born after uncompromised pregnancy. On postnatal (P) days P2–P39, rats were fed control (n-3/n-6 PUFA ratio 1:20) or n-3 PUFA intervention diet (N3PUFA; ratio 1:1). Plasma parameters (P33), kidney cortex lipidomics and proteomics, as well as histology (P39) were studied. We found that the intervention diet tripled PL-DHA content (PC 40:6; P < 0.01) and lowered both PL-AA content (PC 38:4 and lyso-phosphatidylcholine 20:4; P < 0.05) and AA metabolites (HETEs, dihydroxyeicosatrienoic acids, and epoxyeicosatrienoic acids) to 25% in all offspring groups. After ligation, our network analysis of differentially expressed proteins identified an adverse molecular signature indicating inflammation and hypercoagulability. N3PUFA diet reversed 61 protein alterations (P < 0.05), thus mitigating adverse IUGR signatures. In conclusion, an elevated n-3/n-6 PUFA ratio in early diet strongly reduces proinflammatory PLs and mediators while increasing DHA-containing PLs regardless of prior intrauterine conditions. Counteracting a proinflammatory hypercoagulable protein signature in young adult IUGR individuals through early diet intervention may be a feasible strategy to prevent developmentally programmed kidney damage in later life.
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A routinely collected big data set was analyzed to determine the effectiveness of naturalistic inpatient treatment and to identify predictors of treatment outcome and discontinuation.
The sample ...included 878 patients with borderline personality disorder who received non-manualized dialectic behavioral therapy in a psychosomatic clinic. Effect sizes (Hedge's g) were calculated to determine effectiveness. A bootstrap-enhanced regularized regression with 91 potential predictors was used to identify stable predictors of residualized symptom- and functional change and treatment discontinuation. Results were validated in a holdout sample and repeated cross validation.
Effect sizes were small to medium (g = 0.28-0.51). Positive symptom-related outcome was predicted by low affect regulation skills and no previous outpatient psychotherapy. Lower age, absence of work disability, high emotional and physical role limitations and low bodily pain were associated with greater improvement in functional outcome. Higher education and comorbid recurrent depressive disorder were the main predictors of treatment completion. The predictive quality of the models varied, with the best being found for symptom-related outcome (R2 = 18%).
While the exploratory process of variable selection replicates previous findings, the validation results suggest that tailoring treatment to the individual patient might not be based solely on sociodemographic, clinical and psychological baseline data.
•The naturalistic effectiveness of a DBT program for severely impaired BPD inpatients is small to moderate.•Higher education and comorbid recurrent depressive disorder appear to be the main predictors of treatment completion.•Lower age, absence of work disability, high perceived emotional and physical role limitations and low reported bodily pain may positively predict functioning-related change in addition to baseline functioning.•The applied variable selection procedure replicates previous research findings on predictors, but its validation does not appear to be stable.•The identification of stable predictors of treatment outcomes in BPD remains difficult. Tailoring DBT to individual BPD patients should therefore not only be based on demographic and clinical baseline data.
Being born small-for-gestational-age, especially with subsequent catch-up growth, is associated with impaired metabolic health in later-life. We previously showed that a postnatal diet with an ...adapted lipid droplet structure can ameliorate some of the adverse metabolic consequences in intrauterine growth-restricted (IUGR) rats. The aim of the present work was to explore possible underlying mechanism(s) and potential biomarkers. To this end, serum metabolomics was performed in postnatal day (PN) 42 and PN96 samples of the above-mentioned rat offspring, born after uterine vasculature ligation. Blood samples were collected at PN42, directly after a postnatal dietary intervention with either complex lipid matrix (CLM) or control (CTRL) diet, and at PN96 after a subsequent western-style diet (WSD). Offspring of Non-operated (NOP) dams fed CTRL in early life were included as control group. In the PN42 metabolomics data, 11 co-abundance modules of metabolites were identified, of which four were significantly correlated to adult blood glucose levels at PN96. Further analyses showed that Lysophosphatidylcholine(18:2) (LysoPC(18:2)) levels were reduced by ligation (p < 0.01) and restored in CLM fed animals (p < 0.05). LysoPC(18:2) levels at PN42 correlated inversely with adult blood glucose levels. These data indicate that early-life LysoPC(18:2) blood levels may predict adult blood glucose levels and are affected by a postnatal diet with an adapted lipid droplet structure in IUGR offspring.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
This review, addressing developers, users, and researchers of PEM water electrolysis stacks, provides a detailed overview of the most important degradation mechanisms, the underlying influencing ...factors, and the resulting impact on system component degradation. By investigating the significance and the consequences of the degradation mechanisms on stack performance and life-time, it provides a comprehensive understanding of the challenges and impacts associated with PEM water electrolysis technology. Possible qualitative and quantitative statements based on observed degradation phenomena on stack and single cell level as well as from ex-situ examinations are evaluated. The most common diagnostic tools, based on electrochemical, imaging, and physical analysis methods, as well as elemental and structural analysis are described in an application-oriented manner regarding their advantages, possibilities, and limits.
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•Review and explanation of the degradation mechanism of PEM water electrolysis cells.•Summary and evaluation of operating conditions regarding their damaging effects.•Evaluation of possible statements based on observed degradation phenomena.•Summary and application-oriented description of most relevant analysis methods.•The relevance of single-cell or ex-situ analysis for stack development is discussed.
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