Hec1 (highly expressed in cancer 1) or Nek2 (NIMA-related kinase 2) is often overexpressed in cancers with poor prognosis. Both are critical mitotic regulators, and phosphorylation of Hec1 S165 by ...Nek2 is required for proper chromosome segregation. Therefore, inactivation of Hec1 and Nek2 by targeting their interaction with small molecules represents an ideal strategy for tackling these types of cancers. Here we showed that new derivatives of INH (inhibitor for Nek2 and Hec1 binding) bind to Hec1 at amino acids 394-408 on W395, L399 and K400 residues, effectively blocking Hec1 phosphorylation on S165 by Nek2, and killing cancer cells at the nanomolar range. Mechanistically, the D-box (destruction-box) region of Nek2 specifically binds to Hec1 at amino acids 408-422, immediately adjacent to the INH binding motif. Subsequent binding of Nek2 to INH-bound Hec1 triggered proteasome-mediated Nek2 degradation, whereas the Hec1 binding defective Nek2 mutant, Nek2 R361L, resisted INH-induced Nek2 degradation. This finding unveils a novel drug-action mechanism where the binding of INHs to Hec1 forms a virtual death-trap to trigger Nek2 degradation and eventually cell death. Furthermore, analysis of the gene expression profiles of breast cancer patient samples revealed that co-elevated expressions of Hec1 and Nek2 correlated with the shortest survival. Treatment of mice with this kind of tumor with INHs significantly suppressed tumor growth without obvious toxicity. Taken together, the new INH derivatives are suitable for translation into clinical application.
Transforming growth factor beta (TGFβ) signalling regulates extracellular matrix accumulation known to be essential for the pathogenesis of renal fibrosis; latent transforming growth factor beta ...binding protein 4 (LTBP4) is an important regulator of TGFβ activity. To date, the regulation of LTBP4 in renal fibrosis remains unknown. Herein, we report that LTBP4 is upregulated in patients with chronic kidney disease and fibrotic mice kidneys created by unilateral ureteral obstruction (UUO). Mice lacking the short LTBP4 isoform (Ltbp4S
) exhibited aggravated tubular interstitial fibrosis (TIF) after UUO, indicating that LTBP4 potentially protects against TIF. Transcriptomic analysis of human proximal tubule cells overexpressing LTBP4 revealed that LTBP4 influences angiogenic pathways; moreover, these cells preserved better mitochondrial respiratory functions and expressed higher vascular endothelial growth factor A (VEGFA) compared to wild-type cells under hypoxia. Results of the tube formation assay revealed that additional LTBP4 in human umbilical vein endothelial cell supernatant stimulates angiogenesis with upregulated vascular endothelial growth factor receptors (VEGFRs). In vivo, aberrant angiogenesis, abnormal mitochondrial morphology and enhanced oxidative stress were observed in Ltbp4S
mice after UUO. These results reveal novel molecular functions of LTBP4 stimulating angiogenesis and potentially impacting mitochondrial structure and function. Collectively, our findings indicate that LTBP4 protects against disease progression and may be of therapeutic use in renal fibrosis.
Lovastatin is an important statin prescribed for the treatment and prevention of cardiovascular diseases. Biosynthesis of lovastatin uses an iterative type I polyketide synthase (PKS). LovC is a ...trans-acting enoyl reductase (ER) that specifically reduces three out of eight possible polyketide intermediates during lovastatin biosynthesis. Such trans-acting ERs have been reported across a variety of other fungal PKS enzymes as a strategy in nature to diversify polyketides. How LovC achieves such specificity is unknown. The 1.9-Å structure of LovC reveals that LovC possesses a medium-chain dehydrogenase/reductase (MDR) fold with a unique monomeric assembly. Two LovC cocrystal structures and enzymological studies help elucidate the molecular basis of LovC specificity, define stereochemistry, and identify active-site residues. Sequence alignment indicates a general applicability to trans-acting ERs of fungal PKSs, as well as their potential application to directing biosynthesis.
Postprocedural infections by Mycobacterium abscessus complex are increasing worldwide, and the source and route of transmission are infrequently identified. Here the extension of a previous ...clustering of paediatric patients with surgical site infections due to a single strain of the subspecies M. massiliense is reported. The investigation was conducted at a 2200-bed teaching hospital in Taiwan and included microbial surveillance of the environment (water, air, equipment and supplies) and a case–control study. We performed molecular identification and typing of the isolates by a trilocus sequencing scheme, confirmed by multilocus sequencing typing and pulsed-field gel electrophoresis. We investigated 40 patients who developed postprocedure soft tissue or bloodstream infections by M. massiliense (TPE101) during a 3-year period. Thirty-eight patients were identified at hospital A, and one newborn and her mother were identified at hospital B (185 km from hospital A). A case–control study identified the association of invasive procedures (adjusted odds ratio, 9.13) and ultrasonography (adjusted odds ratio, 2.97) (both p <0.05) with acquiring the outbreak strain. Isolates from the cases and unopened bottles of ultrasound transmission gel were all of strain ST48 and indistinguishable or closely related by pulsed-field gel electrophoresis. After replacement of contaminated gel, no new cases were detected during 18 months' follow-up. This investigation identified the use of contaminated gel as the common source causing an outbreak on a larger scale than had been recognized. Our findings halted production by the manufacturer and prompted revision of hospital guidelines.
Background: Until recently, advanced HCC patients with major vessel and cardiac involvement have had an extremely poor prognosis without satisfactory treatment. Case presentation: A 63-year-old ...Taiwanese male presented with metastatic HCC with RA and IVC thrombi, as well as pulmonary metastases that were successfully treated by multimodal management, encompassed by surgical thrombectomy, concurrent systemic sorafenib and locoregional therapies, and immunotherapy. The patient has achieved a complete response over the past 33 months. Conclusions: Through this case report, which shows a successful outcome via multimodal management, a more aggressive approach should be considered when a patient is expected to tolerate the risks and side effects of various treatments.
The study aimed to determine the long-term Staphylococcus aureus colonization patterns and strain relatedness, and the association between maternal and infant colonization in infancy.
A birth cohort ...study was conducted from January 2012 to November 2014. Nasopharyngeal swabs for S. aureus detection were collected from infants at the age of 1, 2, 4, 6 and 12 months and from mothers when their children were 1-month-old.
In total, 254 samples were collected at each planned visit during the first 12-month study. The prevalence of S. aureus colonization decreased in the first year of life, ranging from 61.0% (155/254) at the age of 1 month to 12.2% (31/254) at 12 months. Persistent colonization, defined as a positive culture on four or five occasions, was detected in only 13.8% (35/254) of carriers. Most of the persistent carriers were colonized with methicillin-resistant S. aureus (MRSA) only, and among persistent MRSA carriers, 61.1% (11/18) had indistinguishable genotypes. Of the mothers with MRSA colonization, 77.1% (27/35) had infants who were concomitantly colonized at the age of 1 month; 70.4% (19/27) of the infant–mother paired isolates belonged to indistinguishable or related subtypes, which suggests that surrounding carriers, probably their mothers, may be the possible source for MRSA acquisition in early infancy.
Staphylococcus aureus colonization including MRSA was commonly observed in our cohort. Strains of persistent MRSA among infant–mother pairs were usually of indistinguishable genotypes. Therefore, horizontal spread within households is possibly an important factor related to infant MRSA colonization.
The effects of cell age, reaction temperature, pH value, and salts on the inhibitory activity of shrimp chitosan (98% deacetylated) against Escherichia coli were investigated. The age of a bacterial ...culture affected its susceptibility to chitosan, with cells in the late exponential phase being most sensitive to chitosan. Higher temperature (25 and 37 degrees C) and acidic pH increased the bactericidal effects of chitosan. Sodium ions (100 mM Na(+)) might complex with chitosan and accordingly reduce chitosan's activity against E. coli. Divalent cations at concentrations of 10 and 25 mM reduced the antibacterial activity of chitosan, in the order of Ba(2+) > Ca(2+) > Mg(2+). Chitosan also caused leakage of glucose and lactate dehydrogenase from E. coli cells. These data support the hypothesis that the mechanism of chitosan antibacterial action involves a cross-linkage between the polycations of chitosan and the anions on the bacterial surface that changes the membrane permeability.
The ventilatory efficiency represented cardiovascular, pulmonary, and musculoskeletal performance into an integrate index has been used as long-term and short-term prognostic variables in congestive ...heart failure. The heart failure patients post heart transplantation, whether the ventilatory efficiency was also normalized is still unknown.
This was a cross-sectional study. We measured ventilation to carbon dioxide production slope and oxygen consumption in peak exercise (peak VO2) by cardiopulmonary exercise test, which represented ventilatory efficiency and functional capacity respectively. Strength of hand grip, the 30-second chair stand test, and 6-minute walking test were also evaluated. Patients with ventilation to carbon dioxide production slope <30 were defined as the normal group; others were defined as the abnormal group. Independent t tests and paired t tests were used when appropriate. The level of statistical significance was set at .05.
There were 51 clinically stable post-heart transplantation patients (age 53 ± 12.4 years; 86.3% were male) at 65.14 ± 41.17 months after transplantation. The ventilation to carbon dioxide production slope was 29.2 ± 5.6, which significantly improved compared to that recorded 1 month after heart transplantation (32.6 ± 6.4). There were 20 patients in the abnormal group, characterized by lower 6-minute walking test distance (normal vs abnormal, 422.5 ± 97.8 vs 532.6 ± 87.6 m) and peak VO2 (normal vs abnormal, 14.9 ± 5.3 vs 18.8 ± 5.1 mL/kg/min). The abnormal ventilation to carbon dioxide production slope was significantly correlated with 6-minute walking test distances in multivariate analyses.
Our findings indicate that the ventilation to carbon dioxide production slope is partially abnormal among patients post-heart transplantation. A ventilation to carbon dioxide production slope above the normal range is characterized by a lower peak VO2 during cardiopulmonary exercise test and lower 6-minute walking test distance. The ventilation to carbon dioxide production slope is also significantly negatively correlated with peak VO2, peak work rate, and 6-minute walking test distance. The prognostic utility of the ventilation to carbon dioxide production slope for patients post-heart transplantation requires further investigation.
•Patients post-heart transplantation (HTX) encounter clinical problems that adversely affect their quality of life.•VE/VCO2 predicts serious cardiovascular events in post-HTX patients.•VE/VCO2 is negatively correlated with peak VO2 and work rate and 6MWT distance.•The prognostic utility of VE/VCO2 should be further studied.
Tapeworms (Cestoda) cause neglected diseases that can be fatal and are difficult to treat, owing to inefficient drugs. Here we present an analysis of tapeworm genome sequences using the ...human-infective species Echinococcus multilocularis, E. granulosus, Taenia solium and the laboratory model Hymenolepis microstoma as examples. The 115- to 141-megabase genomes offer insights into the evolution of parasitism. Synteny is maintained with distantly related blood flukes but we find extreme losses of genes and pathways that are ubiquitous in other animals, including 34 homeobox families and several determinants of stem cell fate. Tapeworms have specialized detoxification pathways, metabolism that is finely tuned to rely on nutrients scavenged from their hosts, and species-specific expansions of non-canonical heat shock proteins and families of known antigens. We identify new potential drug targets, including some on which existing pharmaceuticals may act. The genomes provide a rich resource to underpin the development of urgently needed treatments and control.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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