The best-known role of UDP-glucuronosyltransferase enzymes (UGTs) in cancer is the metabolic inactivation of drug therapies. By conjugating glucuronic acid to lipophilic drugs, UGTs impair the ...biological activity and enhance the water solubility of these agents, driving their elimination. Multiple clinical observations support an expanding role for UGTs as modulators of the drug response and in mediating drug resistance in numerous cancer types. However, accumulating evidence also suggests an influence of the UGT pathway on cancer progression. Dysregulation of the expression and activity of UGTs has been associated with the progression of several cancers, arguing for UGTs as possible mediators of oncogenic pathways and/or disease accelerators in a drug-naive context. The consequences of altered UGT activity on tumour biology are incompletely understood. They might be associated with perturbed levels of bioactive endogenous metabolites such as steroids and bioactive lipids that are inactivated by UGTs or through non-enzymatic mechanisms, thereby eliciting oncogenic signalling cascades. This review highlights the evidence supporting dual roles for the UGT pathway, affecting cancer progression and drug resistance. Pharmacogenomic testing of UGT profiles in patients and the development of therapeutic options that impair UGT actions could provide useful prognostic and predictive biomarkers and enhance the efficacy of anti-cancer drugs.
Non-tumoral portal vein thrombosis (PVT) is present at liver transplantation in 5% to 26% of cirrhotic patients, and the prevalence of complex PVT as defined here (grade 4 Yerdel, and grade 3,4 ...Jamieson and Charco) has been reported in 0% to 2.2%. Adequate portal inflow is mandatory to ensure graft and patient survival after liver transplantation. With time, the proposed classifications of non-tumoral chronic PVT have evolved from being anatomy-based, to also incorporating functional parameters. However, none of the currently proposed classifications are directed towards decision-making, regarding the choice of inflow to the graft during transplantation and the outcomes thereof. The present scoping review i) addresses the limits of the currently available classifications in terms of surgical decisiveness, ii) clarifies the concept of physiological or non-physiological portal inflow reconstruction, and subsequently, iii) proposes a new classification of non-tumoral PVT in candidates for liver transplantation; to help tailor the surgical strategy to an individual patient, in order to provide portal inflow to the graft together with control of prehepatic portal hypertension whenever feasible.
The aim of this proof-of-concept study was to evaluate if trained dogs could discriminate between sweat samples from symptomatic COVID-19 positive individuals (SARS-CoV-2 PCR positive) and those from ...asymptomatic COVID-19 negative individuals. The study was conducted at 2 sites (Paris, France, and Beirut, Lebanon), followed the same training and testing protocols, and involved six detection dogs (three explosive detection dogs, one search and rescue dog, and two colon cancer detection dogs). A total of 177 individuals were recruited for the study (95 symptomatic COVID-19 positive and 82 asymptomatic COVID-19 negative individuals) from five hospitals, and one underarm sweat sample per individual was collected. The dog training sessions lasted between one and three weeks. Once trained, the dog had to mark the COVID-19 positive sample randomly placed behind one of three or four olfactory cones (the other cones contained at least one COVID-19 negative sample and between zero and two mocks). During the testing session, a COVID-19 positive sample could be used up to a maximum of three times for one dog. The dog and its handler were both blinded to the COVID-positive sample location. The success rate per dog (i.e., the number of correct indications divided by the number of trials) ranged from 76% to 100%. The lower bound of the 95% confidence interval of the estimated success rate was most of the time higher than the success rate obtained by chance after removing the number of mocks from calculations. These results provide some evidence that detection dogs may be able to discriminate between sweat samples from symptomatic COVID-19 individuals and those from asymptomatic COVID-19 negative individuals. However, due to the limitations of this proof-of-concept study (including using some COVID-19 samples more than once and potential confounding biases), these results must be confirmed in validation studies.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Electron‐rich diazo compounds, such as aryldiazomethanes, are powerful reagents for the synthesis of complex structures, but the risks associated with their toxicity and instability often limit their ...use. Flow chemistry techniques make these issues avoidable, as the hazardous intermediate can be used as it is produced, avoiding accumulation and handling. Unfortunately, the produced stream is often contaminated with other reagents and by‐products, making it incompatible with many applications, especially in catalysis. Herein is reported a metal‐free continuous flow method for the production of aryldiazomethane solutions in a non‐coordinating solvent from easily prepared, bench‐stable sulfonylhydrazones. All by‐products are removed by an in‐line aqueous wash, leaving a clean, base‐free diazo stream. Three successful sensitive metal‐catalyzed transformations demonstrated the value of the method.
Minimizing risks: A continuous flow method for the production of clean aryldiazomethane solutions was developed. The reagents are generated by the fragmentation of easily prepared, bench‐stable mesitylsulfonylhydrazones and purified by an in‐line aqueous wash. A wide array of electron‐rich and electron‐poor aryldiazomethanes was prepared. The quality of the produced streams is demonstrated by their use in three metal‐catalyzed reactions.
•UGT2B15 and UGT2B17 enzymes are involved in androgen inactivation in cancer cells.•miR-376c represses UGT expression and DHT inactivation in prostate cancer cells.•miR-376c is inversely linked to ...UGT2B15/17 in high-grade disease and in metastasis.
Androgens play a central role in prostate cancer progression. Systemic and local androgen bioavailability is controlled by UDP-glucuronosyltransferases conjugating enzymes (UGT), namely UGT2B15, UGT2B17 and UGT2B28. Reporter vector assays in HEK293 cells initially validated in silico-predicted regulatory potential of candidate miRNAs to target UGT transcripts, including miR-376c, miR-409 and miR-494 for UGT2B17, miR-331-5p and miR-376c for UGT2B15 while none were efficient for UGT2B28. miR-376c was shown as the most effective to downregulate UGT2B15 and UGT2B17 through interactions with a site conserved in both UGTs. Ectopic miR-376c expression in prostate cancer cells significantly reduced UGT2B15 and UGT2B17 expression (>32%; P<0.005) with a consequent decrease in dihydrotestosterone glucuronidation (−37%; P<0.001). Consistent with reduced androgen inactivation, ectopic expression of miR-376c changed expression of androgen responsive genes and enhanced cell proliferation with no effect on androgen receptor levels. Sustaining a role of miR-376c in the regulation of androgen-inactivating UGTs, its expression was significantly downregulated in prostatic tumors and further reduced in metastases (P<0.0001), whereas the opposite was observed for UGT2B15/17 (P=0.031). In high-grade tumors (Gleason ≥8), UGT2B15/17 and miR-376c were inversely correlated (r=−0.557; P=0.048) with also a significant relationship in metastases (r=−0.747; P=0.003). In line with a modification in androgen bioavailability, PSA mRNA levels were also negatively correlated to those of UGT2B15/17 (r=−0.573; P=0.01) but positively linked to levels of miR-376c (r=0.577; P=0.039). This study reveals that the androgen-inactivating UGT2B15 and UGT2B17 genes are direct targets of miR-376c and thus may influence steroid metabolism during prostate cancer progression.
The Simmons–Smith reaction of zinc carbenoids with alkenes is a powerful method to access cyclopropanes containing various substitution patterns. This work exploits the high reactivity of ...aryldiazomethanes toward zinc halides to generate aryl-substituted carbenoids catalytically. These carbenoids are able to cyclopropanate various alkenes diastereoselectively, including unfunctionalized substrates such as styrenes. The zinc catalyst can be modified to tolerate the use of free allylic alcohols.
Adrenal 11-oxygenated androgens may support cancer progression in men with prostate cancer owing to their abundance and androgenic potential. We hypothesized that preoperative circulating levels of ...11-oxygenated androgens influence clinical outcomes in men with newly diagnosed localized prostate cancer.
We studied 1,793 treatment-naïve patients and 155 patients who received preoperative treatment with 5α-reductase inhibitors in the prospective PROCURE cohort, for which preoperative plasma samples were obtained prior to radical prostatectomy. Adrenal 11-oxygenated precursors, potent 11-oxygenated androgens and their metabolites (n=7), were quantified using liquid chromatography-tandem mass spectrometry. Circulating levels were evaluated in relation to prognostic factors, disease-free survival, and metastasis-free survival using multivariable Cox proportional hazards models.
At a median follow-up of 93.8 months after surgery, 583 patients experienced biochemical recurrence, 104 developed metastatic disease, and 168 deceased. Higher levels of 11-hydroxytestosterone and 11-ketotestosterone were observed in men with PSA >20 ng/mL and positive nodal status (
< .05). In multivariable analyses, no significant association between 11-oxygenated androgens and disease-free survival was observed. Adrenal 11β-hydroxyandrostenedione, the predominant androgenic 11-ketotestosterone, and its metabolite 11-ketoandrosterone, modeled as quartiles, were associated with metastasis-free survival (
= .06,
= .03, and
= .008, respectively). Significant accumulation of 11-oxygenated androgen precursors and bioactive androgens, but reduced metabolite levels, was observed in patients on 5α-reductase inhibitors (
< .001).
Preoperative circulating 11-oxygenated androgen levels are associated with metastasis-free survival in men with localized prostate cancer undergoing radical prostatectomy and are affected by 5α-reductase inhibitor treatment.
Background
After comparing with open approach, left lateral sectionectomy (LLS) has become standard in terms of short-term outcomes without jeopardizing long-term survival when performed for ...malignancy. The aim of this study was to compare the short-term and economic outcomes of laparoscopic (L-LLS) and robotic (R-LLS) LLS.
Methods
All consecutive patients who underwent L-LLS or R-LLS from 1997 to 2014 were analyzed. Short-term and economic outcomes were compared between the two groups using a propensity score matching (PSM).
Results
Ninety-six consecutive cases of LLS were performed using the laparoscopic (80 cases; 83 %) or robotic (16 cases; 17 %) approach. The two groups were similar for operative and surgical outcomes. Operation time was similar in the R-LLS compared to the L-LLS group (190 vs. 162 min;
p
= 0.10). Perioperative costs were higher (1457 € vs. 576 €;
p
< 0.0001) in the R-LLS group than in the L-LLS group; however, postoperative costs were similar between the two groups (4065 € in the R-LLS group vs. 5459 € in the L-LLS group;
p
= 0.30). Total costs were similar between the two groups (5522 € in the R-LLS group vs. 6035€ in the L-LLS group;
p
= 0.70). The PSM included 14 patients for each group. Surgical and economic outcomes remained similar after PSM, except for total operating time which was significantly longer in the R-LLS group than in the L-LLS group.
Conclusions
Even if feasible and safe, the robotic approach does not seem so far to offer additional benefit in terms of intra- and postoperative outcomes over the laparoscopic approach in patients requiring LLS. Total costs associated with the R-LLS group are not greater than that associated with the L-LLS group, which is the standard of care so far.
Herein we report the discovery of the benzoaimidazo2,1,5-c,dindolizine motif displaying tunable emission covering most of the visible spectrum. The polycyclic core is obtained from readily ...available amides via a chemoselective process involving Tf2O-mediated amide cyclodehydration, followed by intramolecular C–H arylation. Additionally, these fluorescent heterocycles are easily functionalized using electrophilic reagents, enabling divergent access to varied substitution. The effects of said substitution on the compounds’ photophysical properties were rationalized by density functional theory calculations. For some compounds, emission wavelengths are directly correlated to the substituent’s Hammett constants. Easily introduced nonconjugated reactive functional groups allow the labeling of biomolecules without modification of emissive properties. This work provides a straightforward platform for the synthesis of new moderately bright fluorescent dyes remarkable for their chemical stability, predictability, and unusually high excitation–emission differential.
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