The oncogenic receptor ErbB2 modulates gemcitabine and irinotecan/SN-38 chemoresistance of human pancreatic cancer cells via hCNT1 transporter and multidrug-resistance associated protein MRP-2

Pancreatic adenocarcinoma (PDAC) is one of the most deadly cancers because of a lack of early diagnotic markers and efficient therapeutics. The fluorinated analog of deoxycytidine, gemcitabine and emerging FOLFIRINOX protocol (5-fluorouracil (5-FU), irinotecan/SN-38, oxaliplatin and leucovorin) are the main chemotherapies to treat PDAC. The ErbB2/HER2 oncogenic receptor is commonly overexpressed in PDAC. In this context, we aimed to decipher the ErbB2-mediated mechanisms of chemoresistance to the two main chemotherapy protocols used to treat PDAC.ErbB2 knocking down (KD) in CAPAN-1 and CAPAN-2 cells led to an increased sensitivity to gemcitabine and an increased resistance to irinotecan/SN-38 both in vitro and in vivo (subcuteanous xenografts) This was correlated to an increase of hCNT1 and hCNT3 transporters and ABCG2, MRP1 and MRP2 ATP-binding cassette transporters expression and resistance to cell death. We also show that MRP2 is repressed following activation of JNK, Erk1/2 and NF-κB pathways by ErbB2. Finally, in datasets of human PDAC samples, ErbB2 and MRP2 expression was conversely correlated. Altogether, we propose that ErbB2 mediates several intracellular mechanisms linked to PDAC cell chemoresistance that may represent potential targets in order to ameliorate chemotherapy response and allow stratification of patients eligible for either gemcitabine or FOLFIRINOX treatment.     

Spindle pole body-anchored Kar3 drives the nucleus along microtubules from another nucleus in preparation for nuclear fusion during yeast karyogamy

Nuclear migration during yeast karyogamy, termed nuclear congression, is required to initiate nuclear fusion. Congression involves a specific regulation of the microtubule minus end-directed kinesin-14 motor Kar3 and a rearrangement of the cytoplasmic microtubule attachment sites at the spindle pole bodies (SPBs). However, how these elements interact to produce the forces necessary for nuclear migration is less clear. We used electron tomography, molecular genetics, quantitative imaging, and first principles modeling to investigate how cytoplasmic microtubules are organized during nuclear congression. We found that Kar3, with the help of its light chain, Cik1, is anchored during mating to the SPB component Spc72 that also serves as a nucleator and anchor for microtubules via their minus ends. Moreover, we show that no direct microtubule–microtubule interactions are required for nuclear migration. Instead, SPB-anchored Kar3 exerts the necessary pulling forces laterally on microtubules emanating from the SPB of the mating partner nucleus. Therefore, a twofold symmetrical application of the core principle that drives nuclear migration in higher cells is used in yeast to drive nuclei toward each other before nuclear fusion.     

Immediate versus delayed angioplasty in infarct-related arteries with TIMI III flow and ST segment recovery: a matched comparison in acute myocardial infarction patients

Background  Early management of patients with patent infarct-related artery (IRA) and optimal ST resolution in ST elevation myocardial infarction (STEMI) has never been assessed. We compared immediate vs delayed PCI in these patients. Methods  Matched comparison of immediate vs delayed (24 h) PCI in STEMI patients presenting with patent IRA, thrombus-containing lesion and ST resolution ≥70%. Patients were matched for duration of symptoms, intervention type, angiographic data, diabetes. Patients in immediate PCI group received standard therapy in the cathlab. Patients in delayed PCI group received dual antiplatelet therapy, antithrombins, and GPIIb-IIIa inhibitors until PCI. Primary endpoint was procedural success. Secondary endpoints were enzyme release and in-hospital adverse events. Results  Seventy-eight patients were included: 39 per group. Average age 62 years, 75% males. There was a significantly higher procedural success rate in the delayed PCI group (95% success, Vs. 77% in the immediate group, P = 0.008). Initial thrombus burden score did not differ between immediate and delayed PCI groups, but improved significantly in the delayed group between baseline angiography and time of PCI (P = 0.039). There was no difference in major adverse events or bleeding complications between groups. Peak CK levels were significantly higher in the immediate versus delayed PCI group (P = 0.02), although there was no difference between groups in peak CK-MB, peak troponin, or peak CK-MB ratio. Conclusion  Our data suggest that in STEMI patients with patent IRA, optimal ST-segment resolution, and thrombus-containing lesion, deferred PCI when patients are given dual antiplatelet therapy, antithrombin agents, and GPIIb-IIIa inhibitors results in a higher procedural success rate, without an increased risk of MACE.     

S-phase fraction and DNA ploidy in 633 T1T2 breast cancers: a standardized flow cytometric study.

The lack of a standardized methodology for quantifying DNA ploidy and S-phase fraction (SPF) by flow cytometry is hindering routine use of these markers in breast cancer management. In a retrospective clinical multicenter study, we validated a standardized flow cytometry protocol. We tested 633 frozen T(1)T(2), N(0)N(1), M(0) breast tumors obtained in four institutions. Cell preparation was standardized, and precise rules for data interpretation were followed. Three SPF classes were defined on the basis of tertiles after adjustment for ploidy. DNA aneuploidy was observed in 61.0% of cases. No significant difference was observed among centers. Aneuploidy and high SPF were associated with large tumor size, node involvement, high histological grade, and hormone receptor negativity. In the overall population (median follow-up, 69 months), patients with medium and high SPF values had shorter disease-free survival (DFS) than those with low SPF values (P < 0.0001). Ploidy had no significant influence. By Cox analysis, SPF, pN, and estrogen receptor status were independent predictors of DFS (P = 0.0002, P = 0.001, and P = 0.05). In node-negative patients, SPF was the only predictor of DFS (P = 0.01), whereas in node-positive patients, the risk of relapse increased with both high SPF (P = 0.003) and estrogen receptor negativity (P = 0.004). Low SPF values distinguished grade II tumors with a particularly good outcome. Our results strongly support the use of SPF in multicenter studies and clinical trials and suggest that node-negative patients with slowly proliferating tumors do not require systemic adjuvant therapy.     

Reactivation of tuberculosis during temsirolimus therapy

Reactivation of tuberculosis is rare in patients receiving chemotherapy for solid tumours, and poorly documented in patients receiving molecular targeted therapy. We report on a patient with metastatic renal-cell carcinoma treated with temsirolimus, who developed respiratory symptoms and mild fever after 6 weeks of treatment. CT-scan and laboratory tests were consistent with reactivation of tuberculosis. The patient received anti-tuberculosis therapy including rifampicin, a potent CYP3A4/5 inducer. After introduction of rifampicin-based treatment, the patient experienced tumour progression, leaving questionable the potential pharmacokinetic interaction between rifampicin and temsirolimus, a substrate for CYP3A4.     

COVID-19: A year later: Suboptimal prenatal screening of Chlamydia trachomatis and Neisseria gonorrhoeae infections in a Montréal birthing and tertiary care centre: A retrospective cohort study

BackgroundThe Canadian Paediatric Society no longer recommends the use of universal ocular prophylaxis with erythromycin ointment to prevent ophthalmia neonatorum. Screening for Chlamydia trachomatis and Neisseria gonorrhoeae in all pregnant women is considered the most effective way of preventing vertical transmission and ophthalmia neonatorum.ObjectiveThe aims of this study were to assess prenatal screening rates of C. trachomatis and N. gonorrhoeae and to compare sociodemographic factors between those screened and those not screened.MethodsThe list of all women who delivered at a tertiary care hospital in Montréal, Québec, between April 2015 and March 2016, was cross-referenced with the list of samples tested for C. trachomatis and N. gonorrhoeae. Maternal medical records were reviewed for demographic, prenatal and diagnostic information.ResultsOf 2,688 mothers, 2,245 women were screened at least once, but only 2,206 women had at least one valid C. trachomatis and N. gonorrhoeae result the day of delivery (82.1%; 95% CI: 80.6%–83.5%). Infection was detected in 46/2,206 (2.1%) screened women: 42 had C. trachomatis infection, two had N. gonorrhoeae infection and two were co-infected. C. trachomatis infection was more frequent in women younger than 25 years (9.8%; 95% CI: 6.7%–13.8%) than in older women (0.8%; 95% CI: 0.4%–1.3%; p<0.001). Each increase in parity decreased the probability of being tested (adjusted odds ratio=0.89; 95% CI: 0.80%–0.97%; p=0.01). Of those with an initial negative test result, 35/267 (13.1%; 95% CI: 9.3%–17.8%) of women younger than 25 years and 122/1,863 (6.6%; 95% CI: 5.5%–7.8%; p<0.001) of women aged 25 years and older were retested. Subsequent infection was detected in 4/35 (11%) women, all younger than 25.ConclusionSuboptimal screening rates for C. trachomatis and N. gonorrhoeae suggest that current universal ocular prophylaxis cannot be discontinued. Repeating universal screening should be considered, especially among those younger than 25 years.     

Complement activation is a crucial driver of acute kidney injury in rhabdomyolysis

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