Use, response and outcomes of second-line chemotherapy in patients with advanced biliary tract cancers.

INTRODUCTION: First-line chemotherapy for advanced biliary tract cancers has been established as gemcitabine and cisplatin; however, there is currently no recognized standard second-line chemotherapy. The purpose of this study is to review and evaluate the outcomes of second-line chemotherapy for advanced biliary tract cancers. METHODS: Patients who received chemotherapy for unresectable or metastatic biliary tract cancers at BC Cancer between August 2009 and December 2015 were retrospectively studied to identify second-line chemotherapy treatments used and to determine overall survival, time-to-treatment discontinuation and characteristics predicting for improved overall survival. RESULTS: Of 325 patients who received first-line chemotherapy for advanced biliary tract cancer, 90 (30%) received second-line chemotherapy. Median overall survival for patients who received only first-line chemotherapy was 9.5 months versus 17.3 months for patients who received second-line chemotherapy. Median time-to-treatment discontinuation for second-line chemotherapy was 2.0 months. Common drugs used in second-line chemotherapy treatments included capecitabine (30%), 5-fluorouracil and irinotecan (17%) and 5-fluorouracil monotherapy (15%). There was no difference in overall survival for patients who received single-agent second-line chemotherapy compared to doublet second-line chemotherapy. CONCLUSIONS: Patients who are fit enough to receive second-line chemotherapy may benefit in terms of overall survival and should be offered treatment with single-agent therapy. Capecitabine was the most common second-line chemotherapy treatment. The improved median overall survival for patients who received second-line chemotherapy may be impacted by independent patient-specific factors which are unknown at this time.

Dysregulated Zn2+ homeostasis impairs cardiac type-2 ryanodine receptor and mitsugumin 23 functions, leading to sarcoplasmic reticulum Ca2+ leakage.

Aberrant Zn2+ homeostasis is associated with dysregulated intracellular Ca2+ release, resulting in chronic heart failure. In the failing heart a small population of cardiac ryanodine receptors (RyR2) displays sub-conductance-state gating leading to Ca2+ leakage from sarcoplasmic reticulum (SR) stores, which impairs cardiac contractility. Previous evidence suggests contribution of RyR2-independent Ca2+ leakage through an uncharacterized mechanism. We sought to examine the role of Zn2+ in shaping intracellular Ca2+ release in cardiac muscle. Cardiac SR vesicles prepared from sheep or mouse ventricular tissue were incorporated into phospholipid bilayers under voltage-clamp conditions, and the direct action of Zn2+ on RyR2 channel function was examined. Under diastolic conditions, the addition of pathophysiological concentrations of Zn2+ (≥2 nm) caused dysregulated RyR2-channel openings. Our data also revealed that RyR2 channels are not the only SR Ca2+-permeable channels regulated by Zn2+ Elevating the cytosolic Zn2+ concentration to 1 nm increased the activity of the transmembrane protein mitsugumin 23 (MG23). The current amplitude of the MG23 full-open state was consistent with that previously reported for RyR2 sub-conductance gating, suggesting that in heart failure in which Zn2+ levels are elevated, RyR2 channels do not gate in a sub-conductance state, but rather MG23-gating becomes more apparent. We also show that in H9C2 cells exposed to ischemic conditions, intracellular Zn2+ levels are elevated, coinciding with increased MG23 expression. In conclusion, these data suggest that dysregulated Zn2+ homeostasis alters the function of both RyR2 and MG23 and that both ion channels play a key role in diastolic SR Ca2+ leakage.

The complete mitochondrial genome of the Indian leafwing butterfly Kallima paralekta (insecta: Lepidoptera: Nymphalidae).

The Indian leafwing butterfly Kallima paralekta (Horsfield, 1829) (Nymphalidae) is an Asian forest-dwelling, leaf-mimic. Genome skimming by Illumina sequencing permitted assembly of a complete circular mitogenome of 15,200 bp from K. paralekta consisting of 79.5% AT nucleotides, 22 tRNAs, 13 protein-coding genes, two rRNAs and a control region in the typical butterfly gene order. Kallima paralekta COX1 features an atypical CGA start codon, while ATP6, COX1, COX2, ND4, ND4L, and ND5 exhibit incomplete stop codons completed by 3' A residues added to the mRNA. Phylogenetic reconstruction places K. paraleckta within the monophyletic genus Kallima, sister to Mallika in the subfamily Nymphalinae. These data support the monophyly of tribe Kallimini and contribute to the evolutionary systematics of the Nymphalidae.