OATP1B3 is a member of the OATP (organic anion transporting polypeptides) superfamily, responsible for mediating the transport of numerous endogenous and xenobiotic substances. Although initially reported to be exclusively expressed in the liver, several studies reported that OATP1B3 is frequently expressed in multiple types of cancers and may be associated with differing clinical outcomes. However, a detailed investigation on the expression and function of OATP1B3 protein in cancer has been lacking. In this study, we confirmed that colon and pancreatic cancer cells express variant forms of OATP1B3, different from OATP1B3 wild-type (WT) expressed in the normal liver. OATP1B3 variant 1 (V1), the most prevalent form among the variants, contains alternative exonic sequences (exon 2a) instead of exons 1 and 2 present in OATP1B3 WT. The translated product of OATP1B3 V1 is almost identical to OATP1B3 WT, with exception to the first 28 amino acids at the N-terminus. Exogenous expression of OATP1B3 V1 revealed that OATP1B3 V1 undergoes post-translational modifications and proteasomal degradation to a differing extent compared to OATP1B3 WT. OATP1B3 V1 showed only modest transport activity toward cholecystokin-8 (CCK-8, a prototype OATP1B3 substrate) in contrast to OATP1B3 WT showing a markedly efficient uptake of CCK-8. Consistent with these results, OATP1B3 V1 was localized mainly in the cytoplasm with a much lower extent of trafficking to the surface membrane compared to OATP1B3 WT. In summary, our results demonstrate that colon and pancreatic cancer cells express variant forms of OATP1B3 with only limited transport activity and different subcellular localization compared to OATP1B3 WT. These observed differences at the molecular and functional levels will be important considerations for further investigations of the biological and clinical significance of OATP1B3 expression in cancer.
IntroductionSynovial fibroblasts from rheumatoid arthritis show resistance to apoptotic stimuli, indicating they may be difficult to treat. To clearly understand these mechanisms of resistance, rheumatoid and osteoarthritis synovial fibroblasts (RASF and OASF) were exposed to endoplasmic reticulum (ER) stress such as thapsigargin, Ca2+-ATPase inhibitor.MethodsFibroblasts were assessed microscopically for cell viability by trypan blue exclusion and for autophagic cells by LC-3II formation. Caspase-3 activity was measured as aminomethyl-coumarin (AMC) liberated from AC-DEVD-AMC. Immunoblotting was performed to compare protein expression in OASF and RASF.ResultsER stress caused cell death in OASF but not in RASF. Thapsigargin, a Ca2+-ATPase inhibitor, did not change the expression of GRP78, an ER chaperone in OASF and RASF, but induced another ER stress protein, CCAAT/enhancer binding protein (C/EBP) homologous protein (CHOP) differently, showing high levels in OASF and low levels in RASF. Thapsigargin increased the autophagy response in RASF, with autophagosome formation, beclin expression, and LC3-II conversion. Transfection with beclin siRNA inhibited autophagy and increased the susceptibility to ER stress-induced cell death. On the other hand, CHOP siRNA increased autophagy and improved cell survival, especially in RASF, indicating that CHOP is involved in regulation of autophagy and cell death, but that low expression of CHOP protects RASF from apoptosis.ConclusionsAutophagy induction and CHOP under-expression increases cell resistance against ER stress-induced cell death in fibroblasts from rheumatoid arthritis patients.
Background: When a palpable breast mass is detected, a biopsy is usually performed even if the mass reveals probably benign morphologic features on imaging, as there is relatively little data reporting the outcome of such breast masses. Purpose: To determine the negative predictive value for sonographic evaluation of palpable breast masses with probably benign morphology, and to assess whether follow-up may be an acceptable alternative to immediate biopsy. Material and Methods: Of the 1399 sonograms of palpable masses from January 2004 to September 2005, there were 397 patients with masses of probably benign morphology. This study included 274 of these patients (age range 12–64 years, mean age 34 years) with 312 palpable masses that were pathologically confirmed by fine-needle aspiration ( n=7), ultrasound (US)-guided core needle biopsy ( n=180), or surgical biopsy ( n=125). The false-negative rate, negative predictive value (NPV), and 95% confidence interval (CI) were calculated using the SPSS statistical software package for Windows, version 12.0. A P value <0.05 was considered statistically significant. Results: Of the 312 masses, there were 310 benign lesions and two malignancies, resulting in a false-negative rate of 0.6% (NPV 99.4%, P value=0.0432, 95% CI 0.0–1.5%). Conclusion: The negative predictive value of sonography for palpable breast masses with probably benign morphology is high (99.4%). Therefore, short-term imaging follow-up can be an acceptable alternative to immediate biopsy, similar to the management of nonpalpable probably benign lesions (BI-RADS category 3).
Immunotherapy is now established to be a key treatment modality that can improve the outcomes of many cancer patients and appears to be ushering in a new era in cancer treatment. Checkpoint inhibitor drugs have shown preliminary favorable results in esophageal cancer treatment. Adoptive cell therapy and vaccine studies have also shown some promise in various clinical studies. Future endeavors will need to focus on identifying patients who are likely to benefit from immunotherapy, monitoring and managing immune responses and designing optimal combination strategies where immunotherapy agents are combined with other traditional treatment modalities.
Colonization of roots by Pseudomonas chlororaphis O6 (PcO6) involves root surface coverage through surface motility and biofilm formation. Root colonization and the production of antifungal phenazines are important in the ability of the bacterium to protect plants against pathogens. In this in vitro study we report that both biofilm formation and phenazine production are differentially influenced by nutrition and the presence of polyethylene oxide/polypropylene oxide triblock copolymer surfactants (Pluronics). Such surfactants are used for many purposes including agricultural formulations. Four Pluronics differing in molecular weight and in hydrophobic/hydrophilic proportions had distinct effects on biofilm formation and secondary metabolite production, although each increased surface motility, termed swarming, to a similar extent. These findings show that Pluronics had specific metabolic impacts on the bacterium, where both up- and downregulation was achieved depending on the medium and the Pluronic composition. In environmental and agricultural settings, Pluronics may have unanticipated effects on soil microorganisms, while in bioprocessing these effects may be leveraged to regulate metabolite yield.
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