The cyanobacterium Gloeobacter violaceus PCC 7421 uses bacterial-type phytoene desaturase in carotenoid biosynthesis

AbstractCarotenoid composition and its biosynthetic pathway in the cyanobacterium Gloeobacter violaceus PCC 7421 were investigated. β-Carotene and (2S,2′S)-oscillol 2,2′-di(α-l-fucoside), and echinenone were major and minor carotenoids, respectively. We identified two unique genes for carotenoid biosynthesis using in vivo functional complementation experiments. In Gloeobacter, a bacterial-type phytoene desaturase (CrtI), rather than plant-type desaturases (CrtP and CrtQ), produced lycopene. This is the first demonstration of an oxygenic photosynthetic organism utilizing bacterial-type phytoene desaturase. We also revealed that echinenone synthesis is catalyzed by CrtW rather than CrtO. These findings indicated that Gloeobacter retains ancestral properties of carotenoid biosynthesis

Short-term clinicopathological outcome of neoadjuvant chemohormonal therapy comprising complete androgen blockade, followed by treatment with docetaxel and estramustine phosphate before radical prostatectomy in Japanese patients with high-risk localized prostate cancer

<p>Abstract</p> <p>Background</p> <p>To assess the outcome of neoadjuvant chemohormonal therapy comprising complete androgen blockade followed by treatment with docetaxel and estramustine phosphate before radical prostatectomy in Japanese patients with a high risk of localized prostate cancer (PCa).</p> <p>Methods</p> <p>Complete androgen blockade followed by 6 cycles of docetaxel (30 mg/m²) with estramustine phosphate (560 mg) were given to 18 PCa patients before radical prostatectomy. Subsequently, the clinical and pathological outcomes were analyzed.</p> <p>Results</p> <p>No patients had severe adverse events during chemohormonal therapy, and hence they were treated with radical prostatectomy. Two patients (11.1%) achieved pathological complete response. Surgical margins were negative in all patients. At a median follow-up of 18 months, 14 patients (77.8%) were disease-free without PSA recurrence. All 4 patients with PSA recurrence had pathologic T3b or T4 disease and 3 of these 4 patients had pathologic N1 disease.</p> <p>Conclusion</p> <p>We found that neoadjuvant chemohormonal therapy with complete androgen blockade followed by treatment with docetaxel and estramustine phosphate before radical prostatectomy was safe, feasible, and associated with favorable pathological outcomes in patients with a high risk of localized PCa.</p

Post-transplant lymphoproliferative disorder involving the ovary as an initial manifestation: a case report

<p>Abstract</p> <p>Introduction</p> <p>Because the normal ovary is assumed to be devoid of lymphoid tissue, it is unusual for it to be an initial manifestation of malignant lymphoma. This case is the first report, to our knowledge, of post-transplant lymphoproliferative disorder involving the ovary as an initial manifestation.</p> <p>Case presentation</p> <p>Twenty-nine weeks after a living renal transplantation, a 38-year-old Japanese female, whose ethnic origin was Asian, presented with abdominal pain and a chronic high fever. Computed tomography revealed a right ovarian tumor and liver metastases. The patient underwent oophrectomy based on the clinical diagnosis of liver metastasis from the primary ovarian tumor. The pathological diagnosis was Epstein-Barr Virus-associated post-transplant lymphoproliferative disorder. While ovarian malignant lymphoma has a poor prognosis, complete remission of liver involvement in this case was achieved only with a reduction of immunosuppressants.</p> <p>Conclusion</p> <p>Clinicians should remember that malignant lymphoma could initially involve the ovary, especially if the patient is immunosuppressed after transplantation therapy.</p

Cytoplasmic control of Rab family small GTPases through BAG6

Rab family small GTPases are master regulators of distinct steps of intracellular vesicle trafficking in eukaryotic cells. GDP‐bound cytoplasmic forms of Rab proteins are prone to aggregation due to the exposure of hydrophobic groups but the machinery that determines the fate of Rab species in the cytosol has not been elucidated in detail. In this study, we find that BAG6 (BAT3/Scythe) predominantly recognizes a cryptic portion of GDP‐associated Rab8a, while its major GTP‐bound active form is not recognized. The hydrophobic residues of the Switch I region of Rab8a are essential for its interaction with BAG6 and the degradation of GDP‐Rab8a via the ubiquitin‐proteasome system. BAG6 prevents the excess accumulation of inactive Rab8a, whose accumulation impairs intracellular membrane trafficking. BAG6 binds not only Rab8a but also a functionally distinct set of Rab family proteins, and is also required for the correct distribution of Golgi and endosomal markers. From these observations, we suggest that Rab proteins represent a novel set of substrates for BAG6, and the BAG6‐mediated pathway is associated with the regulation of membrane vesicle trafficking events in mammalian cells

Prognostic value of plasminogen activator inhibitor-1 in biomarker exploration using multiplex immunoassay in patients with metastatic renal cell carcinoma treated with axitinib

Background and AimsVascular endothelial growth factor-directed therapies play a significant role in patients with metastatic renal cell carcinoma (mRCC). Biomarkers for predicting treatment efficacy and resistance are required to develop personalized medicine. We evaluated multiple serum cytokine levels in patients with mRCC treated with axitinib to explore predictive biomarkers. MethodsFrom September 2012 to October 2015, serum samples were collected from 44 patients with mRCC before treatment and 4weeks after axitinib initiation. Bio-Plex Pro Human Cancer Biomarker Panels 1 and 2 were used to measure levels of 34 serum biomarkers related to angiogenesis and cell proliferation. ResultsPatients with partial response or stable disease had significantly decreased serum plasminogen activator inhibitor-1 (PAI-1) level from pre-treatment to 4weeks after axitinib initiation compared with those with progressive disease (P = .022). The median progression-free survival (PFS) and median overall survival (OS) in patients with increased serum PAI-1 level from pre-treatment to 4weeks after axitinib initiation were significantly shorter than those with decreased serum PAI-1 level (P = .027 and P = .026, respectively). Increased serum PAI-1 level from pre-treatment to 4weeks after axitinib initiation was an independent prognostic marker for shorter PFS and OS in multivariate analyses (P = .015 and P = .032, respectively). The immunohistochemical staining intensity of PAI-1 in tumor specimens was significantly associated with Fuhrman grade and presence of distant metastasis (P = .026 and P = .010, respectively). ConclusionsThe initial change in serum PAI-1 level in the early stage of axitinib treatment could be a useful prognostic biomarker in patients with mRCC

The impact of obesity and adiponectin signaling in patients with renal cell carcinoma: A potential mechanism for the obesity paradox

Although obesity increases the risk of renal cell carcinoma (RCC), obese patients with RCC experience longer survival than non-obese patients. However, the mechanism of this obesity paradox is unknown. We examined the impact of preoperative BMI, serum total adiponectin (sAd) level, total adiponectin secretion from perinephric adipose tissue, and intratumoral expression of adiponectin receptors on RCC aggressiveness and survival. We also investigated the mechanism underlying enhanced cancer aggressiveness in RCC cells stimulated with exogenous adiponectin. Overweight and obese patients had significantly lower grade cancers than normal patients in all patients and in those without metastasis (p = 0.003 and p = 0.027, respectively). Cancer-specific survival was significantly longer in overweight and obese patients than in normal patients in all patients (p = 0.035). There was a weak inverse correlation between sAd level and BMI in RCC patients (r = -0.344, p = 0.002). Tumor size was slightly correlated with sAd level, and high sAd was significantly associated with poor overall survival rates in patients with non-metastatic RCC (p = 0.035). Adiponectin levels in perinephric adipose tissue and intratumoral AdipoRl/R2 expression were not correlated with RCC aggressiveness or survival. Proliferation significantly increased in 786-0 and Caki-2 cells exposed to exogenous adiponectin, whereas cell invasion and migration were unaffected. In addition, exogenous adiponectin significantly inhibited starvation-and metformin-induced apoptosis, and up-regulated p-AMPK and Bcl-xL levels. In summary, low BMI and high adiponectin levels are associated with aggressive cell behaviors and poor survival in surgically-treated RCC patients. The effects of adiponectin on proliferation and apoptosis might underlie the obesity paradox of RCC

Characterization of prostate cancer detected at repeat biopsy

Research articl

Outcomes of axitinib versus sunitinib as first-line therapy to patients with metastatic renal cell carcinoma in the immune-oncology era

Although combination immune checkpoint inhibitor (immuno-oncology [IO]) therapy is the first-line treatment for metastatic renal cell carcinoma (mRCC), it mostly causes resistance and tumor regrowth. Therefore, an optimal second-line therapy is necessary. Such therapy typically comprises vascular endothelial growth factor receptor-tyrosine kinase inhibitors (VEGFR-TKIs). This study was aimed at comparing the efficacy of two TKIs-axitinib and sunitinib-in mRCC patients. From January 2008 to October 2018, we registered 703 mRCC patients from 8 Japanese institutes. Of these, 408 patients received axitinib or sunitinib as the first-line treatment. Thereafter, efficacy and survival rate were compared between the axitinib and sunitinib groups. To reduce the effects of selection bias and potential confounders, propensity score matching analysis was performed. Axitinib and sunitinib were administered in 274 and 134 patients, respectively. More than 25% of the patients received nivolumab sequence therapy. To calculate the propensity scores for each patient, we performed multivariate logistic regression analysis. The objective response rate, progression-free survival (PFS), cause-specific survival, and overall survival (OS) were significantly better in the axitinib group than in the sunitinib group. Furthermore, the OS was better in the nivolumab-treated patients in the axitinib group. Axitinib showed higher efficacy and afforded greater survival benefits than did sunitinib when administered as first-line therapy in mRCC patients. Thus, from among VEGFR-TKIs, axitinib might be a possible option for application in the middle of IO drug-based treatment sequences

Changes in conditional net survival and dynamic prognostic factors in patients with newly diagnosed metastatic prostate cancer initially treated with androgen deprivation therapy

Background The purpose of this study was to identify predictive factors associated with conditional net survival in patients with metastatic hormone-naive prostate cancer (mHNPC) initially treated with androgen deprivation therapy (ADT). Methods At nine hospitals in Tohoku, Japan, the medical records of 605 consecutive patients with mHNPC who initially received ADT were retrospectively reviewed. The Pohar Perme estimator was used to calculate conditional net cancer-specific survival (CSS) and overall survival (OS) for up to 5 years subsequent to the diagnosis. Using multiple imputation, proportional hazard ratios for conditional CSS and OS were calculated with adjusted Cox regression models. Results During a median follow up of 2.95 years, 208 patients died, of which 169 died due to progressive prostate cancer. At baseline, the 5-year CSS and OS rates were 65.5% and 58.2%, respectively. Conditional 5-year net CSS and OS survival gradually increased for all the patients. In patients given a 5-year survivorship, the conditional 5-year net CSS and OS rates improved to 0.906 and 0.811, respectively. Only the extent of disease score (EOD) >= 2 remained a prognostic factor for CSS and OS up to 5 years; as survival time increased, other variables were no longer independent prognostic factors. Conclusions The conditional 5-year net CSS and OS in patients with mHNPC gradually increased; thus, the risk of mortality decreased with increasing survival. The patient\u27s risk profile changed over time. EOD remained an independent prognostic factor for CSS and OS after 5-year follow-up. Conditional net survival can play a role in clinical decision-making, providing intriguing information for cancer survivors